iloprost and Hypertension--Pulmonary

Perioperative pulmonary hypertension (PH) is an independent risk factor for morbidity and mortality in cardiac surgery. While inhaled prostacyclins (iPGI. We searched PubMed, Embase, the Web of Science, CENTRAL, and the grey literature from inception until April 2021. We included randomized controlled trials investigating the use of iPGI. Thirteen studies were included, comprising 734 patients. Inhaled prostacyclins significantly decreased MPAP compared with placebo (standardized effect size, 0.46; 95% confidence interval [CI], 0.11 to 0.87; P = 0.01) and to intravenous vasodilators (1.26; 95% CI, 0.03 to 2.49; P = 0.045). Inhaled prostacyclins significantly improved the cardiac index compared with intravenous vasodilators (1.53; 95% CI, 0.50 to 2.57; P = 0.004). In contrast, mean arterial pressure was significantly lower in patients treated with iPGI. The results of this systematic review and meta-analysis show that iPGI. PROSPERO (CRD42021237991); registered 26 May 2021.. RéSUMé: OBJECTIF: L’hypertension pulmonaire (HTAP) périopératoire est un facteur de risque indépendant de morbidité et de mortalité en chirurgie cardiaque. Bien que l’inhalation de prostacyclines (iPGI

Topics: Administration, Inhalation; Adult; Cardiac Surgical Procedures; Child; Humans; Hypertension, Pulmonary; Iloprost; Prostaglandins I; Vasodilator Agents

Despite its low incidence, pulmonary hypertension in children places a substantial burden on families and society because survival can be shorter than 10 months and treatment options are limited and ineffective. Drugs to treat pulmonary hypertension include endothelin antagonists, phosphodiesterase type 5 inhibitors and prostacyclin, which is the most widely used to treat pediatric pulmonary hypertension. The main aim of this study was to provide a comprehensive overview of the advantages and disadvantages of prostacyclin and its analogs for treating pulmonary hypertension in children.. To retrieve a thorough collection of studies, we performed a search in PubMed using the following combination of keywords: (Prostacyclins) or (Epoprostenol) or (Iloprost) or (Treprostinil) or (Beraprost), (children) and (pulmonary arterial hypertension). The time limits used for the search were December 1983 to May 2021.. The search retrieved a total of 238 articles. Titles and abstracts of articles were screened for relevance, and all relevant articles published in English were included.. Epoprostenol can be effective against severe pulmonary hypertension. Iloprost can treat severe persistent pulmonary hypertension in newborns and inhaled iloprost can be used in pulmonary vasoreactivity testing. Treprostinil is a long-acting prostacyclin analog, and it shows the highest antiproliferative activity among prostacyclins. Beraprost may be effective in premature infants, but available evidence comes from only one patient, so more clinical testing is needed.

Topics: Antihypertensive Agents; Child; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Prostaglandins I; Pulmonary Arterial Hypertension

Pediatric pulmonary hypertension (PAH) is a rare disease that carries a poor prognosis if left untreated. Although there are published guidelines for the treatment of children with pulmonary hypertension, due to the limited number of robust pediatric clinical trials, recommendations are often based on limited data or clinical experience. Furthermore, many practical aspects of care, particularly for the pediatric patient, are learned through experience and best navigated with a multidisciplinary team. While newer PAH therapies have been approved for adults, there is still limited but expanding experience in pediatrics. This new information will help improve the targets of goal-oriented therapy. Lastly, this review highlights practical aspects in the use of the different therapies available for the treatment of pediatric pulmonary hypertension.

Topics: Adolescent; Adult; Bosentan; Calcium Channel Blockers; Child; Child, Preschool; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Phenotype; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prognosis; Pulmonary Arterial Hypertension; Pyridazines; Pyrimidines; Receptors, Endothelin; Sildenafil Citrate; Sulfonamides; Tadalafil; Young Adult

Pulmonary hypertension (PH), an often unrelenting disease that carries with it significant morbidity and mortality, affects not only the pulmonary vasculature but, in turn, the right ventricle as well. The survival of patients with PH is closely related to the right ventricular function. Therefore, having an understanding of how to manage right ventricular failure (RVF) and acute pulmonary hypertensive crises is imperative for clinicians who encounter these patients. This review addresses the management of these patients in detail, addressing: (a) the pathophysiology of RVF, (b) intensive care monitoring of these patients in the intensive care unit, (c) imaging of the right ventricle, (d) intubation and mechanical ventilation, (e) inotrope and vasopressor selection, (f) pulmonary vasodilator use, (g) interventional and surgical procedures for the acutely failing right ventricle, and (h) mechanical support for RVF.

Topics: Biomarkers; Capnography; Central Venous Pressure; Critical Care; Echocardiography; Epinephrine; Epoprostenol; Extracorporeal Membrane Oxygenation; Heart Failure; Heart Ventricles; Humans; Hypertension, Pulmonary; Iloprost; Intensive Care Units; Milrinone; Nitric Oxide; Radiography, Thoracic; Respiration, Artificial; Spectroscopy, Near-Infrared; Vasodilator Agents; Vasopressins; Ventricular Dysfunction, Right; Ventricular Function, Right

This systematic review and meta-analysis was conducted to investigate the efficacy and safety of the chronic administration of aerosolized iloprost for pulmonary arterial hypertension (PAH).. All the relevant studies were obtained from three databases, namely, PubMed, Web of Science and the Cochrane Library, from the inception of each database to June 1, 2018. In our study, chronic treatment was defined as a period lasting at least 3 months. The rate of each event was analyzed by SPSS as a percentage with 95% confidence intervals (CIs). For the meta-analysis, a randomized effect model or a fixed effect model was applied according to the results of the heterogeneity test.. Ten studies were included in this study, with a total of 370 patients treated with inhaled iloprost, including 214 in five randomized controlled trials and 156 in five prospective clinical trials. Among the patients who received inhaled iloprost, there was a significant improvement in the 6-min walk distance (6MWD) in the short-medium and prolonged treatment groups. Notably, the functionality improved by at least 1 class in 48.7% of the treated patients. In all the pooled studies, the estimated 3-month, 6-month, 1-year and 2-year event-free survival rates were 96.6%, 92.3%, 62.6% and 39.6%, respectively. In addition, there were eight adverse drug responses.. In this systematic review and meta-analysis, inhaled iloprost has been shown to be a safe and well-tolerated agent for PAH in the first 3 months after diagnosis. If used for a prolonged period, aerosol iloprost monotherapy could contribute to an unsatisfactory improvement in vascular remodeling and even a decreased event-free survival rate.

Topics: Animals; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Iloprost; Platelet Aggregation Inhibitors; Prospective Studies; Randomized Controlled Trials as Topic

Pulmonary arterial hypertension (PAH) is a rare, but severe and life-threatening disease characterized by vasoconstriction and remodeling of the pulmonary arterioles, leading to progressive increase in pulmonary vascular resistance and ultimately to right-heart failure. In the last two decades, significant progress in treatment of PAH has been made, with currently 12 drugs approved for targeted therapy. Among these, the stable prostacyclin analogues iloprost and treprostinil have been repurposed for inhalation. The paper highlights the development of the two drugs emphasizing the rationale and advantages of the inhalative approach. Despite substantial advances in the specific, mainly vasodilatory PAH therapy, disease progression is mostly inevitable and mortality remains unacceptably high. Thus, introduction of new drugs targeting the cancer-like remodeling of the diseased pulmonary arteries is urgently needed. Inhalation offers pulmonary selectivity and will hopefully pioneer the repurposing of novel highly potent drugs for effective aerosol therapy of PAH.

Topics: Administration, Inhalation; Antihypertensive Agents; Drug Repositioning; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost

Prostacyclin analogs, such as epoprostenol, treprostinil, iloprost, and beraprost, have long been used for pulmonary arterial hypertension (PAH) treatment, yet their relative efficiency remains disputed. Eligible randomized controlled trials (RCTs) involving the 4 therapies mentioned above were retrieved from PubMed, Embase, and Cochrane (up to August 1, 2015). Odds ratios (ORs) were estimated for dichotomous data (mortality, functional class (FC) amelioration, and discontinuation); standardized mean differences (SMDs) with 95% confidence intervals (CIs) were estimated for continuous data (6-min walk distance [6-MWD]). Patients taking epoprostenol were anticipated to demonstrate more expedient 6-MWD than those taking placebo when network meta-analysis (NMA) was implemented (SMD = 52.19; 95% CI: 24.28-113.39), the trend of which was identical with that of pairwise meta-analysis (SMD = 69.28; 95% CI: 10.43-128.98). Nonetheless, the prominent advantages of treprostinil over placebo (SMD = 30.15; 95% CI: 19.29-40.01) in 6-MWD could not be replicated by NMA. Furthermore, direct and indirect (NMA) comparisons also differed in FC amelioration. For example, the superiority of epoprostenol over placebo as evident with the use of NMA (OR = 42.79; 95% CI: 10.63-301.98) could not be confirmed by pairwise meta-analysis. As suggested by indirect comparisons among 4 prostanoids, epoprostenol appears to result in remarkably favorable FC amelioration comparing to other regimens (all P < 0.05). Participants taking beraprost were more probable to withdraw in comparison with those administrated with iloprost (OR = 10.07; 95% CI: 1.47-160.65). Taking mortality, FC amelioration, discontinuation, and 6-MWD into account, epoprostenol could be recommended as an alternative treatment for patients with moderate/advanced PAH.

Topics: Antihypertensive Agents; Arterial Pressure; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Randomized Controlled Trials as Topic

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.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Bronchodilator Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Nitric Oxide; Off-Label Use; Prostaglandins I; Vasodilator Agents

Pulmonary hypertension is a disease with diverse etiology. According to the New ESC guidelines, pregnancy is contraindicated for a patent with pulmonary hypertension and qualify such patent to class IV NYHA, regardless of the reason of hypertension. Pregnancy is revived for a patient with pulmonary hypertension despite of the fact that recent treatment methods including specific therapy with the endothelin receptor antagonistst (bosentan), phosphodiesterase inhibitors (sildenafil) and prostacyclin analogs (iloprost) were introduced. In the case of coincidence of pregnancy and pulmonary hypertension, patients should be managed in a center with expertise in pulmonary hypertension with all therapeutic options available.

Topics: Antihypertensive Agents; Bosentan; Female; Humans; Hypertension, Pulmonary; Iloprost; Phosphodiesterase Inhibitors; Pregnancy; Pregnancy Complications; Sildenafil Citrate; Sulfonamides

Since continuous IV epoprostenol was approved in the U.S., parenteral prostanoid therapy has remained the gold standard for the treatment of patients with advanced pulmonary arterial hypertension (PAH). Prostanoid agents can be administered as continuous intravenous infusions, as continuous subcutaneous infusions and by intermittent nebulization therapy. This article presents data from clinical trials of available prostanoid agents, and their varied routes of administration. The varied routes of administration allow for the incremental use of this class of agents in advanced PAH, and if PAH progresses. Prostanoids will remain a major component of PAH therapy for the foreseeable future.

Topics: Administration, Inhalation; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous

Inhaled iloprost is attracting growing interest as a potential alternative and/or adjuvant to inhaled nitric oxide in the management of pediatric pulmonary hypertension in the acute and intensive care settings. However, there are currently no formal evidence-based guidelines regarding the use of inhaled iloprost in children with pulmonary hypertension. The aim of this systematic review is to assess the literature concerning the use of inhaled iloprost in children with pulmonary hypertension in the acute setting.. Studies were identified from PubMed and Embase. Internal literature databases and recent congress abstracts (2009 onward) were also searched for relevant publications.. Studies were included if they examined the use of inhaled iloprost in children with pulmonary hypertension in an acute or intensive care setting.. Twenty-eight studies were included in the review. The majority were case studies or case series (n = 17), and in total, the 28 studies represented the treatment of 195 children with iloprost. Iloprost was most frequently studied in children undergoing cardiac surgery (as a bridge to surgery and postoperatively), in children undergoing acute pulmonary vasoreactivity testing, and in neonates with persistent pulmonary hypertension of the newborn. The results of the included studies suggested that inhaled iloprost may have a diverse role in the acute treatment of pediatric pulmonary hypertension and that its acute effects are similar to those of inhaled nitric oxide. However, the iloprost dose was not consistently reported and varied greatly between studies, and several different administration devices were used.. Inhaled iloprost may be useful in the acute treatment of children and neonates with pulmonary hypertension, but clinical data are scarce, and the appropriate dosing of iloprost in different scenarios is uncertain. Well-designed prospective clinical trials are needed.

Topics: Acute Disease; Administration, Inhalation; Adolescent; Child; Child, Preschool; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Vasodilator Agents

This paper provides an overview of the current state of pharmacotherapy in children with pulmonary arterial hypertension (PAH) and a brief introduction to the potentially novel pharmacologic targets for PAH. Currently, 3 classes of drugs including prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase-5 inhibitors are approved for the treatment of PAH in children, which has led to improved hemodynamics, increased exercise capacity and prolonged survival. Despite these improvements, there is still a need to carry out well-designed, randomized, controlled studies with larger samples. In addition, novel drugs targeting other molecular pathways should be developed.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Bosentan; Calcium Channel Blockers; Child; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Iloprost; Sulfonamides

Pulmonary arterial hypertension (PAH) is considered an orphan disease. Prostacyclins are the keystone for PAH treatment. Choosing between the three available prostacyclin therapies could be complicated because there are no comparison studies, so the final decision must be driven by factors such as efficacy, administration route, safety profile and economic aspects.. This study provides a cost-effectiveness and cost-utility comparison of initiating prostacyclin therapy with three different treatment alternatives (inhaled iloprost [ILO], intravenous epoprostenol [EPO] and subcutaneous treprostinil [TRE]) for patients with PAH. The goal of this work is to help physicians with their therapeutic decision-making.. A Markov model was built to simulate a patient cohort with class III PAH according to the classification of the New York Heart Association (NYHA). Four health states corresponding with the NYHA classes plus death were allowed for patients in the model. Changing the treatment was possible when patients worsened from functional class III to IV. The time horizon was 3 years, allowing patients to transition between health states on a 12-week cycle basis. The study perspective was that of the National Health System (NHS) [only direct medical costs were included]. Unitary costs were obtained from the Drug Catalogue and e-Salud Database in 2009 and are given in euros (€). Data on health resources and treatment pathways were informed by a four-member expert panel. Efficacy was obtained from pivotal clinical trials of ILO, EPO and TRE, the latter used in Spain as a foreign medication. Utilities for each health state were obtained from the literature. The final efficacy measure was life-years gained (LYG), and utilities were used to obtain quality-adjusted life-years (QALYs). Costs and effects were discounted at a 3% rate. To check for the robustness of the results, sensitivity analyses were performed.. At the end of the 3 years, in the base case of the deterministic analysis, initiating prostacyclin therapy with iloprost was the less costly strategy (€132,840), followed by treprostinil (€359,869) and epoprostenol (€429,775). Epoprostenol has shown the best efficacy results with 2.73 LYG and 1.78 QALY, followed by iloprost (2.69 LYG and 1.74 QALY) and treprostinil (2.69 LYG and 1.73 QALY). Incremental cost-effectiveness ratios (ICER) and cost-utility ratios (ICUR) of epoprostenol versus iloprost and treprostinil were much above the €30,000 per LYG or QALY threshold commonly used in Spain. Iloprost was dominant compared with treprostinil. In the probabilistic analysis, epoprostenol, when compared with iloprost, was a dominant strategy in 15% of the simulations, but it was not a cost-effective option in 83% of the cases. When compared with treprostinil, epoprostenol was dominant in 43% of the simulations. Iloprost was dominant compared with treprostinil in 45% of the cases and it was a cost-effective alternative in 39% of the simulations.. Initiating prostacyclin treatment with iloprost in patients with PAH, functional class III of the NYHA, is the less costly alternative for the NHS in Spain, with a good efficacy profile when compared with the other alternatives.

Topics: Antihypertensive Agents; Computer Simulation; Cost-Benefit Analysis; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Markov Chains; Models, Economic; Prostaglandins I; Quality-Adjusted Life Years; Spain; Vasodilator Agents

Iloprost (Ventavis, Bayer Schering Pharma, Germany) is a synthetic prostacyclin that is used in its inhalative form for the therapy of pulmonary arterial hypertension. Long-term therapy can increase exercise capacity and quality of life. The use of modern nebulizers especially designed for the administration of iloprost guarantees the pulmonary deposition of the required doses and systematically minimizes side effects. Regarding existing data, inhalative iloprost acts in effective and safe combination with other classes of medication; indeed, such combination therapy is frequently necessary in pulmonary arterial hypertension.

Topics: Administration, Inhalation; Animals; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Evidence-Based Medicine; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Iloprost; Nebulizers and Vaporizers; Risk Assessment; Treatment Outcome; Vasodilation; Vasodilator Agents

Similar to other prostanoids, iloprost is a potent vasodilator with considerable antiproliferative and anti-thrombotic properties, although the relevance of its ability to affect platelet aggregation in this subset of patients is unrecognized. The pathogenesis of pulmonary arterial hypertension (PAH) is a multifactorial and complex process secondary to an innate deficiency of substances that induce vasodilation and an overproduction of substances producing vasoconstriction. The production of endothelial vasoactive mediators such as nitric oxide, prostacyclin, endothelin-1, thromboxane and serotonin affect the growth of smooth muscle cells, which facilitate the development of structural remodeling changes that are characteristic of PAH. There have been remarkable advances in understanding the pathologic processes that are responsible for increasing pulmonary vascular resistance and that result in elevated pulmonary artery pressures in order to reverse and prevent progression of the disease process. The goals of treatment in these patients are to alleviate the patients' symptoms, to improve functional capacity and to prevent the progression of the disease. The prostacyclin analogs, such as iloprost, have given hope to these patients who struggle under the burdens of this complex disease.

Topics: Administration, Inhalation; Animals; Clinical Trials as Topic; Humans; Hypertension, Pulmonary; Iloprost; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) encompasses a number of diseases responsible for a specific set of hemodynamic findings during right heart catheterization. During initial workup, pulmonary vasodilator testing is performed. A positive acute pulmonary vasodilator test predicts better survival and response to calcium channel blocker (CCB) therapy. There is lack of consensus on the preferred agent for determining acute pulmonary vasoreactivity. The ACCP guidelines and the 4(th) World Symposium on Pulmonary Hypertension support the use of intravenous epoprostenol or nitric oxide (NO) as the preferred agents for pulmonary vasodilator testing. A decrease in the mean pulmonary artery pressure by at least 10 mmHg to reach an absolute value of 40 mmHg or less without a decrease in cardiac output is currently considered a positive pulmonary vasodilator test. A positive test by the current recommended criteria is observed in about 10-15% of patients with idiopathic PAH. Approximately half of these patients will experience long-term benefits with CCBs. A positive test may select patients with an earlier or less aggressive form of disease, which may carry a better prognosis. A positive vasodilator test is observed very infrequently in patients with pulmonary arterial hypertension other than idiopathic PAH or anorexigen associated PAH. This article reviews the literature regarding pulmonary vasodilator testing and use of CCB therapy in patients with PAH, while identifying the gaps in knowledge concerning this diagnostic procedure.

Topics: Adenosine; Calcium Channel Blockers; Drug Therapy, Combination; Epoprostenol; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Vasodilation; Vasodilator Agents

The prostacyclins-prostanoids were one of the first medications used to treat pulmonary arterial hypertension (PAH). Three prostanoids have been developed to treat PAH: epoprostenol, treprostinil, and iloprost. In the acute setting, experience is growing, using the inhaled forms of these three medications. Inhalation may improve ventilation/perfusion matching, whereas in the intravenous form these medications may cause nonselective pulmonary vasodilation and may worsen ventilation/perfusion matching. Currently, there are no universal recommendations for dosing delivery of inhaled prostanoids to intubated patients in the intensive care unit setting.

Topics: Administration, Inhalation; Antihypertensive Agents; Child; Critical Care; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost

The aim of the present meta-analysis was to evaluate the efficacy and safety of treating pulmonary arterial hypertension (PAH) with inhaled iloprost, oral bosentan and sildenafil.. The randomized controlled trials on the 3 drugs and placebo were retrieved from the databases MEDLINE, EMBASE, BIOSIS Previews and CNKI up to August 2009. In total 11 studies and 1,391 patients were selected. Compared with placebo, iloprost, bosentan and sildenafil reduced clinical worsening significantly (odds ratio [OR] =0.33, 95% confidence interval [CI] =0.22-0.49, P<0.00001), improved New York Heart Association/World Health Organization functional class (OR =2.81, 95%CI =1.95-4.03, P<0.00001), increased the 6-min walk test by 33.19 m, reduced systolic pulmonary arterial pressure, mean pulmonary arterial pressure and pulmonary vascular resistance, increased the cardiac index by 0.40 L x min(-1) x m(-2) and increased the cardiac output by 0.53 L/min. The incidence of serious adverse events was similar in the medication groups and the placebo group (OR =1.09, 95%CI =0.69-1.71, P=0.72). In terms of the clinical worsening and functional class amelioration, insignificant differences were found among iloprost, bosentan and sildenafil, but iloprost had the highest incidence of serious adverse events among the 3 drugs.. Inhaled iloprost and oral bosentan and sildenafil are effective and safe in treating PAH.

Topics: Antihypertensive Agents; Bosentan; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

This review summarizes the pathophysiology and current therapeutic and drug delivery strategies for pulmonary arterial hypertension (PAH), a rare but devastating disorder of the pulmonary circulation affecting 50,000 to 100,000 persons in the United States. Chief clinical features of PAH include increased mean pulmonary arterial pressure (>25 mm Hg) and right ventricular and smooth muscle hypertrophy. A wide variety of agents have been studied for use as anti-PAH drugs, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, to name a few. However, a major shortcoming of anti-PAH medications is their short half-lives, requiring them to be administered via parenteral routes, which lead to undesirable side effects, including systemic vasodilation. Inhalational delivery of anti-PAH drugs provides an attractive alternative to conventional routes, with ease of administration and minimal systemic vasodilation. Recently, the U.S. Food and Drug Administration approved inhalable iloprost (Ventavis®), a prostacyclin analogue, for PAH treatment. Other drugs being studied for their potential in inhalable PAH therapy include PGE1, treprostinil, vasoactive intestinal peptide, and fasudil. Controlled-release inhalable delivery systems for anti-PAH medications have also been proposed to facilitate long-term and selective vasodilation of pulmonary arteries. Extensive studies are warranted to develop safe and effective drug delivery systems that will provide a better quality of life to patients.

Topics: Administration, Inhalation; Animals; Delayed-Action Preparations; Epoprostenol; Female; Half-Life; Humans; Hypertension, Pulmonary; Iloprost; Lung; Male; Mice; Pulmonary Circulation; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980's, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients.

Topics: Anemia, Sickle Cell; Antihypertensive Agents; Child; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Pyridazines

In the pediatric population, pulmonary hypertension may present as an acute event in the setting of lung or cardiac pathology or as a chronic disease, mainly as idiopathic pulmonary hypertension or associated with congenital heart disease. Recently, new pharmacologic approaches have demonstrated significant efficacy in the management of adults with pulmonary arterial hypertension; these include intravenous epoprostenol, prostacyclin analogs, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. The same treatment strategies are currently used in children. There are only few reports of the use of inhaled iloprost in pediatrics, only one of which reported the use of chronic inhaled iloprost in a significant number of children. This report showed that 1) the acute pulmonary vasodilator response to inhaled iloprost is equivalent to that of inhaled nitric oxide; 2) acute inhalation of iloprost can induce bronchoconstriction 3) the addition of inhaled iloprost can reduce the need for intravenous prostanoid therapy in some patients; 4) most children tolerated the combination of inhaled iloprost and endothelin receptor antagonist or phosphodiesterase inhibitors; 5) Several patients had clinical deterioration during chronic inhaled iloprost therapy and required rescue therapy with intravenous prostanoids. In this review we will discuss the role of inhaled iloprost in acute and chronic pulmonary hypertension in children.

Topics: Acute Disease; Administration, Inhalation; Adult; Antihypertensive Agents; Child; Chronic Disease; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Iloprost; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by an elevated pulmonary arterial pressure and vascular resistance with a poor prognosis. Various pulmonary and extrapulmonary causes are now recognized to exist separately from the idiopathic form of pulmonary hypertension. An imbalance in the presence of vasoconstrictors and vasodilators plays an important role in the pathophysiology of the disease, one example being the lack of prostacyclin. Prostacyclin and its analogues are potent vasodilators with antithrombotic, antiproliferative and anti-inflammatory qualities, all of which are important factors in the pathogenesis of precapillary pulmonary hypertension. Iloprost is a stable prostacyclin analogue available for intravenous and aerosolized application. Due to the severe side effects of intravenous administration, the use of inhaled iloprost has become a mainstay in PAH therapy. However, owing to the necessity for 6 to 9 inhalations a day, oral treatment is often preferred as a first-line therapy. Numerous studies proving the efficacy and safety of inhaled iloprost have been performed. It is therefore available for a first-line therapy for PAH. The combination with endothelin-receptor antagonists or sildenafil has shown encouraging effects. Further studies with larger patient populations will have to demonstrate the use of combination therapy for long-term treatment of pulmonary hypertension.

Topics: Administration, Inhalation; Anesthesia; Antihypertensive Agents; Drug Administration Schedule; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Surgical Procedures, Operative; Treatment Outcome; Vasodilator Agents

To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications.. Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies.. The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out.. In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing. All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

Topics: Antihypertensive Agents; Bosentan; Cost-Benefit Analysis; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; United States; Vasodilator Agents

Pulmonary arterial hypertension is a progressive disease marked by increased pulmonary artery resistance leading to right heart failure and has very high mortality. Survival rates have somewhat improved in recent years due to the development of new drugs and early diagnosis. This review aims to summarize the current therapeutic approach to pulmonary arterial hypertension and share our experience at our center.

Topics: Antihypertensive Agents; Diltiazem; Disease Progression; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nifedipine; Turkey; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. Conventional treatment is based on non-specific drugs (warfarin, oxygen, diuretics). Pure vasodilators like calcium channel antagonists have little or no effect on the vast majority of patients. Although there is no cure for PAH, newer medical therapies have been shown to improve a variety of clinically relevant end-points including survival, functional class, exercise tolerance, haemodynamics, echocardiographic parameters and quality of life measures. Intravenous prostacyclin, was the first introduced drug for treatment of PAH and remains the first-line treatment for the most severe patients. Since then the list of approved drugs for PAH has expanded to include prostacyclin analogues with differing routes of administration, a dual endothelin receptor antagonist, and a phosphodiesterase-5 inhibitor. Novel drugs have also shown promise in experimental trials and are likely to be added to the list of options. This article reviews the current treatments strategies for PAH.

Topics: Bosentan; Diuretics; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones

Despite recent remarkable efforts in the medical treatment options of patients with pulmonary arterial hypertension (PAH) a considerable number of patients need escalations to improve disease related symptoms and pulmonary hemodynamics. Most of the pulmonary vascular vasodilators have been approved in its potency as an initial and sole medical option. However, there is increasing scientific evidence on the reliability, safety and effectiveness of possible combinations. This paper reviews the current scientific literature about medical escalations and combination therapy in patients with PAH.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Drug Therapy, Combination; Exercise Test; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Prostaglandins; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a progressive disease marked by vasoconstriction and vascular remodeling within pulmonary arteries leading to right heart failure and death. Significant advances in understanding the pathobiology of the disease have identified three key pathways involved in progression of this disease, which are the endothelin pathway, the prostacyclin pathway, and the nitric oxide/cyclic guanosine monophosphate pathway. Echocardiogram is the best screening tool to obtain an estimation of the pulmonary artery systolic pressure but right heart catheterization remains the standard by which the diagnosis is made. There are currently six FDA approved therapies for PAH. The mechanistic rationale, evidence behind their use and side effect considerations in utilizing these therapies in PAH patients will be the focus of this review.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Disease Progression; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelium, Vascular; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Prognosis; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Vasoconstriction

Pulmonary arterial hypertension is a group of diseases which forms a small subset of those with elevated pulmonary artery pressure (pulmonary hypertension). The recent development of selective pulmonary vasodilator has lead to a substantial resurgence of interest in what have been previously regarded as rare and incurable diseases. This review aims to describe the spectrum of pulmonary vascular diseases, the evolving understanding as to pathogenesis, the evolving evidence of efficacy for drug therapies, trying to put this into a contemporary Australian context. Several key pathogenic pathways may be involved: prostacycline, Nitric Oxide-cGMP-phosphodiesterase 5 and endothelin- all of which are exploited for therapeutic benefit by newly available drug therapies. A recently modified classification system reasserts the importance of precise diagnosis. The cardinal symptom of exertional dyspnea warrants careful evaluation in an attempt to prevent (frequently occurring) substantial delay in diagnosis. Echocardiogram is the cornerstone of screening for pulmonary arterial hypertension; however, a detailed evaluation including a carefully performed right heart catheterisation with sufficient data to allow calculation of pulmonary vascular resistance is key to accurate diagnosis. These new approaches to therapy are already substantially improving quality of life and prognosis.

Topics: Adolescent; Adult; Aged; Arterioles; Australia; Bosentan; Cardiac Catheterization; Diagnostic Imaging; Disease Progression; Dyspnea; Endothelin A Receptor Antagonists; Epoprostenol; Exercise Test; Female; Forecasting; Heart-Lung Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Male; Middle Aged; Nitric Oxide; Piperazines; Prognosis; Pulmonary Artery; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

Epoprostenol and the structurally related compounds treprostinil, iloprost, and beraprost are collectively referred to as prostanoids. The discovery of epoprostenol in 1976 and unequivocal demonstration of its efficacy in 1996 dramatically altered the approach to therapy for pulmonary arterial hypertension (PAH). Development of prostanoids available through multiple routes of administration and the discovery and development of other agents acting through alternative pathways continue to expand the array of therapeutic options. The use of prostanoids in combination with other PAH drugs and for treating pulmonary hypertensive disorders outside of the PAH classification are areas of ongoing research.

Topics: Antihypertensive Agents; Chronic Disease; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Prostaglandins; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome

Type Sphosphodiesterase inhibitors (FDEI-5) used to be applied as the main drugs for treatment of erectile dysfunction. At present, this pharmacological group is being studied intensively in various fields of clinical medicine, such as pulmonology, cardiology, gastroenterology, gynecology etc. Part II of this system literature review is dedicated to analysis of the results of such application. In many randomized and non-randomized controlled studies sildenafil decreased pulmonary arterial pressure (independently of etiology) and pulmonary vascular resistance; it could be successfully combined with nitric oxide, illoprost, or epoprostenolol. Clinical studies have also demonstrated an increase in physical load tolerance, optimization of PAH studies according to NYHA functional classes, and good tolerance to the drug. In the recent years, antiischaemic effects of FDEI-5 and their ability to inhibit apoptosis have been proved It is possible to draw the conclusion that nature created a universal phosphodiesterase mechanism for the interconnection of biochemical processes that provide the vital activity of the cell and organism. The fact that more than 15 controlled studies of clinical application of sildenafil not for treatment of erectile dysfunction have been planned and commenced confirms the importance of further studies of this mechanism. Further analysis of the results will show how universal this mechanism is.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Bronchodilator Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Therapy; Drug Therapy, Combination; Forecasting; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Myocardial Infarction; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

The therapy of systemic sclerosis (SSc) remains a challenge for dermatology, rheumatology, internal medicine, and other disciplines. Organ involvement, above all kidney and lungs, is a key therapeutic issue. The current developments in organ-specific therapy are the main topic of the article. Finally, possibilities of disease-modifying drugs and value of HSCT are discussed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Fibrosis; Fingers; Gastrointestinal Agents; Hematopoietic Stem Cell Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Kidney Transplantation; Piperazines; Purines; PUVA Therapy; Raynaud Disease; Recurrence; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Ultraviolet Therapy; Vasodilator Agents

Topics: Antihypertensive Agents; Bosentan; Brain Infarction; Calcium Channel Blockers; Humans; Hypertension, Pulmonary; Iloprost; Life Expectancy; Pulmonary Heart Disease; Quality of Life; Sulfonamides

Evidence-based therapies and guidelines for pulmonary arterial hypertension are critiqued.. Morbidity and mortality in pulmonary arterial hypertension reflects failure of right ventricular compensation for increased afterload caused by obstructive pulmonary arterial remodeling. This predominantly reflects excessive proliferation/impaired apoptosis of smooth muscle and endothelial cells, rather than vasoconstriction. To exclude confounding effects of cardiac output and left ventricular end-diastolic pressure, the diagnosis of pulmonary arterial hypertension should require a pulmonary vascular resistance >3 Wood-units, not simply a mean pulmonary arterial pressure >25 mmHg. A 'positive' response (20% fall in pulmonary arterial pressure/pulmonary vascular resistance PAP/PVR) to acute, selective, pulmonary vasodilators (e.g. inhaled nitric oxide), occurs in 20% of patients, portends a favorable prognosis and justifies a trial of calcium channel blockers. Randomized controlled trials support treatment of NYHA class III pulmonary arterial hypertension with oral endothelin antagonists or phosphodiesterase-5 inhibitors. Prostacyclin analogues (inhaled/subcutaneous) are useful adjunctive therapies. Intravenous epoprostenol remains the therapeutic mainstay for class IV PAH. Emerging antiproliferative-proapoptotic therapies that merit investigator-initiated clinical trials include: statins, Imatinib, NONO-ates, anti-survivin, potassium channel modulation, and dichloroacetate.. The diagnostic criteria for pulmonary arterial hypertension should be revised to include PVR. Sildenafil's efficacy and price recommend it as a first-line oral therapy. New pulmonary arterial hypertension-regression therapies and therapeutic combinations offer the potential for cure of pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Benzamides; Bosentan; Calcium Channel Blockers; Comorbidity; Dichloroacetic Acid; Drug Therapy, Combination; Epoprostenol; Evidence-Based Medicine; Fluoxetine; Humans; Hypertension, Pulmonary; Iloprost; Imatinib Mesylate; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins, Synthetic; Pulmonary Artery; Purines; Pyrimidines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Simvastatin; Sulfonamides; Sulfones; Thiophenes; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by vasoconstriction and progressive remodelling of the pulmonary arterial wall leading to right ventricular failure and death. Idiopathic PAH (IPAH) and PAH associated with congenital heart defects account for the majority of paediatric patients with PAH. During the last few decades, several pharmacological approaches have been introduced, including calcium channel-blockers (CCBs), prostacyclin analogues, endothelin receptor antagonists and, most recently, phosphodiesterase inhibitors. This paper reviews the treatment options available to children with a special focus on the initial experience with bosentan. Although CCBs have been shown to increase survival in IPAH, the beneficial effect appears to be limited to a small number of patients, defined as 'responders' to the vasoreactivity testing. With the availability of prostacyclin (intravenous epoprostenol) and then prostacyclin analogues, the treatment options have increased markedly and particularly in patients who have not responded to conventional therapy. Although epoprostenol has been shown to be efficacious in PAH, the drug is not ideal owing to serious complications arising from the invasive mode of application, particularly in children. Phosphodiesterase-5 inhibitors have also shown beneficial effects. Targeting the endothelin (ET) system with the oral, dual ET(A)/ET(B) receptor antagonist, bosentan has been demonstrated to improve the cardiopulmonary haemodynamics, exercise capacity, quality-of-life and survival in adult patients with PAH. Specific ET(A) antagonists may also present the same beneficial profile. Recent experience with bosentan in paediatric patients with PAH indicates that the results obtained in adult patients may be extrapolated to children, thus offering a safe and effective therapy that is easy to administer.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Calcium Channel Blockers; Child; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Phosphodiesterase Inhibitors; Receptors, Endothelin; Sulfonamides; Vasodilator Agents

Pulmonary Arterial Hypertension includes a heterogeneous group of disorders with a common genetic, pathological and hemodinamyc origin. It is characterized by a high pulmonary artery pressure due to a primary vascular disease, as a consequence of genetic and environmental factors. The common pathway is a vascular imbalance towards vasoconstriction and proliferation inside the small vessels. According to the World Health Organization, 2003, Pulmonary Arterial Hypertension is classified as idiopathic, familiar or associated to connective tissue diseases, HIV, drugs, porto-pulmonary hypertension, congenital intracardiac shunts and others. The diagnosis is based in hemodynamics. Echocardiogram is a non invasive and right ventricular catheterization is an invasive diagnostic tool. Follow up is based on a clinical and functional assessment through functional class classification, dyspnea scores and 6-minute walking test. The prognosis is historically devastating but new therapies are changing the natural history of the disease. New treatments have demonstrated improvement in symptoms, hemodynamic profiles and survival. Intravenous, subcutaneous or inhaled prostanoids such as Epoprostenol, Treprostinil or Iloprost respectively have been approved for Pulmonary Arterial Hypertension treatment as well as oral endothelial receptor blockers. They are all considered first line treatments for arterial pulmonary hypertensive patients with even better benefits than lung transplantation. Phosphodiesterase inhibitors (Sildenafil), have been recently approved for the treatment of pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Prognosis; Purines; Sildenafil Citrate; Sulfones

Chronic thromboembolic pulmonary hypertension is one of the most common forms of pulmonary hypertension (PHT), but frequently remains undiagnosed and untreated. Pulmonary thrombendarterectomy is the treatment of choice, but only about 50 % of such patients are operable. About 15 % of patients are not improved by surgery, usually because of residual PHT with advanced vascular changes. Drug treatment has favorable effects in inoperable forms and in postoperative recurrence of PHT.

Topics: Antihypertensive Agents; Bosentan; Endarterectomy; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Pulmonary Embolism; Purines; Recurrence; Sildenafil Citrate; Splenectomy; Sulfonamides; Sulfones; Vasodilator Agents

The clinical condition of patients with chronic pulmonary arterial hypertension (PHT) often deteriorates progressively, despite monotherapy with presently available groups of drugs: prostanoids, endothelin-receptor antagonists and phosphodiesterase-5-inhibitors. In such situations there is in principle the opportunity of giving a combination of drugs, especially as one can expect synergistic effects. Trials with a small number of patients have indicated that the combination of inhaled iloprost and bosentan, inhaled iloprost and sildenafil or bosentan and sildenafil are more efficacious than any one of these drugs taken as monotherapy. The decision when to use a combination treatment should be made on the basis of defined targets that are of significant prognostic value. It should be considered for patients in NYHA class III or IV, if monotherapy has not achieved the desired efficacy. Combination treatment with two or three of the mentioned drugs are being tested as part of controlled studies of their efficacy and safety: they currently constitute the most important therapeutic advances. Analogously to the management of heart failure, combination therapy is likely to be the standard treatment of PHT in future, with the aim of providing optimal results for exertional capacity and lasting functional stability.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Drug Synergism; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc) and a leading cause of death in patients with it. Recent publications suggest that a prevalence of 10-15% is likely. The prognosis remains poor compared to that of idiopathic PAH. WHO recommends annual echocardiography for PAH screening of patients with SSc. Right heart catheterization is necessary to confirm the diagnosis. Nevertheless, more than half of all SSc patients have symptoms classified as WHO functional class III or IV at diagnosis. Prostacyclin therapy, delivered via continuous intravenous infusion (epoprostenol), has been demonstrated to be effective in patients with severe PAH (both idiopathic and scleroderma-related). Prostacyclin analogs (such as treprostinil and iloprost) are other options. Bosentan is the first endothelin receptor antagonist approved in the EU for the treatment of PAH, both idiopathic and related to connective tissue diseases such as scleroderma, in patients in WHO functional class III. Sildenafil by its selective inhibition of phosphodiesterase type 5 is also effective against both types of PAH. It too is now approved in the EU for this purpose in patients in WHO functional class III, but we do not yet have any information about its long-term effects in scleroderma.

Topics: Algorithms; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Cohort Studies; Echocardiography, Doppler; Epoprostenol; European Union; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prevalence; Prognosis; Purines; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Time Factors; Vasodilator Agents; World Health Organization

With the availability of better treatment and prophylactic regimens for the infectious complications of human immunodeficiency virus (HIV), the non-infectious complications are gaining greater attention. HIV-related pulmonary arterial hypertension (HIV-PAH) is one of these. The incidence of HIV-PAH is estimated at 0.5% of HIV-infected individuals. The pathogenesis remains unclear. Patients present with symptoms as diverse as progressive shortness of breath, pedal edema, dry cough, fatigue, syncope, as well as chest pain. Chest X-ray always shows cardiomegaly and prominent pulmonary artery, and evidence of right ventricular hypertrophy can be seen from the electrocardiogram. The pulmonary arterial systolic pressure, diastolic pressure and pulmonary vascular resistance from right heart catheterization are increased. There are a few small studies showing the benefit of prostacyclin analog (epoprostenol and iloprost) and bosentan. The role of antiretrovirals remains controversial, as do those of other agents such as calcium channel blockers and anticoagulants. The prognosis of HIV-PAH is grave. Two thirds of HIV-PAH related mortality is usually secondary to consequences of pulmonary hypertension, with the worst survival noted in New York Heart Association (NYHA) functional class III-IV. The probability of survival in one series was 73%, 60% and 47% at one, two and three years, respectively.

Topics: Disease Progression; HIV Infections; Humans; Hypertension, Pulmonary; Iloprost; Prognosis; Pulmonary Artery; Tomography, X-Ray Computed; Vasodilator Agents

The purpose of this article is to provide nurse practitioners with an understanding of the pathophysiology of pulmonary arterial hypertension (PAH) disease, clinical manifestations, diagnostic evaluation, drug therapy, strategies for health promotion, and relevant care issues for patients and families.. Selected clinical and research articles, as well as current government guidelines.. Symptoms expressed are more apparent as PAH disease progresses, leaving fewer treatment options in advanced disease stages. New drugs are currently being tested for the treatment of PAH; however, the costs of many of the currently approved treatments may be prohibitive.. Earlier recognition of disease symptoms leads to prompt initiation of diagnostic evaluation and referral to specializing medical centers. Upon referral, specialty centers may begin appropriate treatment regimens earlier in the disease process, which could improve clinical outcomes and quality of life.

Topics: Adenosine; Algorithms; Antihypertensive Agents; Bosentan; Bronchodilator Agents; Calcium Channel Blockers; Decision Trees; Diagnosis, Differential; Epoprostenol; Fatal Outcome; Fenfluramine; Health Promotion; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Nitric Oxide; Nurse Practitioners; Primary Health Care; Prognosis; Referral and Consultation; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Sulfonamides; Vasodilator Agents

To evaluate the efficacy of sildenafil for treatment of pulmonary hypertension.. Literature retrieval was accessed through MEDLINE (1977-March 2005), Cochrane Library, and International Pharmaceutical Abstracts (1977-March 2005) using the terms sildenafil and pulmonary hypertension. In addition, reference citations from publications identified were reviewed.. All articles in English identified from the data sources were evaluated. Studies including >5 patients with primarily adult populations were included in the review.. The treatment of pulmonary hypertension is challenging. Sildenafil has recently been studied as monotherapy and in combination with other vasodilators in the management of pulmonary hypertension. Eight hemodynamic studies and 12 clinical trials were reviewed (1 retrospective, 3 double-blind, 8 open-label). Sildenafil reduced pulmonary arterial hypertension and pulmonary vascular resistance/peripheral vascular resistance index and tended to increase cardiac output/cardiac index compared with baseline. Sildenafil was comparable to nitric oxide and at least as effective as iloprost or epoprostenol in terms of its pulmonary vasoreactivity. Combination therapy with iloprost, nitric oxide, or epoprostenol resulted in enhanced and prolonged pulmonary vascular effects. Clinical trials suggest that sildenafil improves exercise tolerance and New York Heart Association functional class, but large, randomized controlled trials are needed to confirm these findings. Overall, sildenafil was well tolerated.. Overall, sildenafil is a promising and well-tolerated agent for management of pulmonary hypertension. Further well-designed trials are warranted to establish its place in the treatment of pulmonary hypertension.

Topics: Adult; Double-Blind Method; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Vasodilator Agents

Idiopathic pulmonary arterial hypertension is a rare but serious and life-threatening disease that leads to right heart failure and death within 2.8 years without specific treatment. This review focuses on the stable prostacyclin analog iloprost, its biologic action and pharmacology and, finally, on its clinical development, efficacy and safety in patients with idiopathic pulmonary arterial hypertension, which led to its approval for this indication. Furthermore, this review assesses the role of iloprost compared with other newly developed drugs, such as the endothelin receptor antagonist bosentan and the phosphodiesterase-5 inhibitor sildenafil, as well as other modes of application of prostacyclin and its analogs for the treatment of idiopathic pulmonary arterial hypertension. Based on the different modes of action of these substances, a combination of these treatments could be most promising for the future.

Topics: Clinical Trials as Topic; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

In the era of new, potent antiretroviral therapy, much more attention is being given to non-infectious complications of HIV diseases, such as cardiomyopathy, pericardial effusion and pulmonary hypertension (PH). PH diagnosis is based on a mean pulmonary artery pressure of more than 25 mmHg at rest, or more than 30 mmHg with exercise. The incidence of PH is about 0.1% per year among HIV-positive patients, while in the general population it is 1 to 2 cases per million people. The histopathology of HIV-associated PH (HAPH) is similar to that of idiopathic PH, although its pathogenesis is still unclear. In patients with HAPH secondary causes of PH must be ruled out, such as intravenous drug abuse, valvulopathy, congenital heart disease and previous tricuspid endocarditis. The treatment of HAPH is not substantially different from that of idiopathic PH and is essentially based on the use of vasodilators. The Regional Authority of Lazio (Italy) has instituted a Registry for PH in HIV-positive patients; its aims are to evaluate the real incidence and prevalence of primitive and secondary PH among patients with HIV infection, and optimise the management of patients with suspected PH through the definition of a diagnostic algorithm.

Topics: Acquired Immunodeficiency Syndrome; Adult; Algorithms; Antihypertensive Agents; Clinical Trials as Topic; Echocardiography; Electrocardiography; Epoprostenol; HIV Infections; HIV Seropositivity; Humans; Hypertension, Pulmonary; Iloprost; Incidence; Infant, Newborn; Italy; Platelet Aggregation Inhibitors; Prevalence; Prognosis; Registries; Risk Factors; Vasodilator Agents

Patients with portal hypertension may develop pulmonary complications such as hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PPHT). PPHT is defined as elevated pulmonary pressure, elevated pulmonary vascular resistance, a normal pulmonary capillary wedge pressure, and portal hypertension in the absence of other known causes pulmonary hypertension. Various factors such as hyperdynamic circulation, volume overload, and circulating vasoactive mediators are suspected to be involved in the pathogenesis of PPHT. The prognosis of patients with severe PPHT is significantly reduced due to the risk of right heart failure. In patients with moderate to severe PPHT liver transplantation is associated with a significantly increased mortality. The chief symptom of PPHT may be dyspnoe in the presence of typical histomorphological alterations comparable with idiopathic pulmonary hypertension. Continuous intravenous application of prostacyclin is currently regarded as the treatment of choice for patients with severe PPHT. Inhaled prostacyclin or its analogue iloprost or oral treatment with the endothelin-receptor antagonist bosentan may be promising alternatives which should be further investigated in randomized controlled trials.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Epoprostenol; Hepatopulmonary Syndrome; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Lung; Pulmonary Wedge Pressure; Sulfonamides; Survival Rate; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and smooth muscle cell proliferation of the pulmonary arterioles, as well as in situ thrombosis of the small pulmonary arteries. Prostacyclin is involved in PAH vascular remodeling. It is unclear if decreased prostacyclin in the lungs is a cause or a consequence of PAH, but the relative lack of prostacyclin and its positive effects on the pulmonary vascular bed support the theory that long-term prostacyclin replacement is effective. Current therapies based on evidence-based medicine include epoprostenol, treprostinil, iloprost, and beraprost, each with limitations based on the drugs' inherent properties and administration route. Treatment of PAH by inhibiting multiple pathways concurrently may produce additive benefit. Because prostacyclin therapy is not curative and does not normalize pulmonary hemodynamics in the majority of cases, combining a prostacyclin with other PAH agents may be a promising approach.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a condition that is characterised by increased pulmonary arterial pressure and vascular resistance that can lead to right ventricular failure and death. A variety of disturbances in pulmonary vascular endothelial and smooth muscle function are present in PAH, including reduced production of vasodilator and antiproliferative substances, such as nitric oxide and prostacyclin, and an overproduction of mitogens, such as endothelin. As a result of these observations, therapies have been developed for PAH that specifically target these pathogenic processes, including prostacyclin analogues and endothelin receptor antagonists. This article reviews iloprost inhalation solution, the most recently approved form of prostacyclin therapy that is delivered directly to the lungs by inhalation.

Topics: Administration, Inhalation; Animals; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Platelet Aggregation Inhibitors; Pulmonary Circulation; Randomized Controlled Trials as Topic; Solutions; Vascular Resistance; Vasodilator Agents

Topics: Anticoagulants; Antihypertensive Agents; Bosentan; Calcium Channel Blockers; Cardiotonic Agents; Diuretics; Drug Monitoring; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Prostaglandins; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

The improved understanding of the pathophysiology of pulmonary vascular diseases over the last decade has brought with it significant changes in disease management. Newer therapies have targeted the cardinal features of pulmonary hypertension, which include pulmonary vasoconstriction and vascular remodelling. In addition to prostacyclin, which had been the mainstay of therapy until recently, other available drugs include other prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase inhibitors. This review will discuss some of the evidence for their use and will look towards the future in the search of treatments that may ultimately modify and even reverse the disease process.

Topics: Adult; Antihypertensive Agents; Arginine; Bosentan; Child; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Phosphodiesterase Inhibitors; Platelet Aggregation Inhibitors; Sulfonamides

Pulmonary arterial hypertension (PAH) is one of the main causes of death in patients with systemic sclerosis (SSc), particularly in its limited forms.. Survival with conventional treatment associated with Epoprostenol is two times less in SSc patients than in idiopathic PAH. WHO recommendations (annually heart echoscreening) must be applied in all patients with SSc. Conventional therapy associates anticoagulation, to avoid excessive exertion, pregnancy, warm baths, no pressurised flights. Calcium-channel blockers give long term survival in patients with positive acute vasodilatator test with nitric oxide (NO) but these patients are very rare in SSc. Diuretics are very useful in treating right heart insufficiency. Randomized control trials in PAH have demonstrated the short term efficacy of i.v. epoprostenol, nebulized iloprost, oral beraprost and oral bosentan, a dual endothelin-1 receptor antagonist. Results in SSc are very limited except for i.v. epoprostenol. Long-term efficacy in terms of survival has been demonstrated in non randomized studies for i.v. epoprostenol and oral bosentan in patients with idiopathic and familial PAH. Atrial septostomy and lung transplantation could be an alternative to treatment, even in SSc patients, in case of refractory evolution.. Randomized control trials with sildenafil and selective endothelin-1 receptor antagonists are ongoing.

Topics: Antihypertensive Agents; Bosentan; Calcium; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Scleroderma, Systemic; Sulfonamides

Two prostacyclins (prostaglandin E(1) and prostaglandin I(2)) are potent vasodilators. Aerosolized prostacyclins reduce pulmonary artery pressure, improve right heart function, and increase arterial oxygenation by improving ventilation/perfusion matching. This report describes aerosolized prostacyclins and compares them to inhaled nitric oxide. I review the types of inhalable prostacyclins and their indications, evidence of efficacy, delivery, and adverse effects.

Topics: Administration, Inhalation; Aerosols; Alprostadil; Dose-Response Relationship, Drug; Epoprostenol; Equipment Design; Humans; Hypertension, Pulmonary; Iloprost; Nebulizers and Vaporizers; Nitric Oxide; Prostaglandins I; Respiratory Distress Syndrome; Respiratory Therapy; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Right

Prostanoids have played a prominent role in the treatment of pulmonary arterial hypertension (PAH). Several compounds and methods of administration have been studied: chronic intravenously infused epoprostenol, chronic subcutaneously infused treprostinil, inhaled iloprost, and oral beraprost. Chronic intravenous epoprostenol therapy has had a substantial impact on the clinical management of patients with severe PAH. It improves exercise capacity, hemodynamics, and survival in patients with idiopathic pulmonary arterial hypertension (IPAH). It also improves exercise capacity and hemodynamics in patients with PAH occurring in association with scleroderma. The complexity of epoprostenol therapy (chronic indwelling catheters, reconstitution of the drug, operation of the infusion pump, and others) has led to attempts to develop other prostanoids with simpler modes of delivery. Treprostinil, a stable prostacyclin analogue with a half-life of 3 h, has been developed for subcutaneous delivery. It has beneficial effects on exercise and hemodynamics, which depend somewhat on the dose achieved. This, in turn, is determined by the patient's ability to tolerate the drug's side effects, including pain and erythema at the infusion site. Inhaled iloprost therapy may provide selectivity of the hemodynamic effects to the lung vasculature, thus avoiding systemic side effects. In a randomized and controlled trial, iloprost resulted in improvement in a combined end point incorporating the New York Heart Association functional class, 6-min walk test, and deterioration or death. Beraprost is the first orally active prostacyclin analogue. In the first of two randomized controlled trials, beraprost increased exercise capacity in patients with IPAH, with no significant changes in subjects with associated conditions. Hemodynamics did not change significantly, and no difference in survival was detected between the two treatment groups. The second study showed that beraprost-treated patients had less disease progression at six months and confirmed the results of the previous trial. However, this improvement was no longer present at 9 or 12 months. In conclusion, though treatment with prostanoids is complicated by their generally short half-lives and complicated drug delivery systems, they continue to play an important role in the treatment of PAH.

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Prostaglandins; Pulmonary Artery; Vasodilator Agents

The haemodynamics and vascular proliferation (remodelling) in pulmonary hypertension are unfavourably affected by a malfunction of the endothelial cells of the pulmonary vessels. A characteristic result is reduced formation of endothelial dilators and increased formation of vasoconstrictors. The favourable effects of a blockade of the endothelin (ET) system with receptor antagonists suggest that the increased formation and limited clearance of ET-1 reaches pathogenetic significance. The therapeutic effects of inhaled iloprost on right cardiac haemodynamics and clinical course, could in addition to the direct vasodilatory effect, also be considered to have a favourable influence on the ET system as a pathophysiologically effective mediator system.

Topics: Administration, Inhalation; Endothelins; Humans; Hypertension, Pulmonary; Iloprost; Prostaglandins; Receptors, Endothelin; Vasodilator Agents

Pulmonary hypertension is a major risk factor in cardiac surgery and has significant impact on morbidity and mortality in the perioperative period. Nitric oxide (NO) is considered to be the gold standard for treatment of pulmonary hypertension in the perioperative setting. The aerosolized administration of the prostacyclin analogue iloprost is a new alternative with similar pulmonary-selective vasodilation and virtually no systemic side-effects. Relevant complications including increased postoperative bleeding have not been observed.

Topics: Administration, Inhalation; Cardiac Surgical Procedures; Endarterectomy; Heart Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Complications; Mitral Valve; Postoperative Complications; Vasodilator Agents

Portopulmonary hypertension (PPHTN) is associated with poor prognosis and high perioperative mortality after orthotopic liver transplantation. This study documents the first case of a patient with PPHTN who was successfully bridged to orthotopic liver transplantation with i.v. iloprost, a stable prostacyclin analogue. The PPHTN had resolved completely 4 months after successful transplantation. In conclusion, portopulmonary hypertension is a relative contraindication to orthotopic liver transplantation, which should be attempted only if pulmonary haemodynamics improve with prostanoids. In this context, iloprost may be a valuable alternative to epoprostenol.

Topics: Alcoholism; Carcinoma, Hepatocellular; Hepatitis C, Chronic; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Middle Aged; Preoperative Care; Vasodilator Agents

Topics: Administration, Inhalation; Antihypertensive Agents; Calcium Channel Blockers; Diuretics; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension is not a rare pathology that is met in a doctor's practice. It has been defined as a mean pulmonary artery pressure >25 mmHg at rest or >30 mmHg at exercise, or by a systolic pulmonary artery pressure >40 mmHg measured by echo-Doppler. The article analyzes pulmonary arterial hypertension, especially primary one, and its classification, diagnosis, and possibilities for medication. The major role in pathogenesis is ascribed for in situ thrombosis, intimal and adventitial proliferation and smooth muscle hypertrophy. Prostacyclin analogues, nitric oxide, calcium channel blockers and endothelin-1 receptor blockers are the most important medicines, which decrease pressure in the pulmonary artery. The clinical case of the 63-year-old woman, who was ill with severe primary pulmonary arterial hypertension, is described in the article.

Topics: Antihypertensive Agents; Bronchodilator Agents; Calcium Channel Blockers; Electrocardiography; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Nitric Oxide; Platelet Aggregation Inhibitors; Radiography, Thoracic; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Ultrasonography, Doppler; Vasodilator Agents

The field of cardiac intensive care is rapidly evolving with nearly simultaneous advances in surgical techniques and adjunctive therapies, respiratory care, intensive care technology and monitoring, pharmacologic research and development, and computing and electronics. The focus of care has now shifted toward reducing morbidity and improving "quality of life" while the survival of infants and children with congenital heart defects, including those with univentricular hearts has dramatically improved during the last three decades. Despite these advances, there remains a predictable fall in cardiac output after cardiopulmonary bypass. This article focuses on early identification and aggressive treatment of the low cardiac output syndrome peculiar to these patients. The authors also briefly review the recent advances in the treatment of pulmonary hypertension, mechanical support, and neurologic surveillance after cardiac surgery.

Topics: Cardiac Output, Low; Cardiac Surgical Procedures; Cardiotonic Agents; Child; Critical Care; Dye Dilution Technique; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Care; Milrinone; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is associated with changes in vascular tone as well as vascular structure, with the relative contribution of each dependent upon the etiology of the increased vascular resistance. Prostacyclin treatment has markedly improved both the therapeutic options and the prognosis of PAH. The beneficial effect of prostacyclin in PAH is linked to the powerful vasodilating capacity and, even more importantly, to the inhibition of platelet aggregation, smooth muscle proliferation and antiinflammatory actions. Since prostacyclin has a very short plasma half-life, continuous intravenous administration via a portable infusion pump must be carried out. Because of the complexity of the delivery and the associated complications, intravenous prostacyclin (epoprostenol) therapy is restricted to patients with late NYHA Class III and Class IV and thus alternative modes of delivery in less advanced PAH are desirable. Recent clinical studies with more stable prostacyclin analogs such as subcutaneously delivered treprostinil, orally active beraprost and aerosolized iloprost have demonstrated beneficial effects of each of these prostanoids, especially in NYHA Class II and III patients and, therefore, these agents should be considered first for prostanoid therapy in the early stages of PAH. Prostaglandins may be more effective in conjunction with endothelin receptor antagonists or phosphodiesterase inhibitors and an increasing number of studies are now addressing the combined efficiency and safety of these combinations. This update will focus on the current development status of PAH therapy with prostacyclin and its analogs. Special attention will be accorded to the selection of patients for prostanoid therapy, therapy monitoring and improvement of therapeutic efficacy by addition of other new therapeutic agents to prostaglandins. Survival benefits and special aspects of bridging-to-transplant therapy are also important aspects of the review.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Pulmonary Circulation; Treatment Outcome

Topics: Administration, Inhalation; Alprostadil; Animals; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Nitroglycerin; Nitroprusside; Phosphodiesterase Inhibitors; Pulmonary Circulation; Respiratory Distress Syndrome; Vasodilator Agents

Pulmonary hypertension is a life-threatening disease characterized by an increase in artery pressure and vascular resistance in the pulmonary circulation. A primary form of pulmonary hypertension with unknown causes is to be distinguished from the far more frequent secondary forms based on known pulmonary and extrapulmonary disorders. An imbalance in the synthesis of vasoconstrictive and vasodilative agents seems to play an important role in the etiology of pulmonary hypertension. This pathophysiological background offers the possibility to develop treatment strategies, including application of vasodilative drugs. The intravenous administration of vasodilative agents, however, lacks pulmonary selectivity leading to systemic side effects. Therefore, the application of aerosol techniques for alveolar deposition of vasodilatory drugs was proposed and several studies with inhaled iloprost, a stable prostacyclin analogue, demonstrated preferential vasorelaxation in the pulmonary circulation, with the maximum pulmonary vasodilatory potency corresponding to that of intravenous prostacyclin. Clinical experiences with long-term inhaled iloprost are available showing sustained effects on exercise capacity and pulmonary hemodynamics in patients with pulmonary hypertension. Due to the necessary frequent inhalations (up to 12 times a day) and the potency of the prostaglandins, the choice of the nebulizer is critical, requiring physical characterization and device comparison studies under the right heart-catheter conditions. The concept of aerosolized vasodilators is meanwhile well established and offers a promising perspective in the treatment of pulmonary hypertension.

Topics: Administration, Inhalation; Aerosols; Humans; Hypertension, Pulmonary; Iloprost; Nebulizers and Vaporizers; Vasodilator Agents

To review the epidemiology, pathophysiology, clinical symptoms, and diagnostic workup of primary pulmonary hypertension (PPH) and to discuss the available data on the current and emerging therapies being used to treat this disorder.. Primary and review articles were identified with a MEDLINE search (1966-December 2001) and through secondary sources.. All articles identified from the data sources were evaluated and all information deemed relevant was included in this review.. In the absence of a definable cause, PPH is a disorder classified by a progressive increase in pulmonary vascular resistance and mean pulmonary artery pressure. A relatively rare condition, PPH has an annual incidence of 1-2 cases per million people, slightly higher in women than men. The prognosis is poor, with a mean survival time of 2.8 years after diagnosis if untreated. Vasoconstriction, vascular remodeling, and thrombosis are hallmarks of the disease process. Anticoagulation and vasodilators are the most commonly employed treatment options, showing benefits in clinical outcomes, hemodynamic parameters, and mortality. Several new vasodilators are being evaluated for the treatment of PPH. Bosentan was recently approved as the first oral agent for the treatment of PPH. Iloprost, treprostinil, and beraprost are investigational agents in Phase III studies.. Until additional studies and experience with these agents become available, calcium-channel blockers (CCBs) remain the first option for therapy. For patients not responding to CCBs, therapeutic options will now include epoprostenol and bosentan. Since there are no comparison trials between these 2 agents, therapeutic decisions should be based on patient-specific concerns. Clinical data and experience support the use of epoprostenol; however, in patients at risk or considered unsuitable candidates, bosentan may become a preferred option. Additional studies are warranted to address the potential therapeutic benefits of combination therapy and long-term benefits of agents to treat PPH.

Topics: Anti-Inflammatory Agents; Anticoagulants; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Vasodilator Agents

Past medical therapy for pulmonary arterial hypertension included the use of calcium-channel antagonists in acute vasoreactive subjects and oral anticoagulants and continuous intravenous administration of epoprostenol in the more severe cases. Recently, the thromboxane inhibitor terbogrel, the prostacyclin analogues treprostinil, beraprost and iloprost, and the endothelin receptor antagonist bosentan have been tested in clinical trials in >1,100 patients. Except for terbogrel, all compounds improved the mean exercise capacity by different degrees, as assessed by the 6-min walk test. In the evaluation of the clinical relevance of exercise capacity improvements, additional elements need to be considered, such as baseline functional class and concomitant favourable effects on combined clinical events (including hospitalisations, mortality and rescue therapies), quality of life and haemodynamics. No trials have shown effects on mortality, as the study protocols were not designed for assessing this end-point. Each new compound presents side-effects that are unpredictable in the individual patient and require appropriate attention upon treatment initiation and maintenance. These new therapeutic options will be available in the near future and will allow tailoring of the most appropriate treatment to the single patient, according to an individualised benefit-to-risk ratio.

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Prognosis; Pyridines; Randomized Controlled Trials as Topic; Severity of Illness Index; Survival Rate; Treatment Outcome; Vasodilator Agents

SEVERITY AND TREATMENT: The management of primitive pulmonary hypertension starts by the evaluation of its severity, based on the New York Heart Association's (NYHA) functional classification and right cardiac catheterization data. Hemodynamic criteria of poor prognosis are: an increase in right atrial pressure > 10 mm Hg, a decrease in cardiac output (cardiac index < 2.2 l/min/m2), an increase in pulmonary vascular resistance > to 20 mm Hg/l/min/m2, and saturation of the oxygen content in venous blood < 63%. These prognostic data will condition treatment. CALCIUM CHANNEL BLOCKERS: Are the only vasodilators that have demonstrated efficacy in primitive pulmonary hypertension (PPH). However, only 20% of patients respond to calcium blockers. To determine a positive response to these agents, a carbon monoxide inhalation test is required during right cardiac catheterization. Prescription of calcium channel blockers to non-responders is often responsible for adverse events, from enhanced dyspnoea to sudden death. Continuous intravenous infusion of epoprostenol has considerably improved the prognosis of PPH and related pulmonary hypertension (PH). Despite the constraints, such treatment should be proposed to NYHA functional class III and IV patients not responding to carbon monoxide tests, until new, equally efficient products have been launched on the market. If epoprostenol fails or provokes severe side effects, pulmonary or cardio-pulmonary transplantation should be envisaged.

Topics: Administration, Oral; Adult; Algorithms; Anticoagulants; Antihypertensive Agents; Calcium Channel Blockers; Cardiac Catheterization; Clinical Trials as Topic; Diuretics; Epoprostenol; Female; Heart Atria; Heart Septum; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Lung Transplantation; Male; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Survival Analysis; Vasodilator Agents

Prostacyclin (PGI2) is a potent and a promising vasodilative agent in the treatment of pulmonary hypertension (PH). Epoprostenol (Flolan), an intravenous PGI2, has been used for PPH, and exerts dramatic effects such as reducing pulmonary vascular resistance and increasing cardiac output leading to an improvement of exercise tolerance. However, continuous i.v. infusion accompanies infection, thrombosis, occlusion, battery problems and variable side effects of PGI2 itself. Uniprost, administered subcutaneously, has a rather long half-life. It also needs an ambulatory infusion pump system. Beraprost, an oral PGI2 analogue, is also effective in mild PH patients. It can be absorbed easily and administered tid, or qid fashion. Inhaled iloprost may be an alternative option, but both iloprost and beraprost require frequent administrations because of their short half-life.

Topics: Administration, Inhalation; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Injections, Subcutaneous

Topics: Antihypertensive Agents; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Iloprost; Prognosis; Vasodilator Agents

Prostacyclin is a substance produced by endothelial cells that induces vasodilation and inhibition of platelet aggregation and of vascular cell migration and proliferation. A dysregulation of the prostacyclin metabolic pathways has been shown in patients with pulmonary arterial hypertension. The clinical use of prostacyclin has been made possible by the synthesis of stable analogues that possesses different pharmacokinetic properties but share similar pharmacodynamic effects. The greatest experience has been collected with intravenous epoprostenol while other compounds like subcutaneous UT-15, inhaled iloprost and oral beraprost are currently in different stages of clinical development. Although favorable results have been reported for each compound, different benefit-to-side effects profiles characterize the various modalities of the administration.

Topics: Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Vasodilation; Vasodilator Agents

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide

Perioperative right ventricular (RV) failure due to pressure overload from pulmonary hypertension (PH) worsens postoperative outcomes after cardiac surgery. Inhaled iloprost is a potent pulmonary vasodilator improving RV performance, ameliorating myocardial and pulmonary ischemia-reperfusion injury and attenuating inflammation. We hypothesized that the prophylactic inhalation of iloprost would reduce postoperative ventilation times after cardiac surgery.. In this phase III, multicentre, randomized, double-blind, placebo-controlled trial, we randomly assigned 253 cardiac surgical patients at high risk of perioperative RV failure to the prophylactic inhalation of 20 µg iloprost or placebo before and during weaning from extracorporeal circulation. The primary endpoint was the duration of postoperative ventilation. Secondary endpoints included perioperative hemodynamics, intensive care unit and hospital length of stay, and 90-day mortality. Safety was assessed by the incidence of adverse events.. Iloprost had no significant effect on the median [interquartile range] duration of postoperative ventilation compared with placebo (720 [470-1170] min vs 778 [541-1219] min, respectively; median decrease, 65 min; 95% confidence interval [CI], - 77 to 210; P = 0.37). While the nebulization of iloprost decreased RV afterload and improved cardiac index, major secondary endpoints were not significantly affected. Ninety-day mortality occurred in 14% of the iloprost patients compared with 14% of the placebo patients (hazard ratio, 0.97; 95% CI, 0.50 to 1.89; P = 0.93). The incidence of adverse events was comparable in both groups.. The prophylactic inhalation of iloprost did not meaningfully improve the outcome in high-risk cardiac surgical patients.. www.clinicaltrials.gov (NCT00927654); registered 25 June, 2009.. RéSUMé: OBJECTIF: L’insuffisance cardiaque droite périopératoire due à une surcharge de pression provoquée par l’hypertension pulmonaire (HP) a un impact négatif sur le pronostic postopératoire après une chirurgie cardiaque. L’iloprost administré par inhalation est un vasodilatateur pulmonaire puissant qui améliore la performance du ventricule droit (VD), réduisant ainsi la lésion d’ischémie-reperfusion myocardique et pulmonaire et atténuant l’inflammation. Nous avons émis l’hypothèse qu’une inhalation prophylactique d’iloprost réduirait les temps de ventilation postopératoire après une chirurgie cardiaque. MéTHODE: Dans cette étude multicentrique de phase III, contrôlée par placebo, à double insu et randomisée, nous avons distribué aléatoirement 253 patients chirurgicaux courant un risque élevé d’insuffisance cardiaque droite périopératoire à une prophylaxie de 20 µg d’iloprost ou d’un placebo par inhalation avant et pendant le sevrage de la circulation extracorporelle. Le critère d’évaluation principal était la durée de ventilation postopératoire. Les critères d’évaluation secondaires étaient les données hémodynamiques périopératoires, la durée de séjour à l’unité de soins intensifs et à l’hôpital, et la mortalité à 90 jours. L’innocuité a été évaluée en fonction de l’incidence d’événements indésirables. RéSULTATS: L’iloprost n’a pas eu d’effet significatif sur la durée médiane [écart interquartile] de ventilation postopératoire par rapport au placebo (720 [470–1170] min vs 778 [541–1219] min, respectivement; réduction médiane, 65 min; intervalle de confiance [IC] 95 %, − 77 à 210; P = 0,37). Bien que la nébulisation d’iloprost ait réduit la post-charge du VD et amélioré l’index cardiaque, cette manœuvre n’a pas eu d’impact significatif sur les critères d’évaluation secondaires majeurs. Une mortalité à 90 jours a été observée chez 14 % des patients ayant reçu de l’iloprost, comparativement à 14 % des patients ayant reçu un placebo (rapport de risque, 0,97; IC 95 %, 0,50 à 1,89; P = 0,93). L’incidence d’événements indésirables était comparable dans les deux groupes. CONCLUSION: L’inhalation prophylactique d’iloprost n’a pas amélioré le pronostic des patients de chirurgie cardiaque à haut risque. ENREGISTREMENT DE L’éTUDE: www.clinicaltrials.gov (NCT00927654); enregistrée le 25 juin 2009.

Topics: Administration, Inhalation; Aged; Cardiac Surgical Procedures; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Iloprost; Length of Stay; Male; Postoperative Complications; Prospective Studies; Respiration, Artificial; Vasodilator Agents; Ventricular Dysfunction, Right

Right ventricular (RV) function is an important prognostic factor of pulmonary arterial hypertension (PAH), but there is insufficient data regarding RV function after long-term inhaled iloprost treatment. We evaluated the effect of long-term iloprost treatment on RV function in patients with Eisenmenger syndrome (ES).. Eleven consecutive patients with ES associated with congenital heart disease underwent echocardiographic measurements at baseline and 48 weeks after iloprost therapy. In addition, we recorded World Health Organization (WHO) functional class, 6-minute walk distance (6MWD), systemic arterial oxygen saturation (SaO. After 48 weeks of iloprost therapy, mean pulmonary arterial pressure (mPAP), pulmonary arterial systolic pressure (PASP), and pulmonary vascular resistance (PVR) were significantly decreased [mPAP, 42.5 (38.5-61.0) to 36.5 (29.1-40.0)mmHg; PASP, 92.6±19.9 to 74.5±23.8mmHg; PVR, 23.4 (19.8-26.0) to 23.4 (19.8-26.0)Wood unit respectively, all p<0.05]. There was also significant improvement in RV myocardial performance index [0.68 (0.61-0.80) to 0.52 (0.51-0.62), p=0.003] and RV longitudinal strain (-15.7±1.6 to -18.1±1.5%, p<0.001). In clinical assessment, WHO functional class (p=0.006), 6MWD (310.6±44.7 to 399.7±80.8m, p<0.001), and SaO. The improvement in echocardiographic parameters of the RV function after 48 weeks of iloprost therapy may provide insight on the efficacy of long-term iloprost treatment for RV functional improvement, which is a prognostic factor in patients with ES.

Topics: Administration, Inhalation; Adult; Echocardiography; Eisenmenger Complex; Exercise Test; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Oxygen; Prospective Studies; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

Monotherapy and sequential combination therapy have been widely used in the treatment of pulmonary arterial hypertension (PAH). There is limited evidence for initial combination therapy in patients with PAH, particularly those with World Health Organization (WHO) functional class III or IV.. Twenty-seven consecutive treatment-naive PAH subjects with WHO functional class III or IV PAH were randomized into 3 groups with a 1:1:1 ratio: a combination therapy group with 125 mg of bosentan twice daily plus 10 μg of iloprost 4-6 times/d; a bosentan monotherapy group with 125 mg of bosentan twice daily; and a iloprost monotherapy group with 10 μg of iloprost 4-6 times/d. Clinical and hemodynamic data were collected at baseline, 6 weeks, and 3 months. The primary end point was the change in the 6-min walk distance (6MWD) from baseline values.. At baseline, there were no differences in demographics, WHO classification, hemodynamics, classification of PAH, or 6MWD among the 3 groups. The 6MWD significantly improved in the combination therapy group compared with the bosentan monotherapy and iloprost monotherapy groups at week 6 (. Initial combination therapy in treatment-naive PAH subjects with WHO functional class III or IV can significantly improve 6MWD, hemodynamics, and quality of life compared with monotherapy. Further studies with large samples and placebo controls are required to assess the tolerability and efficacy of initial combination therapy in patients with PAH. (ClinicalTrials.gov registration NCT01712997).

Topics: Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Pulmonary Artery; Quality of Life; Sulfonamides; Time Factors; Treatment Outcome; Vasodilator Agents; Walk Test

To investigate the effects of intravenous iloprost on pulmonary artery hypertension (PAH) in infants undergoing congenital heart surgery.. In this prospective, randomized study, the study group (n = 15) received a continuous infusion of iloprost (2.0 ng/kg/min) that was delivered immediately after weaning from cardiopulmonary bypass and continued for 72 h postoperatively. Patients in the control group (n = 12) were managed conventionally. The groups were compared in terms of postoperative data, including systolic and mean pulmonary artery (PA) pressures, PA/systemic pressure ratio, lactate level, PAH crisis, ventilation time, reintubation and lengths of intensive care unit (ICU) and hospital stay. Transthoracic echocardiography was used to assess PA pressures at 1 day, 7 days and 30 days after surgery.. No mortality occurred. PAH crisis occurred in 2 (16.6%) patients in the control group and 4 (26.7%) patients in the study group (P = 0.53). Postoperative PA pressures and PA/systemic pressure ratios were similar between the groups (P > 0.05). The durations of ICU (P = 0.40) and hospital (P = 0.98) stays were similar between the groups. Echocardiographic studies demonstrated a significant decrease in postoperative PA pressures in the control (P = 0.001) and study (P = 0.0001) groups. However, no significant change was observed between the groups (P > 0.05). The Tukey multiple comparison test showed a significant decrease in PA pressures at each follow-up in both groups (P < 0.05).. Intravenous iloprost demonstrated no additional benefit over the conventional management of infants with PAH after repair of intracardiac defects. Clinicians may prefer other alternative agents in infants with a high risk of PAH crisis.

Topics: Cardiac Surgical Procedures; Dose-Response Relationship, Drug; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infusions, Intravenous; Male; Postoperative Care; Prospective Studies; Pulmonary Wedge Pressure; Treatment Outcome; Vasodilator Agents

Inhaled iloprost is approved for pulmonary arterial hypertension (PAH) in many countries. IBUKI was a phase III, non-randomized, open-label study of the efficacy and safety of inhaled iloprost in Japanese patients with PAH.. Adults with PAH who were treatment-naïve or administered endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 inhibitors (PDE5-Is) and in NYHA/WHO functional class (FC) III/IV had inhaled iloprost (2.5 µg, increased to 5.0 µg if tolerated) 6-9 times daily for 12 weeks. Eligible patients entered a 40-week extension phase. Endpoints included change from baseline to week 12 in pulmonary vascular resistance (PVR; primary endpoint), other efficacy parameters, and safety. Data were compared with new subgroup analyses of treatment-naïve Western PAH patients from the global phase III AIR study. 27 patients received iloprost: 89% were treated with an ERA and/or PDE5-I; 70% with both. At week 12, PVR improved from baseline by -124 dyn·sec·cm(-5)(95% CI, -177 to -72) and 6-min walking distance increased by 36.0 m (95% CI, 14.9 to 57.1). NYHA/WHO FC improved in 62%; none worsened. Common drug-related adverse events were headache (37%) and cough (15%); 1 patient experienced hypotension; none reported syncope or hemoptysis. There were no deaths and no unexpected long-term safety findings. AIR PAH subgroup analyses showed similar results.. Inhaled iloprost appeared effective and safe in Japanese PAH patients, including ERA- and PDE5-I-treated patients, consistent with findings of the AIR PAH subpopulation and previous iloprost studies.

Topics: Administration, Inhalation; Adult; Asian People; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Iloprost; Japan; Male; Middle Aged; Phosphodiesterase 5 Inhibitors

Congenital heart disease (CHD) can cause pulmonary hypertension (PH) in children, and surgery to correct CHD may be complicated by postoperative pulmonary hypertensive crises (PHC). Clinical data regarding the use of inhaled iloprost to treat children with PH are scarce. Our aim was to determine the efficacy and safety of iloprost in children with PH following surgery to correct CHD. This was a randomized, placebo-controlled study of 22 children (median age 7 months) undergoing surgery to achieve biventricular repair. The combined clinical endpoint was a decrease of more than 20% in the ratio of systolic pulmonary arterial pressure to systolic arterial pressure or pulmonary resistance to systemic resistance, with no PHC or death. Patients were randomized to receive low-dose iloprost (30 ng/kg/min), high-dose iloprost (50 ng/kg/min), or placebo, for 10 min every 2 hr in the first 48 hr after surgery. PHC were experienced by two patients who received placebo and one patient treated with high-dose iloprost. The combined clinical endpoint was reached by six patients administered low-dose iloprost (P = 0.005) and four administered high-dose iloprost (P = 0.077), compared with none in the placebo group. Patients treated with iloprost showed a significant reduction from baseline in mean pulmonary vascular resistance index (-2.2 Wood units, P < 0.05), whereas patients who received placebo showed no significant change. This study supports the use of iloprost to treat children with PH following surgery to correct CHD.

Topics: Blood Pressure; Cardiac Surgical Procedures; Child; Child, Preschool; Double-Blind Method; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Male; Treatment Outcome; Vasodilator Agents

No previous study has been done on whether systemic lupus erythematosus (SLE) disease activity is related to the hemodynamics and right ventricular (RV) function in patients with SLE-associated pulmonary artery hypertension (SLE-APAH).. This study prospectively recruited 54 patients (mean age, 32.8±8.4 years; 92.6% female) with SLE-APAH, including 34 patients with SLE disease activity index (SLEDAI) <5 (low score) and 20 with SLEDAI ≥5 (high score). All patients underwent right heart catheterization and iloprost inhalation, and echocardiography was performed before and immediately after iloprost inhalation. There was no difference in baseline mean pulmonary artery pressure (mPAP) between the 2 groups; pulmonary vascular resistance (PVR) was significantly higher and cardiac index was significantly lower in the low-SLEDAI group. The patients with low SLEDAI had larger RV size and worse RV systolic function on echocardiography. After iloprost inhalation, the patients with low SLEDAI had a greater decrease in mPAP and PVR than those with high SLEDAI, while significantly increased RV systolic function was found only in the low-SLEDAI group.. SLE activity is related to hemodynamics and RV function in SLE-APAH patients, and those with low SLEDAI might have better acute response to vasodilator inhalation.

Topics: Adult; Cardiac Catheterization; Cardiovascular Agents; Echocardiography; Female; Humans; Hypertension, Pulmonary; Iloprost; Lupus Erythematosus, Systemic; Male; Vascular Resistance; Vasodilation; Ventricular Function, Right

The evaluation of pulmonary vascular reactivity plays a significant role in the management of patients with pulmonary hypertension. Inhaled nitric oxide in combination with oxygen (O2) has become widely used as an agent for pulmonary vasodilator testing. However, inhaled nitric oxide is not available in many developing countries. Recently, aerosolized iloprost was suggested as an alternative to nitric oxide for this purpose. In the present study, aerosolized iloprost was used together with O2 in the pulmonary vasoreactivity test of children with severe pulmonary hypertension. Thus, the synergistic effect of both vasodilators was utilized without extending the duration of cardiac catheterization.. The prospective cohort study registered a total of 16 children with severe pulmonary hypertension whose median age was 4.5 years. Hemodynamic parameters were quantified before and after the vasoreactivity test. Increased left-to-right shunt, pulmonary vascular resistance of <6 Woods units (WU)/m(2) and a pulmonary-systemic resistance ratio of <0.3, as well as a decrease >10% in the pulmonary vascular resistance and pulmonary-systemic vascular resistance ratio after the vasoreactivity test were accepted as a positive response. The data were analyzed using Wilcoxon signed-rank and the Mann-Whitney U tests.. Eleven children gave a positive response to the vasoreactivity test, while 5 children did not respond. Pulmonary vascular resistance dropped from 9.98 ± 1.39 WU/m(2) to 5.08 ± 1.05 WU/m(2) (p=0.013) and the pulmonary-systemic vascular resistance ratio fell from 0.68 ± 0.08 to 0.32 ± 0.05 (p=0.003) in the children who were responsive. No side effects were observed related to iloprost administration.. Administration of inhaled iloprost in combination with O2 for pulmonary vasoreactivity testing can be useful for correctly identifying pulmonary vasoreactivity without extending the duration of cardiac catheterization.

Topics: Administration, Inhalation; Adolescent; Child; Child, Preschool; Cohort Studies; Female; Humans; Hypertension, Pulmonary; Iloprost; Infant; Male; Oxygen Inhalation Therapy; Prospective Studies; Treatment Outcome; Vascular Resistance; Vasodilator Agents

To evaluate the therapy efficacy of iloprost combined with low dose tadalafil in adult congenital heart disease (CHD) patients with severe pulmonary arterial hypertension (PAH).. Adult CHD patients with severe PAH were included and divided into the sequential combination therapy group [iloprost: 10 µg/inhalation, 6 times per day for 6 months, and then add oral tadalafil (5 mg/d) till 12 months, n = 32] and upfront combination therapy group [iloprost: 10 µg/inhalation, 6 times per day combined with oral tadalafil (5 mg) for 12 months, n = 36]. Data on 6 min walking test (6MWT), Borg dyspnea score, oxygen saturation measurement, WHO classification, and cardiac catheterization were obtained at baseline, 6 and 12 months.. Seventy-two patients were enrolled in the study and 68 patients completed the study. Pulmonary vascular resistance (PVR) was significantly reduced in the sequential combination therapy group[ (12.96 ± 6.48 ) Wood U vs. (16.94 ± 8.11) Wood U, P < 0.05] and in the upfront combination therapy group [(12.45 ± 7.32) Wood U vs. (16.73 ± 9.28) Wood U, P < 0.05] while pulmonary blood flow [(6.77 ± 3.17) L/min vs. (5.08 ± 2.36) L/min, P < 0.05; (6.95 ± 3.32) L/min vs. (5.03 ± 2.32) L/min, P < 0.05], the 6 MWD were significantly increased [(458 ± 59) m vs. (427 ± 65) m, P < 0.05; (494 ± 59) m vs. (436 ± 62) m, P < 0.01], the Borg dyspnea score (2.04 ± 0.72 vs. 2.52 ± 0.79, P < 0.05; 1.72 ± 0.73 vs. 2.51 ± 0.77, P < 0.01) was significantly improved in both groups at 6 months compared to baseline levels. In the upfront combination therapy group, venous oxygen saturation [(68.4 ± 9.3)% vs. (62.9 ± 9.5)%, P < 0.05] and systemic oxygen saturation during exercise[ (87.2 ± 9.7)% vs. (83.1 ± 15.6)%, P < 0.05]at 6 months were also significantly improved compared to baseline. At month 12, significantly lowered pulmonary artery pressure, PVR, Rp/Rs and increased pulmonary blood flow and cardiac index were evidenced in both groups compared to baseline.. Iloprost combined with low dose tadalafil regimen can effectively reduce PVR, increase 6MWD, and improve cardiopulmonary function in adults CHD patients with severe PAH. Compared with the sequential therapy regimen, the upfront combination therapy regimen can more rapidly improve the clinical symptoms of patients.

Topics: Adolescent; Adult; Carbolines; Female; Follow-Up Studies; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Tadalafil; Treatment Outcome; Young Adult

Inhaled treprostinil is a prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) that may provide a more convenient treatment option for patients receiving inhaled iloprost while maintaining the clinical benefit of inhaled prostacyclin therapy.. In this open-label safety study, 73 PAH patients were enrolled with primarily World Health Organization Class II (56%) or III (42%) symptoms. At baseline, most patients (93%) were receiving 5 μg of iloprost per dose but 38% of patients reported a dosing frequency below the labeled rate of 6-9 times daily. Patients initiated inhaled treprostinil at 3 breaths four times daily (qid) at the immediate next scheduled iloprost dose. The primary objective was to assess the safety of rapid transition from iloprost to inhaled treprostinil; clinical status and quality of life were also assessed.. Most patients (84%) achieved the target treprostinil dose of 9 breaths qid and remained on study until transition to commercial therapy (89%). The most frequent adverse events (AEs) were cough (74%), headache (44%), and nausea (30%), and five patients prematurely discontinued study drug due to AE (n = 3), disease progression (n = 1), or death (n = 1). At week 12, the time spent on daily treatment activities was reduced compared to baseline, with a mean total savings of 1.4 h per day. Improvements were also observed at week 12 for 6-min walk distance (+16.0; P < 0.001), N-terminal pro-B-type natriuretic peptide (-74 pg/mL; P = 0.001), and the Cambridge Pulmonary Hypertension Outcome Review (all domains P < 0.001).. Pulmonary arterial hypertension patients can be safely transitioned from inhaled iloprost to inhaled treprostinil while maintaining clinical status.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Antihypertensive Agents; Arterial Pressure; Drug Administration Schedule; Drug Substitution; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prospective Studies; Pulmonary Artery; Quality of Life; Time Factors; Treatment Outcome; United States; Vasodilation; Vasodilator Agents; Young Adult

We hypothesized that nebulized iloprost would improve ventilation-perfusion matching in patients with pulmonary hypertension and ARDS as reflected by an improved Pao2/Fio2 ratio and Pao2 without adversely affecting lung mechanics or systemic hemodynamics.. Patients with ARDS and pulmonary hypertension were enrolled. With constant ventilator settings, hemodynamics, airway pressures, and gas exchange measured at baseline were compared with values 30 min after administration of 10 μg nebulized iloprost, and again 30 min after a second, larger, 20 μg dose of iloprost, and then a final measurement 2 h after the second dose. The primary outcome variable was Pao2; secondary outcomes were Pao2/Fio2 ratio, mean arterial BP, and lung-compliance ventilatory equivalents for oxygen and CO2.. After informed consent was obtained, 20 patients (nine men, 11 women; median age, 59 years [interquartile range, 44-66 years]) with ARDS were enrolled. Baseline PaO2 improved from a mean (±SD) of 82 (13) mm Hg to 100 (25) mm Hg after both the first and second doses of iloprost, and the baseline mean (±SD) PaO2/FIO2 ratio of 177 (60) improved to 213 (67) and 212 (70) (all P<.01). PaCO2, peak and plateau airway pressures, systemic BP, and heart rate were not significantly changed after iloprost.. The improvement in gas exchange without any detrimental effects on pulmonary mechanics or systemic hemodynamics suggests nebulized iloprost may be a useful therapeutic agent to improve oxygenation in patients with ARDS.. ClinicalTrials.gov; No.: NCT01274481; URL: www.clinicaltrials.gov.

Topics: Administration, Inhalation; Adult; Aged; Comorbidity; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Respiratory Mechanics; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension is of importance in congenital cardiac surgery as being a significant cause of morbidity and mortality. Although therapy options are limited, inhaled nitric oxide (NO) is used as a standard therapy. The present study aimed to compare inhaled NO and aerosolized iloprost in children with secondary pulmonary hypertension who underwent congenital cardiac surgery.. Sixteen children included in the study were randomized into either inhaled NO or aerosolized iloprost group. For both groups, the observation period terminated at 72 h after cardiopulmonary bypass.. There was no significant difference between the groups in terms of mean age, weight, cross clamp time, pump time, and extubation time. No significant change was observed in the arterial tension and central venous pressure of both groups before the operation, 30 min after the pump, 45 min after the pump, and after extubation, whereas an increase was observed in the heart rate and cardiac output, and a decrease was observed in the pulmonary artery pressure. The mean values at the above-mentioned time points showed no difference between the groups. No serious adverse event and mortality was detected.. Both inhaled NO and aerosolized iloprost were found to be effective and comparable in the management of pulmonary hypertension.

Topics: Administration, Inhalation; Aerosols; Antihypertensive Agents; Cardiac Surgical Procedures; Child; Child, Preschool; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Nitric Oxide; Time Factors; Treatment Outcome; Turkey; Vasodilator Agents

Iloprost has been used to test acute pulmonary vasoreactivity in idiopathic pulmonary arterial hypertension (PAH). We aimed to investigate the acute hemodynamic and oxygenation responses and tolerability to 20 µg aerosolized Iloprost in Chinese patients with pulmonary hypertension.. Between March 2005 and May 2010, 212 pulmonary hypertension patients inhaled a single dose of 20 µg Iloprost over 10 - 15 minutes for vasoreactivity testing. The acute hemodynamic and oxygenation responses and adverse events were recorded.. Iloprost decreased total pulmonary resistance ((1747 ± 918) dyn×s×cm(-5) vs. (1581 ± 937) dyn×s×cm(-5), P < 0.001), increased stroke volume ((45.0 ± 22.1) ml vs. (47.0 ± 24.2) ml, P = 0.002), and cardiac output ((3.7 ± 1.7) L/ml vs. (3.9 ± 1.9) L/min, P = 0.009). Heart rate and systemic vascular resistance remained stable during inhalation. However, systemic arterial blood oxygen saturation fell slightly ((91.0 ± 6.8)% vs. (90.3 ± 6.7)%, P = 0.002). Pulmonary and systemic arterial blood pressures declined within 1 - 3 minutes after inhalation initiation and reached their lowest levels within 10 - 15 minutes. Idiopathic PAH responded more favorably than pulmonary hypertension due to other causes (P £0.001) and patients with less severe pulmonary hypertension have better responses to Iloprost. No adverse events requiring medical care or leading to termination of inhalation occurred.. Inhalation of 20 µg Iloprost showed potent and selective pulmonary hemodynamic effects and was well tolerated in the Chinese pulmonary hypertension patients. Patients with idiopathic PAH and less severe pulmonary hypertension responded more favorably to inhalation of Iloprost.

Topics: Administration, Inhalation; China; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost

There is a high incidence of pulmonary hypertension during the lung transplant peri-operative period, and could lead to a haemodynamic deterioration that may require the need of extracorporeal circulation. Our aim was to study the haemodynamic effects on the pulmonary and systemic circulation of the combination of inhaled nitric oxide and iloprost and oral sildenafil in patients with severe pulmonary hypertension during lung transplant surgery.. Seventeen patients received 10μg of nebulised iloprost during the peri-operative period of the lung transplant when their mean pulmonary pressure exceeded 50mmHg. AU the patients received 50mg of oral sildenafil 30min before anaesthetic induction, 20ppm of inhaled nitric oxide after tracheal intubation. The haemodynamic and respiratory variables were recorded at baseline (after anaesthetic induction), prior to the administering of iloprost, and at 5 and 30min after it was given.. The administering of iloprost significantly reduced the pulmonary arterial pressure and significantly increases the cardiac Índex and the right ventrícular ejection fractíon. There were no signíficant changes occurred in the systemic arterial pressure.. The triple combination significantly reduces the pulmonary pressures in the lung transplant peri-operative and should be considered when there is severe pulmonary hypertension during the surgery or during the immediate post-operative period of lung transplantation.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Cystic Fibrosis; Dobutamine; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Complications; Lung Transplantation; Male; Middle Aged; Nebulizers and Vaporizers; Nitric Oxide; Norepinephrine; Piperazines; Preoperative Care; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Inhaled iloprost potentially improves hemodynamics and gas exchange in patients with chronic obstructive pulmonary disease (COPD) and secondary pulmonary hypertension (PH).. To evaluate acute effects of aerosolized iloprost in patients with COPD-associated PH.. A randomized, double blind, crossover study was conducted in 16 COPD patients with invasively confirmed PH in a single tertiary care center. Each patient received a single dose of 10 µg iloprost (low dose), 20 µg iloprost (high dose) and placebo during distinct study-visits. The primary end-point of the study was exercise capacity as assessed by the six minute walking distance.. Both iloprost doses failed to improve six-minute walking distance (p = 0.36). Low dose iloprost (estimated difference of the means -1.0%, p = 0.035) as well as high dose iloprost (-2.2%, p<0.001) significantly impaired oxygenation at rest. Peak oxygen consumption and carbon dioxide production differed significantly over the three study days (p = 0.002 and p = 0.003, accordingly). As compared to placebo, low dose iloprost was associated with reduced peak oxygen consumption (-76 ml/min, p = 0.002), elevated partial pressure of carbon dioxide (0.27 kPa, p = 0.040) and impaired ventilation during exercise (-3.0l/min, p<0.001).. Improvement of the exercise capacity after iloprost inhalation in patients with COPD-associated mild to moderate PH is very unlikely.. Controlled-Trials.com ISRCTN61661881.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Cross-Over Studies; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Oxygen; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange

Detection of pulmonary vasoreactivity is important for the evaluation of patient with pulmonary arterial hypertension (PAH). The present study aimed to investigate the acute hemodynamic responses to adenosine and iloprost in patients with congenital heart defects (CHDs) and severe PAH.. From Mar 2007 to Nov 2009, 75 patients with severe PAH secondary to left-to-right shunt CHDs underwent acute vasodilator test using aerosolized iloprost (n = 50) or intravenous adenosine (n = 25). The hemodynamics were detected and analyzed.. Decreased mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) were observed in 39 and 43 patients in the iloprost group, and in 16 and 19 patients in the adenosine group, respectively. However, the mean PAP was higher than 40 mm Hg in both groups. No significant difference was observed in the age and baseline hemodynamics between the patients with the decrease of PVR and mean pulmonary-to-aortic pressure (Pp/Ps) ratio greater than 10% and the remaining patients. Adenosine decreased both PAP and systemic arterial pressure significantly, while iloprost inhalation selectively reduced the PAP and increased the oxygen saturation of femoral arterial blood and the pulmonary-to-systemic flow (Qp/Qs) ratio. Compared with adenosine, iloprost caused a more profound decline in the Pp/Ps ratio, PVR and pulmonary-to-systemic vascular resistance ratio, and increase in the Qp/Qs ratio.. The acute haemodynamic responses to adenosine and iloprost varied among the patients with CHDs and severe PAH. Different to adenosine, inhaled iloprost exerted selective pulmonary vasodilative effects and was beneficial for pulmonary gas exchange.

Topics: Acute Disease; Adenosine; Administration, Inhalation; Adolescent; Adult; Child; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Severity of Illness Index; Young Adult

Pilot study to compare the effect of inhaled nitric oxide (iNO) and aerosolized iloprost in preventing perioperative pulmonary hypertensive crises (PHTCs).. Guidelines recommend the use of iNO to treat PHTCs, but treatment with iNO is not an ideal vasodilator. Aerosolized iloprost may be a possible alternative to iNO in this setting.. Investigator-initiated, open-label, randomized clinical trial in 15 infants (age range 77-257 days) with left-to-right shunt (11 out of 15 with additional trisomy 21), and pulmonary hypertension (i.e. mean pulmonary artery pressure [PAP] >25 mmHg) after weaning from cardiopulmonary bypass. Patients were randomized to treatment with iNO at 10 ppm or aerosolized iloprost at 0.5 µg/kg (every 2 h). The observation period was 72 h after weaning from cardiopulmonary bypass. The primary endpoint was the occurrence of PHTCs; the secondary endpoints were mean PAP, duration of mechanical ventilation, safety of administration, and in-hospital mortality.. Seven patients received iNO and eight patients received iloprost. During the observation period, 13 of the 15 patients had at least one major or minor PHTC. There was no difference between the groups with regard to the frequency of PHTCs, mean PAP and duration of mechanical ventilation (p > 0.05).. In this pilot study, aerosolized iloprost had a favorable safety profile. Larger trials are needed to compare its efficacy to iNO for the treatment of perioperative pulmonary hypertension. However, neither treatment alone abolished the occurrence of PHTCs.

Topics: Administration, Inhalation; Bronchodilator Agents; Cardiopulmonary Bypass; Heart Diseases; Humans; Hypertension, Pulmonary; Iloprost; Infant; Nitric Oxide; Pilot Projects; Postoperative Complications; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension (PH) can lead to right-side heart failure (RHF) and death. There are no therapeutic recommendations for patients experiencing acute RHF in the course of PH. This study aimed to examine the safety and efficacy of inhaled iloprost in patients with precapillary PH and RHF.. Between October 2007 and December 2008, 7 patients with precapillary PH and RHF were enrolled. Per protocol, iloprost was inhaled hourly for a minimum of 12 hours during a 24-hour period. The starting dose of 2.5 μg was increased hourly by 2.5 μg as long as the increases were tolerated. Safety and efficacy were determined by continuous invasive monitoring of systemic and pulmonary hemodynamic parameters. Systemic pressures remained stable during inhalation (66.1 ± 6.9 mm Hg at baseline and 69.1 ± 6.4 mm Hg immediately after inhalation therapy, P = 0.48). Cardiac index increased from 2.4 ± 0.7 L/min/m(2) to 2.9 ± 0.9 L/min/m(2) (P = .008). Pulmonary vascular resistance decreased from 634.6 ± 218.3 dyn·s·cm(-5) to 489.6 ± 173.8 dyn·s·cm(-5) (P = .044), and N-terminal B-type natriuretic peptide levels decreased from 13,591 ± 10,939 pg/mL to 9,944 ± 8,569 pg/mL (P = .051).. Blood pressure-guided hourly inhalation of iloprost may offer a safe and effective strategy for the treatment of PH patients with RHF.

Topics: Administration, Inhalation; Aged; Blood Pressure Determination; Female; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Natriuretic Peptide, Brain; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Right

Nonselective systemic vasodilators worsen ventilation perfusion (V/Q) matching and gas exchange in patients with chronic obstructive pulmonary disease (COPD). Inhaled iloprost has the potential to act preferentially in ventilated regions of the lung, thereby reducing pulmonary hypertension (PH) while alveolar ventilation is still maintained.. To investigate the acute effects of inhaled iloprost on V/Q matching in patients with COPD and PH.. Ten males with COPD and PH on echocardiography were evaluated before and after inhaling 2 doses of iloprost (2.5 microg). Measurements included lung function, arterial blood gas, 6-min walk test (6MWT) as well as ventilatory equivalents for oxygen (V(E)/VO(2)) and carbon dioxide (V(E)/VCO(2)) taken at baseline, 30 min following each dose of iloprost, and 2 h after the second dose.. Mean differences in V(E)/VCO(2) and V(E)/VO(2) were -13.3 (95% CI -36.5 to -2.7; p = 0.002) and -15.0 (95% CI -36.7 to -0.4; p = 0.02), respectively, and the mean change in (A-a) gradient was -3.7 mm Hg (95% CI -6.1 to -1.0; p = 0.01) after a single dose of iloprost, whereas mean improvement in 6MWT was 49.8 m (95% CI 14.8 to 84.7; p = 0.02). Arterial blood gas, venous admixture, dead space fraction and lung functions were maintained after iloprost. The effects of iloprost were reproducible after the second dose. All measurements returned to baseline 2 h after the last dose. No adverse effects on systemic blood pressure or oxygen saturation were seen.. Iloprost inhalation was safe in patients with COPD and PH, and was associated with improved V/Q matching and exercise tolerance.

Topics: Administration, Inhalation; Aged; Blood Gas Analysis; Exercise Tolerance; Humans; Hypertension, Pulmonary; Iloprost; Male; Nebulizers and Vaporizers; Oxygen Consumption; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Vasodilator Agents

Data on long-term efficacy of bosentan, an oral dual ET receptor antagonist, in SSc-associated pulmonary arterial hypertension (SSc-PAH) are lacking. We aimed to describe the long-term outcome of SSc-PAH treated with first-line monotherapy bosentan followed or not by the addition of prostanoids or sildenafil.. A prospective analysis of 49 consecutive SSc-PAH patients treated with first-line bosentan was performed. New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD) and haemodynamics were assessed at baseline and after 4 and 12 months.. At 4 months, significant improvements in NYHA functional class and haemodynamics were observed with stabilization at 1 year. There was no significant improvement in 6MWD. Overall survival estimates were 80, 56 and 51% at 1, 2 and 3 years, respectively, and were significantly worse than those in a cohort of patients with idiopathic PAH (92, 89 and 79% at 1, 2 and 3 years, respectively; P < 0.0001). Twenty-three patients (47%) died after a mean follow-up of 23 (18) months. In multivariate analysis, baseline and 4-month NYHA functional class and 4-month cardiac index were independent factors associated with overall survival.. In our cohort of consecutive SSc-PAH patients treated with first-line bosentan, improvement in NYHA functional class and haemodynamics was significant after 4 months of treatment and stabilized afterwards. One-year overall survival rate was higher than previously reported in historical series. However, long-term prognosis remains poor. Our study underlines the importance of haemodynamic evaluation 4 months after the start of treatment to provide strong parameters associated with survival-like cardiac index.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Drug Administration Schedule; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Epidemiologic Methods; Epoprostenol; Exercise Test; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

To investigate the long-term safety of inhaled iloprost in patients with pulmonary hypertension (pH), including idiopathic PAH (IPAH group) and other forms of pulmonary hypertension (PHother).. Sixty-three patients (IPAH group, n=40, PHother n=23) were enrolled to receive inhaled iloprost either from baseline or after 3 months in a prospective, open-label 2-year study. Iloprost was inhaled 6-9 times daily with a night pause employing a jet nebulizer delivering an inhaled single dose of 4microg at the mouthpiece. In the case of side effects the single dose was reduced to 2microg. Sixty patients received at least 1 dose of inhaled iloprost. Thirty-six patients completed at least 630 days of therapy (25 IPAH, 11 PHother), 19 patients dropped out prematurely and 8 patients died (3 IPAH, 5 PHother). There were no drug-induced toxicities and only mild to moderate side effects. The most common side effects were coughing and flushing. Two-year survival was estimated at 85% (IPAH group 91%, PHother 78%). A modified analysis was performed to correct for differential drop-out. It included follow-up data from the premature discontinuations and revealed a 2-year survival of 87% [95% CI, 76%-98%] in the IPAH group while the predicted survival was 63%. The iloprost dose increased by 16% over 2 years.. Inhaled iloprost is well tolerated as long-term therapy and no substantial dose increase is required. Although uncontrolled, the data suggest a long-term clinical benefit from continued therapy with inhaled iloprost.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Young Adult

In congenital heart disease with increased pulmonary blood flow and pressure, progressive changes in the vascular structure can lead to irreversible pulmonary hypertension (PH). Pulmonary hemodynamic parameters are used to determine whether surgical correction is no longer indicated. In this study, aerosolized iloprost was used to assess pulmonary vasoreactivity in children with long-standing PH related to congenital heart disease.. Children with long-standing and severe PH secondary to congenital heart disease were included in this study. Various hemodynamic parameters were measured before and after iloprost inhalation (0.5 microg/kg), and vascular resistance was determined. Responders to the iloprost test were defined as those with a decrease in both pulmonary vascular resistance (PVR) and pulmonary-to-systemic vascular resistance ratio (R(p)/R(s)) of >10%.. Eighteen children aged between 7 months and 13 years with long-standing and severe PH secondary to congenital heart disease were studied. Thirteen children had a positive response, resulting in a mean (+/- SD) decrease of PVR from 9.3 +/- 4.6 to 4.6 +/- 2.7 Wood U x m(2) (P < 0.001), and a mean decrease of R(p)/R(s) from 0.54 +/- 0.37 to 0.24 +/- 0.14 (P = 0.005).. Iloprost-induced pulmonary vasodilator responses vary among children with PH related to congenital heart disease. The use of inhaled iloprost in the cardiac catheterization laboratory results in pulmonary vasoreactivity for some of these children particularly a reduction in PVR and the pulmonary-to-systemic vascular resistance ratio.

Topics: Administration, Inhalation; Adolescent; Aerosols; Blood Pressure; Cardiac Catheterization; Child; Child, Preschool; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Infant; Male; Pulmonary Artery; Pulmonary Circulation; Severity of Illness Index; Vascular Resistance; Vasodilation; Vasodilator Agents

There is limited data on the long-term efficacy of intravenous iloprost in patients with pulmonary arterial hypertension (PAH). This retrospective multicentre analysis evaluated the clinical course of patients with PAH treated with i.v. iloprost, in most cases after having received inhaled iloprost as first-line therapy. Between 1997 and 2001, 79 PAH patients were treated with i.v. iloprost and followed until 2007. These patients had advanced and progressive disease as indicated by a mean pulmonary vascular resistance of 1,533 dyn x s x cm(-5) at the time of diagnosis and of 1,858 dyn x s x cm(-5) at the onset of i.v. iloprost therapy. Introduction of i.v. iloprost therapy resulted in initial haemodynamic and clinical improvement. At the end of the observation period, however, 50 (61%) patients had died and 21 (26%) required lung transplantation. Transplantation-free survival rates at 1, 3, and 5 yrs were 86%, 59% and 45%, respectively, after the diagnosis of PAH, and 54%, 31% and 15%, respectively, after the introduction of i.v. iloprost therapy. Predictors of an adverse outcome at baseline were a low 6-min walk distance and a low mixed venous oxygen saturation. In conclusion, despite initial haemodynamic and clinical improvement, overall long-term survival with i.v. iloprost therapy was limited.

Topics: Adult; Disease Progression; Exercise Test; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Oxygen; Retrospective Studies; Time Factors; Treatment Outcome; Vasodilator Agents

Patients with sarcoidosis associated pulmonary hypertension (SAPH) have responded to systemic prostacyclin therapy.. To determine the rate of response to inhaled prostacyclin, iloprost, in SAPH.. Sarcoidosis patients with pulmonary hypertension and no evidence for left ventricular dysfunction were enrolled in an open label, prospective study. Patients underwent right heart catheterization and six minute walk (6MW) test. Quality of life was evaluated using several instruments, including the Saint George Respiratory Questionnaire (SGRQ). Patients received 5 mcg of inhaled iloprost every 2-3 hours while awake. After four months of therapy, patients underwent repeat cardiac catheterization, 6 MW test, and completed quality of life questionnaires.. Of the 22 patients enrolled, 15 completed all 16 weeks of therapy. The most common reasons for study discontinuation included drug associated cough (3 patients) and compliance with the prescribed number of treatments per day (2 patients). Six patients experienced a 20% or greater decrease in pulmonary vascular resistance (PVR) from baseline with five of these six patients also showing > or = 5 mm Hg reduction in PA mean. Although three patients improved the 6MW distance by at least 30 meters, only one had a decrease in PVR. At 16 weeks a significant decrease was reported in the SGRQ activity score (p = 0.0273), with seven patients having a 4 point or greater decrease.. Inhaled iloprost as monotherapy was associated with an improvement in pulmonary hemodynamics and quality of life as assessed by the SGRQ activity score in some sarcoidosis patients with SAPH.

Topics: Administration, Inhalation; Adult; Aged; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prognosis; Pulmonary Wedge Pressure; Quality of Life; Sarcoidosis, Pulmonary; Surveys and Questionnaires; Vasodilator Agents

Prostacyclin inhalation is increasingly used to treat acute pulmonary hypertension and right ventricular failure, although its pharmacodynamic properties remain controversial. Prostacyclins not only affect vasomotor tone but may also have cAMP-mediated positive inotropic effects and modulate autonomic nervous system tone. We studied the role of these different mechanisms in the overall haemodynamic effects produced by iloprost inhalation in an experimental model of acute pulmonary hypertension.. In this prospective, randomized, placebo-controlled animal study, twenty-six pigs (mean weight 35 +/- 2 kg) were instrumented with biventricular conductance catheters, a pulmonary artery flow probe and a high-fidelity pulmonary artery pressure catheter. The effects of inhaled iloprost (50 microg) were studied in the following groups: animals with acute hypoxia-induced pulmonary hypertension, and healthy animals with and without blockade of the autonomic nervous system.. During pulmonary hypertension, inhalation of iloprost resulted in a 51% increase in cardiac output compared with placebo (5.6 +/- 0.7 versus 3.7 +/- 0.8 l/minute; P = 0.0013), a selective reduction in right ventricular afterload (effective pulmonary arterial elastance: 0.6 +/- 0.3 versus 1.2 +/- 0.5 mmHg/ml; P = 0.0005) and a significant increase in left ventricular end-diastolic volume (91 +/- 12 versus 70 +/- 20 ml; P = 0.006). Interestingly, right ventricular contractility was reduced after iloprost-treatment (slope of preload recruitable stroke work: 2.2 +/- 0.5 versus 3.4 +/- 0.8 mWatt.s/ml; P = 0.0002), whereas ventriculo-vascular coupling remained essentially preserved (ratio of right ventricular end-systolic elastance to effective pulmonary arterial elastance: 0.97 +/- 0.33 versus 1.03 +/- 0.15). In healthy animals, inhaled iloprost had only minimal haemodynamic effects and produced no direct effects on myocardial contractility, even after pharmacological blockade of the autonomic nervous system.. In animals with acute pulmonary hypertension, inhaled iloprost improved global haemodynamics primarily via selective pulmonary vasodilatation and restoration of left ventricular preload. The reduction in right ventricular afterload is associated with a paradoxical decrease in right ventricular contractility. Our data suggest that this reflects an indirect mechanism by which ventriculo-vascular coupling is maintained at the lowest possible energetic cost. We found no evidence for a direct negative inotropic effect of iloprost.

Topics: Acute Disease; Administration, Inhalation; Animals; Cardiac Output; Disease Models, Animal; Hypertension, Pulmonary; Iloprost; Prospective Studies; Sus scrofa; Ventricular Function, Left; Ventricular Function, Right

Chronic thromboembolic pulmonary hypertension (CTEPH) is a potential consequence to pulmonary embolism. The histologic picture is similar to idiopathic pulmonary hypertension (IPAH) suggesting that vascular remodeling also contributes to CTEPH. The treatment of choice is pulmonary endarterectomy. However, this treatment option is not adequate for all patients with CTEPH. Currently, no data exist on standard vasodilative therapy for CTEPH. Intravenous and oral prostanoids, both well-known vasodilators in IPAH, have been used with promising results, whereas the same has not been consistently observed for inhaled iloprost.. In this study, we examined acute hemodynamic effects of inhaled iloprost in patients with CTEPH.. In a prospective study, right heart catheterization was performed in 20 patients (mean age 56 years, New York Heart Association class II-IV) at the time of diagnosis of CTEPH. Pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), cardiac output (CO), mean systemic arterial pressure (MAP) and oxygen partial pressure (PaO(2)) were obtained before and 20 min after inhaling 5 mug iloprost. Subsequently, all patients were evaluated for pulmonary endarterectomy. Six patients were eligible for surgery.. Significant changes in pulmonary and systemic hemodynamics were observed following the inhalation of iloprost (before to after inhalation): PVR: 1,057 +/- 404.3 to 821.3 +/- 294.3 dyn.s.cm(-5), p < 0.0001; mPAP: 50.55 +/- 8.43 to 45.75 +/- 8.09 mm Hg, p = 0.0002; CO: 3.66 +/- 1.05 to 4.05 +/- 0.91 l/min, p < 0.0106. MAP and PaO(2) decreased significantly (MAP: 94.15 +/- 11.58 to 89.45 +/- 14.29 mm Hg, p = 0.0111; PaO(2): 7.33 +/- 1.17 to 6.64 +/- 1.25 kPa, p = 0.0260).. Hemodynamic changes directly following inhalation of iloprost suggest a significant contribution of a reversible component of vasoconstriction to pulmonary arterial hypertension in patients with CTEPH.

Topics: Administration, Inhalation; Adult; Aged; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Lung; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Vasoconstriction; Vasodilator Agents

Pulmonary hypertension (PHT) is common in patients undergoing mitral valve surgery and is an independent risk factor for the development of acute right ventricular (RV) failure. Inhaled iloprost was shown to improve RV function and decrease RV afterload in patients with primary PHT. However, no randomized-controlled trials on the intraoperative use of iloprost in cardiac surgical patients are available. We therefore compared the effects of inhaled iloprost vs. intravenous standard therapy in cardiac surgical patients with chronic PHT.. Twenty patients with chronic PHT undergoing mitral valve repair were randomized to receive inhaled iloprost (25 microg) or intravenous nitroglycerine. Iloprost was administered during weaning from cardiopulmonary bypass (CPB). Systemic and pulmonary haemodynamics were assessed with pulmonary artery catheterization and transoesophageal echocardiography. Milrinone and/or inhaled nitric oxide were available as rescue medication in case of failure to wean from CPB.. Inhaled iloprost selectively decreased the pulmonary vascular resistance index after weaning from CPB (208 +/- 108 vs. 422 +/- 62 dyn.s/cm(5)/m(2), P<0.05), increased the RV-ejection fraction (29 +/- 3% vs. 22 +/- 5%, P<0.05), improved the stroke volume index (27 +/- 7 vs. 18 +/- 6 ml/m(2), P<0.05) and reduced the transpulmonary gradient (10 +/- 4 vs. 16 +/- 3 mmHg, P<0.05). In all patients receiving inhaled iloprost, weaning from CPB was successful during the first attempt. In contrast, three patients in the control group required re-institution of CPB and had to be weaned from CPB using rescue medication.. In patients with pre-existing PHT undergoing mitral valve surgery, inhaled iloprost is superior to intravenous nitrogylycerine by acting as a selective pulmonary vasodilator, reducing RV afterload and moderately improving RV-pump performance.

Topics: Administration, Inhalation; Aged; Cardiac Output, Low; Cardiopulmonary Bypass; Catheterization, Swan-Ganz; Echocardiography, Transesophageal; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Milrinone; Mitral Valve Insufficiency; Monitoring, Intraoperative; Nitroglycerin; Postoperative Complications; Prospective Studies; Stroke Volume; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

The objective of this study was to compare the efficacy of inhaled iloprost and nitric oxide (iNO) in reducing pulmonary hypertension (PHT) during cardiac surgery immediately after weaning from cardiopulmonary bypass (CPB).. A prospective randomized study.. A single-center university hospital.. Forty-six patients with PHT (mean pulmonary artery pressure (mPAP) > or = 26 mmHg preoperatively at rest, after anesthesia induction, and at the end of CPB) scheduled to undergo cardiac surgery were enrolled.. Patients were randomly allocated to receive iloprost (group A, n = 23) or iNO (group B, n = 23) during weaning from CPB.. Heart rate, mean arterial pressure, central venous pressure, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure, and left atrial pressure were recorded continuously. Iloprost and iNO were administered immediately after the end of CPB before heparin reversal. Both substances caused significant reductions in mean PAP (mPAP) and pulmonary vascular resistance (PVR) and significant increases in cardiac output 30 minutes after administration (p < 0.0001). However, in a direct comparison, iloprost caused significantly greater reductions in PVR (p = 0.013) and mPAP (p = 0.0006) and a significantly greater increase in cardiac output (p = 0.002) compared with iNO.. PHT after weaning from CPB was significantly reduced by the selective pulmonary vasodilators iNO and iloprost. However, in a direct comparison of the 2 substances, iloprost was found to be significantly more effective.

Topics: Administration, Inhalation; Aged; Cardiopulmonary Bypass; Cardiovascular Surgical Procedures; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide; Prospective Studies

To describe the clinical and haemodynamic effects during the first 6 months of continuous intravenous iloprost treatment in patients with idiopathic pulmonary arterial hypertension (IPAH) and relevant disease progression despite continued mono therapy with aerosolized iloprost.. Twenty-four IPAH patients with clinical decompensation to NYHA class IV despite therapy with aerosolized iloprost and optimized conservative treatment were assessed clinically, haemodynamically and by cardiopulmonary exercise testing for at least 6 months. Upon switching from inhaled to intravenous iloprost all patients improved clinically (NYHA III) while pulmonary vascular resistance (PVR) and right atrial pressure decreased from 2386 +/- 243 to 1381 +/- 124 dyne .s .cm(-5) and 12 +/- 1 to 8.5 +/- 1 mmHg, respectively (both p < 0.05). Despite this acute improvement haemodynamic (PVR increased from 1462+/-223 to 1978 +/- 327 dyne .s .cm(-5)) and clinical (4 deaths, 4 transplantations) deterioration occurred with continued intravenous treatment during the following 6 months.. In the group of patients described in this report the clinical and haemodynamic deterioration occurring while on mono therapy with inhaled iloprost could be stopped by switching to continuous application of intravenous iloprost. However, with continued intravenous therapy only a subgroup of patients could clinically be stabilized and transplanted successfully.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Exercise Tolerance; Female; Germany; Heart Atria; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Lung Transplantation; Male; Middle Aged; Pulmonary Artery; Severity of Illness Index; Treatment Failure; Vascular Resistance; Vasodilator Agents

Pulmonary endothelial function is known to be impaired in subjects with idiopathic pulmonary arterial hypertension (IPAH), but peripheral endothelial dysfunction and its predictive value for pulmonary vasoreactivity have not been previously investigated.. Measurements of peripheral endothelium-dependent and endothelium-independent vasoreactivity using flow-mediated dilation (FMD) and nitroglycerin-mediated dilation of the brachial artery were performed in 18 patients with severe IPAH (15 women; mean age 50 years [95% confidence interval 46-55 years], mean pulmonary artery pressure [PAP] 51 mm Hg [43-59 mm Hg], pulmonary vascular resistance [PVR] 1239 dyn s cm(-5) [861-1618 dyn s cm(-5)] at baseline) and in 36 age- and sex-matched controls. In patients with IPAH, acute pulmonary vasoreactivity was measured as pulmonary vascular response to inhaled iloprost (PVRII) during pulmonary catheterization.. Compared to controls, patients with IPAH demonstrated impaired peripheral endothelial function (FMD, 0.19 [0.07-0.31] vs 0.38 [0.30-0.44] mm among controls; P =.002). No such impairment was observed for nitroglycerin-mediated dilation (0.34 [0.23-0.46] vs 0.36 [0.20-0.51] mm among controls; P = .679). Among patients with IPAH, iloprost lowered mean PAP by 8.2 mm Hg (2.0-14.5 mm Hg) (P = .001) and PVR by 395 dyn s cm(-5) (109-680 dyn s cm(-5)) (P < .001). Subsequent analysis of the association between peripheral endothelial function and PVRII disclosed a correlation of FMD with the percent decrease in mean PAP (r = .65, P = .003) and PVR (r = 0.67, P = .002), in which patients with IPAH with the greatest PVRII also exhibited the highest FMD values.. Idiopathic pulmonary arterial hypertension is associated with peripheral endothelial dysfunction. Peripheral endothelium-dependent vasoreactivity correlates with the PVRII. It remains to be established if FMD has the potential as a clinical tool for noninvasive estimation of pulmonary vasoreactivity in IPAH.

Topics: Administration, Inhalation; Adult; Brachial Artery; Endothelium, Vascular; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitroglycerin; Pulmonary Circulation; Vascular Resistance; Vasodilation

Prostaglandins and nitric oxide play a pivotal role in the regulation of macro- and microcirculatory blood flow distribution. Interference with both mediator systems have been implicated in cerebrovascular dysfunction. Inhaled iloprost (long-acting prostacyclin analogue) and the phosphodiesterase-5 inhibitor sildenafil have recently shown efficacy in the treatment of chronic pulmonary hypertension. We investigated the impact of these agents on cerebral microcirculatory regulation in patients suffering from this disease.. In 11 patients suffering from severe pulmonary hypertension, a functional transcranial Doppler test utilizing a visual stimulation paradigm was undertaken to measure the evoked flow velocity in the posterior cerebral artery. Measurements were performed in parallel to right heart catheterization and pharmacological testing of the pulmonary vasoreactivity. After assessment of baseline measurements, inhaled iloprost and oral sildenafil were given consecutively for testing of cerebral and pulmonary vascular function. The data gained from the Doppler measurements were compared to data from 22 healthy volunteers.. Both substances provoked a significant reduction of pulmonary arterial pressure and vascular resistance, accompanied by minor changes in systemic vascular resistance. In contrast to these superimposable hemodynamic profiles opposite effects were observed regarding cerebral vascular tone: cerebral microvascular reactivity, as assessed by attenuation and time rate parameters, was significantly improved by sildenafil, but slightly worsened by iloprost.. Sildenafil has beneficial effects on cerebral vascular reactivity indicative of an improvement in neurovascular coupling in patients with pulmonary hypertension. These results warrant further investigations of the influence of sildenafil on dynamic vascular function in the brain independent of the underlying disease.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Blood Flow Velocity; Blood Pressure; Brain; Case-Control Studies; Cerebrovascular Circulation; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Piperazines; Posterior Cerebral Artery; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Ultrasonography, Doppler, Transcranial; Vascular Resistance; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is fatal if untreated. Intravenous epoprostenol improves exercise capacity and haemodynamics in PAH, and increases survival in idiopathic PAH (IPAH). To evaluate the effects of subcutaneous (SC) treprostinil, a longer-acting prostacyclin analogue, followed by the addition of other PAH therapies if needed, 860 PAH patients treated with SC treprostinil for up to 4 yrs were followed. Survival is reported as Kaplan-Meier estimates. For 332 IPAH patients with baseline haemodynamics, observed survival is also compared with predicted survival using the National Institute of Health formula. Out of the 860 patients, 199 (23%) discontinued due to adverse events, 136 (16%) died, 117 (14%) discontinued due to deterioration, 29 (3%) withdrew consent and 11 (1%) underwent transplantation. In total, 97 patients (11%) switched from SC treprostinil to an alternative prostacyclin analogue; bosentan was added in 105 patients (12%) and sildenafil in 25 (3%). In conclusion, survival was 87-68% over 1-4 yrs for all 860 patients and 88-70% over 1-4 yrs with subcutaneous treprostinil monotherapy. For the idiopathic pulmonary arterial hypertension subset with baseline haemodynamics (n = 332), survival was 91-72% over 1-4 yrs. In contrast, predicted survival was 69-38% over 1-4 yrs. The safety profile for long-term subcutaneous treprostinil was consistent with previous short-term trials with no unexpected adverse events.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Bosentan; Child; Cohort Studies; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Injections, Subcutaneous; Male; Middle Aged; Placebos; Sulfonamides; Survival Rate; Treatment Outcome

Small, open-label studies suggest that combinations of existing therapies may be effective for pulmonary arterial hypertension (PAH).. To evaluate the safety and efficacy of adding inhaled iloprost, a prostacyclin analog, to the endothelin receptor antagonist bosentan in patients with PAH.. In a randomized, multicenter, double-blind trial, inhaled iloprost (5 mug) or placebo was added to stable monotherapy with bosentan for 12 wk. Efficacy endpoints included change from baseline in 6-min-walk distance (6-MWD), modified New York Heart Association (NYHA) functional class, hemodynamic parameters, and time to clinical worsening.. A total of 67 patients with PAH (55% idiopathic PAH, 45% associated PAH, 94% NYHA class III, and mean baseline 6-MWD of 335 m) were randomized. At Week 12, patients receiving iloprost had a mean increase in 6-MWD of 30 m (p = 0.001); placebo patients had a mean 6-MWD increase of 4 m (p = 0.69), with a placebo-adjusted difference of +26 m (p = 0.051). NYHA status improved by one class in 34% of iloprost versus 6% of placebo patients (p = 0.002). Iloprost delayed the time to clinical worsening (p = 0.0219). Improvements were noted in postinhalation placebo-adjusted change in mean pulmonary artery pressure (-8 mm Hg; p < 0.001) and pulmonary vascular resistance (-254 dyn x s x cm(-5); p < 0.001). Combination therapy was well tolerated.. Within the limitations of a relatively small sample size, results of this study demonstrate that the addition of inhaled iloprost in patients with PAH with reduced exercise capacity on bosentan monotherapy is safe and efficacious.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Bosentan; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Sulfonamides; Vasodilator Agents

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are the major classes of pulmonary hypertensive disorders according to the World Health Organization; both lead to right heart failure and death. A better understanding of disease mechanisms has led to the suggestion that the thromboembolic and nonthromboembolic types of pulmonary hypertension may share pathophysiologic features. We therefore compared acute vasoreactivity and proximal pulmonary artery compliance in patients with PAH and CTEPH during the initial diagnostic heart catheterization.. Right heart catheterization using a flow-directed Swan-Ganz catheter was performed in patients with CTEPH (n = 22) and PAH (n = 35). Pulmonary hemodynamics were assessed at baseline, during the inhalation of 40 ppm of nitric oxide, and 30 min after the inhalation of 10 mug of iloprost. To assess the proximal pulmonary artery compliance, the pulse pressure (PP) [systolic-diastolic pressure] and the fractional PP (PPf) [divided by the mean pressure] were calculated.. Both vasodilators produced similar hemodynamic improvement, and the difference between CTEPH and PAH was not significant. The baseline PP and PPf did not vary between the two groups.. Patients with PAH and CTEPH show similar acute vasoreactivity to inhaled nitric oxide and iloprost, and have similar pulmonary artery compliance. These findings support the presence of some shared pathophysiologic pathways in both disorders and may lead to therapeutic implications in patients with inoperable CTEPH.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Bronchodilator Agents; Cardiac Catheterization; Chronic Disease; Compliance; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Lung; Middle Aged; Nitric Oxide; Pulmonary Artery; Pulmonary Embolism; Vasodilation; Vasodilator Agents; World Health Organization

The objective of this study was to present our clinical experience about scleroderma-related pulmonary hypertension in the patients treated with intermittent iloprost infusions. Eighty-one patients affected by systemic sclerosis (12 men, 69 women; 30 with diffuse pattern and 51 with limited pattern; mean age 55.1 years; mean duration of disease 105.3 months) have been treated with cyclic iloprost infusions for at least 15 months (range 15-126 months). During the last 4 months all patients underwent Doppler echocardiography in order to estimate the value of systolic pulmonary artery pressure. In 14 subjects (17.2%) systolic pulmonary artery pressure was = or > 35 mmHg. Four patients presented high systolic pulmonary artery pressure associated with pulmonary fibrosis (mean value 40.5 +/- 4.5 mmHg). Ten women (one with diffuse pattern of disease and nine with limited form) showed isolated high systolic pulmonary artery pressure; one of these patients underwent right heart catheterization which resulted normal. The remaining nine patients (mean age of 67.1 years; age at the onset of scleroderma 52.2 years) showed estimated systolic pulmonary artery pressure values between 35 and 50 mmHg. Among these patients affected by isolated pulmonary hypertension only one has been receiving bosentan in association with iloprost infusions. None of our scleroderma patients treated with cyclic iloprost infusions developed severe isolated pulmonary hypertension. In systemic sclerosis the multiple effects of iloprost on endothelium, platelets and cytokine network may counteract the vasospastic profile of lung microvasculature in pulmonary arterial hypertension and the consequent vascular wall remodelling, thus preventing the development of severe illness.

Topics: Adult; Aged; Aged, 80 and over; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Pilot Projects; Scleroderma, Systemic; Vasodilator Agents

Addition of inhaled iloprost to bosentan may have beneficial effects in patients with idiopathic pulmonary arterial hypertension (IPAH). A multicentre, open, randomised, controlled trial was performed to assess the safety and efficacy of inhaled iloprost in patients with IPAH who had already been treated with bosentan. The trial was terminated early after a futility analysis predicted failure with respect to the predetermined sample size. At that time, 40 patients were randomised to receive either bosentan alone (control group) or bosentan plus inhaled iloprost (combination group) for a 12-week period. The primary end-point, change in 6-min walking distance, was not met (mean changes +1 m and -9 m in the control and combination group, respectively). These results may have been skewed by three outliers in the iloprost group who presented with severe clinical worsening. None of the secondary end-points including functional class, peak oxygen uptake, and time to clinical worsening differed significantly between groups. The current study failed to show a positive effect of adding inhaled iloprost to bosentan in idiopathic pulmonary arterial hypertension patients. Further studies involving larger sample sizes and long-term follow-up are needed to determine the efficacy of adding inhaled iloprost to bosentan in patients with idiopathic pulmonary arterial hypertension.

Topics: Administration, Inhalation; Adult; Aged; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Exercise Test; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Sulfonamides; Vasodilator Agents

Since the presence of pulmonary hypertension (PHT) affects the prognosis of the patients, it is important to manage and evaluate PHT. The aim of this study was to compare the hemodynamic effects of inhaled nitroglycerin and iloprost during early postoperative period, in patients with PHT undergoing mitral valve replacement surgery.. One hundred patients with PHT (mean pulmonary artery pressure (MPAP) >25 mmHg at rest), were randomized to receive either inhalation of nitroglycerin (group I; n=50) or iloprost (group II; n=50) in the postoperative period. In both groups, baseline hemodynamic parameters were recorded before the treatment (T(0)). Then, patients in group I received 20 microg.kg(-1) nitroglycerin and those in group II received 2.5 microg.kg(-1) iloprost. The same parameters were recorded immediately after the end of the treatment (T(1)).. In both study groups MPAP and pulmonary vascular resistance (PVR) were found to be significantly lower at T(1) when compared to that of T(0) period (p<0.05). MPAP and PVR were significantly lower and mean arterial pressure (MAP) was significantly higher in group II when compared to group I at T(1) period (p<0.05). In addition to decreases in PVR and MPAP, iloprost also increased cardiac output (CO)(4.9+/-1.3 vs 5.1+/-0.9, p<0.05) and stroke volume (SV)(48+/-13 vs 56+/-13, p<0.05).. Inhaled iloprost and nitroglycerin, both effectively reduce MPAP and PVR without affecting MAP, systemic vascular resistance (SVR) and CO. However, iloprost seems to be a more powerful pulmonary vasodilator, therefore we suggest iloprost inhalation in patients with severe PHT.

Topics: Drug Therapy, Combination; Female; Follow-Up Studies; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Mitral Valve; Nitroglycerin; Preoperative Care; Prospective Studies; Pulmonary Wedge Pressure; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a progressive disease with a bad prognosis. Prostanoids are well established in the medical treatment of this disease. Treatment of patients with progressive disease despite prostanoids remains a therapeutic challenge. In this study, we examined the effect of adding bosentan, an endothelin antagonist, to existing prostanoid therapy on exercise capacity (6-min walking distance [6MWD]) and right ventricular (RV) function (Tei index) in patients with progressive pulmonary hypertension.. Prospective, nonrandomized, open-label study.. University hospital.. Sixteen patients with pulmonary hypertension (PAH, n = 10; pulmonary hypertension due to other cause, n = 6) with progressive disease receiving either beraprost (n = 3), inhaled iloprost (n = 10), or iloprost IV (n = 3).. Combination therapy with bosentan (final dosage, 125 mg bid) was initiated following an interval of 3-months minimum of unchanged prostanoid therapy.. Tei index, 6MWD, and New York Heart Association (NYHA) functional class were assessed prior to the initiation of combination therapy (baseline), at 6 months after initiation of combination therapy, and every 3 months thereafter. Two patients were followed up for 6 months only; all remaining patients reached a mean follow-up period (+/- SD) of 13.5 +/- 5.0 months (range, 9 to 22 months). 6MWD increased by 42.5 +/- 66 m at 6 months and 44.6 +/- 66 m at the last follow-up (both time points vs baseline, p < 0.001), and Tei index improved by -0.13 +/- 0.08 at 6 months and - 0.13 +/- 0.11 at the last follow-up (both time points vs baseline, p < 0.001). All patients reported subjective improvements. Nine of 16 patients exhibited improvement in NYHA functional class at 6 months. No side effects occurred that required dose adjustment or discontinuation of the study medication.. Bosentan administered to patients with progressive pulmonary hypertension receiving prostanoids resulted in an increased exercise capacity and an improved RV function. Bosentan therefore appears to be well suited for combination therapy with prostanoids in selected patients pending results of ongoing randomized trials.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prospective Studies; Prostaglandins; Sulfonamides; Ultrasonography; Vasodilator Agents

Pulmonary endarterectomy (PEA) is the standard therapy for patients with chronic thromboembolic pulmonary hypertension (CTEPH). In the immediate postoperative period, persistent pulmonary hypertension increases the risk of acute respiratory or right heart failure. In pulmonary arterial hypertension, prostanoid inhalation has been found to improve pulmonary hemodynamics, right ventricular function, gas exchange, and clinical outcome. We report the results of a double-blinded randomized trial with the aerosolized prostacyclin analogue iloprost in patients with residual pulmonary hypertension after PEA.. Twenty-two patients (age, 55+/-13 years; 8 females; propofol- and sufentanil-based anesthesia; pressure-controlled mechanical ventilation) were randomized to receive either a single dose of 25 microg aerosolized iloprost (iloprost group; n=11) or normal saline (placebo group; n=11) immediately after postoperative ICU admission. Primary endpoints were changes in gas exchange, pulmonary and systemic hemodynamics, and clinical outcome.. Iloprost significantly enhanced cardiac index (CI) and reduced mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance [PVR (dynscm(-5))] in contrast to placebo. Placebo: pre-inhalation 413+/-195 versus post-inhalation 404+/-196 at 30 min (p=0.051), 415+/-189 at 90 min (p=0.929). Iloprost: pre-inhalation 503+/-238 versus post-inhalation 328+/-215 at 30 min (p=0.001), 353+/-156 at 90 min (p=0.003). Blood oxygenation remained unchanged.. In addition to the effect of PEA, iloprost reduces residual postoperative pulmonary hypertension, decreases right ventricular afterload and may facilitate the early postoperative management after PEA.

Topics: Administration, Inhalation; Adult; Aged; Carbon Dioxide; Double-Blind Method; Endarterectomy; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Oxygen; Partial Pressure; Prospective Studies; Pulmonary Artery; Pulmonary Gas Exchange; Treatment Outcome; Vasodilator Agents

Combination therapy may improve outcome in patients with severe pulmonary arterial hypertension (PAH). PAH patients were treated according to a goal-oriented therapeutic strategy. Patients who did not reach the treatment goals with monotherapy received combination treatment according to a predefined strategy, including bosentan, sildenafil and inhaled iloprost. Intravenous iloprost and lung transplantation were reserved for treatment failures. End points were overall survival, transplantation-free survival, and survival free from transplantation and intravenous prostanoid treatment. Between January 2002 and December 2004, 123 consecutive patients with PAH were treated according to the novel approach. Survival at 1, 2 and 3 yrs was 93.0, 83.1 and 79.9%, respectively, which was significantly better than the survival of a historical control group, as well as the expected survival. Compared to the historical control group, the use of combination treatment also significantly improved the combined end point of death, lung transplantation and need for intravenous iloprost treatment. In conclusion, a therapeutic approach utilising combinations of bosentan, sildenafil and inhaled iloprost in conjunction with a goal-oriented treatment strategy provides acceptable long-term results in patients with severe pulmonary arterial hypertension, and reduces the need for intravenous prostaglandin treatment and lung transplantation.

Topics: Administration, Inhalation; Algorithms; Antihypertensive Agents; Bosentan; Decision Support Systems, Clinical; Drug Administration Schedule; Drug Therapy, Combination; Female; Germany; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Analysis; Survival Rate; Treatment Outcome

The pulmonary circulation is an important site for the production and clearance of endothelin (ET)-1, a potent vasoactive and mitogenic peptide. In healthy individuals, 40% to 50% of circulating ET-1 is removed on each passage through the lungs resulting in an arteriovenous ratio of <1, whereas many patients with pulmonary arterial hypertension (PAH) have ratios >1, indicating reduced clearance or increased release of endothelin. The influence of inhaled prostanoids on endothelin clearance is unknown.. In a prospective investigation, plasma concentrations of big endothelin-1 (big ET-1, Elisa) were measured in 15 patients with pulmonary hypertension undergoing right heart catheterization with iloprost inhalation (4 m, 11 f, aged 35 to 75 years, mean pulmonary arterial pressure (PAPm) 54+/-2.3 mm Hg, pulmonary vascular resistance (PVR) 1061+/-141 dyn x sec x cm(-5)). There was a significant transpulmonary gradient for big ET-1 with 31% +/-11% higher concentrations in the radial artery than in the pulmonary artery (P<0.001). After inhalation of iloprost a significant decrease in the AV-ratio from 1.31+/-0.11 to 0.92+/-0.06 (P<0.007) was observed. The pulmonary net release of 3.10+/-0.65 pmol/min big ET-1 at baseline decreased to -1.24+/-1.32 pmol/min (P=0.013) within 15 minutes indicating a restored balance. Patients under long-term treatment with iloprost (n=7) tended to have a lower net release and AV-ratio for big ET-1 than patients without pretreatment.. An increase in pulmonary clearance of big-ET could be a mechanism contributing to the beneficial effects of inhaled prostanoids in the treatment of PAH.

Topics: Administration, Inhalation; Adult; Aged; Endothelin-1; Endothelins; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Protein Precursors; Pulmonary Circulation

We sought to investigate the impact of adjunct sildenafil on exercise capacity and hemodynamic parameters in patients with pulmonary arterial hypertension (PAH) who fulfilled predefined criteria of deterioration despite ongoing treatment with inhaled iloprost.. Inhaled iloprost is an effective therapy in PAH. The phosphodiesterase-5 inhibitor sildenafil exerts pulmonary vasodilation and may amplify prostanoid efficacy.. Of 73 PAH patients receiving long-term inhaled iloprost treatment, 14 fulfilled criteria of deterioration unresponsive to conventional treatment. These patients received adjunct oral sildenafil over a period of nine to 12 months, leaving the inhalative iloprost regimen unchanged.. Before iloprost therapy, the baseline 6-min walking distance was 217 +/- 31 m (mean +/- SEM), with an improvement to 305 +/- 28 m within the first three months of iloprost treatment and a subsequent decline to 256 +/- 30 m after 18 +/- 4 months. Adjunct therapy with sildenafil reversed the deterioration and increased the 6-min walk distance to 346 +/- 26 m (p = 0.002, Wilcoxon test) at three months of combined therapy, with a sustained efficacy up to 12 months (349 +/- 32 m, p = 0.002). The distribution of New York Heart Association functional classes (IV/III/II) improved from September 9, 2000, before sildenafil, to January 8, 2003, after nine to 12 months with sildenafil. All hemodynamic variables changed favorably: pulmonary vascular resistance decreased from 2,494 +/- 256 before sildenafil to 1,950 +/- 128 dynes.s.cm(-5).m(2) after three months of adjunct sildenafil (p = 0.036). Two patients died of severe pneumonia during the period of combined therapy. No further serious adverse events occurred. CONCLUSIONS; In patients with severe PAH deteriorating despite ongoing prostanoid treatment, long-term adjunct oral sildenafil improves exercise capacity and pulmonary hemodynamics. A combination of prostanoids and sildenafil is an appealing concept for future treatment of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Primary pulmonary hypertension (PPH) is a life-threatening disease. Nonparenteral prostanoids, i.e. aerosolised iloprost or oral beraprost sodium show beneficial therapeutic effects but are not sufficiently active in all patients with this devastating disease. The purpose of the present study was to determine whether the endothelin-receptor antagonist bosentan is safe and effective in patients with PPH already receiving nonparenteral prostanoids. The effect of bosentan as add-on medication was studied in 20 patients with PPH, who received either inhaled iloprost (n=9) or oral beraprost (n=11) for a median period of 16+/-13 months, by means of the 6-min walk test and cardiopulmonary exercise testing. After 3 months of administration of bosentan in addition to prostanoids, the walking distance in the 6-min walk test increased by 58+/-43 m. Cardiopulmonary exercise testing revealed an increase in maximal oxygen consumption from 11.0+/-2.3 to 13.8+/-3.6 mL x kg(-1) x min(-1) accompanied by significant improvements in anaerobic threshold, oxygen pulse and minute ventilation/carbon dioxide production slope. Peak systolic blood pressure increased from 120+/-17 to 139+/-21 mmHg. Combination treatment was well tolerated by all patients. It is concluded that the addition of the endothelin-receptor antagonist bosentan to inhaled iloprost or oral beraprost therapy appears to be safe for patients with primary pulmonary hypertension, resulting in a marked increase in exercise capacity. Therefore, rigorous studies should address whether combination treatment is more effective than either therapeutic intervention alone.

Topics: Administration, Inhalation; Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pilot Projects; Sulfonamides; Treatment Outcome; Vasodilator Agents

Inhalation of iloprost, a stable prostacyclin analog, is an effective therapy for pulmonary hypertension with few side effects. This approach may, however, be handicapped by limitations of currently available nebulization devices. We assessed whether the physical characterization of a device is sufficient to predict drug deposition and pharmacologic effects.. We investigated the effects of a standardized iloprost aerosol dose (5 micro g; inhaled within approximately 10 min) in 12 patients with severe pulmonary hypertension in a crossover design employing three well-characterized nebulizers. The nebulizers use different techniques to increase efficiency and alveolar targeting (Ilo-Neb/Aerotrap [Nebu-Tec; Elsenfeld, Germany], Ventstream [MedicAid; Bognor Regis, UK], and HaloLite [Profile Therapeutics; Bognor Regis, UK]). Measurements were performed using a Swan-Ganz catheter and determination of arterial iloprost plasma levels.. During inhalation of iloprost, the pulmonary vascular resistance decreased substantially (baseline, approximately 1,250 dyne.s.cm(-5); decrease, - 35.5 to - 38.0%) and pulmonary artery pressure decreased substantially (baseline, approximately 58 mm Hg; decline, - 18.4 to -21.8%), whereas the systemic arterial pressure was largely unaffected. Cardiac output and mixed venous and arterial oxygen saturation displayed a marked increase. The pharmacodynamic profiles with the three devices were superimposable. Moreover, rapid entry of iloprost into the systemic circulation was noted, peaking immediately after termination of the inhalation maneuver, with very similar maximum serum concentrations (158 pg/mL, 155 pg/mL, and 157 pg/mL), and half-lives of serum levels (6.5 min, 9.4 min, and 7.7 min) for the three nebulizers, respectively. Interestingly, the "half-life" of the pharmacodynamic effects in the pulmonary vasculature (eg, decrease in pulmonary vascular resistance, ranging between 21 and 25 min) clearly outlasted this serum level-based pharmacokinetic half-life.. A standardized dose of aerosolized iloprost delivered by different nebulizer types induces comparable pharmacodynamic and pharmacokinetic responses. Pulmonary vasodilation, persisting after disappearance of the drug from the systemic circulation, supports the hypothesis that local drug deposition largely contributes to the preferential pulmonary vasodilation in response to inhaled iloprost.

Topics: Administration, Inhalation; Adult; Aged; Cross-Over Studies; Equipment Design; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nebulizers and Vaporizers; Severity of Illness Index; Vasodilator Agents

Uncontrolled studies suggested that aerosolized iloprost, a stable analogue of prostacyclin, causes selective pulmonary vasodilatation and improves hemodynamics and exercise capacity in patients with pulmonary hypertension.. We compared repeated daily inhalations of 2.5 or 5.0 microg of iloprost (six or nine times per day; median inhaled dose, 30 microg per day) with inhalation of placebo. A total of 203 patients with selected forms of severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (New York Heart Association [NYHA] functional class III or IV) were included. The primary end point was met if, after week 12, the NYHA class and distance walked in six minutes were improved by at least one class and at least 10 percent, respectively, in the absence of clinical deterioration according to predefined criteria and death.. The combined clinical end point was met by 16.8 percent of the patients receiving iloprost, as compared with 4.9 percent of the patients receiving placebo (P=0.007). There were increases in the distance walked in six minutes of 36.4 m in the iloprost group as a whole (P=0.004) and of 58.8 m in the subgroup of patients with primary pulmonary hypertension. Overall, 4.0 percent of patients in the iloprost group (including one who died) and 13.7 percent of those in the placebo group (including four who died) did not complete the study (P=0.024); the most common reason for withdrawal was clinical deterioration. As compared with base-line values, hemodynamic values were significantly improved at 12 weeks when measured after iloprost inhalation (P<0.001), were largely unchanged when measured before iloprost inhalation, and were significantly worse in the placebo group. Further significant beneficial effects of iloprost treatment included an improvement in the NYHA class (P=0.03), dyspnea (P=0.015), and quality of life (P=0.026). Syncope occurred with similar frequency in the two groups but was more frequently rated as serious in the iloprost group, although this adverse effect was not associated with clinical deterioration.. Inhaled iloprost is an effective therapy for patients with severe pulmonary hypertension.

Topics: Administration, Inhalation; Dyspnea; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Vasodilator Agents; Walking

An elevated pulmonary vascular resistance (PVR) is described as a predictor of postoperative right heart failure and increased mortality in patients undergoing orthotopic heart transplantation. The use of intravenous vasodilators is limited by their systemic effects. We evaluated the pulmonary and systemic hemodynamic effects of inhaled nitric oxide (NO) and inhaled aerosolized iloprost (IP) in heart transplant candidates with elevated PVR.. Fourteen male heart transplant candidates due to dilative or ischemic cardiomyopathia with elevated PVR (> or = 180 dyn s cm(-5)) were included in the study. Increasing concentrations of NO (5, 10 and 30 ppm) and 50 microg aerosolized IP were administered by inhalation. Hemodynamic measurements preceded and followed administration of each agent.. Inhalation of IP, 10, and 30 ppm NO reduced PVR and mean pulmonary artery pressure (MPAP), but did not affect blood pressure or systemic vascular resistance. Comparing the effectiveness of 10 ppm NO and IP, we found a significant higher reduction of MPAP in patients treated with IP. An increase of cardiac index and stroke index could only be shown with IP-inhalation.. Inhaled iloprost induces pulmonary vasodilation which is significantly greater than the effects of 10 and 30 ppm NO. The results of our study show, that inhaled iloprost induces a reliable hemodynamic response in the evaluation of heart transplant candidates. Further advantages of iloprost inhalation are the lack of adverse reactions and toxic side effects and an easier administration. Due to this facts we recommend iloprost as a routine screening drug for vascular reactivity in HTx-candidates. Based on our results it would be of great interest to investigate the role of iloprost in management of postoperative right heart insufficiency following cardiac transplantation.

Topics: Administration, Inhalation; Adult; Aerosols; Dose-Response Relationship, Drug; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide; Oxygen Consumption; Preoperative Care; Pulmonary Artery; Vascular Resistance; Vasodilator Agents

Severe pulmonary hypertension (PH) is a major cause of right ventricular (RV) dysfunction. Various iv vasodilator modalities have been used with limited results because of lack of pulmonary selectivity. The aim of the present controlled study was to evaluate the efficacy of inhaled iloprost, a synthetic prostacyclin analogue, in patients with elevated pulmonary vascular resistance (PVR) immediately after separation from cardiopulmonary bypass (CPB).. Twelve patients with persistent PH after discontinuation of CPB were included in the study. In all patients standard hemodynamic monitoring was used. Inhaled iloprost was administered via nebulized aerosol at a cumulative dose of 0.2 micro g*kg(-1) for a total duration of 20 min. Complete sets of hemodynamic measurements were performed before inhalation (baseline), during and after cessation of the inhalation period. Echocardiographic monitoring of RV function was also used.. Inhaled iloprost induced a reduction in the transpulmonary gradient at the end of the inhalation period in comparison to baseline (9.33 +/- 3.83 mmHg vs 17.09 +/- 6.41 mmHg, P < 0.05). The mean pulmonary artery pressure to systemic artery pressure ratio decreased over this period (0.28 +/- 0.08 vs 0.45 +/- 0.17, P < 0.05). A statistically significant decrease of the PVR to systemic vascular resistance ratio was also observed (0.15 +/- 0.05 vs 0.21 +/- 0.05, P < 0.05). Improved indices of RV function were observed in echocardiographic monitoring.. Inhaled iloprost appears to be a selective pulmonary vasodilator and may be effective in the initial treatment of PH and the improvement of RV performance in the perioperative setting.

Topics: Administration, Inhalation; Aged; Cardiopulmonary Bypass; Electrocardiography; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Monitoring, Intraoperative; Postoperative Complications; Pulmonary Circulation; Vascular Resistance; Vasodilator Agents; Ventricular Function, Right

Aerosolized iloprost causes specific pulmonary vasodilation for about 60 mins in patients with severe primary and secondary pulmonary hypertension. Repeated daily inhalations are currently in use for chronic treatment. The aim of the current study was to evaluate if phosphodiesterase type 3 and 4 inhibition might amplify the prostanoid effect on pulmonary vasodilatation by stabilization of intracellular second messenger cyclic adenosine monophosphate.. Uncontrolled clinical trial.. Medical intensive care unit, Department of Internal Medicine, University Hospital, Giessen, Germany.. A total of 11 patients with precapillary pulmonary hypertension (eight with primary pulmonary hypertension; one with pulmonary hypertension associated with calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia [CREST syndrome]; one with pulmonary hypertension associated with systemic lupus erythematodes, and one with chronic pulmonary embolism) were included. All were classified as New York Heart Association class III or class IV.. During right heart catheterization, a single inhalation with iloprost (1.4 microg per inhalation) was performed, and hemodynamics and gas exchange variables were recorded for the next 2.5 hrs. After the iloprost effects had completely leveled off, the dual-selective phosphodiesterase types 3 and 4 inhibitor tolafentrine was infused in seven patients and aerosolized in five patients at doses that were per se ineffective (80 mg per 2.5 hrs intravenously; approximately 0.8 mg deposited by aerosol), followed by a second iloprost inhalation procedure.. Decrease in pulmonary vascular resistance, duration of drug effect, safety, and tolerability of combined pharmacologic intervention.. The decrease in pulmonary vascular resistance to sole iloprost nebulization lasted for approximately 60 mins. This response was enhanced and prolonged to approximately 120 mins in the presence of both infused and aerosolized tolafentrine, without loss of pulmonary selectivity. No adverse events were observed.. These data support the principle that subthreshold selective phosphodiesterase types 3 and 4 inhibition amplifies the lung vasodilatory response to inhaled iloprost, with minute doses being sufficient via the inhalative route.

Topics: Adult; Aerosols; Aged; Area Under Curve; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Naphthyridines; Phosphodiesterase Inhibitors; Statistics, Nonparametric; Vascular Resistance; Vasodilation; Vasodilator Agents

Inhalation of the stable prostacyclin analogue iloprost is being studied for treatment of pulmonary hypertension. The selective phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation.. To evaluate the safety and effectiveness of oral sildenafil, alone and in combination with inhaled iloprost, for treatment of pulmonary hypertension.. Randomized, controlled, open-label trial.. Intensive care unit.. 30 patients with severe pulmonary arterial hypertension (n = 16), chronic thromboembolic pulmonary hypertension (n = 13), or pulmonary hypertension due to aplasia of the left pulmonary artery (n = 1), all classified as New York Heart Association class III or IV.. All patients received inhaled nitric oxide and aerosolized iloprost (inhaled dose, 2.8 microg). They were then randomly assigned to receive 12.5 mg of oral sildenafil, 50 mg of sildenafil, 12.5 mg of sildenafil plus inhaled iloprost, or 50 mg of sildenafil plus inhaled iloprost.. Systemic and pulmonary arterial pressure, pulmonary arterial occlusion pressure, cardiac output, central venous pressure, peripheral arterial oxygen saturation, and arterial and mixed venous blood gases were measured during right-heart catheterization by using a Swan-Ganz catheter.. In rank order of pulmonary vasodilatory potency (maximum reduction of pulmonary vascular resistance and increase in cardiac index), 50 mg of sildenafil plus iloprost was most effective, followed by 12.5 mg of sildenafil plus iloprost. Iloprost alone and 50 mg of sildenafil were almost equally effective but were less potent than the combination regimens, and the least potent treatments were 12.5 mg of sildenafil and nitric oxide. In patients who received 50 mg of sildenafil plus iloprost, the maximum change in pulmonary vasodilatory potency was -44.2% (95% CI, -49.5% to -38.8%), compared with -14.1% (CI, -19.1% to -9.2%) in response to nitric oxide. With administration of 50 mg of sildenafil plus iloprost, the area under the curve for reduction in pulmonary vasodilatory resistance surpassed that of administration of 50 mg of sildenafil alone and iloprost alone combined, the vasodilatory effect lasted longer than 3 hours, and systemic arterial pressure and arterial oxygenation were maintained. No serious adverse events occurred.. Although limited by the small sample and lack of long-term observations, the study shows that oral sildenafil is a potent pulmonary vasodilator that acts synergistically with inhaled iloprost to cause strong pulmonary vasodilatation in both severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Analysis of Variance; Area Under Curve; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Aerosolized iloprost, a stable prostacyclin analog, improves functional capacity even in patients with pulmonary hypertension who did not show a vigorous hemodynamic response after iloprost inhalation at rest. We therefore speculated that aerosolized iloprost elicits more beneficial effects on pulmonary hemodynamics during exercise than at rest.. A prospective, open, uncontrolled study at a university hospital.. Sixteen patients with primary or secondary pulmonary hypertension.. Right-heart catheterization at rest and during exercise before and after the inhalation iloprost, 14 to 28 microg.. Before iloprost treatment, exercise increased mean (+/- SD) pulmonary artery pressure (PAPm) from 45 +/- 8 to 70 +/- 13 mm Hg, cardiac output from 3.7 +/- 1.0 to 5.8 +/- 2.4 L/min, and pulmonary vascular resistance (PVR) from 904 +/- 322 to 1,013 +/- 432 dyne.s.cm(-5) (each p < 0.05). After recovery, iloprost reduced PAPm from 44 +/- 8 to 41 +/- 6 mm Hg, increased cardiac output from 3.7 +/- 1.0 to 4.9 +/- 1.4 L/min, and lowered PVR from 902 +/- 350 to 636 +/- 248 dyne x s x cm(-5) (each p < 0.05). During exercise after iloprost, PAPm increased to 57 +/- 8 mm Hg, cardiac output to 7.0 +/- 3.0 L/min, and PVR to 673 +/- 279 dyne x s x cm(-5) (each p < 0.05 vs first exercise test). Systemic BP was not altered significantly by iloprost treatment during exercise.. Aerosolized iloprost treatment exerts more favorable effects on pulmonary hemodynamics during exercise than at rest. These findings explain the functional improvement observed in patients with pulmonary hypertension who show only a moderate pulmonary vasodilatory response during iloprost inhalation at rest. Whether these beneficial effects have prognostic significance needs to be elucidated by further study.

Topics: Administration, Inhalation; Aerosols; Blood Pressure; Cardiac Catheterization; Cardiac Output; Exercise Test; Female; Heart Rate; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prospective Studies; Pulmonary Artery; Pulmonary Circulation; Rest; Vascular Resistance; Vasodilator Agents

Inhaled nitric oxide (iNO) has been used to assess the vasodilator capacity of the pulmonary vascular bed in children with congenital heart disease and elevated pulmonary vascular resistance. Inhaled iloprost is a pulmonary vasodilator for the long-term treatment of pulmonary hypertension (PHT). Because these 2 vasodilators act through different pathways (release of cGMP or cAMP, respectively), we compared the pulmonary vasodilator capacity of each.. A total of 15 children with congenital heart disease and PHT who had elevated pulmonary vascular resistance (preoperative, n=10; immediately postoperative, n=5) were first given 20 ppm of iNO for 10 minutes; then, after baseline values were reached again, they were given aerosolized iloprost at 25 ng. kg(-1). min(-1) for another 10 minutes. Finally, iNO and iloprost were given simultaneously for 10 minutes. With iNO, the pulmonary vascular resistance and systemic vascular resistance ratio decreased from 0.48+/-0.38 to 0.27+/-0.16 (P:<0.001). Similarly, iloprost decreased the ratio from 0.49+/-0.38 to 0.26+/-0.11 (P:<0.05). The combination had no additional effect on the resistance ratio. Plasma cGMP increased from 17.6+/-11.9 to 34.7+/-21.4 nmol/L during iNO (P:<0.01), and plasma cAMP increased from 55.7+/-22.9 to 65.1+/-21.2 nmol/L during iloprost inhalation (P:<0.05).. In children with PHT and congenital heart disease, both iNO and aerosolized iloprost are equally effective in selectively lowering pulmonary vascular resistance through an increase in cGMP or cAMP, respectively. However, the combination of both vasodilators failed to prove more potent than either substance alone. Aerosolized iloprost might be an alternative to iNO for early testing of vascular reactivity and for the postoperative treatment of acute PHT.

Topics: Administration, Inhalation; Aerosols; Analysis of Variance; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infant; Lung; Nitric Oxide; Pulmonary Circulation; Vascular Resistance; Vasodilator Agents

Inhalation of iloprost, a stable prostacyclin analogue, is a promising perspective in the treatment of pulmonary hypertension. In initial clinical studies, a conventional jet nebulizer system was successfully used to decrease pulmonary vascular resistance and pressure, requiring however, up to twelve inhalations of 12-15 min per day. The aim of this study was to investigate if the application of an equal dose of iloprost at a drastically reduced duration of inhalation with the use of a more efficient ultrasonic nebulizer, leads to comparable haemodynamic effects, without escalation of side effects. The physical features of the jet nebulizer system (Ilo-Neb) and the ultrasonic nebulizer (Multisonic Compact) were characterized by laser diffractometry and a Tc99m-tracer technique. Mass median aerodynamic diameters were 3.2 microm for the jet and 3.9 microm for the ultrasonic nebulizer. Total output (mean+/-SD) was 60+/-7 microL.min(-1) (jet) and 163+/-15 microL.min(-1)(ultrasonic), and efficiency of the devices was 39+/-3% (jet) and 86+/-5% (ultrasonic). Based on these data, a total inhalative dose of 2.8 microg iloprost was delivered by jet nebulization within 12 min and by ultrasonic nebulization within 4 min, in 18 patients with severe primary and secondary pulmonary hypertension (New York Heart Association class III and IV), in a randomized crossover design. Haemodynamics were assessed by right heart catheterization. Inhalation with the ultrasonic device and jet nebulizer, reduced mean+/-SEM pulmonary artery pressure from 54.3+/-2.1 to 47.1+/-2.0 and from 53.5+/-2.2 to 47.0+/-2.2 mmHg, respectively, and mean+/-SEM pulmonary vascular resistance from 1,073+/-109 to 804+/-87 and from 1,069+/-125 to 810+/-83 dyn.s.cm(-5), respectively. Both modes of aerosolization were well tolerated. In conclusion, due to the markedly higher efficiency and output of the ultrasonic device, wastage of drug is largely avoided and the duration of inhalation can be shortened to one-third, with comparable haemodynamic effects and without enforcing side effects.

Topics: Administration, Inhalation; Aerosols; Blood Pressure; Cardiac Output; Humans; Hypertension, Pulmonary; Iloprost; Nebulizers and Vaporizers; Particle Size; Pulmonary Artery; Pulmonary Circulation; Pulmonary Wedge Pressure; Vascular Resistance; Vasodilator Agents; Venous Pressure

Pulmonary arterial hypertension (PAH), defined as elevated pulmonary arterial pressure and pulmonary vascular resistance, is an end-point of a variety of conditions. The only therapy that has been shown to improve both quality of life and survival is intravenous prostacyclin (prostaglandin I2 (PGI2), epoprostenol). The effect of long-term aerosolized iloprost (Ilomedin, Schering, Berlin, Germany and Vienna, Austria), a stable prostacyclin analogue and potent vasodilator, on haemodynamics and functional status was investigated in 12 patients with severe pulmonary hypertension. Haemodynamic measurements and vasodilator testing by right heart catheterization were performed prior to and after long-term iloprost inhalation therapy. Haemodynamic improvement or increased exercise tolerance was not observed in any of the patients. After a mean+/-SD treatment period of 10+/-5 months, mean+/-SD pulmonary vascular resistance had increased from 11+/-3 Wood Units (mmHg.L(-1).min) to 13+/-4 Wood Units, with unchanged arterial oxygen saturation (92+/-4%, versus 91+/-4%). Within the study period, three patients went into right heart failure and had to be placed on intravenous epoprostenol. The authors conclude that inhaled iloprost in addition to conventional therapy in the presently recommended dose of 100 microg.day(-1) delivered in 8-10 2 h portions, is not an efficient vasodilator therapy in severe pulmonary hypertension. It remains to be shown whether dose increases and/or combination protocols will be effective, or whether inhalation of iloprost may be safe for selected cases of pulmonary hypertension.

Topics: Administration, Inhalation; Adolescent; Adult; Aerosols; Aged; Blood Pressure; Cardiac Output; Chronic Disease; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Oxygen; Prospective Studies; Pulmonary Circulation; Pulmonary Embolism; Vascular Resistance; Vasodilator Agents

The application of iloprost, a stable prostacyclin analogue, by inhalation has been shown to improve hemodynamic variables in patients with primary pulmonary hypertension. However, repetitive inhalations are required due to its short-term effects. One potential approach to prolong and increase the vasorelaxant effects of aerosolized iloprost might be to combine use with phosphodiesterase inhibitors.. The short-term effects of 8.4 to 10.5 microgram of aerosolized iloprost, the phosphodiesterase type 5 inhibitor sildenafil, and the combination thereof were compared in 5 patients with primary pulmonary hypertension. Aerosolized iloprost resulted in a more pronounced decrease in mean pulmonary arterial pressure (PAP) than sildenafil alone (9.4+/-1.3 versus 6.4+/-1.1 mm Hg; P<0.05). The reduction in mean PAP after sildenafil was maximal after the first dose (25 mg). The combination of sildenafil plus iloprost lowered mean PAP significantly more than iloprost alone (13.8+/-1.4 versus 9.4+/-1.3 mm Hg; P<0.009). No significant changes in heart rate or systemic arterial pressure were observed during any treatment. The treatments were well tolerated, without major adverse effects.. Sildenafil caused a long-lasting reduction in mean PAP and pulmonary vascular resistance, with a further additional improvement after iloprost inhalation. These data suggest that small doses of a phosphodiesterase type 5 inhibitor may be a useful adjunct to inhaled iloprost in the management of pulmonary hypertension.

Topics: Administration, Inhalation; Administration, Oral; Blood Pressure; Cardiac Output; Cough; Drug Therapy, Combination; Female; Headache; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nausea; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents

To assess the outcome of patients with CREST syndrome associated severe pulmonary hypertension treated by aerosolized iloprost in a noncomparative study.. Five patients with CREST syndrome associated severe pulmonary hypertension were treated with 100 microg/day of aerosolized iloprost. New York Heart Association functional class and exercise tolerance (6 min walk test) were assessed at baseline, after one month, and then every 6 months. A right heart catheterization was performed at baseline in all but one patient. Systolic pulmonary artery pressure (PAP) was measured with Doppler echocardiography after one month and every 6 months.. The mean followup was 13.2 +/- 8.8 months (median 6, range 6-24). Subjective quality of life improved in all patients. NYHA functional class decreased from Class III to II in 3 patients, from Class III to I in one patient, and from Class IV to III in one patient. At 6 months, the distance walked in 6 min had increased from 352 +/- 48 to 437 +/- 56 m (p = 0.06). At one month the mean systolic PAP was 58 +/- 13 vs 81 +/- 9 mm Hg at baseline (p = 0.04). At 6 months the mean systolic PAP was 57 +/- 13 mm Hg (p = 0.06). The improvement of both clinical and hemodynamic status was maintained in the 2 patients treated for 2 years. Neither adverse effects nor need to increase the daily dose of iloprost were observed. One patient died of right heart failure and one patient did not experience any improvement of exercise tolerance and hemodynamics.. Aerosolized iloprost might be potentially useful as treatment for CREST syndrome associated pulmonary hypertension. However, patients who could benefit from this treatment will probably have to undergo careful criteria selection.

Topics: Administration, Inhalation; Adult; Aged; CREST Syndrome; Dyspnea; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pulmonary Wedge Pressure; Quality of Life; Treatment Outcome; Vasodilator Agents

We sought to compare the acute hemodynamic effects of inhaled nitric oxide (NO) and aerosolized iloprost in primary pulmonary hypertension (PPH).. Inhalation of the stable prostacyclin analogue iloprost has recently been described as a novel therapeutic strategy for PPH and may offer an alternative to continuous intravenous infusion of prostacyclin or inhalation of NO.. During right heart catheterization, 35 patients with PPH sequentially inhaled 40 ppm of NO and 14 to 17 microg of iloprost, and the effects on hemodynamics and blood gases were monitored.. Both NO and iloprost caused significant increases in cardiac output, mixed-venous oxygen saturation and stroke volume as well as significant decreases in pulmonary artery pressure and pulmonary vascular resistance, whereas only inhaled iloprost significantly increased the arterial PO2 (p = 0.01). Compared with inhaled NO, aerosolized iloprost was more effective in reducing pulmonary artery pressure (-8.3 +/- 7.5 mm Hg vs. -4.3 +/- 8.8 mm Hg; p = 0.0001) and the pulmonary vascular resistance (-447 +/- 340 dynes x s x cm(-5) vs. -183 +/- 305 dyne x s x cm(-5); p < 0.0001). Furthermore, aerosolized iloprost caused a significantly greater increase of the cardiac output compared with NO (+0.7 +/- 0.6 liter/min vs. +0.3 +/- 0.4 liter/min; p = 0.0002) and had a more pronounced effect on the mixed-venous oxygen saturation (p = 0.003).. During acute drug testing, aerosolized iloprost was more potent than inhaled NO as a pulmonary vasodilator in PPH at the doses used in this study.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Cardiac Output; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide; Oxygen; Pulmonary Wedge Pressure; Vascular Resistance; Vasodilator Agents

Inhaled aerosolized iloprost, a stable prostacyclin analogue, has been considered a selective pulmonary vasodilator in the management of pulmonary hypertension.. To assess the efficacy of inhaled iloprost in the treatment of life-threatening pulmonary hypertension.. Open, uncontrolled, multicenter study.. Intensive care units and pulmonary hypertension clinics at six university hospitals in Germany.. 19 patients who had progressive right-heart failure despite receiving maximum conventional therapy (12 with primary pulmonary hypertension, 3 with pulmonary hypertension related to collagen vascular disease without lung fibrosis, and 4 with secondary pulmonary hypertension).. Inhaled iloprost, 6 to 12 times daily (50 to 200 microg/d).. Right-heart catheterization and distance walked in 6 minutes at baseline and after 3 months of therapy.. During the first 3 months of therapy, New York Heart Association functional class improved in 8 patients and was unchanged in 7 patients. Four patients died, 3 of right-heart failure and 1 of sepsis. The acute hemodynamic response to inhaled iloprost was predominant pulmonary vasodilatation with little systemic effect at baseline and at 3 months (data available for 12 patients). Hemodynamic variables were improved at 3 months, and the distance walked in 6 minutes improved by 148 m (95% CI, 4.5 to 282 m; P = 0.048). Of the 15 patients who continued to use inhaled iloprost, 8 stopped: Four had lung transplantation, 1 switched to intravenous prostacyclin therapy, and 3 died. Seven patients are still receiving inhaled iloprost (mean +/-SD) duration of therapy, 536 +/- 309 days; mean dosage, 164 +/- 38 microg/d).. Inhaled iloprost may offer a new therapeutic option for improvement of hemodynamics and physical function in patients with life-threatening pulmonary hypertension and progressive right-heart failure that is refractory to conventional therapy.

Topics: Administration, Inhalation; Adult; Aged; Exercise Tolerance; Female; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pulmonary Gas Exchange; Statistics, Nonparametric; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I2 caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mmHg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn.s.cm-5 (p < 0.005, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left-shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn.s.cm-5. In contrast, both intravenous PGI2 and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition PGI2 infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI2 analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI2 or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Antihypertensive Agents; Calcium Channel Blockers; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Male; Middle Aged; Nitric Oxide; Oxygen Inhalation Therapy; Pulmonary Fibrosis; Respiratory Function Tests; Vasodilator Agents

The continuous infusion of prostacyclin has been shown to improve exercise capacity and survival in patients with primary pulmonary hypertension (PPH). Inhalation of iloprost, a stable analog of prostacyclin, might be an alternative therapy for PPH, selectively acting on the pulmonary vascular bed through ventilation-matched alveolar deposition of the drug. We investigated the short-term effects of iloprost inhalation on exercise capacity and gas exchange in patients with PPH.. In 11 patients with PPH, we performed 2 consecutive cardiopulmonary exercise tests before and after the inhalation of 17 microgram of iloprost. Patients had marked pulmonary hypertension (mean pulmonary artery pressure 65 mm Hg), and inhalation resulted in a decrease in pulmonary vascular resistance (1509 versus 1175 dyne. s(-1). cm(-5), P<0.05). Arterial blood gases remained unchanged (PaO(2) 69.3 versus 66.8 mm Hg; PaCO(2) 29.6 versus 28.8 mm Hg). Iloprost significantly (P<0.05) improved exercise duration (379 versus 438 seconds), peak oxygen uptake (12.8 versus 14.2 mL. kg(-1). min(-1)), VE-versus-V CO(2) slope (58 versus 51.4).. The present data show that iloprost inhalation exerts pulmonary vasodilatation and improves symptoms and exercise capacity in patients with PPH. The data also suggest that iloprost inhalation is a suitable treatment for PPH. Whether these effects are maintained during long-term treatment and are paralleled by improvement in prognosis remains to be determined.

Topics: Administration, Inhalation; Adult; Exercise Test; Heart; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Lung; Middle Aged; Physical Endurance; Respiration; Vasodilator Agents

Continuous intravenous infusion of epoprostenol (prostacyclin) is an effective treatment for primary pulmonary hypertension. This approach requires the insertion of a permanent central venous catheter, with the associated risk of serious complications. Recently, aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension.. We evaluated the effects of aerosolized iloprost on exercise capacity and hemodynamic variables over a one-year period in patients with primary pulmonary hypertension.. Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a daily dose of 100 or 150 microg for at least one year. The mean (+/-SD) distance covered in the six-minute walk test increased from 278+/-96 m at base line to 363+/-135 m after 12 months (P<0.001). During the same period, the mean pulmonary arterial pressure before the inhalation of iloprost declined from 59+/-10 mm Hg to 52+/-15 mm Hg (P=0.006), cardiac output increased from 3.8+/-1.4 liters per minute to 4.4+/-1.3 liters per minute (P=0.02), and pulmonary vascular resistance declined from 1205+/-467 dyn x sec x cm(-5) to 925+/-469 dyn x sec x cm(-5) (P<0.001). The treatment was generally well tolerated, except for mild coughing, minor headache, and jaw pain in some patients.. Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Exercise Tolerance; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Vasodilator Agents

Follow-up data for 81 consecutive patients with primary pulmonary hypertension (PPH) and pulmonary hypertension related to connective tissue diseases or liver cirrhosis, entered into a multicenter registry in Berlin between 1/96 and 11/99, are described. At entry into the registry the diagnosis of PPH was known for 22 +/- 32 months. Hemodynamically, these patients were characterized by a right atrial pressure of 8.6 +/- 5 mmHg, a mean pulmonary arterial pressure of 58.9 +/- 17 mmHg, a cardiac index of 1.8 +/- 0.6 l/min/m2 and a pulmonary vascular resistance of 1574 +/- 787 dyn x s x cm-5. In about one third of the patients, a restrictive and/or obstructive pulmonary physiology was found while the majority showed signs compatible with small airway disease. Furthermore, diffusion abnormalities were found in about 65% of the patients. When added to conventional medical therapy the treatment with inhaled or continuously infused prostanoids represents a major improvement in the treatment of patients with PPH. Aerosolized iloprost therapy was started in 51 patients and was continued for 12 and 24 months in 20 and 6 patients, respectively. This therapy was well tolerated without any significant changes in pulmonary function or signs of toxicity. About 25% of these patients had to be switched to continuous intravenous therapy due to progressive clinical and hemodynamic deterioration. About two thirds of these "rescue patients" could be stabilized on intravenous therapy and discharged from the hospital. Based on the currently available evidence, the continuous infusion of prostanoids represents an important part of the standard therapy in the treatment of patients with PPH. These first long-term data on inhaled iloprost therapy in this patient group illustrate the potential value of this well-tolerated and effective treatment within the concept of a differentiated treatment plan for patients with PPH. However, the true importance of prostanoid inhalation in comparison to continuous intravenous therapy in PPH remains to be determined in randomized controlled trials.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Berlin; Child; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Long-Term Care; Male; Middle Aged; Registries

Primary pulmonary hypertension and pulmonary hypertension associated with collagen vascular disease or HIV infection are rapidly progressive fatal diseases in spite of conventional medical therapy. Continuous intravenous infusion of prostacyclin has been shown to prolong life in severe primary pulmonary hypertension, and aerosolised prostacyclin has been used successfully on a short-term basis in patients with pulmonary hypertension. We investigated the effects of acute administration of aerosolised prostacyclin or its analogue iloprost in 5 patients with severe pulmonary hypertension; 4 of these patients were followed over a period of 7 months. On acute testing, mean pulmonary artery pressure decreased from 59 to 46 mm Hg (p = 0.01); echocardiographically estimated systolic pulmonary pressure further declined from 66 mm Hg after 2 days' treatment to 54 mm Hg after 7 months (p = 0.03). Symptom-limited walking distance significantly improved from 42 to 87 m after 2 days' treatment (p = 0.003); a further 2- to 8-fold increase was observed in single patients during follow-up. In severe pulmonary hypertension, aerosolised prostacyclin or iloprost improves exercise capacity and lowers pulmonary artery pressure beyond the level achieved on acute exposure.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Antihypertensive Agents; Epoprostenol; Exercise Test; Female; Hemodynamics; HIV Seropositivity; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pulmonary Wedge Pressure

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I(2) caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mm Hg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn. s. cm(-)(5) (p < 0.05, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn. s. cm(-)(5). In contrast, both intravenous PGI(2) and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition, PGI(2) infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI(2) analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI(2) or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.

Topics: Administration, Inhalation; Adult; Aged; Atrial Function, Right; Calcium Channel Blockers; Drug Therapy, Combination; Epoprostenol; Female; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Lung; Male; Middle Aged; Nifedipine; Nitric Oxide; Pulmonary Fibrosis; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Vascular Resistance; Vasodilator Agents; Ventilation-Perfusion Ratio; Vital Capacity

To compare prostacyclin with an analogue, iloprost, in treatment of severe pulmonary hypertension.. Eight patients with severe pulmonary hypertension: primary in five, thromboembolic pulmonary hypertension in three.. All patients underwent right heart catheterisation. Mean (SEM) right atrial pressure was 9.9 (2.2) mm Hg, mean pulmonary artery pressure 67.4 (3.0) mm Hg, cardiac index 1.75 (0.13) l/min/m2 and mixed venous oxygen saturation 59.1(3.1)%. Continuous intravenous epoprostenol (prostacyclin, PGI2) or iloprost was given for phase I (three to six weeks); the patients were then crossed over to receive the alternate drug in an equivalent phase II.. Exercise tolerance was measured at baseline and at the end of phase I and II with a 12 minute walk; distance covered, rest period, percentage drop in arterial oxygen saturation (delta Sao2%) and percentage rise in heart rate (delta HR%).. Walking distance covered rose from (mean (SEM)) 407.5 (73) to 591 (46) m with PGI2 (p = 0.004) and to 602.5 (60) m while on iloprost (p = 0.008). Rest period decreased from 192 (73) seconds at baseline to 16 (16) seconds with PGI2 (p = 0.01) and to 58 (34) seconds with iloprost (p = 0.008). Delta HR% was 37.5(6)% at baseline, 35(3)% on PGI2, and 24(6)% on iloprost (p = 0.04).. Both intravenous PGI2 and iloprost caused significant improvement in exercise tolerance. Iloprost offers an alternative to PGI2 treatment of severe pulmonary hypertension.

Topics: Adult; Antihypertensive Agents; Cardiac Catheterization; Cross-Over Studies; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Vasodilator Agents

To determine the effects of short-term, maximum-tolerated-dose and long-term, optimum-dose iloprost treatment of severe pulmonary hypertension associated with systemic sclerosis (SSc) and the primary antiphospholipid syndrome (APS).. Three patients with SSc and 2 with APS who had failed to respond to oral vasodilator therapy for pulmonary hypertension were enrolled in a 32-week, open, prospective trial. Short-term infusion of maximum-tolerated doses and continuous infusion of optimum doses of iloprost were carried out following baseline cardiac catheterization. Catheterization was repeated at 2 and 32 weeks. All 5 patients completed the study and continued therapy for an average of 82 weeks (range 58-103).. Acute infusion of maximum tolerated doses significantly ameliorated the cardiac index (0.92 liters/minute/m2; P < 0.01), pulmonary artery O2 saturation (10.6%; P < 0.05), and pulmonary resistance (-6.7 units; P < 0.05). After 2 weeks of continuous infusion of optimum doses, there was improvement in pulmonary resistance (> or = 16%) and pulmonary artery O2 saturation (> 30%) in the 2 patients with primary APS. After 2 and 32 weeks, the 3 SSc patients showed variable hemodynamic responses. New York Heart Association functional class and exercise tolerance improved in all patients. There was 1 episode of bacteremia, and 1 patient died after 72 weeks of study.. Continuous iloprost infusion may improve exercise tolerance and quality of life in patients with severe pulmonary hypertension associated with SSc and primary APS.

Topics: Adolescent; Adult; Antiphospholipid Syndrome; Connective Tissue Diseases; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Time Factors

Patients with systemic sclerosis (SSc) do not exhibit a normal increase in the diffusing capacity for carbon monoxide (DLCO) on assuming the supine position. We sought to determine whether a potent prostacyclin derivative and vasodilator, iloprost, would reverse this defect.. Fourteen patients with SSc were enrolled in a randomized, double-blind, placebo-controlled study of iloprost. Patients were tested before and during 3 days of iloprost or placebo infusion with both upright and supine pulmonary function studies.. The results of baseline pulmonary function studies including DLCO were not significantly altered by iloprost. Furthermore, iloprost did not alter the abnormal postural DLCO response.. These results suggest that the pulmonary vascular defects seen in this group of patients are not a consequence of reversible pulmonary vasospasm.

Topics: Adult; Aged; Carbon Monoxide; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Pulmonary Diffusing Capacity; Respiratory Function Tests; Scleroderma, Systemic; Supination

Twelve patients with severe primary pulmonary hypertension and pronounced disability unresponsive to oral vasolidators were assessed as to their suitability for heart-lung transplantation. During routine right heart catheterisation, intravenous infusions of both prostacyclin (PG1(2] and its synthetic analogue, iloprost (IL), were given in random order. The dose of each drug was increased whilst the improvements in cardiac output (Q) and pulmonary vascular resistance (PVR) were recorded. The maximum rate of each infusion was determined by the onset of side effects or a fall in mean systemic blood pressure of more than 20 per cent. The mean maximum dose of PG1(2) was 6 +/- 2 ng/kg/min and that of IL 3.4 +/- 1.8 ng/kg/min, and both infusions achieved similar haemodynamic effects. In this open, randomised study, intravenous IL was as effective as prostacyclin in lowering PVR, but with a lower infused dose. Iloprost may have an important role in the acute assessment of patients with primary pulmonary hypertension, and when available for prescription should be assessed as an alterative long-term intravenous vasodilator to prostacyclin.

Topics: Adult; Child; Dose-Response Relationship, Drug; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Vasodilator Agents

Persistent pulmonary hypertension of the neonate can cause acute and life-threatening hypoxia, but preterm neonates are not suitable candidate to extra-corporeal life support. We report the unique case of an extremely preterm neonates with life-threatening persistent pulmonary hypertension refractory to triple vasodilator therapy (nitric oxide, iloprost, and bosentan), which has been successfully treated with the addition of adenosine continuous infusion.

Topics: Adenosine; Administration, Inhalation; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Nitric Oxide; Vasodilator Agents

To determine the efficacy and safety of endotracheal instillation of iloprost as a rescue therapy for persistent pulmonary hypertension of the newborn.. Neonates diagnosed with persistent pulmonary hypertension who were unresponsive to standard treatment protocol applied for persistent pulmonary hypertension in our unit, and who were being followed up with mechanical ventilation, were included in the study. Iloprost was instilled endotracheally as a rescue treatment. Systolic pulmonary artery pressure, oxygen saturation index, mean airway pressure, fraction of inspired oxygen, preductal and postductal venous oxygen saturation, heart rate, and blood pressure were recorded before and after 30 minutes of endotracheal iloprost instillation. Adverse events after endotracheal iloprost were recorded.. Twenty neonates were included. The median gestational age and birth weight were found to be 37 (30.5-38) weeks and 2975 (2125-3437.5) grams, respectively. When compared to the period before endotracheal iloprost instillation, systolic pulmonary artery pressure, oxygen saturation index, mean airway pressure, and fraction of inspired oxygen values significantly decreased (p < 0.001, p < 0.001, p = 0.021, p = 0.001, respectively), whereas preductal and postductal oxygen saturation values significantly increased 30 minutes after the endotracheal iloprost instillation (p = 0.002, p < 0.001, respectively). There were no significant differences in heart rate and blood pressure values before and after the iloprost administration. No adverse events were observed.. Endotracheal instillation of iloprost was found to be an effective and safe therapy for persistent pulmonary hypertension unresponsive to conventional treatment.

Topics: Administration, Inhalation; Blood Pressure; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Oxygen; Trachea; Vasodilator Agents

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

Topics: Acetamides; Adult; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Lupus Erythematosus, Systemic; Pulmonary Arterial Hypertension; Pyrazines; Quality of Life

Topics: Administration, Inhalation; Heart Ventricles; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

The study aimed to evaluate the effects of inhaled iloprost on oxygenation indices in neonates with persistent pulmonary hypertension of the newborn (PPHN).. We conducted a retrospective chart review of 30 patients with PPHN from January 2014 to November 2018, who did not respond to inhaled nitric oxide (iNO) alone and received inhaled iloprost. Twenty-two patients met the inclusion criteria and eight patients were excluded from the study (complex cardiac disease and extreme prematurity). Patients were categorized as responders or nonresponders (patients who required extracorporeal membrane oxygenation or died). Oxygenation index, mean airway pressure (MAP), and arterial partial pressure of oxygen (PaO. Among a total of 22 patients who were included in the study, 10 were classified as nonresponders as they required either extracorporeal membrane oxygenation or died. Gestational age and gender did not differ between responders and nonresponders. The median PaO. Inhaled iloprost is well tolerated and seems to have beneficial effects in improving oxygenation indices in neonates with PPHN who do not respond to iNO. There is a need of well-designed prospective trials to further ascertain the benefits of using inhaled iloprost as an adjunct treatment in neonates with PPHN who do not respond to iNO alone.. · Inhaled iloprost seems to have beneficial effects in improving oxygenation indices in PPHN.. · Inhaled iloprost is generally well tolerated in newborns with PPHN.. · There is a need for prospective randomized controlled trials to further ascertain the benefits of using inhaled iloprost..

Topics: Administration, Inhalation; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Nitric Oxide; Oxygen; Persistent Fetal Circulation Syndrome; Prospective Studies; Retrospective Studies; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a severe, life-threatening disorder despite the availability of specific drug therapy. A lack of endogenous prostacyclin secondary to downregulation of prostacyclin synthase in PAH may contribute to vascular pathologies. Therefore, prostacyclin and its analogs including inhaled iloprost may decrease pulmonary arterial pressure and ventricular pressure.. Here, we studied that acute effects of iloprost used in pulmonary vasoreactivity testing on the intracardiac conduction system in patients with PAH. A total of 35 (15 idiopathic PAH, 20 congenital heart disease) patients with PAH were included in this prospective study. Patients were divided into two groups: 22 patients with negative pulmonary vasoreactivity in group 1 and 13 with positive pulmonary vasoreactivity in group 2. Electrophysiological parameters including basic cycle length, atrium-His (AH) interval, His-ventricle (HV) interval, PR interval, QT interval, QRS duration, Wenckebach period, and sinus node recovery time (SNRT) were evaluated before and after pulmonary vasoreactivity testing in both groups.. The AH interval (81 [74-93]; 80 [65.5-88], p = 0.019) and SNRT (907.7 ± 263.4; 854.0 ± 288.04, p = 0.027) was significantly decreased after pulmonary vasoreactivity testing. Mean right atrium pressure was found to be correlated with baseline AH (r = 0.371, p = 0.031) and SNRT (r = 0.353, p = 0.037).. Inhaled iloprost can improve cardiovascular performance in the presence of PAH, primarily through a reduction in right ventricular afterload and interventricular pressure. Decreased pressure on the interventricular septum and ventricles leads to conduction system normalization including of the AH interval and SNRT due to resolution of inflammation and edema.. HINTERGRUND: Die pulmonalarterielle Hypertonie (PAH) ist eine schwere, lebensbedrohliche Erkrankung trotz spezifischer medikamentöser Behandlung. Ein Mangel an endogenem Prostazyklin infolge einer Herabregulierung der Prostazyklinsynthase bei PAH kann zu Gefäßerkrankungen beitragen. Daher können Prostazyklin und seine Analoga einschließlich des inhalativen Iloprost den pulmonalarteriellen Druck und den Ventrikeldruck senken.. In der vorliegenden Studie wurden die akuten Wirkungen von dem zur Prüfung der pulmonalen Vasoreaktivität eingesetzten Iloprost auf das intrakardiale Erregungsleitungssystem bei Patienten mit PAH untersucht. In die prospektive Studie wurden 35 Patienten mit PAH (15 mit idiopathischer PAH, 20 mit kongenitaler Herzerkrankung) eingeschlossen. Die Patienten wurden in 2 Gruppen eingeteilt: 22 Patienten mit negativer pulmonaler Vasoreaktivität in Gruppe 1 und 13 mit positiver pulmonaler Vasoreaktivität in Gruppe 2. Vor und nach der Prüfung der pulmonalen Vasoreaktivität wurden elektrophysiologische Parameter einschließlich grundlegender Zyklusdauer, Atrium-His(AH)-Intervall, His-Ventrikel(HV)-Intervall, PR-Intervall, QT-Intervall, QRS-Dauer, Wenckebach-Periode und Sinusknotenerholungszeit (SKEZ) in beiden Gruppen gemessen.. Das AH-Intervall (81 [74–93]; 80 [65,5–88], p = 0,019) und die SKEZ (907,7 ± 263,4; 854,0 ± 288,04; p = 0,027) waren nach Prüfung der pulmonalen Vasoreaktivität signifikant erniedrigt. Der mittlere Druck im rechten Vorhof erwies sich als mit dem Ausgangs-AH-Intervall korreliert (r = 0,371; p = 0,031) und SKEZ (r = 0,353; p = 0,037).. Inhalatives Iloprost kann die kardiovaskuläre Leistung bei Vorliegen einer PAH verbessern, in erster Linie durch eine Reduktion der rechtsventrikulären Nachlast und des interventrikulären Drucks. Ein verminderter Druck auf das Interventrikularseptum und die Ventrikel führt zur Normalisierung des Erregungsleitungssystems einschließlich des AH-Intervalls und der SKEZ aufgrund der Rückbildung von entzündlichen Veränderungen und Ödemen.

Topics: Administration, Inhalation; Humans; Hypertension, Pulmonary; Iloprost; Prospective Studies; Pulmonary Arterial Hypertension; Vasodilator Agents

To evaluate clinical efficacy, safety and tolerability of long-term inhaled iloprost treatment in the daily practice for the management of pulmonary arterial hypertension (PAH).. A total of 115 patients with PAH on inhaled iloprost treatment were included. New York Heart Association (NYHA) functional class, brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and 6-minute walk distance (6MWD) were recorded at baseline and at 3rd to 24th month visits. Safety and tolerability of iloprost treatment were also evaluated during follow-up, as were the survival, clinical worsening, and the related risk factors.. The treatment was associated with an increase in the percentage NYHA functional class II (from 0.0% at enrolment to 36.2% at 24th month visit) patients but no significant difference was noted in 6MWD values. Clinical worsening was observed in 63.5% patients, while survival rate was 69.6%. NT-proBNP levels were significantly higher in non-survivors than in survivors (p=0.042). Cox regression analysis revealed the association of female sex [odds ratio (OR)=0.318; 95% confidence interval (CI), 0.128-0.792; p=0.014] and scleroderma-related PAH (OR=0.347; 95% CI, 0.140-0.860; p=0.022) with significantly lower risk (3.14 fold and 2.88 fold, respectively) of mortality.. Our findings indicate favorable efficacy, safety, and tolerability of long-term iloprost treatment in the management of PAH, whereas improved NYHA functional class was not accompanied with a significant change in 6MWD values. Patient age was a risk factor for clinical worsening, while female sex, scleroderma subtype, and lower NT-proBNP levels were associated with significantly lower mortality risk.

Topics: Female; Humans; Hypertension, Pulmonary; Iloprost; Prospective Studies; Pulmonary Arterial Hypertension; Treatment Outcome

Pulmonary arterial hypertension restricts the ability of patients to perform routine physical activities. As part of pulmonary arterial hypertension treatment, inhaled iloprost can be administered via a nebulizer that tracks inhalation behavior. Pulmonary arterial hypertension treatment is guided by intermittent clinical measurements, such as 6-minute walk distance, assessed during regular physician visits. Continuous digital monitoring of physical activity may facilitate more complete assessment of the impact of pulmonary arterial hypertension on daily life. Physical activity tracking with a wearable has not yet been assessed with simultaneous tracking of pulmonary arterial hypertension medication intake.. We aimed to digitally track the physical parameters of patients with pulmonary arterial hypertension who were starting treatment with iloprost using a Breelib nebulizer. The primary objective was to investigate correlations between changes in digital physical activity measures and changes in traditional clinical measures and health-related quality of life over 3 months. Secondary objectives were to evaluate inhalation behavior, adverse events, and changes in heart rate and sleep quality.. We conducted a prospective, multicenter observational study of adults with pulmonary arterial hypertension in World Health Organization functional class III who were adding inhaled iloprost to existing pulmonary arterial hypertension therapy. Daily distance walked, step count, number of standing-up events, heart rate, and 6-minute walk distance were digitally captured using smartwatch (Apple Watch Series 2) and smartphone (iPhone 6S) apps during a 3-month observation period (which began when iloprost treatment began). Before and at the end of the observation period (within 2 weeks), we also evaluated 6-minute walk distance, Borg dyspnea, functional class, B-type natriuretic peptide (or N-terminal pro-B-type natriuretic peptide) levels, health-related quality of life (EQ-5D questionnaire), and sleep quality (Pittsburgh Sleep Quality Index).. Of 31 patients, 18 were included in the full analysis (observation period: median 91.5 days, IQR 88.0 to 92.0). Changes from baseline in traditional and digital 6-minute walk distance were moderately correlated (r=0.57). Physical activity (daily distance walked: median 0.4 km, IQR -0.2 to 1.9; daily step count: median 591, IQR -509 to 2413) and clinical measures (traditional 6-minute walk distance: median 26 m, IQR 0 to 40) changed concordantly from baseline to the end of the observation period. Health-related quality of life showed little change. Total sleep score and resting heart rate slightly decreased. Distance walked and step count showed short-term increases after each iloprost inhalation. No new safety signals were identified (safety analysis set: n=30).. Our results suggest that despite challenges, parallel monitoring of physical activity, heart rate, and iloprost inhalation is feasible in patients with pulmonary arterial hypertension and may complement traditional measures in guiding treatment; however, the sample size of this study limits generalizability.. ClinicalTrials.gov NCT03293407; https://clinicaltrials.gov/ct2/show/NCT03293407.. RR2-10.2196/12144.

Topics: Administration, Inhalation; Adult; Heart Rate; Humans; Hypertension, Pulmonary; Iloprost; Prospective Studies; Pulmonary Arterial Hypertension; Quality of Life; Treatment Outcome; Vasodilator Agents; Walking

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance that can lead to right ventricular failure and death. The use of medications that affect the prostacyclin pathway is an important treatment strategy in PAH. Inhaled iloprost is a prostacyclin analogue, and selexipag is an oral, non-prostanoid, prostacyclin IP receptor agonist. Data are limited on transitioning patients from inhaled iloprost to selexipag. In this case report, we describe the successful transition of a 57-year-old female with heritable PAH from inhaled iloprost to selexipag over 8 weeks in an out-patient setting. After initiation of selexipag, the patient's inhaled iloprost dose was gradually reduced and eventually discontinued. The patient tolerated the transition well with stable symptoms, 6-minute walk distance, and pulmonary hemodynamics. Additional studies are needed to better define the comparative efficacy and safety of inhaled iloprost and selexipag.

Topics: Acetamides; Antihypertensive Agents; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Pulmonary Arterial Hypertension; Pyrazines

Assessing reversibility of pulmonary vascular changes through vasoreactivity testing (VRT) optimizes end-stage heart failure patient selection for heart transplant. All efforts should be made to unload the left ventricle and reduce pulmonary vascular resistance to effectively exclude irreversible pulmonary hypertension.. We reviewed our centre's cardiac transplant registry database (2009-2017) for VRT and compared haemodynamic responses with 40 ppm inhaled NO (n = 14), 14-17 μg inhaled iloprost (n = 7), and 24 h 0.1 μg/kg/min intravenous levosimendan (n = 14). Response to levosimendan was assessed by repeat right heart catheterization within 72 h. Baseline clinical and haemodynamic features were similar between groups. VRT was well tolerated in all patients. All drugs effectively reduced pulmonary artery pressures and transpulmonary gradient while increasing cardiac index, although levosimendan had a greater impact on cardiac index increase (P = 0.036). Levosimendan was the only drug that reduced pulmonary artery wedge pressure (P = 0.004) and central venous pressures (P < 0.001) and increased both left and right ventricular stroke work indexes (P = 0.020 and P = 0.042, respectively) and cardiac power index (P < 0.001) compared with NO and iloprost. Right ventricular end-diastolic pressures and central venous pressure were only decreased by levosimendan. The rate of positive responses (≥10 mmHg decrease or final mean pulmonary artery pressure ≤40 mmHg with increased/unaltered cardiac index) was lower with inhaled iloprost (14%) than with either levosimendan or NO (71% and 64%, respectively; P < 0.05).. Levosimendan may be a safe and effective alternative for pulmonary hypertension reversibility assessment or a valuable pre-test medical optimization tool in end-stage heart failure patient assessment for heart transplantation offering extended haemodynamic benefits. Whether it increases the rate of positive responses or allows a better selection of candidates to heart transplantation remains to be established.

Topics: Administration, Inhalation; Heart Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Simendan

Acute vasoreactivity testing (AVT) which reflects the compliance of the pulmonary vascular bed has been proven to be of prognostic value. The purpose of the present study is to explore the sex differences of hemodynamics during the AVT and their impact on event-free survival in patients with chronic thromboembolic pulmonary hypertension (CTEPH).. Eighty-six patients underwent a right heart catheterization and AVT at Shanghai Pulmonary Hospital from February 2009 to February 2018. Univariate and multiple stepwise regression analysis were performed to determine the predictors of independent event-free survival, and receiver operating characteristic curve was plotted to determine the cut-off value of independent parameters in CTEPH.. There were no significant differences in both demographics and hemodynamics between male and female patients with CTEPH. Except ΔPVR/PVR showed a significantly higher difference in female than male patients (P = 0.034). Male patients had higher mRAP of pre- and post-AVT than female patients in the event-free subgroup, while, female patients showed higher PVR of pre-AVT than male patients in the event subgroup (P < 0.05). The mRAP and SvO. Hemodynamics during the AVT varied between male and female patients with CTEPH. Both sexes displayed unique hemodynamic responses that were independently able to predict event-free survival. Therefore, better estimates of prognosis in CTEPH can be made when sex differences are also taken into consideration.

Topics: Administration, Inhalation; Adult; Aged; Cardiac Catheterization; China; Chronic Disease; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Lung; Male; Middle Aged; Predictive Value of Tests; Prognosis; Progression-Free Survival; Pulmonary Embolism; Pulmonary Wedge Pressure; Regression Analysis; ROC Curve; Sex Characteristics; Vasodilator Agents

BACKGROUND Kyphoscoliosis is an anatomical deformity of the spine often accompanied by an array of respiratory complications, pulmonary hypertension being among the most severe ones. At present, evidence-based treatment options for kyphoscoliosis-related pulmonary hypertension remain limited to the correction of hypoxemia through ventilatory support and long-term oxygenation. CASE REPORT We report a case of a 61-year-old female with severe kyphoscoliosis-related pulmonary hypertension who was admitted to a university hospital in September 2018 due to progressive dyspnea and respiratory failure. She was diagnosed with pulmonary hypertension in 2016 and had been on endothelin receptor antagonist (ambrisentan) and oxygen therapy ever since. Upon admission, the patient presented with severe depression of peripheral oxygen saturation (SpO₂ at 75%). The patient declined further treatment hours after hospitalization, despite optimized supportive oxygen therapy. Ambrisentan was discontinued and replaced by inhaled iloprost. Over the course of the next 4 days, the patient showed symptomatic improvement and was discharged on Day 5. Right heart catheterization follow-up in February 2019 showed no worsening in pulmonary hemodynamic parameters compared to the time of initial diagnosis. CONCLUSIONS Managing the respiratory decline in kyphoscoliosis-related pulmonary hypertension can be challenging since these patients tend to deteriorate despite current treatment options. Our case reports on the use of vasoactive agents as a safe and effective treatment option in addition to established therapeutic regimen.

Topics: Female; Humans; Hypertension, Pulmonary; Iloprost; Kyphosis; Middle Aged; Scoliosis; Vasodilator Agents

REHAP is a voluntary, observational Spanish registry of patients with pulmonary arterial hypertension. We analyzed the experience (use and effectiveness) with inhaled iloprost (inh-ILO) in real-life conditions during a 3-year period.. Patients included were those with PAH ≥14 years recruited during 1998-2016 who had received inh-ILO. Variables were collected at the beginning of treatment (0 ± 3 months) and 12 ± 3/36 ± 6 months follow-up. Effectiveness was assessed in the intent-to-treat population as changes in functional class and/or physical performance and transplant-free survival from the beginning of treatment. Stopping inh-ILO-related survival was also assessed. Subanalyses included treatment strategy (first-line therapy -monotherapy or upfront combination- or sequential therapy) and risk of clinical worsening/death.. Inh-ILO was the most frequently used prostanoid in Spain, rendering 267 patients eligible for analysis. Median age was 54 years; 61% were WHO FC III. Sixty (23%) patients started inh-ILO as monotherapy, 27 (10%) as upfront combination and 180 (67%) sequentially. At 3-year follow-up significant clinical improvements were observed; however, transplant-free survival rate was 54%, being poorer in patients at high risk (63% vs. 85% in low risk patients; P < 0.001) and similar in the three treatment strategies. Only 25% patients remained on inh-ILO. Three-year after stopping inh-ILO-related survival rate was 24.7%.. Data from the REHAP collected during 3 years shows that inh-ILO has low effectiveness independently of the treatment strategy used, with a 3-year survival rate of 54% despite significant clinical improvements, probably due to the use in high-risk patients. Discontinuation rate was as high as 75%.

Topics: Administration, Inhalation; Adult; Aged; Cause of Death; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prospective Studies; Pulmonary Wedge Pressure; Registries; Retrospective Studies; Spain; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Ventricular Function, Right

Acute right ventricular dysfunction is a challenging problem in the immediate postoperative period following orthotopic heart transplantation. There are no prior reports of the use of inhaled iloprost in the setting of acute right ventricular dysfunction and acute pulmonary hypertension. Our hypothesis was that the use of inhaled iloprost in heart transplant recipients would be associated with a reduction in the duration of mechanical ventilation compared to patients being treated with continuous inhaled epoprostenol. Additionally, we hypothesized that the change in inhaled vasodilatory therapy would not be associated with a significant change in postoperative bleeding or use of vasoactive medications.. We reviewed charts of 80 consecutive patients undergoing heart transplantation at our institution between July 1, 2003, and August 8, 2008. From July 1, 2003 to March 13, 2006, epoprostenol was our primary vasodilator; subsequently epoprostenol was replaced with iloprost. We included 39 subjects who received epoprostenol and 40 subjects who received iloprost. Data were collected on the use of inhaled vasodilators, comparing periods before and after our institutional protocol change. Demographic data, hemodynamic values, drain output, and any requirement for vasoactive medication infusions were collected. Our primary end point was the natural logarithm of duration of mechanical ventilation. Secondary end points were hemodynamic values and length of ICU and hospital stay.. Subjects treated with iloprost were mechanically ventilated for 0.36 ± 0.20 (adjusted mean ± SE) log days, which was shorter (. Use of inhaled iloprost was associated with shorter duration of mechanical ventilation compared to inhaled epoprostenol, without safety concerns.

Topics: Administration, Inhalation; Adult; Epoprostenol; Female; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Outcome and Process Assessment, Health Care; Postoperative Complications; Respiration, Artificial; Retrospective Studies; Vasodilator Agents; Ventricular Dysfunction, Right

Pulmonary arterial hypertension (PAH) is a fatal complication in patients with connective tissue disease (CTD).. The objective of the study was to study the prognostic value of the acute pulmonary vasoreactivity test with inhaled iloprost and its association with clinical deterioration in a tertiary care academic medical center.. We conducted a prospective study of patients with CTD and the diagnosis of PAH established by right heart catheterization. Patients were classified into classic responders, partial responders, and non-responders. The association of the pulmonary response and clinical deterioration was analyzed.. We enrolled 25 patients (mean age of 47 ± 13.4 years); 88% were female. The most frequent rheumatologic diagnosis was systemic lupus erythematosus, in 16 (64%) patients. Seventy-two percent of patients were classified as non-responders, and 28% were partial responders. Patients with a partial response had lower right atrial pressure values (5.1 ± 3.1 vs. 8.5 ± 3.2, p = 0.01) and greater systolic pulmonary arterial pressure (87.6 ± 8.1 vs. 72.4 ± 16.2, p = 0.02), compared with non-responders. Non-responders had a tendency for a shorter time to clinical deterioration than partial responders (17.8 vs. 41.1 months, p = 0.052).. Patients with a partial response to the acute pulmonary vasodilator test with inhaled iloprost had a longer clinical deterioration-free period than non-responders.

Topics: Administration, Inhalation; Adult; Blood Pressure; Cardiac Catheterization; Connective Tissue Diseases; Female; Humans; Hypertension, Pulmonary; Iloprost; Lupus Erythematosus, Systemic; Male; Middle Aged; Phenotype; Prognosis; Prospective Studies; Time Factors; Vasodilator Agents

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.

Topics: Acetates; Administration, Oral; Animals; Biological Availability; Carbamates; Drug Discovery; Hypertension, Pulmonary; Rats; Receptors, Prostaglandin; Structure-Activity Relationship

Prostacyclin (PGI

Topics: Acetamides; Acetates; Animals; beta-Arrestins; Cell Proliferation; CHO Cells; Contractile Proteins; Cricetinae; Cricetulus; Cyclic AMP; Epoprostenol; Extracellular Matrix; Humans; Hypertension, Pulmonary; Iloprost; Male; Muscle Contraction; Muscle Relaxation; Pyrazines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Epoprostenol

Pulmonary hypertension may coexist with certain diseases in neonates. Iloprost inhalation is one of the treatments which cause selective pulmonary vasodilatation. Inhalation is not an easy way of drug administration in mechanically ventilated infants; as some exhibit desaturations during inhalation. Moreover, inhalation of drug requires cessation of mechanical ventilation, if patient is on high frequency oscillatory ventilation. We presented two patients with pulmonary hypertension; term baby with congenital diaphragmatic hernia and preterm baby with respiratory distress syndrome; who had iloprost instillation during mechanical ventilation treatment. Iloprost instillation was well tolerated with no side effects in the term patient with diaphragmatic hernia; whereas severe blood pressure fluctuations were observed in the preterm infant. This report may courage administration of iloprost in term neonates with resistant pulmonary hypertension.

Topics: Administration, Inhalation; Female; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Male; Respiratory Distress Syndrome, Newborn; Treatment Outcome; Vasodilator Agents

Some biomarkers play important roles in the endothelial dysfunction of patients with pulmonary arterial hypertension (PAH), including nitric oxide (NO), endothelin-1 (ET-1), asymmetric dimethylarginine (ADMA), galectin-3 (Gal-3), B-type natriuretic peptide (BNP), and uric acid (UA). However, studies on these biomarkers in pulmonary artery blood in congenital heart disease-PAH (CHD-PAH) and the effect of iloprost on the regulation of biomarkers are lacking. This study investigated potential CHD-PAH biomarkers and their association with the severity of disease. The effect of iloprost on the regulation of these biomarkers was also studied. A total of 31 patients with CHD-PAH were enrolled. Seven with positive effects of iloprost (the average reduction in mPAP 11.13±1.73 mm Hg) and 19 with negative effects of iloprost (the average reduction in mPAP 4.21±4.87 mm Hg; iloprost positive group [IPG] vs iloprost negative group [ING], P<.01) and five age-matched controls were studied. The pulmonary artery blood sample was collected before and after inhaling iloprost, and the plasma concentrations of Gal-3, ADMA, ET-1, and NO were measured. A significant positive linear relationship was observed between mPAP and plasma ET-1, BNP, ADMA, and UA levels in all patients with CHD-PAH. ET-1, ADMA, BNP, and UA levels had a significant linear relationship with mean pulmonary arterial pressure, which could be used to predict the severity of CHD-PAH. ET-1 might be a potential biomarker to pre-evaluate the effect of iloprost on CHD-PAH. Iloprost could affect the expression of Gal-3 and, therefore, the process of fibrosis could be influenced by iloprost.

Topics: Biomarkers; Female; Heart Diseases; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged

During cardiac operations, weaning from cardiopulmonary bypass (CPB) may prove challenging as a result of superimposed acute right ventricular dysfunction in the setting of elevated pulmonary vascular resistance (PVR). The aim of this study was to retrospectively evaluate the effect of inhaled milrinone versus inhaled iloprost in patients with persistent pulmonary hypertension following discontinuation of CPB. Eighteen patients with elevated PVR post-bypass were administered inhaled milrinone at a cumulative dose of 50 μg kg

Topics: Administration, Inhalation; Aged; Aged, 80 and over; Arterial Pressure; Cardiopulmonary Bypass; Dose-Response Relationship, Drug; Echocardiography, Transesophageal; Female; Follow-Up Studies; Heart Diseases; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Milrinone; Postoperative Complications; Retrospective Studies; Treatment Outcome; Vascular Resistance; Vasodilator Agents

There are few published data on the efficacy of i.v. iloprost in pulmonary arterial hypertension (PAH). We present long-term outcomes in PAH patients receiving i.v. iloprost in a large UK referral centre.. Eighty patients with idiopathic PAH (iPAH, n = 46) or PAH associated with connective tissue disease (CTD-PAH, n = 34) were identified as receiving domiciliary i.v. iloprost between January 1999 and April 2015. Baseline characteristics, doses achieved, functional class at follow-up and survival data were retrieved from hospital databases.. Median maximum dose achieved was 4.6 ng/kg/min in the iPAH group and 5.0 ng/kg/min in CTD-PAH patients. Exercise capacity significantly improved in the first 6 months of therapy in IPAH patients. Overall 1-, 3- and 5-year survival was 78%, 64% and 52% in iPAH (P = 0.002) and 64%, 26% and 21% in CTD-PAH. Independent predictors of survival were age and exercise capacity.. We report improved survival to that previously reported in iPAH patients treated with domiciliary i.v. iloprost. This may be in part related to higher administered doses. Patients with CTD-PAH had poorer survival, reinforcing the need for early transplantation referral in suitable patients.

Topics: Administration, Intravenous; Adult; Connective Tissue Diseases; Female; Humans; Hypertension, Pulmonary; Iloprost; Long Term Adverse Effects; Male; Middle Aged; Survival Analysis; Treatment Outcome; United Kingdom; Vasodilator Agents

Right atrium function and ventricular function have significant prognostic value in pulmonary arterial hypertension patients. Acute changes in right ventricular synchrony and right atrium function postiloprost inhalation have not been evaluated.. Cross-sectional study. Consecutive pulmonary arterial hypertension patients (group I from Nice classification) were included. Echocardiographic right atrium and right ventricular function pre- and postiloprost inhalation, including a right ventricular dyssynchrony index and right atrium function using speckle tracking, were performed in all patients.. Twenty pulmonary arterial hypertension patients, 44±7 years and 90% females, were included. After iloprost inhalation, we observed a significant increment in right ventricular fractional area change and a significant decrease in right ventricular dyssynchrony index (21.4±5.6% vs 26.1±4.0 %, P=.007 and 79±44 vs 32±22 mseconds, P<.01, respectively), also an improvement in right atrium reservoir function (8.6±3.1% vs 11.7±3.5 %, P=.002).. Iloprost inhalation induces acute changes in right ventricular function, dyssynchrony, and right atrium performance that may add relevant clinical information in the management and risk stratification of pulmonary arterial hypertension patients.

Topics: Administration, Inhalation; Adult; Atrial Function, Right; Cross-Sectional Studies; Echocardiography; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Iloprost; Male; Pulmonary Artery; Retrospective Studies; Vasodilator Agents; Ventricular Function, Right

The clinical significance of acute vasoreactivity testing (AVT) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) remains unclear. We analyzed changes in hemodynamics and oxygenation dynamics indices after AVT in patients with CTEPH using patients with pulmonary arterial hypertension (PAH) as controls.. We analyzed retrospectively the results of AVT in 80 patients with PAH and 175 patients with CTEPH registered in the research database of Beijing Chao-Yang Hospital between October 2005 and August 2014. Demographic variables, cardiopulmonary indicators, and laboratory findings were compared in these two subgroups. A long-term follow-up was conducted in patients with CTEPH. Between-group comparisons were performed using the independent-sample t-test or the rank sum test, within-group comparisons were conducted using the paired t-test or the Wilcoxon signed-rank test, and count data were analyzed using the Chi-squared test. Survival was estimated using the Kaplan-Meier method and log-rank test.. The rates of positive response to AVT were similar in the CTEPH (25/175, 14.3%) and PAH (9/80, 11.3%) groups (P > 0.05). Factors significantly associated a positive response to AVT in the CTEPH group were level of N-terminal pro-brain natriuretic peptide (≤1131.000 ng/L), mean pulmonary arterial pressure (mPAP, ≤44.500 mmHg), pulmonary vascular resistance (PVR, ≤846.500 dyn·s-1·m-5), cardiac output (CO, ≥3.475 L/min), and mixed venous oxygen partial pressure (PvO2, ≥35.150 mmHg). Inhalation of iloprost resulted in similar changes in mean blood pressure, mPAP, PVR, systemic vascular resistance, CO, arterial oxygen saturation (SaO2), mixed venous oxygen saturation, partial pressure of oxygen in arterial blood (PaO2), PvO2, and intrapulmonary shunt (Qs/Qt) in the PAH and CTEPH groups (all P > 0.05). The survival time in patients with CTEPH with a negative response to AVT was somewhat shorter than that in AVT-responders although the difference was not statistically significant (χ2 =3.613, P = 0.057). The survival time of patients with CTEPH who received calcium channel blockers (CCBs) was longer than that in the group with only basic treatment and not shorter than that of patients who receiving targeted drugs or underwent pulmonary endarterectomy (PEA) although there was no significant difference between the four different treatment regimens (χ2 =3.069, P = 0.381).. The rates of positive response to AVT were similar in the CTEPH and PAH groups, and iloprost inhalation induced similar changes in hemodynamics and oxygenation dynamics indices. A positive response to AVT in the CTEPH group was significantly correlated with milder disease and better survival. Patients with CTEPH who cannot undergo PEA or receive targeted therapy but have a positive response to AVT might benefit from CCB treatment.

Topics: Administration, Inhalation; Adult; Aged; Arterial Pressure; Atrial Natriuretic Factor; Calcium Channel Blockers; Endarterectomy; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Protein Precursors; Retrospective Studies; Software; Vasodilator Agents

This report describes the case of a neonate with d-transposition of the great arteries and severe pulmonary arterial hypertension stabilised in the post-operative period with continuous iloprost nebulisation. To our knowledge, this is the first documented method of treating post-operative severe pulmonary arterial hypertension with continuous inhaled iloprost in a patient with complex CHD. We found this method of delivering the drug very effective in stabilising haemodynamic swings in the setting of severe pulmonary arterial hypertension.

Topics: Administration, Inhalation; Arteries; Fatal Outcome; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Nitric Oxide; Transposition of Great Vessels; Vasodilator Agents

Patients with severe pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD) present a poor outcome. Specific PH treatment could improve the clinical and hemodynamic status of these patients but may worsen arterial blood gases.. Our study retrospectively included 28 patients with severe precapillary PH (mean pulmonary arterial pressure >35 mm Hg) associated with mild-to-moderate COPD [forced expiratory volume in 1 s (FEV1) >50% predicted]. All patients underwent specific pulmonary arterial hypertension (PAH) treatment as mono-, bi- or triple therapy.. Our single-center study was conducted based on retrospective data of 537 right heart catheterizations (RHCs) performed on patients with COPD from January 2004 to June 2014. An echocardiography, comprehensive blood tests, pulmonary function tests, and a high-resolution computed tomography were performed before the RHCs. All patients underwent RHC with a Swan-Ganz catheter.. Compared to baseline, patients treated with specific PAH drugs showed a significant increase in cardiac index at long term (2.5 ± 0.7 liters/min/m2 at baseline vs. 3.2 ± 0.6 liters/min/m2 at 6/12 months; p = 0.003) as well as a decrease in pulmonary vascular resistance in the long term (8.4 ± 4.2 Wood units at baseline vs. 5 ± 1.7 Wood units at 6/12 months; p = 0.008). There was a slight decrease in arterial oxygen tension (PaO2) after 3 months of treatment (-2.4 ± 7.21 mm Hg; p = 0.066). During a median follow-up of 3 years, 12 patients (42.8%) died (including all causes of death).. This preliminary report suggests that the use of specific PH therapy in severe PH associated with mild-to-moderate COPD can improve pulmonary hemodynamic parameters, with worsening of PaO2, which had no clinical significance and did not lead to specific PAH therapy withdrawal in any patient.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Gas Analysis; Calcium Channel Blockers; Carbon Dioxide; Endothelin Receptor Antagonists; Epoprostenol; Female; Forced Expiratory Volume; Humans; Hypertension, Pulmonary; Iloprost; Kaplan-Meier Estimate; Male; Middle Aged; Partial Pressure; Phosphodiesterase 5 Inhibitors; Proportional Hazards Models; Pulmonary Diffusing Capacity; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Vasodilator Agents; Vital Capacity

Combination therapy is frequently used to treat patients with pulmonary hypertension but few studies have compared treatment regimens. This study examined the long-term effect of different combination regimens of inhaled iloprost and oral sildenafil on survival and disease progression.. This was a retrospective study of patients in the Giessen Pulmonary Hypertension Registry who received iloprost monotherapy followed by addition of sildenafil (iloprost/sildenafil), sildenafil monotherapy followed by addition of iloprost (sildenafil/iloprost), or upfront combination therapy (iloprost + sildenafil). The primary outcome was transplant-free survival (Kaplan-Meier analysis). When available, haemodynamic parameters and 6-minute-walk distance were evaluated.. Overall, 148 patients were included. Baseline characteristics were similar across treatment groups; however, the iloprost + sildenafil cohort had higher mean pulmonary vascular resistance and pulmonary arterial pressure than the others. Transplant-free survival differed significantly between groups (P = 0.007, log-rank test). Cumulative transplant-free survival was highest for patients who received iloprost/sildenafil (1 year survival: iloprost/sildenafil, 95.1%; sildenafil/iloprost, 91.8%; iloprost + sildenafil, 62.9%); this group also remained on monotherapy significantly longer than the sildenafil/iloprost group (median 17.0 months vs 7.0 months, respectively; P = 0.004). Compared with pre-treatment values, mean 6-minute-walk distance increased significantly for all groups 3 months after beginning combination therapy.. In this observational study of patients with pulmonary hypertension receiving combination therapy with iloprost and sildenafil, cumulative transplant-free survival was highest in those who received iloprost monotherapy initially. However, owing to the size and retrospective design of this study, further research is needed before making firm treatment recommendations.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Cohort Studies; Disease Progression; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Kaplan-Meier Estimate; Lung Transplantation; Male; Middle Aged; Registries; Retrospective Studies; Sildenafil Citrate; Survival Rate; Vasodilator Agents

Invasive assessment of haemodynamics (ventricular, pulmonary) and testing of acute vasoreactivity in the catheterisation laboratory remain the gold standard for the diagnosis of pulmonary hypertension (PH) and pulmonary hypertensive vascular disease. However, these measurements and the interpretation thereof are challenging due to the heterogeneous aetiology of PH in childhood and potentially confounding factors in the catheterisation laboratory. Patients with pulmonary arterial hypertension (PAH) associated with congenital heart disease who have a cardiovascular shunt need to undergo a completely different catheterisation approach than those with idiopathic PAH lacking an anatomical cardiovascular defect. Diagnostic cardiac catheterisation of children with suspected PH usually includes right and left heart catheterisation, particularly for the initial assessment (ie, at the time of diagnosis), and should be performed in experienced centres only. Here, we present graded consensus recommendations for the invasive evaluation of children with PH including those with pulmonary hypertensive vascular disease and/or ventricular dysfunction. Based on the limited published studies and our own experience we suggest a structured catheterisation protocol and two separate definitions of positive acute vasoreactivity testing (AVT): (1) AVT to assess prognosis and indication for specific PH therapy, and (2) AVT to assess operability of PAH associated with congenital heart disease. The protocol and the latter definitions may help in the systematic assessment of these patients and the interpretation of the obtained data. Beyond an accurate diagnosis in the individual patient, such a structured approach may allow systematic decision making for the initiation of a specific treatment and may assist in estimating disease progression and individual prognosis.

Topics: Administration, Inhalation; Adolescent; Anesthesia, General; Anesthesia, Local; Cardiac Catheterization; Child; Conscious Sedation; Consensus; Disease Management; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Oxygen; Prognosis; Pulmonary Artery; Pulmonary Circulation; Respiration, Artificial; Vascular Resistance; Vasodilator Agents; Ventricular Function

Acute pulmonary hypertension (PH) complicates the course of several cardiovascular, pulmonary and other systemic diseases in children. An acute rise of RV afterload, either as exacerbating chronic PH of different aetiologies (eg, idiopathic pulmonary arterial hypertension (PAH), chronic lung or congenital heart disease), or pulmonary hypertensive crisis after corrective surgery for congenital heart disease, may lead to severe circulatory compromise. Only few clinical studies provide evidence on how to best treat children with acute severe PH and decompensated RV function, that is, acute RV failure. The specific treatment in the intensive care unit should be based on the underlying pathophysiology and not only be focused on so-called 'specific' or 'tailored' drug therapy to lower RV afterload. In addition therapeutic efforts should aim to optimise RV preload, and to achieve adequate myocardial perfusion, and cardiac output. Early recognition of patients at high risk and timely initiation of appropriate therapeutic measures may prevent the development of severe cardiac dysfunction and low cardiac output. In patients not responding adequately to pharmacotherapy, (1) novel surgical and interventional techniques, temporary mechanical circulatory support with extracorporeal membrane oxygenation, (2) pumpless lung assist devices (3) and/or lung or heart-lung transplantation should be timely considered. The invasive therapeutic measures can be applied in a bridge-to-recovery or bridge-to-lung transplant strategy. This consensus statement focuses on the management of acute severe PH in the paediatric intensive care unit and provides an according treatment algorithm for clinical practice.

Topics: Acute Disease; Administration, Inhalation; Administration, Intravenous; Adolescent; Cardiac Output; Child; Consensus; Critical Care; Disease Management; Disease Progression; Endothelium-Dependent Relaxing Factors; Extracorporeal Membrane Oxygenation; Heart-Lung Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Intensive Care Units, Pediatric; Lung Transplantation; Nitric Oxide; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Prostaglandins; Sildenafil Citrate; Vasodilator Agents; Ventricular Dysfunction, Right

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subset of pulmonary hypertension caused by acute and recurrent pulmonary emboli. Pulmonary thromboendarterectomy is the treatment of choice, but 10-50% of patients are ineligible for this procedure. We describe the case of a 25-year-old, morbidly obese (228-kg, body mass index 83.5 kg/m(2) ) pregnant woman (G3 P2 ) who presented at 24 weeks' gestation; bilateral pulmonary angiography revealed filling defects and confirmed the diagnosis of CTEPH. The patient was evaluated and deemed to present too high of a risk for pulmonary thromboendarterectomy, so a multidisciplinary team initiated medical therapy. Sildenafil 20 mg orally 3 times/day was started at week 24 of gestation, and inhaled iloprost was added at 26 weeks and titrated to 5 µg inhaled every 2 hrs in order to optimize hemodynamic status prior to a cesarean section delivery scheduled to be performed 6 weeks later. At 32 weeks of gestation, the patient's pulmonary arterial systolic pressure was 77 mm Hg, right atrial pressure was 15 mm Hg, and pulmonary capillary wedge pressure of 16 mm Hg, and a healthy 1741-g male infant was delivered by cesarean section. The patient was transferred back to the medical intensive care unit in stable condition and discharged home 9 days following the procedure. Pharmacotherapeutic strategies for patients with CTEPH who become pregnant are limited to phosphodiesterase type 5 inhibitors and prostacyclin analog therapies due to the teratogenicity of the other drug classes used to treat the disorder (endothelin receptor antagonists and soluble guanylate cyclase stimulators). To our knowledge, this is the first case report of inhaled iloprost use in addition to oral sildenafil to improve patient symptomatology and hemodynamics during the peripartum period of a young pregnant patient with inoperable CTEPH. This drug therapy was used safely, with no noted adverse effects to the newborn or to the patient.

Topics: Administration, Inhalation; Adult; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Iloprost; Pregnancy; Pregnancy Complications; Pulmonary Embolism

Pulmonary hypertension (PH) in children is a serious disorder, for which the major goal of treatment is to prevent progressive vascular remodeling, and improve clinical status and survival. Iloprost is approved for the treatment of PH in adults; however, few studies have evaluated its effects in children. The objective of this study is to analyze the long-term effects of inhaled iloprost treatment in children with PH. A retrospective study was conducted in patients treated with iloprost between 2000 and 2012. Patients with left-right cardiac shunt and persistent PH of the newborn were excluded. The cohort comprised 22 patients (15 females) with a median age of 2.6 years. Twelve patients had pulmonary arterial hypertension including idiopathic (n = 6), hereditary (n = 2) and associated (congenital heart disease [n = 3], and schistosomiasis [n = 1]). One patient had pulmonary veno-occlusive disease, six patients had PH secondary to lung disease and three had multifactorial PH. Median mean pulmonary arterial pressure was 55 mmHg and median pulmonary vascular resistance was 15.5 Wood units. Good tolerability was observed, with the exception of one case of recurring abdominal pain. PH resolved in two patients, with functional capacity improvement in 10 patients and stabilization in three patients. The clinical condition of six patients deteriorated; two died, and two received lung transplants. In conclusion, the results of this uncontrolled study showed that iloprost was effective and well tolerated in children. However, further research is needed to support this study, as PH is a serious condition that can require organ transplantation or result in death.

Topics: Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Male; Nebulizers and Vaporizers; Retrospective Studies; Vasodilator Agents

Prostacyclin and its analogues improve cardiac output and functional capacity in patients with pulmonary arterial hypertension (PAH); however, the underlying mechanism is not fully understood. We hypothesised that prostanoids have load-independent beneficial effects on the right ventricle (RV). Angio-obliterative PAH and RV failure were induced in rats with a single injection of SU5416 followed by 4 weeks of exposure to hypoxia. Upon confirmation of RV dysfunction and PAH, rats were randomised to 0.1 μg·kg(-1) nebulised iloprost or drug-free vehicle, three times daily for 2 weeks. RV function and treadmill running time were evaluated pre- and post-iloprost/vehicle treatment. Pulmonary artery banded rats were treated 8 weeks after surgery to allow for significant RV hypertrophy. Inhaled iloprost significantly improved tricuspid annulus plane systolic excursion and increased exercise capacity, while mean pulmonary artery pressure and the percentage of occluded pulmonary vessels remained unchanged. Rats treated with iloprost had a striking reduction in RV collagen deposition, procollagen mRNA levels and connective tissue growth factor expression in both SU5416/hypoxia and pulmonary artery banded rats. In vitro, cardiac fibroblasts treated with iloprost showed a reduction in transforming growth factor (TGF)-β1-induced connective tissue growth factor expression, in a protein kinase A-dependent manner. Iloprost decreased TGF-β1-induced procollagen mRNA expression as well as cardiac fibroblast activation and migration. Iloprost significantly induced metalloproteinase-9 gene expression and activity and increased the expression of autophagy genes associated with collagen degradation. Inhaled iloprost improves RV function and reverses established RV fibrosis partially by preventing collagen synthesis and by increasing collagen turnover.

Topics: Animals; Collagen; Cyclic AMP-Dependent Protein Kinases; Echocardiography; Fibroblasts; Fibrosis; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Iloprost; Indoles; Male; Matrix Metalloproteinase 9; Microscopy, Phase-Contrast; Physical Conditioning, Animal; Procollagen; Pyrroles; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta1; Vasodilator Agents; Ventricular Function, Right

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by abnormally elevated blood pressure of the pulmonary circulation. Without treatment, PAH progresses rapidly to right ventricular (RV) failure and even death. Cardiac magnetic resonance imaging (CMRI) has been an accurate and reproducible tool to assessment of RV morphology and function, which are important factors in the prognosis of patients with PAH. The aim of this study is to investigate acute RV response to inhalation of aerosolized iloprost in patients with PAH using CMRI.. From March 2012 to March 2014, 48 patients with PAH underwent CMRI before and immediately after inhalation of iloprost with a single dose of 20 μg over 15 min-20 min. RV function parameters derived from CMRI images were analyzed before and after iloprost inhalation, including end-diastolic volume (EDV), end-diastolic area (EDA), end-systolic volume (ESV), end-systolic area (ESA), stroke volume (SV), ejection fraction (EF) and cardiac output (CO). Percentage of RV area change was also calculated [%RVAC=(EDA-ESA)/EDA×100%]. Wilcoxon's Sign Rank Test or Paired Samples t-Test was used to compare the differences of RV function parameters before and after inhalation.. After iloprost inhalation, all patients showed significant decrease in RV EDV and RV ESV (P=0.007, P<0.001 respectively). Whereas, there were significant increase in RV SV (P=0.014), RV EF (P=0.009) and %RVAC (P=0.006). RV CO had no significant difference before and after inhalation (P=0.851).. Inhalation of iloprost can immediately improve RV function in patients with PAH, and noninvasive evaluation of the acute response with CMRI is feasibility.. 背景与目的 肺动脉高压（pulmonary arterial hypertension, PAH）是以肺循环压力异常增高为特征的进展性疾病，可引起右心室（right ventricle, RV）功能进行性衰竭，最终导致死亡。因此RV功能的评估在PAH的诊断、随访中起着重要作用。心脏磁共振成像（cardiac magnetic resonance imaging, CMRI）成为无创评价心室功能的参照标准，尤其是RV功能。本研究通过CMRI评估吸入伊洛前列素对PAH患者RV功能影响的即刻效应。方法 2012年3月-2014年3月PAH患者48例，吸入单剂量20 μg的伊洛前列素溶液前、后立即进行CMRI检查，测量RV的舒张末期容积（end-diastolic volume, EDV）、收缩末期容积（end-systolic volume, ESV）、每搏输出量（stroke volume, SV）、射血分数（ejection fraction, EF）、心输出量（cardiac output, CO）、舒张末期面积（end-diastolic area, EDA）及收缩末期面积（end-systolic area, ESA）。RV面积变化百分比（percentage of RV area change, %RVAC）由公式［%RVAC=（EDA-ESA）/EDA×100%］计算获得。采用Wilcoxon符号秩和检验或配对t检验分析吸入伊洛前列素前、后RV功能参数变化。P<0.05为差异有统计学意义。结果 吸入伊洛前列素后，患者的RV功能改善，RV EDV、RV ESV显著下降（P=0.007, P<0.001），RV SV、RV EF及%RVAC增加（P=0.014, P=0.009, P=0.006），RV CO无变化（P=0.851）。结论 吸入伊洛前列素能立即明显改善PAH患者的RV功能，CMRI能准确、无创地评估该即刻效应。.

Topics: Adolescent; Adult; Aged; Child; Female; Humans; Hypertension, Pulmonary; Iloprost; Magnetic Resonance Imaging; Male; Middle Aged; Radiography; Stroke Volume; Ventricular Dysfunction, Right; Ventricular Function, Right; Young Adult

Topics: Adult; Blood Pressure; Cardiotonic Agents; Dopamine; Drug Therapy, Combination; Electrocardiography; Fatal Outcome; Female; Gestational Age; Heart Rate; Humans; Hypertension, Pulmonary; Iloprost; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications, Cardiovascular; Ultrasonography

Idiopathic pulmonary arterial hypertension (IPAH) remains a devastating and incurable, albeit treatable condition. Treatment response is not uniform and parameters that help to anticipate a rather benign or a malignant course of the disease are warranted. Acute pulmonary vasoreactivity testing during right heart catheterisation is recommended to identify a minority of patients with IPAH with sustained response to calcium channel blocker therapy. This study aimed to evaluate the prognostic significance of a residual pulmonary vasodilative reserve in patients with IPAH not meeting current vasoresponder criteria.. Observational right heart catheter study in 66 (n=66) patients with IPAH not meeting current vasoresponse criteria. Pulmonary vasodilative reserve was assessed by inhalation of 5 µg iloprost-aerosol.. Sixty-six (n=66) of 72 (n=72) patients with IPAH did not meet current definition criteria assessed during vasodilator testing to assess pulmonary vasodilatory reserve. In those, iloprost-aerosol caused a reduction of mean pulmonary artery pressure (Δ pulmonary artery pressure-11.4%; p<0.001) and increased cardiac output (Δ cardiac output +16.7%; p<0.001), resulting in a reduction of pulmonary vascular resistance (Δ pulmonary vascular resistance-25%; p<0.001). The magnitude of this response was pronounced in surviving patients. A pulmonary vascular resistance reduction of ≥30% turned out to predict outcome in patients with IPAH.. Residual pulmonary vasodilative reserve during acute vasodilator testing is of prognostic relevance in patients with IPAH not meeting current definitions of acute vasoreactivity. Therefore vasoreactivity testing holds more information than currently used.

Topics: Calcium Channel Blockers; Cardiac Catheterization; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prognosis; Vascular Resistance; Vasodilator Agents

Pulmonary artery hypertension (PAH) is devastating disease that has very serious outcomes. Dysregulated angiogenesis is one of the main responsible courses in pathophysiology of disease. Our experimental research intends to find out and compare the angiogenic effects of medications used sildenafil, iloprost, and bosentan in the treatment of PAH.. This study was performed in Department of Biochemistry and Cancer and Stem Cell Research Laboratory of our institutes between August and October 2014. Angiogenic activity of sildenafil, iloprost, and bosentan were examined in vivo in chick chorioallantoic membrane (CAM) model and in vitro tube formation assay of human umbilical vein endothelial cells (HUVECs). Proliferative activity of these three agents was also determined through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on HUVECs.. In CAM assay, when compared to the control and drug groups, treatment with sildenafil solutions resulted in a significant dose-dependent increase (budding, sprouting, extravasation) on CAM vessel growth. While there was no significant proliferative effect with iloprost and bosentan, presence of sildenafil caused a statistically significant proliferation on HUVECs following 24 and 48 h incubation (p < 0.05) compared to the control group. Comparing the tube length/area ratio values, there was statistically significant increase in sildenafil group with respect to the other 2 groups (p < 0.05). Iloprost and bosentan did not show a significant effect.. The results provide evidence that sildenafil but not iloprost and bosentan induces angiogenesis in vitro and in vivo. Dysregulated angiogenesis, as an important pathophysiological part in the progression of PAH, may be triggered by the chronic ingestion of sildenafil in the long treatment period and may cause negative effects.

Topics: Angiogenesis Inducing Agents; Animals; Bosentan; Cell Proliferation; Chick Embryo; Dose-Response Relationship, Drug; Human Umbilical Vein Endothelial Cells; Humans; Hypertension, Pulmonary; Iloprost; Sildenafil Citrate; Sulfonamides

The aim of the current study is to evaluate acute vasoreactivity test (AVT) results in severe pulmonary hypertension patients with chronic obstructive pulmonary disease and to compare the demographical, clinical, and laboratory variables in positive and negative cases.. This retrospective, clinical study was performed on 29 cases in the departments of cardiology and chest diseases of our tertiary care center. AVT was positive in 12 (41.4%) cases and negative in 17 (58.6%) cases. Demographical variables, cardiopulmonary indicators, and laboratory findings were compared in these two subgroups.. The mean age was 62.3±7.8 years for AVT negative group, while it was 64.8±7.3 years in AVT positive group (P=0.38). Except for the changes in systolic, diastolic, and mean pulmonary arterial pressures before and after iloprost administration, there were no statistically significant differences regarding any of the parameters under investigation in both groups.. Despite the high rate of positivity for AVT in severe pulmonary hypertension patients with chronic obstructive pulmonary disease, none of the variables under investigation displayed a noteworthy difference between AVT negative and positive groups. Identification of factors likely to influence AVT results is important for establishment of appropriate treatment protocols especially for AVT negative cases.

Topics: Administration, Inhalation; Aged; Arterial Pressure; Cardiac Output; Diagnostic Techniques, Cardiovascular; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Predictive Value of Tests; Prognosis; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Retrospective Studies; Severity of Illness Index; Tertiary Care Centers; Turkey; Vasodilator Agents

To study the clinical and hemodynamic characteristics of a group of patients with Functional Class (FC) IV pulmonary arterial hypertension (PAH) developing in the presence of diffuse connective tissue diseases (DCTD) and to evaluate the efficacy of intravenous iloprost.. The study enrolled 59 patients with PAN-DCTD, including 7 who had FC IV and 8 who developed this condition during a follow-up. The diagnosis of PAH was based on pulmonary artery catheterization findings. FC IV was diagnosed using the conventional New York Heart Association classification. All the patients received PAH-specific therapy (bosentan, sildenafil); the patients with FC IV had combined therapy; 4 patients were treated with intravenous iloprost calculated with reference to 0.5-2.5 ng/kg/min for 15 days. In addition to the patients with FC IV, 3 patients with unstable FC Ill were given iloprost. Besides targeted therapy, all the patients received standard treatment, including diuretics, and ionotropic therapy.. Evaluation of hemodynamics in patients with different FCs revealed the most important differences in right atrial pressure, cardiac output, cardiac index, and pulmonary vascular resistance. A linear relationship was seen between the level of this indicator and FC, the closest correlation being for hemodynamic parameters characterizing right ventricular systolic function. There were no changes in mean pulmonary artery pressure; only the patients with FC IV were found to have its slight elevation (from 52 ± 15 to 55 ± 11 mm Hg). Pulmonary artery wedge pressure remained unchanged regardless of FC. Intravenous iloprost was noted to have an obvious positive effect on both clinical and hemodynamic parameters. Catheterization verified improvement in 6 out of the 7 patients; no hemodynamic changes were found in 1 patient during 15-day therapy.. The patients with FC IV PAH-DCTD have clinical and hemodynamic features responsible for a fatal prognosis. The results of using intravenous iloprost in patients with decompensated PAH associated with scleroderma systematica convince to use its PAH-specific tablets in cases of verified clinical deterioration when taking its dosage form.. Цель исследования. Изучение клинико-гемодинамических особенностей группы пациентов с легочной артериальной гипертонией (ЛАГ), развивающейся при диффузных заболеваниях соединительной ткани (ДЗСТ) с IV функциональным классом (ФК), и оценка эффективности внутривенного илопроста. Материалы и методы. В исследование включили 59 пациентов с ЛАГ-ДЗСТ, из них у 7 был IV ФК, у 8 такое состояние развилось в процессе наблюдения. Диагноз ЛАГ устанавливали на основании данных катетеризации легочной артерии. IV ФК диагностировали на основании общепринятой классификации Нью-Йоркской ассоциации сердца. Все пациенты получали специфическую для ЛАГ терапию (бозентан, силденафил), пациенты с IV ФК - комбинированную терапию, 4 больным проводили терапию внутривенным илопростом в течение 15 дней из расчета 0,5-2,5 нг/кг/мин. Кроме больных с IV ФК илопрост назначали 3 пациентам с нестабильным III ФК. Помимо целевой терапии, все пациенты получали стандартное лечение, в том числе диуретики, а также инотропную терапию. Результаты. При оценке гемодинамики пациентов разных ФК наиболее значимые различия получены по давлению в правом предсердии, сердечному выбросу, сердечному индексу и легочному сосудистому сопротивлению. Отмечена линейная зависимость между уровнем этих показателем и ФК, причем наиболее тесная корреляция - для гемодинамических показателей, характеризующих систолическую функцию правого желудочка. Изменений среднего ДЛА не выявлено, лишь у пациентов IV ФК отмечено незначимое его повышение (с 52±15 до 55±11 мм рт.ст.). Давление заклинивания легочной артерии оставалось неизменным вне зависимости от ФК. Отмечено очевидное положительное влияние внутривенного илопроста как на клинические, так и на гемодинамические показатели. При катетеризации улучшение подтверждено у 6 пациентов из 7, у 1 больного за 15-дневный курс терапии гемодинамических изменений не выявлено. Заключение. Пациенты с ЛАГ-ДЗСТ IV ФК имеют клинико-гемодинамические особенности, обусловливающие фатальный прогноз. Результаты применения внутривенного илопроста у пациентов с декомпенсированной ЛАГ, ассоциированной с системной склеродермией, убеждают в необходимости применения этой лекарственной формы в случаях подтвержденного клинического ухудшения на фоне приема таблетированных препаратов, специфических для ЛАГ.

Topics: Adult; Aged; Comorbidity; Connective Tissue Diseases; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Severity of Illness Index; Treatment Outcome; Vasodilator Agents

To investigate the efficacy and safety of inhaled iloprost on top of other pulmonary hypertension (PH) specific therapies for patients with PH and severe right heart failure.. We consecutively enrolled WHO functional class IV patients with PH and chronic thromboembolic pulmonary hypertension (CTEPH) in Shanghai Pulmonary Hospital from January 2011 to January 2013. Inhaled iloprost was administrated to all enrolled patients, oral endothelin antagonist receptors (ERAs) and/or type 5 phosphodiasterase inhibitors (PDE5-I) were also used as basis therapies. The in-hospital outcomes and the changes of right heart functional parameters were observed.. Twenty-four patients with PH and 5 patients with CTEPH were enrolled. After a mean treatment duration of (23 ± 13) days, 3 patients dead and significant improvement was observed in the remaining 26 patients. Compared with the baseline, heart rate decreased from (99 ± 14) to (91 ± 12) bpm (P = 0.001), plasma NT-proBNP level decreased from 5 823 (3 029-13 248) to 3 220 (1 678-6 720) ng/L (P < 0.001), tricuspid annular plane systolic excursion (TAPSE) increased from (1.3 ± 0.4) to (1.4 ± 0.3) cm (P = 0.018), right ventricular diameter decreased (left-to-right diameter from (57 ± 11) to (53 ± 10) mm, P = 0.040, and superoinferior diameter from (69 ± 11) to (64 ± 16) mm, P = 0.027), Tbil also decreased from (41 ± 34) to (26 ± 17) µmol/L (P < 0.001). No severe side effects were observed.. The strategy of inhaled iloprost on top of other PAH-specific target therapy medications is effective and safe for PH patients with severe right heart failure.

Topics: Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Natriuretic Peptide, Brain; Peptide Fragments; Vasodilator Agents; Ventricular Dysfunction, Right

This study was performed to examine the effectiveness and safety of oral sildenafil and inhaled iloprost in term newborns with persistent pulmonary hypertension of the newborn (PPHN).. Oral sildenafil and inhaled iloprost were administered to 27 and 20 neonates, respectively, for treatment of persistent pulmonary hypertension. All patients were term infants at 37 gestational weeks or older. In the sildenafil group, 14 patients had meconium aspiration syndrome, 8 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, 1 had transient tachypnea, and 1 had idiopathic PPHN. In the iloprost group, 9 patients had meconium aspiration syndrome, 7 had asphyxia (hypoxic ischemic encephalopathy stages II and III), 3 had congenital pneumonia, and 1 had transient tachypnea. Sildenafil citrate was administered via an oral feeding tube. Iloprost was administered endotracheally to patients on mechanical ventilation using a jet nebulizer.. Iloprost appeared to be more effective than sildenafil in the treatment of PPHN with regard to time to adequate clinical response, ventilatory parameters, duration of drug administration, duration of mechanical ventilation, duration of return to normal values of respiratory failure indices, use of MgSO4 as a second vasodilator and requirement for support with inotropic agents. We observed no side effects on blood pressure or homeostasis in any of the patients in the iloprost group. Systemic hypotension was significantly elevated in the sildenafil group. Four and three infants died of PPHN in the sildenafil and iloprost groups, respectively. Pulmonary systolic arterial pressure decreased to normal levels in the remaining 40 patients, and they were discharged from hospital.. We suggested that inhaled iloprost may be a safe and effective treatment choice in newborn infants with persistent pulmonary hypertension. In cases where treatment with inhaled iloprost, ECMO or INO is not possible, oral sildenafil can be an alternative therapy option in the treatment of PPHN.

Topics: Administration, Oral; Female; Humans; Hypertension, Pulmonary; Hypoxia-Ischemia, Brain; Iloprost; Infant, Newborn; Male; Meconium Aspiration Syndrome; Nebulizers and Vaporizers; Pneumonia; Retrospective Studies; Sildenafil Citrate; Tachypnea; Vasodilator Agents

Topics: Administration, Inhalation; Adult; Carbolines; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Male; Tadalafil; Young Adult

Congenital extrahepatic portocaval shunt (CEPS) is a rare anomaly of the mesenteric vasculature in which the intestinal and splenic venous drainage bypasses the liver and drains directly into the inferior vena cava, the left hepatic vein or the left renal vein. This uncommon disease is frequently associated with other malformations and mainly affects females. Here we report a case of pulmonary arterial hypertension associated with CEPS (Abernethy type 1b shunt) in a 20-yr-old man who was incidentally diagnosed during evaluation of multiple nodules of the liver. The patient was treated by inhalation of iloprost (40 µg/day) with improved condition and walking test. Physicians should note that congenital portocaval shunt may cause pulmonary hypertension.

Topics: Echocardiography, Doppler; Humans; Hypertension, Pulmonary; Iloprost; Liver; Magnetic Resonance Imaging; Male; Thoracic Arteries; Tomography, X-Ray Computed; Vasodilator Agents; Vena Cava, Inferior; Young Adult

Inhaled nitric oxide (iNO) is considered standard therapy for pediatric postcardiac surgical pulmonary hypertension (PH). Limited data suggest that inhaled iloprost (inIlo), an aerosolized prostacyclin, may be a feasible and more affordable therapeutic alternative. The goal of this study was to determine if significant hemodynamic change or adverse events would occur in postoperative congenital heart surgery (CHS) patients with PH after their transition from iNO to inIlo. This retrospective review investigated CHS patients with postoperative PH (mean pulmonary artery pressure [mPAP] >25 mmHg) between January 1, 2010 and December 31, 2011 who transitioned from iNO to inIlo. By protocol, CHS patients receiving stable doses of iNO were gradually transitioned to inIlo. After full transition, the patients received inIlo every 2 h, with a final dosing range of 1.25-5 μg/dose. Both PAP and systemic arterial pressure (SAP) were invasively measured during the transition period. Seven patients ages 10 days to 1.5 years completed the protocol. Measurements of mPAP (p = 0.27) and systolic PAP (p = 0.25) did not differ between iNO and inIlo therapy alone. No serious adverse events or complications (bleeding or thrombocytopenia) occurred. The ratio of systolic PAP to SAP decreased in all patients receiving inIlo alone (p = 0.03). Pulmonary hypertension in postoperative CHS patients can be managed successfully with inIlo, and the measured hemodynamics with this agent are similar to those observed with iNO. For the management of postoperative PH, inIlo may be a reasonable alternative, thus reducing the need for costly iNO. Larger confirmatory studies would more robustly facilitate its integration into standard care.

Topics: Administration, Inhalation; Cardiac Surgical Procedures; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Male; Nitric Oxide; Postoperative Complications; Retrospective Studies; Treatment Outcome; Vasodilator Agents

A 38-year-old male was diagnosed with unrepaired ventricular septal defect associated with severe pulmonary arterial hypertension, cyanosis, and significant exercise intolerance. His echocardiogram showed right ventricular dysfunction and moderate pericardial effusion with no signs of cardiac tamponade. He was treated with an intensive course of inhaled iloprost and sildenafil. He showed a dramatic clinical response; his saturation went up from 60% on admission to 90% on minimal oxygen with significant improvement in his symptoms and signs of heart failure and total resolution of pericardial effusion. On follow up 3 and 6 weeks later, he was stable and could walk 360 meters in a 6 minutes walk test with disappearance of pericardial effusion. With unavailability of intravenous prostacyclin, we have shown in this case that intensive administration of inhaled iloprost could be used intensively as a rescue therapy in severe cases of pulmonary arterial hypertension with excellent results. 

Topics: Administration, Inhalation; Adult; Exercise Test; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Iloprost; Male; Pericardial Effusion; Pericarditis; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents

Eisenmenger syndrome (ES) occurs as the most advanced form of pulmonary arterial hypertension (PAH) in patients with congenital heart disease. In this study, we aimed to evaluate the management of ES patients, follow-up and specific PAH treatment applying and clinical outcomes during 5 years.. During the period of the month between May 2008 and 2013 ES female patients were included in the study and followed an average for 5 years. Clinical findings, brain natriuretic peptide levels, transthoracic and right heart catheterization findings, 6-min walking test distance were recorded. PAH specific treatment as bosentan, iloprost and sildenafil was given to patients according to guidelines. The patients were evaluated with 3 months intervals as requirement for hospitalization, combination treatment, and mortality.. A total of 12 patients were included in the study. All of the patients were women, the mean age was 36.5. As prognostic echocardiographic data, the patients had high pulmonary artery pressure (109.81 ± 24.94 mmHg) related with increased right ventricular wall thickness, elevated right atrial pressure, severe pulmonary regurgitation in 40%, shortened pulmonary acceleration time, diminished myocardial tissue Doppler velocities of the left and right ventricles, increased right atrium area/left atrial area ratio (1.35 ± 0.40), lower right ventricular fractional area change. During the follow-up period of 5 years, a total of 16 events occurred. Combination treatment was required in 8 patients.. Eisenmenger syndrome is a multi-system affecting disease and due to high morbidity and mortality risk patients with ES should be followed by specialized centers. PAH specific treatment improves the disease course and survival of patients.

Topics: Adult; Antihypertensive Agents; Bosentan; Echocardiography; Eisenmenger Complex; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Laser-Doppler Flowmetry; Piperazines; Pulmonary Wedge Pressure; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Turkey

A 51-year-old woman (Case A) who had suffered from pulmonary Langerhans' cell granulomatosis for four years presented with progressive exertional dyspnea. A 39-year-old man (Case B) with pulmonary Langerhans' cell granulomatosis for eight years presented with right heart failure.. In Case A we found fixed airflow obstruction, hypoxemia, pulmonary fibrosis, bronchiectasis, severe precapillary pulmonary hypertension and a reduced right ventricular function, in Case B moderate airflow obstruction, hypoxemia, pulmonary fibrosis, emphysema and severe precapillary pulmonary hypertension.. Pulmonary hypertension due to pulmonary Langerhans' cell granulomatosis was assumed in both patients. After treatment with sildenafil, the woman has experienced long-term improvement for 2.5 years so far. An initially planned lung transplantation was therefore postponed. During inhaled iloprost the man also showed hemodynamic and clinical improvement and was stable for several years. Five years later recurrent right heart failure required an increase in iloprost dose; lung transplantation was then performed.. Although no approved drug is available for pulmonary hypertension in Langerhans' cell granulomatosis specific targeted therapies can lead to hemodynamic and long-term clinical improvement. Treatment could be helpful for selected patients with pulmonary hypertension in Langerhans' cell granulomatosis.

Topics: Adult; Drug Therapy, Combination; Female; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension secondary to respiratory disease most often occurs as a complication of chronic obstructive pulmonary disease, which currently constitutes one of the leading causes of death. Some patients with hypoxaemia reveal "out of proportion" pulmonary hypertension with inappropriate increase of pulmonary artery pressure. Iloprost, analogue of prostacyclin, dilates systemic vessels and pulmonary vessels in particular if administered by inhalation. It appears to be important, life-saving, complementary therapy. However, there is no evidence for its routine use in out of proportion arterial pulmonary hypertension. This case study presents a 44-year old man with chronic obstructive pulmonary disease and "out of proportion" pulmonary hypertension. We present the results of his treatment with iloprost.. In a patient with "out of proportion" pulmonary hypertension due to chronic obstructive pulmonary disease, inhaled iloprost led to improvement in clinical status and echocardiographic parameters, including a reduction of right ventricular systolic pressure.

Topics: Adult; Blood Pressure; Humans; Hypertension, Pulmonary; Iloprost; Male; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Vasodilator Agents

Intravenous (IV) prostacyclin (epoprostanol) and its analogs (iloprost and treprostinil) are effective in treating pulmonary artery hypertension (PAH). Although prostacyclins are available for inhaled and subcutaneous delivery, IV administration of prostacyclins, sometimes in combination with other agents, such as bosentan or sildenafil, is considered the most aggressive method to manage PAH. This report attempts to help clinicians determine when to initiate IV treatment of PAH and when to refer a patient with PAH to a center for treatment. IV prostacyclin therapy initiation is suggested when patients exhibit World Health Organization functional class IV symptoms. The Registry to EValuate Early And Long-term Pulmonary Arterial Hypertension disease management (REVEAL) risk calculator can help determine a patient's 1-year mortality with PAH and characterize the clinical course, treatment, and predictors of outcomes in patients with PAH. Referring physicians can screen their patients for PAH and refer even before the diagnosis has been confirmed so that the center can facilitate the diagnostic process and provide suggestions for initial therapy selection and provide other collaborative and supportive services. Alternatively, the physician can diagnose and initiate early therapy with a plan to involve the pulmonary hypertension center at the need for IV therapy or consideration for transplantation, working closely with the patient to ensure stability. Physicians and pulmonary centers must develop good methods of communication to ensure effective diagnosis and management.

Topics: Disease Management; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Platelet Aggregation Inhibitors; Purines; Referral and Consultation; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Administration, Inhalation; Critical Care; Diuretics; Furosemide; Heart Failure; Humans; Hydrazones; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pyridazines; Simendan; Thromboembolism; Vasodilator Agents; Ventricular Dysfunction, Right

Intravenous prostanoid therapy is one cornerstone of therapy for patients with pre-capillary pulmonary hypertension (PH). Long-term central venous catheters expose patients to infectious complications.. We report the incidence of catheter-related infection (CRI) and the spectrum of bacteria for ambulatory PH patients treated with iloprost via non-tunnelled central venous catheters from our Swiss referral centre in Zurich.. Data from 15 PH patients treated with intravenous iloprost between May 2000 and June 2012 were reviewed.. We found 11 CRI in 4 cases by two different organisms. Pathogens found were Brevibacterium (55%), Micrococcus luteus (18%), coagulase-negative Staphylococcus (9%) and Staphylococcus aureus (9%), as well as unusual organisms such as Agrobacterium tumefaciens or Delftia tsuruhatensis. The overall CRI rate was 1.28 per 1,000 catheter days, or 0.47 per year.. The incidence of CRI using long-term, non-tunnelled central venous catheters in PH patients treated with iloprost is low. Uncommon, rare pathogens causing CRI were found in a substantial number of patients.

Topics: Adult; Catheter-Related Infections; Central Venous Catheters; Female; Humans; Hypertension, Pulmonary; Iloprost; Incidence; Male; Middle Aged; Switzerland; Vasodilator Agents

Topics: Administration, Inhalation; Humans; Hypertension, Pulmonary; Iloprost; Nebulizers and Vaporizers; Pulmonary Embolism; Tomography, Spiral Computed; Treatment Outcome; Ultrasonography; Vasodilator Agents

There are limited data on the effect of iloprost therapy in patients with Eisenmenger syndrome (ES). The aim of our study was to evaluate the effect of inhaled iloprost therapy on exercise capacity, quality of life (QoL), cardiac function, and hemodynamics in patients with ES. Eighteen consecutive patients with ES and exertional dyspnea according to the World Health Organization functional class III or IV were prospectively recruited. Exercise capacity was assessed by a 6-minute walk test, and QoL was measured on a 12-Item Short-Form Health Survey. Echocardiographic measurements included peak systolic and mean pulmonary arterial pressures, pulmonary vascular resistance, and myocardial performance index of the right ventricle (RV). All patients underwent comprehensive evaluation at baseline and after 24 weeks of treatment. Of the 18 patients with ES, 13 were included for analysis. After 24 weeks of iloprost therapy, 6-minute walk test distance significantly increased (289.1 ± 76.9 to 369.5 ± 93.4 m, p = 0.032) in addition to concomitant improvements in the 12-Item Short-Form Health Survey physical and mental component summaries (20.6 ± 19.3 to 52.6 ± 28.0, p <0.05; 33.9 ± 19.7 to 54.9 ± 21.3, p <0.05, respectively). RV myocardial performance index improved significantly after treatment (0.80 ± 0.31 to 0.59 ± 0.12, p = 0.042). Pulmonary arterial pressure and pulmonary vascular resistance did not improve with iloprost therapy. This study showed that 24 weeks of inhaled iloprost therapy in patients with ES led to significant improvements in exercise capacity, QoL, and RV function. These results likely explain the symptomatic relief reported by patients with ES receiving iloprost therapy.

Topics: Administration, Inhalation; Adult; Cohort Studies; Echocardiography, Doppler; Eisenmenger Complex; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prospective Studies; Quality of Life; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the "multiple hit" concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as "add-on" therapy or initial "up front" therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.

Topics: Aminorex; Antihypertensive Agents; Appetite Depressants; Bosentan; Dasatinib; Epoprostenol; Familial Primary Pulmonary Hypertension; Fenfluramine; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Iloprost; Phenylpropionates; Piperazines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridazines; Pyrimidines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Thiazoles; Vasodilator Agents

The treatment of choice for congenital heart disease (CHD) with pulmonary arterial hypertension (PAH) is still controversial. We assessed the efficacy and safety of perioperative inhaled iloprost therapy in CHD with PAH.. Among 45 patients with a ventricular septal defect and/or an atrial septal defect with PAH, 28 patients were treated with inhaled iloprost before and after surgery. Perioperative clinical parameters and plasma B-type natriuretic peptide (BNP) were evaluated.. No statistical difference in the estimated right ventricular systolic pressure (e-RVP), the e-RVP-to-systemic pressure ratio, and preoperative BNP levels between the iloprost group and the control group were found. Among the iloprost group, oxygen saturation was increased significantly after iloprost inhalation therapy (p = 0.0052). The iloprost group was also significantly correlated with less use of inhaled nitric oxide in the immediate postoperative period compared to the control group (p = 0.021). The durations of mechanical ventilation (p = 0.018), ICU stay (p = 0.005), and chest tube use (p = 0.039) were significantly shorter in the iloprost group compared to the control group. The plasma BNP, checked on 7th day of postoperatively, was lower in the iloprost group than in the control group (p = 0.008).. Perioperative inhaled iloprost therapy showed the benefit of cardiac functional improvement and early weaning of postoperative supportive care in the management of CHD with PAH.

Topics: Administration, Inhalation; Adolescent; Adult; Child; Child, Preschool; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Iloprost; Infant; Perioperative Care; Retrospective Studies; Vasodilator Agents; Young Adult

Topics: Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

Topics: Administration, Inhalation; Child, Preschool; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Infant; Male; Retrospective Studies; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is an increasingly recognised serious illness with insidious onset, delayed diagnosis, complex diagnostic algorithms and poor prognosis, but with recently available effective treatments.. To efficiently diagnose and to offer treatment for PAH, we established a multidisciplinary service in 2005, where patients attend a clinic staffed by specialists in cardiology, respiratory medicine, rheumatology and immunology in a tertiary referral hospital setting.. We studied the first 200 patients referred. Serology, echocardiography, lung function tests, high-resolution computed tomography, World Health Organisation Class determination and 6-min walk tests and/or right heart catheterisation were performed, as clinically indicated.. Of the 200 patients seen, 66 had confirmed pulmonary hypertension (mean pulmonary artery pressure > 25 mmHg) diagnosed on echocardiography ± right heart catheterisation. Of these patients, 58 had catheter-proven PAH (mean pulmonary artery pressure > 25 mmHg with mean wedge pressure < 15 mmHg). Underlying diagnoses for the confirmed PAH patients were idiopathic (32), scleroderma-associated (14), other connective tissue disease (4) and associated with congenital heart disease (8). Patients with confirmed PAH were commenced on PAH-specific therapy--initially bosentan in the majority but sildenafil, and iloprost were occasionally used initially for patient-specific reasons. Median time from when the patient first called the clinic to prescription of therapy was 16 days (interquartile range; 0-31 days). All surviving patients with PAH have attended for regular 6-monthly follow-up visits with a 100% retention rate up to 4 years.. A multidisciplinary clinic can provide efficient diagnosis and rapid triage to PAH-specific therapy, if appropriate. Retention rates remain high, at follow up.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allergy and Immunology; Bosentan; Cardiac Catheterization; Cardiology; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Kaplan-Meier Estimate; Male; Mass Screening; Middle Aged; Outpatient Clinics, Hospital; Patient Care Team; Piperazines; Prospective Studies; Pulmonary Medicine; Purines; Rheumatology; Sildenafil Citrate; Sulfonamides; Sulfones; Tertiary Care Centers; Ultrasonography; Young Adult

Pulmonary hypertension (PH) is a life-threatening disease that causes endothelial dysfunction in the pulmonary vascular bed. Systemic endothelial dysfunction has also been reported in PH. This study compared the systemic and pulmonary vascular responses and some blood biomarkers of endothelial function in monocrotaline (MCT)-induced PH of rats. It also investigated the effect of sildenafil and iloprost treatment. MCT application induced elevation in the right ventricular pressures of the rat heart that had been reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated pulmonary artery were decreased in the PH group and this failure was reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated thoracic aorta were similar in all groups. Serotonin-induced contractions of the pulmonary artery were augmented by PH. In the isolated aorta, serotonin-stimulated contraction was not different in the control and MCT groups, but sildenafil and iloprost treatment decreased serotonin responses. The nitric oxide (NO) level in systemic circulation was not significantly changed by PH. However, sildenafil and iloprost treatments caused a decrease in the plasma level of NO. Asymmetric dimethylarginine levels in plasma were significantly decreased after MCT application and were not recovered by sildenafil and iloprost treatment. Total antioxidant capacity and H2S level of plasma were similar in all groups. Results of this study showed that MCT-induced PH caused specific toxic effects on pulmonary vasculature without any functional effects on the aorta. In addition, it was also demonstrated that sildenafil and iloprost treatments were effective in the MCT-induced PH.

Topics: Animals; Aorta, Thoracic; Arginine; Disease Models, Animal; Endothelium, Vascular; Hydrogen Sulfide; Hypertension, Pulmonary; Iloprost; Male; Monocrotaline; Nitric Oxide; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

The purpose of this study was to evaluate the hemodynamic effects of inhaled nitric oxide (NO) plus aerosolized iloprost in patients with pulmonary hypertension/right ventricular dysfunction after cardiac surgery.. A retrospective study.. A single center.. Eight consecutive patients with valve disease and postextracorporeal circulation (ECC) pulmonary hypertension/right ventricular dysfunction.. The continuous inhalation of nitric oxide (10 ppm) and iloprost, 10 μg, in repeated doses.. The hemodynamic profile was obtained before inhalation, during the administration of inhaled NO alone (prior and after iloprost), and after the first 2 doses of iloprost. Tricuspid annular velocity and tricuspid annular plane systolic excursion were estimated at baseline and before and after adding iloprost. At the end of the protocol, there were significant decreases in pulmonary vascular resistance (p < 0.001), the mean pulmonary arterial pressure (p < 0.001), and the mean pulmonary artery pressure/mean arterial pressure ratio (p = 0.006). Both tricuspid annular velocity (p < 0.001) and tricuspid annular plane systolic excursion (p < 0.001) increased. The cardiac index (p < 0.001) and venous blood oxygen saturation (p = 0.001) increased throughout the evaluation period. Each iloprost dose was associated with further decreases in pulmonary vascular resistances/pressure. By comparing data at the beginning of inhaled NO with those after the second dose of iloprost, the authors noticed decreases in pulmonary vascular resistances (p = 0.004) and the mean pulmonary artery pressure (p = 0.017) and rises in tricuspid annular velocity (p < 0.001) and tricuspid annular systolic plane systolic excursion (p < 0.001).. Inhaled NO and iloprost significantly reduced pulmonary hypertension and contributed to the improvement in right ventricular function. Inhaled NO and iloprost have additive effects on pulmonary vasculature.

Topics: Aerosols; Aged; Arterial Pressure; Cardiac Surgical Procedures; Electrocardiography; Extracorporeal Circulation; Female; Heart Valves; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide; Risk; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

Catheter-related blood stream infection (CR-BSI) in patients with pulmonary hypertension (PH) receiving intravenous iloprost via an indwelling central line has previously not been fully described. Recent studies have suggested a link between the pH of prostanoid infusions and the rate and nature of CR-BSI. We have investigated CR-BSI in patients receiving intravenous iloprost at our unit. Databases and hospital records were interrogated for all patients receiving intravenous iloprost between September 2007 and June 2012. Fifty-nine patients received intravenous iloprost via an indwelling central catheter with a total of 23,072 treatment days. There were 15 episodes of CR-BSI, identified using a systematic screening protocol, involving 11 patients giving an overall CR-BSI rate of 0.65/1,000 treatment days. CR-BSI rate for Gram-positive organisms was 0.26/1,000 treatment-days and for Gram-negative organisms was 0.39/1,000 treatment-days. The pH of iloprost in typical dosing regimens was comparable to the pH used in standard-diluent treprostinil and dissimilar to alkaline epoprostenol infusions. The proportion of Gram-negative CR-BSI was similar to that reported for standard-diluent treprostinil. CRP was normal on admission in 33 % of cases of confirmed CR-BSI and remained normal in 13 % of cases. CR-BSI rates with intravenous iloprost are comparable to those observed for other prostanoids. The high proportion of Gram-negative organisms observed and the neutral pH of iloprost infusions support the previously hypothesised link between pH and antimicrobial activity. Although usually elevated during a CR-BSI, CRP may be normal in early infection and a normal result cannot completely exclude infection.

Topics: Administration, Intravenous; Adult; Aged; Bacteremia; Catheter-Related Infections; Central Venous Catheters; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged

The objective of this study was to evaluate the incidence of the most severe vascular complications, such as pulmonary arterial hypertension, scleroderma renal crisis, and digital necrosis requiring amputation, in a monocentric group of systemic sclerosis (SSc) patients cyclically treated with intravenous iloprost. We reviewed the record-charts of 115 patients affected by SSc (18 men and 97 women, mean age 58.9.1 ± 14.2 years) regularly receiving iloprost for at least 3 years; the mean duration of the treatment was 98.8 ± 37.5 months (a total of 946.8 years of therapy). Demographic and clinical features were recorded. None of the patients died of SSc-associated vascular complications. After iloprost administration digital gangrene requiring amputation developed in 2 patients who had concomitant peripheral arterial disease (a total of 3 episodes; annual incidence of 0.31 for 100 years of iloprost therapy). Four patients were diagnosed with pulmonary arterial hypertension during iloprost treatment (annual incidence of 0.42 for 100 years of drug therapy); in none of the cases did the complication show a progressive course. No cases of scleroderma renal crisis were observed. With the limits of an observational study and in the absence of a control group, our experience suggests that prolonged cyclic iloprost therapy may limit the incidence/progression of severe digital and visceral SSc-vasculopathy.

Topics: Adult; Aged; Amputation, Surgical; Familial Primary Pulmonary Hypertension; Female; Finger Injuries; Gangrene; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Peripheral Arterial Disease; Scleroderma, Systemic; Severity of Illness Index; Toes; Vasodilator Agents

Systemic sclerosis (SSc) is a chronic disease of unknown etiology which affects the vascular system and connective tissue. A wide series of studies showed an increased prevalence of cancer in patients with SSc than the normal population. Prostacyclin (PGI2) is an endogenously produced element that is basically synthesized by arachiodonic acid through prostacyclin synthesis in vascular system endothelial cells. Iloprost is a stable analogue of PGI2 which is used in the treatment of pulmonary arterial hypertension (PAH). In a limited number of animal models, the anti-metastatic activity of PGI2 is observed. Herein, we report iloprost treatment of a 60-year-old-woman with SSc, who lately developed PAH as a complication of her disease and lung adenocarcinoma as a co-incidence simultaneously. These two mortal complications were both treated successfully with inhaled iloprost until her death due to gastrointestinal complications of SSc.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Administration, Inhalation; Antihypertensive Agents; Antineoplastic Agents; Biopsy; Disease Progression; Familial Primary Pulmonary Hypertension; Fatal Outcome; Female; Gastrointestinal Diseases; Humans; Hypertension, Pulmonary; Iloprost; Immunohistochemistry; Lung Neoplasms; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Scleroderma, Systemic; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Bosentan; Ductus Arteriosus, Patent; Female; Humans; Hypertension, Pulmonary; Iloprost; Septal Occluder Device; Sulfonamides; Vasodilator Agents

We investigated the short-term and medium-term results in patients with pulmonary arterial hypertension (PAH) associated with atrial septal defect (ASD) undergoing transcatheter closure. Fifteen patients with severe PAH associated with ASD who underwent successful occluder implantation from 2007 to 2010 were included. Clinical, echocardiographic, and hemodynamic data were reviewed. Severe PAH was defined as pulmonary arterial systolic pressure measured by catheterization was ≥60 mmHg and pulmonary vascular resistance (PVR) ≥6 Wood Units (WU). Compared with baseline, the 6-minwalking distance significantly increased by 29.7 ± 26.3 m (P < 0.001) at 3 months (short-term) and 65.4 ± 63.6 m (P < 0.001) at 23.4 ± 9.7 months (medium-term), World Health Organization function class considerably improved after postclosure short-term and medium-term. Repeat cardiac catheterization (n = 7) showed that mean pulmonary arterial pressure decreased from 51.6 ± 9.4 mmHg at baseline to 21.0 ± 3.8 mmHg (P < 0.001) at follow-up of 12 months. The PVR decreased by 5.6 ± 1.1 WU (P < 0.001). Through carefully selected patients with severe PAH associated with ASD, transcatheter closure can be safely performed with a promising short-term and medium-term outcome. Trial occlusion is an effective way for deciding the reversibility of severe PAH in ASD patients. The role of aerosolized iloprost for pulmonary vasoreactivity testing in patients with severe PAH secondary to ASD requires further investigation.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Arterial Pressure; Cardiac Catheterization; Catheterization, Swan-Ganz; Chi-Square Distribution; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Heart Septal Defects, Atrial; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Predictive Value of Tests; Pulmonary Artery; Recovery of Function; Retrospective Studies; Septal Occluder Device; Severity of Illness Index; Time Factors; Treatment Outcome; Ultrasonography; Vascular Resistance; Walking; Young Adult

Topics: Administration, Inhalation; Aged; Eating; Female; Gastrointestinal Hemorrhage; Humans; Hypertension, Pulmonary; Iloprost; Male; Risk Factors; Vasodilator Agents

We performed a retrospective analysis of patients with pulmonary arterial hypertension receiving inhaled iloprost in a single centre to evaluate long-term tolerability, safety, and efficacy of chronic inhaled iloprost therapy in children.. A total of 20 patients with either idiopathic or associated pulmonary arterial hypertension were treated with iloprost between April, 2003 and January, 2010. The median age and weight of the patients were 3.8 years--ranging from 4 months to 19 years--and 12.3 kilograms--ranging from 4 to 73 kilograms-- respectively. Pulmonary arterial hypertension was idiopathic or hereditary in eight patients (40%) and associated with congenital cardiac disease in 12 patients (60%).. Of the 20 patients, 15 had combined therapy--12 patients with two and three patients with three different classes of drugs. In all, six patients died during follow-up. The median follow-up time was 18 months, ranging from 6 to 74 months. The 6-minute walking test was performed in 7 out of 20 patients at baseline and on follow-up. The median 6-minute walking test increased from 420 to 490 metres after iloprost therapy (p = 0.028). After initiation of iloprost therapy, one patient complained of headache and another had a rash around his mouth, none necessitating discontinuation of therapy. Overall compliance with inhaled iloprost was good.. Pulmonary hypertension is associated with significant morbidity and mortality. Careful assessment of each patient and timely combination of specific vasodilator therapy is needed to improve clinical outcomes. This study suggests that inhaled iloprost, with or without concomitant endotelin receptor antagonist and/or phosphodiesterase inhibitor, is safe and efficacious for treatment of pulmonary arterial hypertension in children.

Topics: Administration, Inhalation; Adolescent; Child; Child, Preschool; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Iloprost; Infant; Longitudinal Studies; Male; Retrospective Studies; Treatment Outcome; Vasodilator Agents; Young Adult

To describe a series of ex-preterm infants admitted to pediatric intensive care unit due to impending hypoxaemic respiratory failure complicated by pulmonary hypertension (PH) who were treated electively combining noninvasive ventilation (NIV) and nebulized iloprost (nebILO).. Open uncontrolled observational study.. Pediatric Intensive Care Unit, University Hospital.. Ten formerly preterm infants with impending hypoxaemic respiratory failure and PH, of whom eight had moderate to severe bronchopulmonary dysplasia.. Median age and body weight were 6.0 (2.75-9.50) months and 4.85 (3.32-7.07) kg, respectively. We observed a significant early oxygenation improvement in terms of PaO(2) /FiO(2) increase (P = 0.001) and respiratory rate reduction (P = 0.01). Hemodynamic also improved, as shown by heart rate (P = 0.002) and pulmonary arterial pressure systolic/systolic systemic pressure (PAPs/SSP) ratio reduction (P = 0.0137). NebILO was successfully weaned in positive response cases: 4 infants were discharged on oral sildenafil. Three patients failed noninvasive modality and needed invasive mechanical ventilation; hypoxic-hypercarbic patients were most likely to fail noninvasive approach. Only one patient requiring invasive ventilation died and surviving babies had a satisfactory 1-month post-discharge follow-up. CONCLUSIONS.: The noninvasive approach combining NIV and nebILO for ex-preterm babies with impending respiratory failure and PH resulted to be feasible and quickly achieved significant oxygenation and hemodynamic improvements.

Topics: Administration, Inhalation; Female; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Infant; Infant, Newborn; Infant, Premature; Male; Positive-Pressure Respiration; Respiratory Insufficiency; Retrospective Studies; Treatment Outcome; Vasodilator Agents

It is believed that growth factors play an important role in vascular remodeling that is evident in pulmonary hypertension (PH) pathogenesis. In the present study, the vascular endothelial growth factor (VEGF) levels in serum and pulmonary artery samples of rats have been analyzed with monocrotaline (MCT)-induced PH after treatments with iloprost, bosentan, and sildenafil. Serum VEGF and pulmonary artery VEGF levels were found to be significantly lower in MCT groups compared with control groups and significantly higher in treatment groups compared with MCT groups. In conclusion, treatment strategies directed at increasing VEGF levels may be reasonable in PH management.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Bosentan; Female; Hypertension, Pulmonary; Iloprost; Monocrotaline; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Sulfones; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vasodilator Agents

In acute respiratory distress syndrome (ARDS), pulmonary hypertension is associated with a poor prognosis. Prone position is effective to improve oxygenation whereas inhaled iloprost can treat pulmonary hypertension. However, combination of these interventions has not been examined before. The hypothesis was that this combination had additive effects on oxygenation and pulmonary hemodynamics as compared with each intervention alone.. In a prospective, randomized cross-over study, ten pigs were anesthetized, intubated and ventilated with volume controlled ventilation. Carotid, jugular venous and pulmonary artery catheters were inserted. ARDS was induced with oleic acid (0.20 mL/kg). Measurements were repeated in randomized different sequences of prone or supine positions with or without iloprost inhalation (220 ng/kg/min) (four combinations). Systemic and pulmonary arterial pressures; arterial and mixed venous blood gases; and Qs/Qt and the resistances were recorded.. Iloprost decreased pulmonary artery pressures (for MPAP: P=0.034) in both supine (37±10 vs. 31±8 mmHg; P<0.05) and prone positions (38±9 vs. 29±8 mmHg; P<0.05); but did not obtain a significant improvement in oxygenation in both positions. Prone position improved the oxygenation (p<0.0001) compared to supine position in both with (361±140 vs. 183±158 mmHg, P<0.05) or without iloprost application (331±112 vs. 167±117 mmHg, P<0.05); but did not achieve a significant decrease in MPAP.. Although iloprost reduced pulmonary arterial pressures, and prone positioning improved oxygenation; there are no additive effects of the combination of both interventions on both parameters. To treat both pulmonary hypertension and hypoxemia, application of iloprost in prone position is suggested.

Topics: Administration, Inhalation; Animals; Blood Pressure; Carotid Arteries; Cross-Over Studies; Drug Evaluation, Preclinical; Hypertension, Pulmonary; Hypoxia; Iloprost; Jugular Veins; Male; Oleic Acid; Oxygen; Prognosis; Prone Position; Prospective Studies; Pulmonary Artery; Random Allocation; Respiration, Artificial; Respiratory Distress Syndrome; Sus scrofa; Swine

The prostacyclin analogues, iloprost and treprostinil are extensively used in treating pulmonary hypertension. Their binding profile and corresponding biochemical cellular responses on human prostanoid receptors expressed in cell lines, have now been compared. Iloprost had high binding affinity for EP1 and IP receptors (Ki 1.1 and 3.9 nM, respectively), low affinity for FP, EP3 or EP4 receptors, and very low affinity for EP2, DP1 or TP receptors. By contrast, treprostinil had high affinity for the DP1, EP2 and IP receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, FP and TP receptors. In functional assays, iloprost had similar high activity in elevating cyclic AMP levels in cells expressing the human IP receptor and stimulating calcium influx in cells expressing EP1 receptors (EC50 0.37 and 0.3 nM, respectively) with the rank order of activity on the other receptors comparable to the binding assays. As with binding studies, treprostinil elevated cyclic AMP with a similar high potency in cells expressing DP1, IP and EP2 receptors (EC50 0.6, 1.9 and 6.2 nM, respectively), but had low activity at the other receptors. Activation of IP, DP1 and EP2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP1 receptors can provoke vasoconstriction, and hence may offset the IP-receptor mediated vasodilator effects of iloprost. Treprostinil may therefore differ from iloprost in its overall beneficial pulmonary vasorelaxant profile and other pharmacological actions, especially in diseases where the IP receptor is down-regulated.

Topics: Antihypertensive Agents; Binding, Competitive; Calcium; Cell Culture Techniques; Cyclic AMP; Epoprostenol; HEK293 Cells; Humans; Hypertension, Pulmonary; Iloprost; Radioligand Assay; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP2 Subtype; Transfection

Inhaled iloprost (average >30 µg/d) has been considered an effective treatment for severe pulmonary hypertension (PH). Further evidence also showed that low-dose iloprost given intravenously was equally effective as high-dose iloprost in the therapy of systemic sclerosis.. Patients with pulmonary hypertension will benefit from inhalation of low-dose iloprost.. Sixty-two patients with PH were enrolled and initiated with neubulizedlow-dose iloprost (2.5 µg per inhalation, 6× daily) for 24 weeks in 13 medical centers in China. Efficacy endpoints included changes in 6-minute walk distance (6MWD), World Health Organization functional class (WHO-FC), and hemodynamic parameters.. Fourteen patients (22.6%) prematurely discontinued the study: 8 due to clinical worsening (6 in WHO-FCIII-IV at baseline), 4 because of protocol change, and 2 patients lost during follow-up. In the remaining 48 patients, 6MWD was increased from 356 ± 98 meters to 414 ± 99 meters (P < 0.001) and WHO-FC improved significantly (P = 0.006) after 24-week inhalation therapy. Cardiac output, cardiac index, and mixed venous oxygen saturation improved significantly compared with baseline (n = 34, P < 0.05). Most of the hemodynamic parameters improved significantly in patients in WHO-FC II (P < 0.05) but not in patients in WHO-FCIII-IV.. Low-dose iloprost inhalation significantly improved exercise capacity and functional status in patients with PH. It was well tolerated. The improvement of hemodynamics was confirmed in patients with WHO-FCI-II but not in patients with WHO-FCIII-IV, suggesting the importance of early treatment in patients with advanced disease stages.

Topics: Administration, Inhalation; Adult; China; Exercise Tolerance; Female; Health Status Indicators; Heart Rate; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Oxygen Consumption; Prospective Studies; Statistics as Topic; Time Factors; Treatment Outcome

Topics: Animals; Hypertension, Pulmonary; Iloprost; Male; Oxygen; Prone Position; Respiratory Distress Syndrome

Pulmonary hypertension and right ventricular (RV) dysfunction may complicate the implantation of a left ventricular assist device (LVAD). We examined whether inhaled vasodilators can sufficiently reduce RV afterload, avoiding the need for temporary RV mechanical support.. The study includes 7 patients with RV dysfunction after LVAD insertion. Treatment consisted of inotropes, inhaled nitric oxide (10 ppm), and iloprost (10 μg) in repeated doses. Full hemodynamic profile was obtained before inhalation, during administration of inhaled NO alone (before and after iloprost), as well as after the first two doses of inhaled iloprost. Tricuspid annular velocity was estimated at baseline and before and after adding iloprost.. There was a statistically significant reduction in pulmonary vascular resistance (PVR), mean pulmonary artery pressure (MPAP), RV systolic pressure, and pulmonary capillary wedge pressure, and a considerable increase in LVAD flow, LV flow rate index, and tricuspid annular velocity at all points of evaluation versus baseline. By the end of the protocol, MPAP/mean systemic arterial pressure, and PVR/systemic vascular resistance ratios were reduced by 0.17±0.03 (95% confidence interval, 0.10 to 0.25, p=0.001) and 0.12±0.025 (95% confidence interval, 0.06 to 0.18; p=0.003), respectively. The tricuspid annular velocity increased by 2.3±0.18 cm/s (95% confidence interval, 1.83 to 2.73 cm/s; p<0.001). Pairwise comparisons before and after iloprost showed an important decrease in PVR (p=0.022), MPAP (p=0.001), pulmonary capillary wedge pressure (p=0.002), and RV systolic pressure (p<0.001), and a rise in tricuspid annular velocity (p=0.008).. Inhaled vasodilators mainly affected the pulmonary vasculature. Combination treatment with inhaled NO and iloprost sufficiently decreased PVR and MPAP on the basis of an additive effect, improved RV function, and avoided the need for RV assist device.

Topics: Administration, Inhalation; Adult; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Failure; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide; Pulmonary Wedge Pressure; Retrospective Studies; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome; Vascular Resistance; Ventricular Dysfunction, Right

We treated 2 very low birth weight (VLBW) infants with respiratory distress syndrome suffering from refractory hypoxic respiratory failure complicated with severe pulmonary hypertension with inhaled iloprost. The first infant was an 800 gram male and the second case was a 920 gram female. Echocardiography revealed a right to left shunt through patent duct in the first case; suprasystemic pulmonary arterial pressure was estimated by using tricuspid regurgitation of moderate severity in the second case. Inhaled iloprost was started in those infants when conventional therapies including the administration of exogenous surfactant and high-frequency oscillatory ventilation failed. After the commencement of therapy, the clinical condition of the infants improved dramatically. Pulmonary arterial pressure returned to normal levels within five days. We suggest that inhaled iloprost may be helpful by improving oxygenation and reducing the need for aggressive mechanical ventilation in some cases of severe hypoxaemic respiratory failure in VLBW infants.

Topics: Administration, Inhalation; Female; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Male; Respiratory Distress Syndrome, Newborn; Vasodilator Agents

Topics: Antihypertensive Agents; Cardiac Surgical Procedures; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Vasodilator Agents

The aim of the present study was to retrospectively evaluate response to therapy in 73 patients affected by systemic sclerosis (SSc) who underwent long-term cyclic treatment with intravenous iloprost for peripheral vascular involvement (average duration of treatment 54.12±41.04 months). Seventy-three SSc patients were enrolled. Data were collected by reviewing clinical records and by phone or direct interview. Patients underwent a thorough physical examination at the end of follow up. The incidence of severe vascular manifestations was also assessed. Statistical analysis was performed by Wilcoxon's signed rank test and descriptive statistics using Statview software. In this study cohort, 55 of 73 (75.2%) patients had a history of ischemic digital ulcers (DUs); 28 patients (38.4%) had active DUs at the beginning of treatment. Skin ulcers healed completely in 25 of 28 patients (89.3%) at the end of the first treatment. However, 40 of 55 patients (72.6%) relapsed after an average of 24 months. There was a significant correlation between relapse rate and/or number of ulcers and clinical factors (diffuse subset, changes in results of Allen's test, NT-pro BNP levels). The annual incidence of pulmonary arterial hypertension (PAH) was 2.34 (95%CI: 0.94-4.83) per 100 person years, the rate of gangrene was 2.7%, and no cases of scleroderma renal crisis were recorded. The incidence of PAH and of digital gangrene was higher than that observed in unselected SSc case series. These data suggest that our patients treated with iloprost have a higher vascular involvement than large case series of unselected SSc patients. A number of clinical factors are correlated to the severity of vascular involvement and could have an impact on the response to therapy. The clinical significance of these findings requires clarification and further investigation is needed.

Topics: Humans; Hypertension, Pulmonary; Iloprost; Scleroderma, Systemic; Skin Ulcer; Ulcer

Topics: Female; Heart Failure; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Iloprost; Male; Nitric Oxide; Ventricular Dysfunction, Right

Topics: Adenosine; Administration, Inhalation; Antihypertensive Agents; Bronchodilator Agents; Catheterization, Swan-Ganz; Epoprostenol; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Pulmonary Artery; Vasodilator Agents

To compare the acute hemodynamic effects of aerosolized iloprost and inhaled nitric oxide (NO) in adult congenital heart disease (CHD) patients with severe pulmonary arterial hypertension (PAH).. One hundred and eighty five adult CHDs with severe PAH were nonrandomized into two groups (iloprost, n=127; NO, n=58). Various hemodynamic parameters were measured before and after iloprost or NO inhalation.. Iloprost and NO inhalation resulted in significant reductions in pulmonary arterial pressure (from 110.6±21.8 mmHg to 105.5±22.3 mmHg, p<0.05; from 113.1±18.7 mmHg to 107.2±19.9 mmHg, p<0.05, respectively) and pulmonary vascular resistance (PVR) (from 13.4±8.3 Wood units to 9.6±6.4 Wood units, p<0.01; from 13.7±7.1 Wood units to 9.3±4.9 Wood units, p<0.01, respectively) and increases in pulmonary blood flow (from 6.7±3.3 L/min to 9.4±5.8 L/min, p<0.05; from 6.6±3.1 L/min to 9.6±5.9 L/min, p<0.01, respectively) and the Qp/Qs ratio (from 1.5±0.8 to 2.1±1.4, p<0.01; from 1.5±0.8 to 2.0±1.3, p<0.01, respectively). When the effects of inhaled iloprost and NO were compared, similar reductions in pulmonary arterial pressure and pulmonary vascular resistance were observed. Aerosolized iloprost and inhaled nitric oxide (iNO) were generally well tolerated and no patient experienced any side effects during inhalation.. Aerosolized iloprost can be effectively and safely used and might be an alternative to NO for testing pulmonary vascular reactivity and treating severe PAH in adult CHD patients.

Topics: Administration, Inhalation; Adolescent; Adult; Aerosols; Aged; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide; Severity of Illness Index; Young Adult

To summary the efficacy and safety of aerosolized iloprost in patients with pulmonary hypertensive crisis.. On the basis of conventional therapy, aerosolized iloprost (10 µg per time for 10 - 15 min in 2 hours interval, 8 times per day) was administered to four patients with idiopathic pulmonary arterial hypertension and pulmonary hypertensive crisis. Blood pressure, heart rate, systemic artery oxygen saturation, systolic pulmonary arterial pressure (sPAP) measured by echocardiography and the adverse events were analyzed.. After aerosolized iloprost therapy, sPAP was significantly decreased and systemic artery oxygen saturation was improved. Adverse events (nausea, vomiting, diarrhea, dry cough) were observed in two patients, and the iloprost use was stopped in one patient due to severe vomiting and diarrhea.. Aerosolized iloprost could significantly reduce the sPAP and improve the systemic artery oxygen saturation in patients with pulmonary hypertension crisis.

Topics: Administration, Inhalation; Adult; Blood Pressure; Child; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Young Adult

Intravenous prostacyclin (iv PGI) and inhaled Iloprost (inh ilo) are established therapies in pulmonary arterial hypertension (PAH), however comparative data are lacking.. We performed a long-term open label comparison trial of iv PGI or high dose inh ilo in 24 patients with severe PAH: 12 patients (9 female, 40 +/- 14 years, 10 idiopathic PAH, 2 PAH in connective tissue disease CTD) received iv PGI, whereas 12 patients (7 female, 43 +/- 12 years, 5 IPAH, 6 CTD, 1 porto-pulmonary hypertension) were commenced on inh ilo with a median dose of 120 μg/24 h. Haemodynamic parameters and 6 min walking distance (6MWD) at baseline did not differ between both groups.. After 3 months therapy, patients on iv PGI showed a significant increase in 6MWD from 220 to 280 m (p < 0.01), whereas patients on high dose inh ilo increased 6MWD from 200 to 275 m (p < 0.05). The event free follow up was 23 [1-76] months in the iv PGI2I group, and 16 [7-38] months in the high dose inh ilo group (p < 0.05). Patients with a 6MWD ≥ 300 m after 3 months therapy had a significantly longer event free follow up [16 vs. 35 months; p < 0.004].. In this patient population with severe pulmonary hypertension of different etiologies, event free follow up on treatment with iv PGI is significantly longer compared to high dose inh ilo. The 6MWD after 3 months treatment might be predictive for long term outcome.

Topics: Administration, Inhalation; Adolescent; Adult; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Male; Middle Aged

To investigate the immediately effects of inhaled aerosolized iloprost in adult patients with severe pulmonary arterial hypertension (PAH) secondary to congenital heart diseases (CHD).. Adult patients with severe PAH secondary to CHD (n = 165) were included in this study. Right heart catheterization was performed, Pulmonary and systemic blood flow, the oxygen consumption VO(2) (ml/min) were calculated using Fick's principle. Pulmonary vascular resistances (PVR) were calculated with standard formulas and indexed to body surface area. Hemodynamic parameters were measured before and after iloprost inhalation (20 µg).. Post iloprost inhalation, heart rate, mean aortic pressure, pulmonary systolic pressure to aortic systolic pressure ratio all remained un changed (P > 0.05), while pulmonary artery pressure (PAP) were significantly reduced and Qp significantly increased from (7.2 ± 4.8) L/min to (9.9 ± 7.2) L/min (P < 0.01), PVR was also significantly reduced from (13.4 ± 8.7) Wood units to (9.5 ± 6.6) Wood units (P < 0.01), and left-to-right shunt volume increased from (3.2 ± 4.4) L/min to (5.5 ± 7.0) L/min (P < 0.01) and right-to-left shunt volume decreased from (1.0 ± 1.0) L/min to (0.7 ± 0.7) L/min (P < 0.01). Subgroup analysis showed that adult patients with patent ductus arteriosus and/or ventricular septal defects are more likely to develop severe pulmonary arterial hypertension or Eisenmenger syndrome than patients with atrial septal defects.. Inhaled Aerosolised iloprost use is effective and safe for adult patients with severe pulmonary arterial hypertension secondary to congenital heart diseases.

Topics: Administration, Inhalation; Adolescent; Adult; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Male; Vascular Resistance; Young Adult

While new pharmacological approaches have been demonstrated to effectively manage PH in adults, few reports have addressed PH treatment in neonates and infants. This case report describes the successful management of severe PH secondary to bronchopulmonary dysplasia, respiratory syncytial virus infection, and hypoxia in a preterm 4-month-old with the long-term use of orally administered sildenafil and inhaled iloprost.

Topics: Administration, Inhalation; Administration, Oral; Bronchopulmonary Dysplasia; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Infant; Infant, Newborn; Infant, Premature; Male; Piperazines; Purines; Respiratory Syncytial Virus Infections; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

The European League Against Rheumatism/EULAR Scleroderma Trials and Research group (EULAR/EUSTAR) has published recommendations for the management of systemic sclerosis (SSc). Members of the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research Group were surveyed regarding their level of agreement with the recommendations.. A survey containing the 14 EULAR/EUSTAR recommendations asked participants to indicate their level of agreement with each on a 10-point scale, from 0 (not at all) to 9 (completely agree). The survey was sent to 117 people, and 66 replies were received (56% response rate).. Exceptions to generally high agreement included the use of iloprost and bosentan for digital vasculopathy, methotrexate for skin involvement, and bosentan and epoprostenol for pulmonary arterial hypertension (PAH; all < 69% agreement, defined as ≥ 7 rating). Vasculopathy and PAH treatment had differences in agreement between North America and Europe (p < 0.006). Respondents who were EULAR/EUSTAR recommendation authors shared a similar level of agreement compared to those who were not, except for the use of proton pump inhibitors for the prevention of SSc-related gastroesophageal reflux disease, esophageal ulcers, and strictures.. EULAR/EUSTAR recommendations were relatively well accepted among SSc experts. Overall reduced agreement may be due to the modest efficacy of some agents (such as methotrexate for the skin). Some regional disagreement is likely because of access differences.

Topics: Bosentan; Canada; Epoprostenol; Europe; Health Surveys; Humans; Hypertension, Pulmonary; Iloprost; Methotrexate; North America; Practice Guidelines as Topic; Scleroderma, Systemic; Skin Diseases; Societies, Medical; Sulfonamides; Treatment Outcome; Vascular Diseases

The development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones.. Five groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezosentan via an intraperitoneally implemented osmotic pump, or by orally administered sildenafil. An additional group underwent sham surgery. Four weeks later, the lung responsiveness to increasing doses of an intravenous infusion of methacholine (2, 4, 8 12 and 24 μg/kg/min) was determined by using the forced oscillation technique to assess the airway resistance (Raw).. BHR developed in the untreated rats, as reflected by a significant decrease in ED50, the equivalent dose of methacholine required to cause a 50% increase in Raw. All drugs tested prevented the development of BHR, iloprost being the most effective in reducing both the systolic pulmonary arterial pressure (Ppa; 28%, p = 0.035) and BHR (ED50 = 9.9 ± 1.7 vs. 43 ± 11 μg/kg in ACS control and iloprost-treated rats, respectively, p = 0.008). Significant correlations were found between the levels of Ppa and ED50 (R = -0.59, p = 0.016), indicating that mechanical interdependence is primarily responsible for the development of BHR.. The efficiency of such treatment demonstrates that re-establishment of the balance of constrictor/dilator mediators via various signalling pathways involved in PHT is of potential benefit for the avoidance of the development of BHR.

Topics: Administration, Oral; Airway Resistance; Analysis of Variance; Animals; Antihypertensive Agents; Blood Pressure; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelins; Hypertension, Pulmonary; Iloprost; Infusion Pumps, Implantable; Infusions, Parenteral; Lung; Lung Volume Measurements; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Prostaglandins I; Purines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Signal Transduction; Sildenafil Citrate; Sulfones; Tetrazoles; Time Factors; Vasoactive Intestinal Peptide; Vasodilator Agents

In the past 5-10 years, drug treatment of idiopathic pulmonary arterial hypertension has evolved considerably. Experience and results from use of such updated treatment in Norway has not been reported.. 32 patients newly diagnosed with idiopathic pulmonary arterial hypertension, were consecutively assessed with respect to hemodynamics and physical capacity. The results after three months were compared with those after 12 months. Observed survival was compared with estimated survival from the time when only conventional treatment was available.. The patients (78% women) were 42 ± 14 years, had dyspnea in NYHA class 2.9 ± 0.4 and a maximal oxygen uptake of 12.0 ± 3.9 ml/kg/min (37 ± 13% of the expected). Updated treatment led to significantly improved hemodynamics and physical capacity, which persisted during follow-up. During 43 ± 31 months follow-up, seven patients died while two underwent bilateral lung transplantation. Observed transplantation-free survival was 81% after one, two and three years, while that for estimated transplantation-free survival was 70%, 58% and 49% respectively.. Treatment of idiopathic pulmonary arterial hypertension with updated treatment improves hemodynamics and thereby symptoms. Mortality remains high, but is probably lower than it was when only conventional treatment was available.

Topics: Adult; Airway Resistance; Antihypertensive Agents; Bosentan; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Lung Volume Measurements; Male; Middle Aged; Oxygen Consumption; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Intravenous periodic Iloprost is proven effective in the treatment of Raynaud phenomenon (RP) related to connective tissue disorder (CTD). It's well known that synthetic prostaglandins are effective drugs for the treatment of pulmonary arterial hypertension (PAH), and that PAH is frequently associated with CTD.. The aim of the study is to evaluate in the chronic effect of cyclic intravenous Iloprost on pulmonary arterial pressure.. We studied 17 consecutive patients with CTD (14 systemic sclerosis, 3 mixed CTD) and RP, at the entry and after at least 6months of treatment of RP with cyclic Iloprost. On both occasions, in all patients we performed transthoracic Doppler echocardiography and we determined NT-proBNP plasma levels, NYHA functional class, 6 Minute-Walk Distance (6MWD).. At follow-up (8.2±1.9months; range 6-12) mean values of pulmonary arterial systolic pressure (PASP) significantly decreased (from 32.2±9.2 to 29.2±7.6mmHg, p<0.04) and mean values of 6MWD significantly increased (from 407.5±101.5 to 448.3±89.9m, p<0.01). Moreover, we observed a significant direct correlation between PASP and NT-proBNP values and a significant inverse correlation both between NT-proBNP and 6MWD values and between PASP and 6MWD values.. Our results suggest that cyclic intravenous Iloprost may protect against the development or worsening of PAH in patients with CTD and RP.

Topics: Adult; Aged; Cardiovascular Agents; Connective Tissue Diseases; Dose-Response Relationship, Drug; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Pulmonary Wedge Pressure; Retrospective Studies; Time Factors; Treatment Outcome

Topics: Adult; Antihypertensive Agents; Bosentan; Combined Modality Therapy; Drug Therapy, Combination; Extracorporeal Membrane Oxygenation; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

The majority of patients with idiopathic pulmonary arterial hypertension (IPAH) in functional classes II and III are currently being treated with non-parenteral therapies, including endothelin receptor antagonists (ERA), phosphodiesterase (PDE)-5 inhibitors, inhaled iloprost or combinations of these substances. If these treatments fail, current guidelines recommend the addition of parenteral prostanoid therapy. There is, however, limited evidence for the efficacy of parenteral prostanoids when added to combinations of non-parenteral therapies.. In this retrospective, multicentre study we collected data from consecutive IPAH patients receiving intravenous iloprost in addition to optimized non-parenteral therapy between Jan 2002 and Dec 2009. Analyses included 6 min walk distance (6MWD), functional class, need for transplantation, and survival.. During the observation period, 50 patients were treated with intravenous iloprost in addition to non-parenteral therapy; 44% of the patients were on dual combination therapy and 52% on triple combination. Three months after initiation of iloprost, functional class had improved in 24% of the patients and the median 6MWD had increased from 289 m to 298 m (n.s.). During the observation period, 22 patients (44%) died and 14 (28%) underwent lung transplantation. The probabilities of LuTx-free survival at 1, 3 and 5 years following iloprost initiation were 38%, 17% and 17%, respectively. A 6MWD < 300 m and persistent functional class IV at 3 months after initiation of intravenous iloprost were predictors of an adverse outcome.. In essence, late initiation of intravenous iloprost in IPAH patients who previously failed to respond to non-parenteral therapies appears to be of limited efficacy in the majority patients. Alternative therapeutic options are currently not available, underlying the need for the development of new drugs.

Topics: Administration, Oral; Adult; Drug Therapy, Combination; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Male; Middle Aged; Phosphodiesterase Inhibitors; Retrospective Studies; Survival Analysis; Treatment Outcome; Vasodilator Agents

To explore the immediate effects of inhaled aerosolized iloprost on right heart function in adult patients with pulmonary arterial hypertension (PAH).. A total of 30 PAH patients were recruited. Right heart catheterization and echocardiography were performed before and immediately after the inhalation of iloprost (20 µg).. After inhalation, the values of mean pulmonary artery pressure (PAPm) and pulmonary vascular resistances (PVR) decreased markedly (42.5 ± 9.6 to 34.4 ± 11.9 mm Hg, P < 0.001; 9.6 ± 5.7 Wood unit to 7.1 ± 4.8 Wood unit, P < 0.001). And the value of tricuspid annular systolic motion peak velocity (TASm) increased markedly [(10.7 ± 2.1) cm/s vs (11.9 ± 2.5) cm/s, P < 0.01]. The baseline level of TASm was higher in acute responders than non-responders [(12.0 ± 2.2) cm/s vs (10.1 ± 1.8) cm/s, P = 0.01] and TASm increased markedly after inhalation in non-responders [(10.1 ± 1.8) cm/s vs (11.6 ± 2.3) cm/s, P < 0.01].. The inhalation of iloprost decreases the levels of PAPm and PVR and improve right heart functions in adult PAH patients. For non-responders, right heart function is worse and more benefits may be achieved after the inhalation of iloprost.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prospective Studies; Vasodilator Agents; Ventricular Function, Right; Young Adult

We report a case of a 6-year-old boy with fixed severe pulmonary artery hypertension secondary to a ventricular septal defect (VSD) together with a patent ductus arteriosus (PDA). As a preliminary step, PDA embolization was performed following therapy with inhaled prostacyclin over a period of 6 months. Further, the patient underwent successful surgical VSD closure. We postulate that a staged procedure with long-term prostaglandin therapy might be capable of reducing pulmonary artery resistance and permitting total correction in a patient once considered to have inoperable pulmonary arteriopathy.

Topics: Administration, Inhalation; Child; Combined Modality Therapy; Ductus Arteriosus, Patent; Embolization, Therapeutic; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Iloprost; Male; Septal Occluder Device; Vasodilator Agents

Portopulmonary hypertension (PoPH) is a serious condition without an established treatment. Drugs used to treat pulmonary hypertension may have detrimental effects on portal hypertension. This study was designed to assess in patients with PoPH the acute effects of inhaled iloprost (iILO) on pulmonary and hepatic hemodynamics and to evaluate the clinical outcome after 12 months of treatment. We conducted 2 separate studies. In the first one, 21 patients with PoPH were acutely tested with 2.8 microg of iILO. Pulmonary and hepatic hemodynamics were assessed at the baseline and through 60 minutes after iILO. In the second one, we retrospectively evaluated 12 patients treated with iILO (30 microg/day) for more than 1 year. The 6-minute walk distance (6MWD), functional class (FC), and echocardiogram were analyzed at the baseline and after 12 months of treatment. In the acute study, iILO rapidly reduced pulmonary artery pressure (PAP; -16% + or - 8%, P < 0.001) and pulmonary vascular resistance (-18% + or - 14%, P < 0.001). The cardiac output did not change initially but decreased after 30 minutes. The hepatic venous pressure gradient (HVPG) and hepatic blood flow did not vary through the study. Pulmonary vasodilation induced by iILO was inversely related to HVPG. In the long-term evaluation, iILO improved FC by 1 or more in 7 patients (P = 0.04) and increased 6MWD by 67 + or - 59 m at 12 months (P < 0.001). No change in systolic PAP was observed. Two patients died because of hepatic complications, and 4 additional patients presented clinically significant events that were related to hepatic disease in 2 and worsening of pulmonary hypertension in 2. We conclude that in patients with PoPH, iILO produces rapid and selective pulmonary vasodilation without altering the hepatic hemodynamics. Its long-term use may provide sustained improvements in symptoms and exercise tolerance in some patients with PoPH. A randomized, controlled trial is warranted to establish its clinical role in this serious condition.

Topics: Administration, Inhalation; Adult; Blood Pressure; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Circulation; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Pulmonary hypertension (PH) is an independent risk factor for increased mortality in patients undergoing heart surgery. Existing chronic PH may be exacerbated by acute post-bypass PH, and this can lead to acute right ventricular failure. The prevention and treatment of right ventricular failure in cardiac surgery is based on three principles: optimize right ventricular preload, improve right ventricular contractility, minimize right ventricular afterload. The last of these may involve specific measures such as the inhalation of nitric oxide (NO) or of the stable prostacyclin analogue iloprost. The advantage of these inhalable substances is their pulmonary selectivity, and the subsequent reduction in systemic side effects. In order to avoid disastrous results in high-risk cardiac surgical patients, intra- and post-operative monitoring with pressure lines, a qualified team that pays attention to details, and an aggressive and early treatment in the operating room with inhaled iloprost and/or NO is necessary. The philosophy of 'wait and see' should be abandoned in favour of 'be suspicious and act early'. In a prospective randomized trial, the efficacies of inhaled iloprost and of inhaled NO in the therapy of PH immediately following weaning from cardiopulmonary bypass in cardiac surgical patients were compared. Iloprost proved to be significantly more effective with respect to mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output than inhaled NO.

Topics: Adult; Cardiac Surgical Procedures; Heart Diseases; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Perioperative Care; Postoperative Complications; Risk Factors; Vasodilator Agents

Congenital heart disease (CHD) is responsible for pulmonary hypertension (PH) in children in about 50% of cases. This pre-operative dynamic pulmonary hypertension can be superimposed and aggravated by acute post-operative PH or persist as chronic PH, especially in children who are not operated on early enough. Inhaled iloprost, a stable prostacyclin analogue, is used for the post-operative management of PH in infants and children with CHD. In a prospective open-label proof-of-concept study, the efficacies of inhaled nitric oxide (iNO) and inhaled iloprost were directly compared. Primary endpoints were the occurrence of a major or minor pulmonary hypertensive crisis. No significant difference between the effects of iNO versus iloprost on peri-operative PH was observed. Neither substance on its own prevented pulmonary hypertensive crises in high-risk infants, so a combination of both substances should be tested in future trials. In China, there are more than 4 million untreated CHD patients. More than 50% of them are untreated adults. Acute pulmonary vasoreactivity tests were performed in CHD patients between 9 months and 43 years of age using inhaled iloprost, in order to find out whether a pre-operative response to inhaled iloprost is a good predictor for the post-operative performance of these patients. The results showed that patient selection criteria for surgery should include both a 20% reduction in pulmonary vascular resistance (PVR) index after iloprost inhalation and a resulting PVR index <11 Wood U/m(2). CHD children between 14 days and 11 years of age took part in a placebo-controlled pilot study that investigated the role of aerosolized iloprost in the treatment of PH after corrective surgery. They received either low- or high-dose iloprost or placebo. Inhaled iloprost significantly improved haemodynamics in a dose-dependent manner and prevented reactive PH and pulmonary hypertensive crises in most of these mechanically ventilated children after CHD repair.

Topics: Cardiac Surgical Procedures; Child; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Perioperative Care; Postoperative Complications; Risk Factors; Vasodilator Agents

There are several animal models for studying human pulmonary hypertension (PH). An increased flow model in pigs was developed at the University Hospital in Heidelberg in order to simulate congenital heart disease. The high pulmonary blood flow is achieved by installation of a Blalock-Taussig anastomosis. In order to further improve this model by adding a pressure component, the left pulmonary artery is ligated. An acute model, which is used at the Innsbruck Medical University, addresses another disease entity. Human meconium is placed deeply into the trachea of the pigs in order to induce an acute respiratory distress syndrome-like response in the lungs. Animals were randomly assigned to four treatment groups. Inhaled iloprost, due to its pulmonary and intrapulmonary selectivity, was the only substance that significantly reduced intrapulmonary shunt volumes. In humans, PH encompasses multiple disease subtypes. Pulmonary arterial hypertension (PAH) accounts for only 6% of PH cases, however, all existing treatments are indicated only for PAH. This means that for 94% of patients with PH, no specific medication is available. Therefore, huge efforts have been made to better understand the pathophysiology of PH and to detect new signalling pathways that may allow new compounds to be developed that will ultimately improve the prognosis of PAH and non-PAH PH patients. Promising new substances include riociguat, a stimulator of the soluble guanylate cyclase (sGC), as well as cinaciguat, a sGC activator, and an elastase inhibitor. Riociguat (BAY 63-2521) is an oral agent that targets the intact/native form of sGC. It enhances the sensitivity of sGC to low levels of bioavailable nitric oxide (NO) and is also capable of stimulating native sGC independently of NO. Thus, unlike phosphodiesterase-5 inhibitors, the effect of riociguat is not limited by low NO levels. In a multicentre open-label phase II study, riociguat exerted strong and significant effects on pulmonary haemodynamics and exercise capacity in patients with PAH and in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is currently being evaluated in phase III clinical trials both in PAH and in CTEPH patients. Clinical studies with riociguat in earlier development stages have addressed PH in lung diseases and systolic left ventricular failure. An elastase inhibitor is currently being investigated in phase I clinical trials in patients with PH owing to chronic obstructive pulmona

Topics: Animals; Disease Models, Animal; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Pyrazoles; Pyrimidines; Vasodilator Agents

There are only a few reports of pulmonary hypertension (PH) in hypersensitivity pneumonitis (HP) and an approved vasomodulatory therapy for PH does not exist at all for interstitial lung disease (ILD), particularly for HP.. The case of a 53-year-old woman with chronic HP and severe life-threatening PH treated with a combined specific vasomodulatory therapy is reported. Sustained clinical and hemodynamic improvement was achieved.. Further investigation of PH in HP and specific vasomodulatory therapy is necessary.

Topics: Alveolitis, Extrinsic Allergic; Chronic Disease; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Phenylpropionates; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable pulmonary arterial hypertension (PAH). Mutations lead to reduced Smad1/5-driven expression of inhibitor of DNA binding protein 1 (Id1) and loss of the growth suppressive effects of BMPs. The impact of existing PAH therapies on BMP signaling is lacking.. Because prostacyclin analogues are effective treatments for clinical PAH, we hypothesized that these agents enhance Smad1/Id1 signaling.. Iloprost alone induced Id1 expression in human pulmonary artery smooth muscle cells (PASMCs), an effect that was independent of Smad1/5 activation but dependent on a cAMP-responsive element in the Id1 promoter. In addition, iloprost and treprostinil enhanced BMP-induced phosphorylation of Smad1/5 and Id1 expression in a cAMP-dependent manner. The mechanism involved suppression of inhibitory Smad, Smad6. Furthermore, iloprost rescued the deficit in Smad1/5 phosphorylation and Id gene expression in PASMCs harboring mutations in BMPR-II and restored growth suppression to BMP4 in mutant PASMCs. We confirmed a critical role for Id1 in PASMC proliferation. Reduced expression of Id1 was observed in concentric intimal lesions of heritable PAH cases. In the monocrotaline rat model of PAH, associated with reduced BMPR-II expression, we confirmed that treprostinil inhibited smooth muscle cell proliferation and prevented progression of PAH while enhancing Smad1/5 phosphorylation and Id1 gene expression.. Prostacyclin analogues enhance Id1 expression in vitro and in vivo and restore deficient BMP signaling in BMPR-II mutant PASMCs.

Topics: Animals; Antihypertensive Agents; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type II; Cell Proliferation; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Inhibitor of Differentiation Protein 1; Male; Monocrotaline; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Phosphorylation; Promoter Regions, Genetic; Pulmonary Artery; Rats; Rats, Sprague-Dawley; RNA Interference; Smad Proteins; Smad1 Protein; Smad5 Protein; Smad6 Protein; Transfection; Up-Regulation

Prostacyclin analogs, used to treat idiopathic pulmonary arterial hypertension (IPAH), are assumed to work through prostacyclin (IP) receptors linked to cyclic AMP (cAMP) generation, although the potential to signal through peroxisome proliferator-activated receptor-γ (PPARγ) exists.. IP receptor and PPARγ expression may be depressed in IPAH. We wished to determine if pathways remain functional and if analogs continue to inhibit smooth muscle proliferation.. We used Western blotting to determine IP receptor expression in peripheral pulmonary arterial smooth muscle cells (PASMCs) from normal and IPAH lungs and immunohistochemistry to evaluate IP receptor and PPARγ expression in distal arteries.. Cell proliferation and cAMP assays assessed analog responses in human and mouse PASMCs and HEK-293 cells. Proliferative rates of IPAH cells were greater than normal human PASMCs. IP receptor protein levels were lower in PASMCs from patients with IPAH, but treprostinil reduced replication and treprostinil-induced cAMP elevation appeared normal. Responses to prostacyclin analogs were largely dependent on the IP receptor and cAMP in normal PASMCs, although in IP(-/-) receptor cells analogs inhibited growth in a cAMP-independent, PPARγ-dependent manner. In IPAH cells, antiproliferative responses to analogs were insensitive to IP receptor or adenylyl cyclase antagonists but were potentiated by a PPARγ agonist and inhibited (∼ 60%) by the PPARγ antagonist GW9662. This coincided with increased PPARγ expression in the medial layer of acinar arteries.. The antiproliferative effects of prostacyclin analogs are preserved in IPAH despite IP receptor down-regulation and abnormal coupling. PPARγ may represent a previously unrecognized pathway by which these agents inhibit smooth muscle proliferation.

Topics: Animals; Antihypertensive Agents; Blotting, Western; Cell Proliferation; Down-Regulation; Epoprostenol; HEK293 Cells; Humans; Hypertension, Pulmonary; Iloprost; Immunohistochemistry; Mice; Muscle, Smooth, Vascular; PPAR gamma; Prostaglandins, Synthetic; Receptors, Epoprostenol; Rosiglitazone; Thiazolidinediones; Vasodilator Agents

To evaluate the efficacy of iloprost in acute vasodilatation test during cardiac catheterization and to explore a useful hemodynamic indication regarding operability in the patients with severe pulmonary hypertension (PH) related to congenital heart disease (CHD).. The clinical data of 46 patients [mean age (12 ± 9) years] with severe PH related to CHD from June 2006 to December 2008 was retrospectively analyzed. All patients underwent standard right and left cardiac catheterization and a trial of inhaled iloprost test during cardiac catheterization. The mean pulmonary arterial pressure was (80 ± 13) mm Hg (1 mm Hg = 0.133 kPa) and pulmonary vascular resistance index was (17 ± 10) wood.m². A positive response to inhaled iloprost was defined as a decrease of at least 20% in pulmonary vascular resistance index (PVRI) without changes on systemic artery pressure. Patients with positive response to iloprost underwent cardiac surgical repair. The pulmonary artery pressure and PVRI was monitored by Swan-Ganz catheter postoperatively.. Of the 46 patients, 29 (63.1%) showed a positive response after iloprost inhalation, defined by a significant reduction in PVRI from (15 ± 6) wood.m(2) at baseline to (9 ± 4) wood.m² in response to iloprost inhalation therapy (P < 0.05). The ratio of pulmonary to systemic resistance (Rp/Rs) decreased from 0.7 ± 0.2 to 0.4 ± 0.2 (P < 0.05). Seventeen patients (36.9%) didn't respond to iloprost displayed only little changes in PVRI [from (21 ± 10) wood.m(2) to (19 ± 9) wood.m²] and Rp/Rs (from 1.0 ± 0.5 to 0.9 ± 0.5). Out of 29 positive patients, 21 (72%) underwent successful cardiac surgical repair with a reduction of mean pulmonary arterial pressure (mPAP) to an average of (27 ± 10) mm Hg after the operation. Only 2 patients out of the 17 patients from the negative group were referred to surgery. Their mPAP was greater than 45 mm Hg.. A significant reduction in pulmonary artery pressure after cardiac surgery was observed in patients with positive response to inhaled iloprost. Inhaled iloprost may be a valuable tool in the preoperative evaluation of patients with severe PH related to CHD.

Topics: Administration, Inhalation; Adolescent; Child; Child, Preschool; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infant; Lung; Male; Preoperative Care; Retrospective Studies; Vasodilator Agents; Young Adult

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension (PH) have been adopted for Germany. Invasive hemodynamic data obtained by right heart catheterization are essential to confirm the diagnosis, test vasoreactivity, assess severity and guide therapy in PH patients. The definition of PH is resting on a mean pulmonary artery pressure ≥ 25 mm Hg obtained by right heart catheterization. Furthermore, a pulmonary capillary wedge pressure > 15 mm Hg excludes pre-capillary PH. Vasoreactivity testing is part of the diagnostic work-up in pulmonary arterial hypertension. Recent data on the use of inhaled iloprost update these guidelines and are of special importance due to the frequent diagnostic use of iloprost in Germany. Other aspects of invasive hemodynamic data in certain PH subgroups as well as their measurement and interpretation in children are discussed. Several aspects of right heart catheterization in PH justify a detailed commentary, and in some areas an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Paediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups were initiated, one of which was specifically addressing the invasive hemodynamic evaluation of patients with PH. This commentary summarizes the results and recommendations of this working group.

Topics: Administration, Inhalation; Catheterization, Swan-Ganz; Child; Evidence-Based Medicine; Germany; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Pulmonary Wedge Pressure; Vascular Resistance; Vasodilator Agents

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Sulfonamides; Vasodilator Agents

Prostacyclin is a pulmonary vasodilator and is produced by prostacyclin synthase and stimulates adenylate cyclase (AC) via the prostacyclin receptor (IP) to produce cAMP. Forskolin is a direct stimulant of AC. Phosphodiesterase 3 hydrolyzes cAMP and is inhibited by milrinone.. To characterize the prostacyclin-AC-cAMP pathway in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN).. University-based laboratory animal facility.. Lambs delivered to time-dated pregnant ewes.. Fifth generation pulmonary arteries (PA) and lung parenchyma were isolated from control fetal lambs (n = 8) and fetal lambs with PPHN induced by antenatal ductal ligation (n = 9). We studied relaxation responses to various agonists (milrinone, forskolin, prostacyclin, and iloprost, a prostacyclin analog) that increase cAMP in PA after half-maximal constriction with norepinephrine and pretreatment with propranolol +/- indomethacin. Lung protein levels of prostacyclin synthase, IP, AC2, and phosphodiesterase 3A were analyzed by Western blot and cAMP by enzyme-linked immunoassay.. Milrinone relaxed control and PPHN PA and pretreatment with indomethacin significantly impaired this response. Relaxation to milrinone, prostacyclin, and iloprost were significantly impaired in PA from PPHN lambs. Pretreatment with milrinone markedly enhanced relaxation to prostacyclin and iloprost in PPHN PA, similar to relaxation in control PA. Relaxation to forskolin was similar in control and PPHN PAs indicating normal AC activity. Protein levels of prostacyclin synthase and IP were decreased in PPHN lungs compared with control, but AC2, cAMP, and phosphodiesterase 3A remained unchanged.. Prostacyclin and iloprost are dilators of PAs from PPHN lambs and their effect is enhanced by milrinone. This combination therapy may be an effective strategy in the management of patients with PPHN.

Topics: Animals; Animals, Newborn; Blotting, Western; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Hypertension, Pulmonary; Iloprost; Male; Milrinone; Pregnancy; Pregnancy, Animal; Probability; Pulmonary Artery; Random Allocation; Reference Values; Sensitivity and Specificity; Sheep, Domestic; Vasodilation

Pulmonary hypertension (PH) is a common complication of sarcoidosis that is associated with increased mortality. The pathogenesis of PH in sarcoidosis is uncertain, and the role of pulmonary arterial hypertension (PAH)-specific therapies remains to be determined.. We conducted a retrospective study of patients with sarcoidosis and PH at two referral centers. New York Heart Association (NYHA) functional class, exercise capacity, hemodynamic data, pulmonary function tests, and survival were collected and analyzed.. Twenty-two sarcoidosis patients treated with PAH-specific therapies were identified. After a median of 11 months of follow-up, NYHA class was improved in nine subjects. Mean 6-min walk distance (n = 18) increased by 59 m (p = 0.032). Patients with a higher FVC experienced a greater increment in exercise capacity. Among 12 patients with follow-up hemodynamic data, mean pulmonary artery pressure was reduced from 48.5 +/- 4.3 to 39.4 +/- 2.8 mm Hg (p = 0.008). The 1- and 3-year transplant-free survival rates were 90% and 74%, respectively.. PAH-specific therapy may improve functional class, exercise capacity, and hemodynamics in PH associated with sarcoidosis. Prospective, controlled trials of PAH therapies for sarcoidosis are warranted to verify this apparent benefit. Mortality among the study population was high, highlighting the need for urgent evaluation at a lung transplant center.

Topics: Administration, Inhalation; Administration, Oral; Aged; Antihypertensive Agents; Bosentan; Cohort Studies; Drug Therapy, Combination; Epoprostenol; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Piperazines; Probability; Purines; Respiratory Function Tests; Retrospective Studies; Risk Assessment; Sarcoidosis; Severity of Illness Index; Sildenafil Citrate; Statistics, Nonparametric; Sulfonamides; Sulfones; Survival Rate; Treatment Outcome

It has been widely accepted that development of porto-pulmonary hypertension (POPH) is independent of the cause of portal hypertension. The degree of hepatic damage and liver function do not correlate with predisposition to POPH or its severity. However, portal hypertension has been confirmed as a prerequisite for developing pulmonary hypertension. Transthoracic echocardiography is the best screening test for the presence of POPH, but a diagnosis of POPH can be established only by right heart catheterization. Randomized controlled trials comparing the efficacy and safety of different pharmacologic strategies are lacking in patients with POPH. The general management includes diuretics and oxygen supplementation. Notably, moderate to severe POPH predisposes candidates for orthotopic liver transplantation to a higher risk of perioperative mortality. Vasomodulating pharmacologic agents are used in patients with moderate to severe POPH to decrease pulmonary arterial hypertension, thereby permitting liver transplantation to be performed safely. Epo-prostenol is the best-studied medication, and bosentan appears promising.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Echocardiography; Epoprostenol; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Transplantation; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Pulmonary hypertension is an important complication of COPD. A small subset of patients with COPD have severe pulmonary hypertension (PH) that is out of proportion to the mild increase in pulmonary arterial pressure observed commonly. Severe PH associated with COPD is associated with increased morbidity and mortality. Treatment options in this group of patients are limited with no conclusive evidence of benefit when drugs approved for treatment of pulmonary arterial hypertension are used. We describe a patient with severe PH associated with COPD who improved clinically and hemodynamically when treated with inhaled iloprost. The improvement was sustained for 2 years. Severe PH in patients with COPD needs to be recognized and novel treatment approaches considered.

Topics: Administration, Inhalation; Aged; Blood Gas Analysis; Dose-Response Relationship, Drug; Drug Administration Schedule; Echocardiography, Transesophageal; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Male; Maximum Tolerated Dose; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Risk Assessment; Severity of Illness Index; Treatment Outcome; Vasodilator Agents

The aim of this study was to confirm the utility of aerosolised iloprost for identifying long-term responders to calcium channel blockers (CCBs) in patients with idiopathic pulmonary arterial hypertension (IPAH). While undergoing right heart catheterisation, 74 patients with IPAH sequentially received incremental infusions of adenosine and aerosolised iloprost. The effects of the two vasodilators on haemodynamic parameters were recorded. All acute responders identified by aerosolised iloprost were subsequently treated with high doses of a CCB and were re-evaluated after 12 months. Both adenosine and iloprost produced significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance, and significant increases in cardiac index. Adverse effects were experienced by 35 out of the 74 patients with adenosine, but by only two with iloprost. Aerosolised iloprost identified more acute responders than infused adenosine (10 versus eight, respectively) according to the criteria recommended in recent consensus guidelines. Nine responders identified by iloprost were followed-up after 12 months of high-dose CCB therapy. Five had normal or near-normal haemodynamics and a World Health Organization functional classification of I or II after 12 months. Aerosolised iloprost is an appropriate new agent to identify long-term responders to CCBs in patients with IPAH. It is as effective in this regard as infused adenosine but is better tolerated.

Topics: Adenosine; Administration, Inhalation; Adolescent; Adult; Aerosols; Aged; Calcium Channel Blockers; Cardiac Catheterization; Child; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Vasodilator Agents

A right heart catheterization with reversibility testing is recommended for the diagnosis and treatment of pulmonary arterial hypertension. In this 24 years-old woman, the inhalation of 5 microg iloprost transiently decreased mean pulmonary artery pressure from 62 to 36 mmHg and pulmonary vascular resistance from 11.0 to 4.9 Wood units, meeting the criteria of a "positive response". The echocardiographic examination showed normalization of right heart chamber dimensions and of the right ventricular performance (Tei) index. Pulsed tissue Doppler imaging of the right ventricle showed a decrease in the isovolumic relaxation time from 102 to 73 ms, and an increase of the E/A ratio from 0.72 to 1.38, together with marked improvements in mid-apical free wall systolic strain and strain rate. A positive response to reversibility testing of pulmonary arterial hypertension may be associated with quasi normalization of right ventricular function, in spite of still elevated pulmonary artery pressure.

Topics: Administration, Inhalation; Adult; Blood Pressure; Cardiac Catheterization; Echocardiography, Doppler; Female; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents; Ventricular Dysfunction, Right

To determine the effects of inhaled nitric oxide (NO) and aerosolized iloprost on pulmonary hemodynamics and lung edema formation in a rat model of pulmonary hypertension due to congestive heart failure (CHF).. Prospective, randomized, controlled study.. Research laboratory.. One hundred sixty male Sprague-Dawley rats.. CHF was induced by supracoronary aortic banding whereas sham-operated rats served as controls. CHF rats or controls inhaled NO, aerosolized iloprost, or 0.9% NaCl for 3 minutes each. Additional CHF groups received intravenous infusions of iloprost, sodium nitroprusside, or 0.9% NaCl. For prolonged drug administration over 150 minutes, NO was inhaled continuously whereas aerosolized iloprost was administered for 3 minutes each at 45-minute intervals.. Dose-response relations in rats with CHF showed a maximal pulmonary-selective reduction in blood pressure at 20 ppm NO and 2.5 microg/mL aerosolized iloprost, with iloprost therapy resulting in a greater decrease in pulmonary arterial pressure (PAP). At these doses, both vasodilators decreased pulmonary vascular resistance and increased venous oxygen saturation (Svo2) in the absence of systemic hemodynamic effects. No pulmonary or systemic effects were detected in rats with CHF inhaling 0.9% NaCl or in control rats inhaling NO or iloprost. Intravenous infusion of iloprost or sodium nitroprusside not only reduced pulmonary but also systemic vascular resistance. During prolonged inhalation, NO caused a stable reduction in PAP, whereas PAP decreased even further during repetitive iloprost inhalations. After 150 minutes, iloprost-treated rats had a higher Svo2 and lesser edema as compared with animals with CHF inhaling NO or untreated rats with CHF, although differences in wet/dry weight ratio did not reach statistical significance (p < 0.06).. Inhaled vasodilators may offer an effective, safe, and pulmonary-selective strategy for the treatment of pulmonary hypertension in left heart disease, and inhaled iloprost may be superior to NO in this condition.

Topics: Administration, Inhalation; Aerosols; Animals; Heart Failure; Hypertension, Pulmonary; Iloprost; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a life-threatening disease of the pulmonary arterioles, which, in the absence of effective therapy, progresses rapidly to right heart failure and death. Opening of a patent foramen ovale (PFO) is common in patients with severe pulmonary hypertension (PH), resulting in resistive hypoxemia. We report the case of a 40-year-old woman with idiopathic pulmonary hypertension (iPAH) in New York Heart Association (NYHA) class III to IV, who was admitted in the intensive care unit with hemodynamic compromise and severe hypoxemia due to right-to-left shunt throughout a PFO. Combination therapy initially with inhaled iloprost and sildenafil, and then addition of an endothelin A receptor-selective antagonist (sitaxsentan), resulted in impressive improvement in oxygenation with reversal of the right-to-left shunt and marked improvement in functional class of the patient.

Topics: Adult; Antihypertensive Agents; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Epoprostenol; Female; Foramen Ovale, Patent; Humans; Hypertension, Pulmonary; Iloprost; Isoxazoles; Piperazines; Purines; Sildenafil Citrate; Sulfones; Thiophenes; Treatment Outcome; Vasodilator Agents

Topics: Adenosine; Administration, Inhalation; Diltiazem; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Vasodilator Agents

Primary pulmonary hypertension (PPH) is diagnosed in case of pulmonary hypertension of unexplained etiology. When PPH occurs in members of a family it should be diagnosed as familial PPH. Genetic anticipation has been described in familial PPH. We present a case of two children (4-year-old boy and 8-year-old girl) who died due to complications of familial PPH and their 39-year-old mother who has been treated due to PPH for two years. This case is interesting due to the scarcity of such reports, seriousness of the disease and genetic anticipation of familial PPH.

Topics: Adult; Anticipation, Genetic; Child; Child, Preschool; Echoencephalography; Electrocardiography; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Platelet Aggregation Inhibitors

Topics: Algorithms; Clinical Trials as Topic; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Time Factors; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a significant disease process characterized by elevated pulmonary vascular resistance leading to increased right ventricular afterload and ultimately progressing to right ventricular dysfunction and often death. Irreversible remodeling of the pulmonary vasculature is the hallmark of pulmonary hypertension and frequently leads to progressive functional decline in patients with PAH despite treatment with currently available therapies. Metabolites of the arachidonic acid cascade play an important homeostatic role in the pulmonary vasculature, and dysregulation of pathways downstream of arachidonic acid plays a central role in the pathobiology of PAH. Cyclooxygenase-2 (COX-2) is up-regulated in pulmonary artery smooth muscle cells (PASMC) and inflammatory cells during hypoxia and plays a protective role in the lung's response to hypoxia. We recently demonstrated that absence of COX-2 was detrimental in a mouse model of hypoxia-induced pulmonary hypertension. Exposure of COX-2 null mice to hypoxia resulted in severe pulmonary hypertension characterized by enhanced pulmonary vascular remodeling and significant up-regulation of the endothelin-1 receptor ET(A)R in the lung after hypoxia. Absence of COX-2 in vitro led to enhanced contractility of PASMC after exposure to hypoxia, which could be attenuated by iloprost, a prostaglandin I(2) analog. These findings suggest that selective inhibition of COX-2 may have detrimental pulmonary vascular consequences in patients with preexisting pulmonary hypertension or underlying hypoxemic lung diseases. Here, we discuss our recent data demonstrating the adverse consequences of COX-2 inhibition on pulmonary vascular remodeling and PASMC contractility.

Topics: Animals; Arachidonic Acid; Cell Proliferation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Pulmonary Artery; Signal Transduction; Vasoconstriction; Vasodilator Agents

Iloprost, as a stable analog of endogenous prostacyclin, has far-reaching pharmacological effects. For several years already it has been used successfully in its intravenous and inhalative forms for treating patients with pulmonary hypertension (PH). Since the development of efficient nebulizers that guarantee a constant output of the effective agent, inhalative iloprost has become an important alternative in the drug treatment of PH. Inhalative iloprost is an effective and safe partner for other classes of substances in combination therapy, which is becoming ever more frequently necessary. In addition, it is also used in the acute testing of pulmonary vasoreactivity and in intensive care therapy of manifest right heart failure.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Critical Care; Drug Therapy, Combination; Female; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Male; Middle Aged; Pulmonary Circulation; Vasodilator Agents

Topics: Administration, Inhalation; Algorithms; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Lung Transplantation; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

To study the acute oxygen kinetic effect of inhaled iloprost in pulmonary artery hypertension and chronic thromboembolic pulmonary hypertension.. Twenty-two and 24 patients who were admitted to our hospital between June 2006 and January 2009 with confirmed diagnosis of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) respectively were enrolled to this study. During right heart catheterization, the hemodynamics and oxygen kinetics were monitored at baseline and after inhaling Iloprost (20 micrograms).. At baseline, the arterial partial pressure of oxygen (PaO2) was (63 +/- 10) mm Hg (1 mm Hg = 0.133 kPa) and (59 +/- 10) mm Hg respectively in PAH and CTEPH patients, and the oxygen delivery index (DO2I) and oxygen consumption index (VO2I) were (458 +/- 136) ml x min(-1) x m(-2) and (135 +/- 53) ml x min(-1) x m(-2) in PAH patients respectively, and (386 +/- 92) ml x min(-1) x m(-2) and (131 +/- 43) ml x min(-1) x m(-2) in CTEPH patients respectively. Three minutes after inhaling Iloprost, for PAH and CTEPH patients, the pulmonary shunt rate (Qs/Qt) all increased significantly (all P < 0.05, respectively) as well as the difference of oxygen partial pressure between pulmonary alveoli and artery (P[A-a]O2, all P < 0.05, respectively), and the arterial oxygen content (CaO2) all decreased significantly (all P < 0.05, respectively). The oxygenation parameters of mixed venous blood, oxygen extractive rate and DO2I did not change significantly, but VO2I declined to different extent. The extent of change after inhaling Iloprost for all oxygen kinetic parameters were similar between PAH and CTEPH patients. At baseline, mixed venous oxygen saturation (SvO2), venous oxygen content (CvO2) and DO2I in CTEPH patients were lower than those in PAH patients. After inhaling Iloprost, in CTEPH patients, PaO2, SvO2 and CvO2 were lower than those in PAH patients.. There were hypoxemia and abnormality of oxygen kinetics in PAH and CTEPH patients. After inhaling Iloprost, pulmonary shunt increased without improvement in oxygen kinetics. Oxygenation should be monitored closely and supply oxygen supplied for CTEPH when inhaling Iloprost.

Topics: Administration, Inhalation; Adult; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Oxygen; Oxygen Consumption; Pulmonary Artery; Vasodilator Agents

Topics: Child; Drug Eruptions; Facial Dermatoses; Humans; Hypertension, Pulmonary; Iloprost; Male; Vasodilator Agents

To compare the acute hemodynamic effects of adenosine versus iloprost in patients of pulmonary arterial hypertension (PAH) complicated with connective tissue diseases.. During right heart catheterization, 18 patients of PAH complicated with connective tissue diseases sequentially received intravenous infusion of adenosine and inhaled iloprost. After the baseline hemodynamic data were obtained, an adenosine infusion was started and titrated to the maximal tolerated dose. The hemodynamic parameters were allowed to return to baseline. Then inhalation of iloprost was administered. The effects of both medicines on the patient's hemodynamics were monitored.. As compared with the baseline values, the systolic pulmonary artery pressure and pulmonary vascular resistance significantly decreased [(71 +/- 30) vs (80 +/- 29) mm Hg and (712 +/- 440) vs (824 +/- 464) dyn x s x cm(-5) respectively, both P < 0.05) while the heart rate increased significantly [(93 +/- 17) vs (83 +/-16) beat/min, P < 0.05] in the adenosine group. Inhaled iloprost could also lower the systolic pulmonary artery pressure [(66 +/- 29) vs (79 +/- 28) mm Hg, P < 0.05], mean pulmonary artery pressure [(43 +/- 19) vs (52 +/- 19) mm Hg, P < 0.05] and pulmonary vascular resistance [(632 +/- 440) vs (816 +/- 448) dyn x s x cm(-5), P < 0.05] without any effect upon heart rate. Inhaled iloprost exerted more potent effect on lowering mean pulmonary artery pressure and pulmonary vascular resistance than adenosine (P < 0.05). The two medicines did not affect cardiac output, pulse oxygen saturation or systemic blood pressure. The side effects were fewer in the iloprost inhalation group than the adenosine group.. During acute vasodilator testing, inhaled iloprost was more potent than infused adenosine as a pulmonary vasodilator in PAH complicated with connective tissue diseases.

Topics: Adenosine; Adult; Antihypertensive Agents; Blood Pressure; Cardiac Catheterization; Connective Tissue Diseases; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Prospective Studies; Vasodilation; Vasodilator Agents; Young Adult

To evaluate the acute effects of inhaled iloprost on hemodynamics and oxygenation in chronic thromboembolic pulmonary hypertension (CTEPH).. A prospective study was made. Eighteen patients with CTEPH were enrolled. At right heart catheterisation, iloprost was inhaled at 20 microg for 10 - 15 min. Compare the value of heart rate (HR), mean blood pressure (mBP), mean pulmonary arterial hypertension (mPAP), right atrium pressure (RAP), pulmonary arterial wedge pressure (PAWP), cardiac output (CO), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), arterial partial pressure of oxygen (PaO2), arterial oxygen saturation (SaO2), mixed venous saturation (SvO2), pulmonary shunt fraction (Qs/Qt), alveolar-arterial partial pressure of oxygen [P ( A-a) O2] before to after inhaled iloprost in these patients.. Significant changes (before to after inhalation): mPAP, (53 +/- 11) to (47 +/- 14) mm Hg (P < 0.01); PVR, (821 +/- 194) to (681 +/- 199) dyn x s x cm(-5) (P < 0.01); RAP, (10 +/- 6) to (7 +/- 6) mm Hg (P < 0.01). However, HR, PAWP, mBP, CO and SVR had no significant changes. At the same time, inhaled iloprost significantly decreased PaO2 from (58 +/- 11) to (52 +/- 6) mm Hg (P < 0.01) and increased Qs/Qt from (27 +/- 11)% to (33 +/- 9)% (P < 0.01)and P(A-a) O2 from (86 +/-39) to (93 +/- 38) mm Hg (P < 0.01).. Inhaled iloprost might instantly improve hemodynamics in CTEPH, but at the same time it increased arteriovenous shunts which resulted in lower PaO2.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Oxygen; Partial Pressure; Prospective Studies; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Vasodilator Agents; Young Adult

Increased pulmonary vascular resistance causing pulmonary artery hypertension is a major problem in the treatment of congenital diaphragmatic hernia with a strong association to mortality. We here report a patient with intractable pulmonary hypertension at 4 weeks of age unresponsive to conventional treatment. After administration of the platelet-derived growth factor (PDGF) receptor antagonist imatinib, pulmonary artery pressure gradually decreased to acceptable levels and the patient's clinical condition gradually improved.

Topics: Benzamides; Bosentan; Combined Modality Therapy; Continuous Positive Airway Pressure; Diuretics; Enteral Nutrition; Extracorporeal Membrane Oxygenation; Heart Failure; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Imatinib Mesylate; Infant, Newborn; Male; Nitric Oxide; Piperazines; Protein Kinase Inhibitors; Purines; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Sildenafil Citrate; Sulfonamides; Sulfones

Pulmonary hypertensive crisis (PHC) is a significant contributor to the morbidity and mortality of surgery for congenital heart defect. Management of such a potentially fatal complication has been evolving for the past decades. Inhaled iloprost has been reported as an alternative treatment for this condition. We evaluated the use of aerosolized iloprost as a rescue therapy for PHC in children undergoing congenital heart surgery.. In this clinical study, 12 high risk children were monitored in order to identify postoperative PHC after congenital heart repair. Factors being monitored included pulmonary artery pressure, systemic blood pressure, left atrial pressure, transcutaneous oximetry and heart rate. PHC was defined as an acute rise in pulmonary pressure which causes cardiopulmonary compromise as reflected by desaturation and hypotension. Despite conventional medical treatment to prevent postoperative PHC, children with PHC were therefore administered with aerosolized iloprost (0.5 microg/kg).. Eight of the 12 children had one or more episodes of PHC, secondary to the pulmonary vasoreactivity. All responded to the aerosolized iloprost treatment, as demonstrated by a fall in their mean pulmonary pressure from 47.9 + or - 14.9 to 30.2 + or - 7.9 mmHg (p=0.012) and a rise in the arterial saturation from 82.2 + or - 16.7 to 93.4 + or - 11.5 % (p=0.012) while mean systemic blood pressure tended to increase from 59.4 + or - 12.1 to 64 + or - 10.3 mmHg (p=0.16).. In medical setting with limited access to the nitric oxide, inhaled iloprost is consider to be an effective alternative treatment for postoperative PHC in children undergoing congenital heart surgery.

Topics: Administration, Inhalation; Adolescent; Child; Child, Preschool; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Infant; Postoperative Complications; Prospective Studies

This study investigated the short- and long-term outcome of children with pulmonary arterial hypertension (PAH) treated with inhaled iloprost.. Inhaled iloprost has been approved for the treatment of adults with PAH, but little is known about the effects in children with PAH.. We evaluated the acute effects of inhaled iloprost on hemodynamic status and lung function and the response to long-term therapy in 22 children (range 4.5 to 17.7 years) with PAH (idiopathic, n = 12; congenital heart disease, n = 10). Cardiac catheterization, standard lung function testing before and after iloprost inhalation, 6-min walk test, World Health Organization functional class, and hemodynamic parameters were monitored.. Acute administration of inhaled iloprost lowered mean pulmonary artery pressure equivalent to the response to inhaled nitric oxide with oxygen. Acute iloprost inhalation reduced forced expiratory volume in 1 s and mid-volume forced expiratory flow by 5% and 10%, respectively, consistent with acute bronchoconstriction. At 6 months, functional class improved in 35%, decreased in 15%, and remained unchanged in 50% of children. Sixty-four percent of patients continued receiving long-term iloprost therapy, 36% stopped iloprost, due to lower airway reactivity, clinical deterioration, or death. In 9 patients on chronic intravenous prostanoids, 8 transitioned from intravenous prostanoids to inhaled iloprost, which continued during follow-up.. Inhaled iloprost caused sustained functional improvement in some children with PAH, although inhaled iloprost occasionally induced bronchoconstriction. Most patients tolerated the transition from intravenous to inhaled prostanoid therapy. Clinical deterioration, side effects, and poor compliance, owing to the frequency of treatments, could limit chronic treatment in children.

Topics: Administration, Inhalation; Adolescent; Age Factors; Child; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Male; Multivariate Analysis; Probability; Respiratory Function Tests; Retrospective Studies; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild-to-moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second(-1) cm(-5). The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long-term consequences.

Topics: Adult; Blood Pressure; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Diseases; Liver Transplantation; Male; Piperazines; Pulmonary Artery; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

We present a case of scleroderma complicated by severe pulmonary hypertension. The use of a three-drug (bosentan, iloprost, and sildenafil) approach contributed to significant improvement of both the clinical conditions and the pulmonary hemodynamics. Combining three pulmonary vasodilators with different mechanisms of action could benefit patients with severe pulmonary hypertension resistant to conventional therapy.

Topics: Bosentan; Drug Therapy, Combination; Electrocardiography; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia.. To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2-deficient mice to a model of chronic normobaric hypoxia. COX-2-null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2-deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2-deficient mice had significant upregulation of the endothelin-1 receptor (ET(A)) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ET(A) receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2-deficient PASMCs with iloprost, a prostaglandin I(2) analog, and prostaglandin E(2) abrogated the potent contractile response to hypoxia and restored the wild-type phenotype.. Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ET(A) receptor expression and increased PASMC hypertrophy. COX-2-deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2-derived prostaglandin I(2) or prostaglandin E(2).

Topics: Animals; Blood Pressure; Cells, Cultured; Chronic Disease; Collagen; Cyclooxygenase 2; Dinoprostone; Endothelin-1; Gels; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Iloprost; Mice; Mice, Mutant Strains; Muscle Contraction; Muscle, Smooth, Vascular; Pulmonary Artery; Receptor, Endothelin A; Traction; Vasoconstriction; Vasodilator Agents

Iloprost is effective for the treatment of pulmonary hypertension. It acts through elevation of cAMP by binding to the prostacyclin receptor (IP receptor). However, there is evidence that patients with severe pulmonary hypertension have decreased expression of the IP receptor in the remodeled pulmonary arterial smooth muscle.. We hypothesized that prostanoid receptors other than the IP receptor are involved in signal transduction by iloprost.. Immunoblotting was used to detect the IP and prostanoid EP4 receptor in lung tissue from patients with idiopathic pulmonary arterial hypertension, and immunohistochemistry was used to detect these receptors in lung sections from rats treated with monocrotaline (MCT28d). Protein and mRNA were isolated from pulmonary arterial smooth muscle cells (PASMCs) from control and MCT28d rats treated with AH6809 (an EP2 receptor antagonist) and AH23848 (an EP4 receptor antagonist) in combination with iloprost. Intracellular cAMP was also assessed in these tissues.. IP receptor expression was reduced in idiopathic pulmonary arterial hypertension patient lung samples and MCT28d rat lungs compared with the controls. Reverse transcriptase-polymerase chain reaction and immunoblotting of MCT28d rat PASMC extracts revealed scant expression of the IP receptor but stable expression of EP4 receptor, compared with controls. Iloprost-induced elevation in intracellular cAMP in PASMCs was dose-dependently reduced by AH23848, but not by AH6809.. Iloprost mediates vasodilatory functions via the EP4 receptor in the case of low IP receptor expression associated with pulmonary arterial hypertension. This is a previously unrecognized mechanism for iloprost, and illustrates that the EP4 receptor may be a novel therapeutic approach for the treatment of pulmonary arterial hypertension.

Topics: Animals; Cells, Cultured; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Iloprost; Lung; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Vasodilator Agents

Chronic left-heart failure is often associated with the development of pulmonary venous hypertension. In heart transplant candidates this is of great significance because the healthy donor heart has to compensate the increased right-ventricular afterload. Right-ventricular dysfunction is still responsible for 19% of all early deaths after orthotopic heart transplantation. Careful preoperative assessment of pulmonary vascular resistance by right-heart catheterization is essential. Reversibility testing is generally carried out to clarify therapeutic options for the post-transplant period. The objective of this case series is to report our institutional experience with inhaled iloprost compared to the common used oxygen/nitroglycerin method for reversibility testing.. Right-heart catheterization was performed in 23 patients with severely impaired left-ventricular function (EF < or = 25%, pVO2 < or = 14 ml/kg/min, NYHA III or IV) with combined pulmonary venous hypertension (TPG > 12 mm Hg and or PVR > 250 dyn x s x cm(-5)). An intraindividual comparison was performed between of the hemodynamic effect with oxygen/nitroglycerin s.l. and inhaled iloprost.. The transpulmonary gradient fell significantly from an initial 16 mm Hg to 13 mm Hg on oxygen/nitroglycerin s.l. compared to 10 mm Hg on inhaled iloprost. Pulmonary vascular resistance fell significantly from an initial 344 dyn x s x cm(-5) to 270 dyn x s x cm(-5) on oxygen/nitroglycerin s.l. compared to 209 dyn x s x cm(-5) on inhaled iloprost. On inhaled iloprost a moderate systemic effect was noticed.. In heart transplant candidates with pulmonary venous hypertension reversibility testing with inhalation of iloprost is a save method and significantly more effective than the combination of inhaled oxygen plus nitroglycerin s.l.

Topics: Administration, Inhalation; Adult; Aged; Cardiac Catheterization; Female; Heart Failure; Heart Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitroglycerin; Oxygen Inhalation Therapy; Pilot Projects; Vascular Resistance; Vasodilator Agents

Nebulised iloprost is established therapy of severe pulmonary hypertension; however, the effects on the bronchoalveolar compartment have not been investigated so far. We studied the short- and long-term effects of nebulised iloprost on pulmonary function tests and gas exchange in 63 patients with severe pulmonary hypertension (idiopathic n=17, chronic thromboembolism n=15, connective tissue disease n=12, congenital heart disease n=11, respiratory diseases n=8). Patients received iloprost in increasing dose up to 140 micro g iloprost/24h via an ultrasonic nebuliser. Short-term effects were assessed before and after every nebulisation: peak expiration flow decreased in mean by 1.9% (423+/-98 to 415+/-98) and percutaneous oxygen saturation increased in mean by 0.7% (90+/-6 to 91+/-5) post-nebulisation. There were no significant differences concerning underlying diagnosis or dose of nebulised iloprost. Within 3 months, 9 patients stopped treatment due to non-compliance with frequent nebulisations (n=3), or severe side effects (n=4); 2 patients with additional obstructive lung disease developed bronchoconstriction. Long-term effects were assessed by pulmonary function tests and gas exchange parameters at baseline and after 3 months treatment. There were no significant differences after 3 months therapy neither in FEV(1), FVC, TLC, residual volume nor in diffusions capacity, SO(2) at rest and during 6 min walking test, also in respect of the underlying diseases. However, there was a significant increase in 6 min walking distance (6 MWD) after 3 months (246+/-113 to 294+/-115 m, P<0.05). In conclusion, treatment with nebulised iloprost leads to functional improvement in severe pulmonary hypertension without systematic adverse short- and long-term effects on pulmonary function test or gas exchange. Patients with additional obstructive lung disease might develop bronchoconstriction. Severe side effects leading to discontinuation of treatment occurred in 9% of patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Connective Tissue Diseases; Female; Forced Expiratory Flow Rates; Heart Diseases; Humans; Hypertension, Pulmonary; Iloprost; Lung; Male; Middle Aged; Nebulizers and Vaporizers; Peak Expiratory Flow Rate; Pulmonary Embolism; Respiratory Function Tests; Sulfur Dioxide; Treatment Outcome; Vasodilator Agents; Vital Capacity

Parathyroid hormone-related protein (PTHrP) is an endothelial-derived vasoactive peptide. This study investigated whether bioactive PTHrP is locally released in a pressure-dependent way.. A PTHrP antibody directed against the midregional part of PTHrP was used to analyze PTHrP in plasma samples. The biological activity of this PTHrP-like peptide was investigated in vitro. Plasma values were determined in samples from the left pulmonary artery and the arteria femoralis, taken under basal conditions and after the application of oxygen or iloprost to lower the pulmonary pressure. Twenty young patients (mean age 6.5 years), who were catheterized for an analysis of the reactivity of the pulmonary bed, were investigated. Endothelial function was investigated by acetylcholine responsiveness.. The antibody recognized a 30-kDa protein with in vitro PTHrP-like activity. In 11 patients (responders) with intact endothelial function, the PTHrP values determined in the left pulmonary artery were higher than those in the arteria femoralis. The local increase in the PTHrP concentration was reduced when either oxygen or iloprost lowered the pressure. Nine patients with endothelial dysfunction did not show any concentration gradients at any time (nonresponders).. The local concentration of bioactive PTHrP is increased in patients with pulmonary hypertension and normal endothelial function.

Topics: Acetylcholine; Adolescent; Blood Pressure; Child; Child, Preschool; Endothelium, Vascular; Female; Femoral Artery; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Male; Mechanotransduction, Cellular; Oxygen; Parathyroid Hormone-Related Protein; Pulmonary Artery; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a severe and progressive disease. The prostacyclin analogue iloprost is effective against PAH, but requires six to nine inhalations per day. The feasibility of liposomes to provide a sustained release formulation to reduce inhalation frequency is evaluated from a technological point of view.. Liposomal formulations consisting of di-palmitoyl-phosphatidyl-choline (DPPC), cholesterol (CH) and polyethyleneglycol-di-palmitoyl-phosphatidyl-ethanolamine (DPPE-PEG) were prepared. Their physico-chemical properties were investigated using dynamic light scattering, atomic force microscopy and differential scanning calorimetry. Stability of liposomes during aerosolization using three different nebulizers (air-jet, ultrasonic and vibrating mesh) was investigated with respect to drug loading and liposome size, pre- and post-nebulization.. The phospholipid composition affected the diameters of liposomes only slightly in the range of 200-400 nm. The highest iloprost loading (12 microg/ml) and sufficient liposome stability (70% drug encapsulation post-nebulization) was observed for the DPPC/CH (70:30 molar ratio) liposomes. The formulation's stability was confirmed by the relatively high phase transition temperature (53 degrees C) and unchanged particle sizes. The incorporation of DPPE-PEG in the liposomes (DPPC/CH/DPPE-PEG, 50:45:5 molar ratio) resulted in decreased stability (20-50% drug encapsulation post-nebulization) and a phase transition temperature of 35 degrees C. The vibrating mesh nebulizer offered a number of significant advantages over the other nebulizers, including the production of small aerosol droplets, high output, and the lowest deleterious physical influence upon all investigated liposomes.. Iloprost-loaded liposomes containing DPPC and CH components yield formulations which are well suited to aerosolization by the vibrating mesh nebulizer. The investigation of sustained release effects for the treatment of PAH in ex vivo and in vivo models is under way.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Administration, Inhalation; Aerosols; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Cholesterol; Drug Carriers; Drug Compounding; Drug Stability; Excipients; Hypertension, Pulmonary; Iloprost; Liposomes; Microscopy, Atomic Force; Nebulizers and Vaporizers; Particle Size; Polyethylene Glycols; Pulmonary Alveoli; Ultrasonics; Vasodilator Agents

The rapid desensitization of the human prostacyclin (IP) in response to agonist binding has been shown in cell culture. Phosphorylation of the IP receptor by protein kinase C (PKC) has been suggested to be involved in this process.. In this study we investigated the vasodilatory effects of iloprost, a stable prostacyclin analogue, in perfused rabbit lungs. Continuous infusion of the thromboxane mimetic U46619 was employed to establish stable pulmonary hypertension. A complete loss of the vasodilatory response to iloprost was observed in experiments with continuous iloprost perfusion, maintaining the intravascular concentration of this prostanoid over a 180 min period. When lungs under chronic iloprost infusion were acutely challenged with inhaled iloprost, a corresponding complete loss of vasoreactivity was observed. This desensitization was not dependent on upregulation of cAMP-specific phosphodiesterases or changes in adenylate cyclase activity, as suggested by unaltered dose-response curves to agents directly affecting these enzymes. Application of a prostaglandin E1 receptor antagonist 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809) or the PKC inhibitor bisindolylmaleimide I (BIM) enhanced the vasodilatory response to infused iloprost and partially prevented tachyphylaxis.. A three-hour infusion of iloprost in pulmonary hypertensive rabbit lungs results in complete loss of the lung vasodilatory response to this prostanoid. This rapid desensitization is apparently not linked to changes in adenylate cyclase and phosphodiesterase activation, but may involve PKC function and co-stimulation of the EP1 receptor in addition to the IP receptor by this prostacyclin analogue.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Cell Culture Techniques; Colforsin; Cyclic AMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Female; Hypertension, Pulmonary; Iloprost; Infusions, Parenteral; Lung; Male; Myocytes, Smooth Muscle; Rabbits; Receptors, Epoprostenol; Vasodilator Agents

Topics: Drug Administration Schedule; Electrocardiography; Fatal Outcome; Female; Heart Failure; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Intracranial Aneurysm; Male; Nitric Oxide; Oxygen; Pneumothorax; Respiration, Artificial; Vasodilator Agents

Topics: Administration, Intranasal; Administration, Oral; Animals; Bosentan; Drug Evaluation, Preclinical; Endothelin A Receptor Antagonists; Epoprostenol; Forecasting; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Isoxazoles; Life Expectancy; Lung Transplantation; Monocrotaline; Piperazines; Platelet-Derived Growth Factor; Purines; Randomized Controlled Trials as Topic; Rats; Sheep; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Vasodilator Agents

Epoprostenol significantly improves function and survival in patients with pulmonary arterial hypertension (PAH) but is associated with many risks and side effects. Furthermore, effective oral therapy is now available. We report our long-term experience with 13 patients from among 118 treated with epoprostenol who were able to be weaned to oral therapy, including 6 with persistently abnormal hemodynamics (mean pulmonary artery pressure > or = 35 mm Hg).. Oral therapy with bosentan (n = 11) or sildenafil (n =2) was started before weaning epoprostenol in all but 1 patient. Right heart catheterization was performed when patients reached a dose of 2 ng/kg/min, and epoprostenol was discontinued with hemodynamic monitoring. Functional class and 6-minute walk test were assessed at regular intervals. Repeat right heart catheterization was performed 1 year after discontinuation of epoprostenol.. Nine patients remained on oral therapy alone for up to 46 months. Four patients deteriorated in functional class, and 2 of them resumed epoprostenol therapy. Inhaled iloprost was started in another patient. One additional patient died, unrelated to PAH. Twelve patients underwent right heart catheterization at the time of epoprostenol discontinuation. Hemodynamic evaluation 13.2 +/- 0.9 months later showed that the 5 patients with normal or nearly normal hemodynamics at the time of discontinuation of epoprostenol had no deterioration, whereas 4 of the 7 patients with abnormal hemodynamics had worsened. The 6-minute walk test at last follow-up was not significantly changed from maximal distance on epoprostenol (420 +/- 94 vs 412 +/- 95 meters).. Weaning from epoprostenol to sildenafil or bosentan with sustained clinical improvement is possible, even with persistent pulmonary hypertension; however, patients with persistently abnormal hemodynamics are at risk for hemodynamic and clinical deterioration and require close follow-up.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Antihypertensive Agents; Blood Pressure; Bosentan; Cardiac Catheterization; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Male; Middle Aged; Piperazines; Purines; Retreatment; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance; Vasodilator Agents

Iloprost is a stable prostacyclin analogue that is associated with a longer duration of vasodilatation and has been approved for inhalative use with 6 or 9 inhalations during the daytime and a night pause. It is not known if during the night pause rebound pulmonary hypertension occurs. The aim of this study was to assess the hemodynamics in iloprost-treated patients during the daytime and at night.. We enrolled 5 adult patients (aged 45 +/- 10 years) with idiopathic pulmonary arterial hypertension (IPAH) and chronic inhaled iloprost therapy for at least 12 months. Further medication remained unchanged during the study period. Hemodynamics were monitored by right heart catheterization.. After 30-60 min of nebulized iloprost, mean pulmonary arterial pressures (PAP) decreased from 68 +/- 15 to 51 +/- 18 mm Hg (p = 0.004). After 6 h off-medication sleeping time, mean PAP initially increased until 2 a.m. and decreased subsequently until wake-up time at 6 a.m. Mean PAP, cardiac index and pulmonary vascular resistance at night were not significantly different from the values during the day.. In this study, patients with IPAH and chronic nebulized iloprost therapy did not reveal a rebound pulmonary hypertension during off-medication sleeping time.

Topics: Adolescent; Adult; Blood Pressure; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Vascular Resistance

This case report describes the treatment of reperfusion lung oedema after pulmonary thromboendarterectomy using intravenous iloprost infusion in a 52-year-old woman diagnosed with chronic thromboembolic pulmonary hypertension.

Topics: Endarterectomy; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Complications; Pulmonary Edema; Pulmonary Embolism; Reperfusion Injury

Chronic alveolar hypoxia induces pulmonary hypertension, evident from elevated pulmonary artery pressure (PAP), pulmonary vascular resistance, right ventricular hypertrophy (RVH), and increased muscularization of the pulmonary vasculature. Additionally, the vasoconstrictor response to acute hypoxia (HPV) may be reduced in the remodeled vasculature. However, no direct comparison of different treatments on the various parameters characterizing pulmonary hypertension has been performed yet. Against this background, we compared the effects of inhaled NO, infused iloprost, a stable prostacyclin analogue, and oral sildenafil, a phosphodiesterase 5 inhibitor, on hypoxia-induced pulmonary hypertension.. Exposure of rabbits to chronic hypoxia (FiO(2)=0.10) for 42 days. Treatment with infused iloprost, oral sildenafil, and inhaled nitric oxide.. We quantified PAP, pulmonary vascular resistance, RVH, vascular remodeling, vasoreactivity, and the strength of HPV. Chronic hypoxia resulted in an increase in (a) the right ventricle/(left ventricle+septum) ratio from 0.26+/-0.01 to 0.44+/-0.01, (b) PAP, and (c) the degree of muscularization from 14.0+/-4.0% to 43.5+/-5.3%. Treatment with iloprost and sildenafil, but not with NO, prevented the increase in muscularization. In contrast, RVH was strongly inhibited by sildenafil, whereas NO had some minor, and iloprost had no effect. Only iloprost reduced PAP compared to NO and sildenafil. The downregulation of HPV was abrogated only by NO.. We demonstrated (a) that the parameters characterizing hypoxia-induced pulmonary hypertension are not functionally linked, (b) that the downregulation of HPV under chronic hypoxia can be prevented by inhaled NO but not by sildenafil and iloprost, and (c) that iloprost is particularly effective in preventing vascular remodeling and sildenafil in preventing RVH.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hypertension, Pulmonary; Hypoxia; Iloprost; Nitric Oxide; Piperazines; Purines; Rabbits; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Novel treatments, such as prostanoids or endothelin receptor antagonists, have been introduced for various forms of pulmonary arterial hypertension, but the long-term effects of these treatments on portopulmonary hypertension (PPHT) are unknown. In a retrospective analysis, the present authors assessed the safety and efficacy of inhaled iloprost, a prostacyclin analogue, and bosentan, an endothelin receptor antagonist, in patients with PPHT. In total, 31 consecutive patients with Child class A or B cirrhosis and severe PPHT were treated for up to 3 yrs with either inhaled iloprost (n = 13) or bosentan (n = 18), and the effects on exercise capacity, haemodynamics and survival were evaluated. In the iloprost group, the survival rates at 1, 2 and 3 yrs were 77, 62 and 46%, respectively. In the bosentan group, the respective survival rates were 94, 89 and 89%. Event-free survival rates, i.e. survival without transplantation, right heart failure or clinical worsening requiring the introduction of a new treatment for pulmonary hypertension, was also significantly better in the bosentan group. Bosentan had significantly better effects than inhaled iloprost on exercise capacity, as determined by the 6-min walk test, as well as on haemodynamics. Both treatments proved to be safe, especially in regards of liver function. In the present series of patients with well-preserved liver function and severe portopulmonary hypertension, treatment with both inhaled iloprost and bosentan appeared to be safe. Patients treated with bosentan had higher survival rates, but prospective controlled studies are required to confirm these findings.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Bosentan; Catheterization; Disease-Free Survival; Female; Hemodynamics; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Male; Platelet Aggregation Inhibitors; Proportional Hazards Models; Sulfonamides; Treatment Outcome

Topics: Administration, Inhalation; Half-Life; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

The treatment of pulmonary arterial hypertension (PAH) in pregnancy is reviewed.. PAH is a disease characterized by narrowing of the pulmonary arteries and increased vascular resistance. Women with PAH should avoid becoming pregnant, as the physiological, cardiovascular, and pulmonary changes that occur during pregnancy can exacerbate the condition. However, several viable treatment options are available to improve the outcomes in this patient population, including inhaled nitric oxide, calcium-channel blockers, targeted pulmonary vasodilators, and sildenafil. Epoprostenol, a naturally occurring prostaglandin and vasodilator, is a pregnancy category B drug. Reproductive studies in rats and rabbits have found no impaired fertility or fetal harm at 2.5-4.8 times the recommended human dosage of epoprostenol. Most of the published case reports describe initiating epoprostenol 2-4 ng/kg/min i.v. several weeks before or near the time of delivery. Iloprost is a pregnancy category C drug but has demonstrated benefit in pregnant patients with PAH, with no congenital abnormalities and no postpartum maternal or infant mortality reported. Sildenafil causes vasodilation of the pulmonary vascular bed and vasodilation in the systemic circulation. Two case reports have described the successful treatment with sildenafil, a pregnancy category B drug, of pregnant patients with PAH. Patients with idiopathic PAH or chronic thromboembolic PAH should receive full-dose subcutaneous low-molecular-weight heparin therapy instead of warfarin for bleeding prophylaxis during pregnancy.. Targeted pulmonary vasodilators are viable treatment options for pregnant patients with PAH. Early recognition and management of worsening symptoms are essential to improve outcomes for both the mother and infant.

Topics: Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Purines; Sildenafil Citrate; Sulfones; Thromboembolism; Vasodilator Agents

Survival after idiopathic pulmonary arterial hypertension (IPAH) diagnosis is often shorter than the waiting time for grafts. Iloprost and bosentan improve outcome in advanced IPAH (New York Heart Association Functional Class III), but there is controversy about the limits of their efficacy in end-stage (Class IV) IPAH.. We investigated the impact of iloprost (prostacyclin analog) and bosentan (endothelin-receptor antagonist) therapy on the outcome of patients with IPAH after listing for transplantation (Tx) to answer the following questions: (1) How efficient is this treatment in reducing mortality on waiting lists? (2) Is Tx still most promising for survival once recurrent right heart failure emerges, or can this treatment improve survival to an extent that exceeds post-Tx survival? We assessed the outcome of our IPAH patients listed for Tx between September 1996 and September 2005 in relation to kind and duration of medical treatment.. Among 59 listed patients, 24 (40.7%) died before Tx, after 2.9 months (median). With iloprost and/or bosentan treatment the mortality on Tx lists was 33.3%, whereas with calcium-channel blockers it reached 64.3% (p < 0.05). Patients with iloprost and/or bosentan therapy showed similar survival, regardless of whether they responded to vasodilator testing. Survival after listing was better for patients who were transplanted than for those who received iloprost and/or bosentan but not Tx (p = 0.017). Iloprost and bosentan treatment allowed the withdrawal of 3 patients from Tx lists.. Iloprost and bosentan allowed the effective bridge-to-transplant treatment in IPAH. However, with this treatment the mortality rate on Tx lists remained high and survival benefit was lower than from transplantation.

Topics: Adult; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Female; Heart-Lung Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Male; Middle Aged; Platelet Aggregation Inhibitors; Sulfonamides; Vasodilator Agents; Waiting Lists

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Phosphodiesterase Inhibitors; Piperazines; Purines; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Aerosolized iloprost, an inhaled synthetic analogue of prostacyclin, is an approved therapy for stage III and IV pulmonary hypertension. However, currently iloprost is delivered via a device that requires a clinically stable patient who can use a hand-held nebulizer. We designed separate aerosol delivery systems to nebulize iloprost to critically ill patients during (1) mechanical ventilation and (2) spontaneous breathing that requires a high fraction of inspired oxygen. The goal was to deliver doses similar to the currently approved high-efficiency I-neb nebulizer system.. For the intubated patient we used the high-efficiency AeroTech II jet nebulizer and a breath-actuated ventilator circuit, without humidification. For spontaneous breathing, our delivery system consisted of a Pulmanex Hi-Ox disposable oxygen mask and an AeroTech II nebulizer. With a nebulizer charge of 20 microg, the drug presented to the patient (inhaled mass) was captured on a filter and analyzed using radioactivity (technetium-99m). The accuracy of the radiolabel was quantified by directly measuring iloprost with high-performance liquid chromatography and comparing the results. A cascade impactor measured particle distribution.. A line of identity confirmed that the radiolabel accurately represented the drug. The mean +/- SD inhaled mass was 6.02 +/- 0.87 microg (n = 5) on the ventilator and 3.77 +/- 0.46 microg (n = 5) during spontaneous ventilation. The mass median aerodynamic diameter and fine-particle fraction were 0.7 microm, 0.99, and 0.7 microm, 0.99, respectively.. Clinically effective doses of iloprost can be delivered to patients who require high-flow oxygen or mechanical ventilation.

Topics: Administration, Inhalation; Aerosols; Chromatography, High Pressure Liquid; Critical Illness; Equipment Design; Humans; Hypertension, Pulmonary; Iloprost; Masks; Nebulizers and Vaporizers; Vasodilator Agents

Doppler echocardiography is useful in the initial evaluation and long-term follow-up of patients with pulmonary artery hypertension. Aerosolised iloprost has been shown to reduce pulmonary pressure immediately after inhalation. We report the echocardiographic findings in a patient with severe pulmonary hypertension, before and after the inhalation of aerosolized iloprost. These findings illustrate the acute influence of iloprost in right and left ventricular hemodynamics and morphology. These findings were reproduced in subsequent echocardiographic evaluations.

Topics: Administration, Inhalation; Adult; Echocardiography; Female; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents; Ventricular Function

Topics: Bosentan; Hemodynamics; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Patient Care; Sulfonamides; Survival Analysis

Topics: Aged; Chronic Disease; Dose-Response Relationship, Drug; Endarterectomy; Humans; Hypertension, Pulmonary; Iloprost; Male; Platelet Aggregation Inhibitors; Prostaglandins; Pulmonary Embolism

This paper describes a 61-year-old woman who presented with mixed connective tissue disease, which was complicated by the development of pulmonary arterial hypertension (PAH). Her condition worsened rapidly, with development of haemopthysis, tachypnoe and cardiac arrest. Doppler echocardiography showed a high systolic pulmonary arterial pressure (98 mmHg), confirmed by the right heart catheterization. Vasculopathy of the pulmonary artery vessels was detected following open lung biopsy. No pulmonary embolism was found. Because of suspicion of flare of her underlying disease, which leads to PAH, immunosuppressive treatment was started with high doses of corticosteroid and cyclophosphamide, in combination with the prostacyclin analogue, Iloprost, and low molecular weight heparin. The therapy resulted in slow recovery over 6 weeks, with control echocardiography showing normalization of the high pulmonary pressure, and the patient being capable of returning to everyday activities.

Topics: Autoantibodies; Biopsy; Echocardiography, Doppler; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Mixed Connective Tissue Disease; Vasodilator Agents

Pulmonary hypertension secondary to valvular heart disease is a cause of acute right heart failure during valve replacement operations. This study compares the hemodynamic effects of intravenous use of iloprost and nitroglycerin in patients with pulmonary hypertension undergoing valvular replacement surgery. We sought to determine the acceptable doses of these medications for use in surgery to decrease mean pulmonary artery pressure to <30 mmHg without causing systemic side effects. The plasma nitric oxide levels that were obtained from pulmonary mixed venous blood have been compared to demonstrate the difference in the action mechanism of these drugs.. Eighteen patients undergoing mitral or aortic and mitral valvular replacement with pulmonary hypertension >25 mmHg were included in the study. The 2 groups received iloprost or nitroglycerin via a central pulmonary catheter, and the hemodynamic parameters were evaluated before incision (T1), 10 minutes after chest opening (T2), and 5 minutes and 20 minutes after cardiopulmonary bypass (T3 and T4). The plasma nitric oxide levels were obtained from the mixed venous blood at the T1 and T4 intervals.. The data have been analyzed for each group and for repeated measurements of hemodynamic parameters at T1-T4 time points. The analysis of hemodynamic parameters before (T1 and T2) and after (T3 and T4) bypass showed similar responses depending on the use of either iloprost or nitroglycerin. The administration of iloprost after bypass (T3) at a dosage of 1.25 to 2.5 ng/kg per minute reduced mean pulmonary artery pressure (from 28.8 +/- 7.89 to 20.63 +/- 6.39 mmHg) and pulmonary vascular resistance (from 226.88 +/- 101.93 to 118.00 +/- 82.36 dyn sec cm -5) better than nitroglycerin at a dosage of 0.5 to 1 microg/kg per minute (from 23.20 +/- 5.20 to 18.50 +/- 5.10 mmHg and from 160.80 +/- 39.76 to 137.40 +/- 56.54 dyn sec cm -5, respectively). Iloprost causes significant increase in cardiac output (from 4.91 +/- 0.91 to 5.49 +/- 0.91 L/min) compared to nitroglycerin (from 5.23 +/- 0.80 to 5.27 +/- 0.74 L/min). The plasma nitric oxide levels of the iloprost group did not show an increase from T1 to T4, whereas the nitroglycerin group levels did (P <.05).. Intravenous use of both iloprost and nitroglycerin effectively reduces mean pulmonary artery pressure, although only the iloprost group was accompanied by an increase in cardiac output. During operation, where abrupt management of pulmonary hypertension is required, systemic use of iloprost or nitroglycerin at appropriate doses via a pulmonary artery catheter offers adequate relief of hypertension and is well tolerated without any significant adverse effects. The plasma nitric oxide levels did not rise with the use of iloprost.

Topics: Adult; Aged; Antihypertensive Agents; Cardiac Output; Female; Heart Failure; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Nitric Oxide; Nitroglycerin; Vasodilator Agents

We report the case of a 43-year-old male with liver cirrhosis based on a chronically active hepatitis C.. Before liver transplantation right-ventricular pressure values of 36 mmHg (+ central venous pressure) were measured whereas, after transplantation, he developed severe pulmonary hypertension with pressure values up to 90 mmHg. These elevated pressure values correlated inversely with graft function. Given the diagnosis of portopulmonary hypertension, we initiated treatment with intravenous epoprostenol and inhalative iloprost but both treatments were not tolerated because of systemic side effects. A combined heart-lung transplantation was considered but the patient died from insufficient cardiac function.. The case report discusses the present diagnostic and therapeutic state of the art in portopulmonary hypertension and reveals basic problems of the present screening strategy.

Topics: Adult; Antihypertensive Agents; Drug Combinations; Epoprostenol; Fatal Outcome; Hepatitis C; Humans; Hypertension, Pulmonary; Iloprost; Liver Cirrhosis; Liver Transplantation; Male; Treatment Failure; Vasodilator Agents

In Europe intravenous (IV) iloprost, an alternative to epoprostenol, is an accepted treatment option for severely compromised patients with idiopathic pulmonary arterial hypertension (IPAH). Once initiated, this therapy usually has to be continued lifelong or as bridging to transplantation. In our paper we describe two patients with IPAH in World Health Organisation (WHO) functional classes II and III while on treatment with continuous IV iloprost monotherapy or combination therapy with continuous IV iloprost plus oral bosentan, respectively. The duration of IV iloprost therapy was 4.5 and 2.5 years, respectively. Because of life-threatening or recurring catheter-related complications during long-term IV iloprost therapy, these patients were switched to non-invasive combination therapy consisting of oral bosentan plus aerosolized iloprost (patient 1) and oral bosentan plus aerosolized iloprost plus oral sildenafil (patient 2), respectively. After four weeks of additional bosentan therapy, stepwise reduction and discontinuation of IV iloprost were performed within eight hours in the patient in WHO class II, and within five days in the patient in WHO class III. Simultaneously, therapy with aerosolized iloprost was started in the first patient and with aerosolized iloprost plus sildenafil in the second patient. Both patients were safely switched from IV iloprost to non-invasive combination therapy while WHO classification of functional status remained unchanged for at least 12 and 14 months, respectively. These data suggest that selected patients with complications due to IV iloprost treatment can be safely switched to non-IV combination therapies.

Topics: Antihypertensive Agents; Bosentan; Drug Administration Schedule; Drug Combinations; Female; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Middle Aged; Patient Selection; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Drug Combinations; Epoprostenol; Hepatitis C; Humans; Hypertension, Pulmonary; Iloprost; Liver Cirrhosis; Liver Transplantation; Male; Treatment Failure; Vasodilator Agents

Endothelial dysfunction is likely to contribute to the pathogenesis of idiopathic Pulmonary Arterial Hypertension (iPAH). We hypothesize that there are different patterns of endothelial cell function, which we studied in 17 children with iPAH.. Pulmonary flow reserve was determined by acetylcholine infusion into segmental pulmonary arteries utilizing quantitative angiography and intra-arterial Doppler flow wire. Depending on the reactivity of the pulmonary to systemic arterial pressure ratio to short-term oxygen and intravenous epoprostenol or aerosolized iloprost responders and nonresponders were classified. In 7 responders to oxygen-prostanoid administration the pressure ratio decreased from 0.9 +/- 0.2 to 0.31 +/- 0.11 (p = 0.01), the mean pulmonary flow reserve showed an excessive increase to 3.6 +/- 2.0 (p = 0.01) after infusion of acetylcholine. In 10 non-responders the pressure ratios remained unchanged during oxygen-prostanoid testing. 4 of 5 patients without any effect to acetylcholine died despite long-term epoprostenol treatment. The other 5 nonresponders to oxygen-prostanoid showed an impaired but significant increase of the pulmonary flow reserve of 1.6 +/- 1.1 (p = 0.01). 2 of these patients did not only improve clinically, but regained vascular reactivity by additional therapy with sildenafil.. Endothelial reactivity in iPAH is either extensive, impaired or absent. Acetylcholine infusion casts a light on the pathogenesis and has implications for therapy.

Topics: Acetylcholine; Adolescent; Blood Pressure; Child; Child, Preschool; Endothelial Cells; Epoprostenol; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infant; Lung; Piperazines; Purines; Regional Blood Flow; Sildenafil Citrate; Sulfones; Vasodilator Agents

We describe the case of a pregnant woman with idiopathic pulmonary arterial hypertension, a responder in right heart catheterization, followed since the first trimester in outpatient consultations, admitted to hospital at 23 weeks gestation. She was treated with inhaled iloprost until delivery (at 34 weeks gestation) and continuous infusion of iloprost throughout the perioperative period and following days. This line of therapy has proved efficacious in previous cases. The authors present echocardiographic images that document acute changes in ventricular synchrony during inhalation of iloprost.

Topics: Administration, Inhalation; Adult; Female; Humans; Hypertension, Pulmonary; Iloprost; Pregnancy; Pregnancy Complications, Cardiovascular; Vasodilator Agents

Idiopathic pulmonary arterial hypertension (IPAH) is an uncommon and devastating disease which, if untreated, progresses rapidly and leads to right heart failure and death. The course of the disease has been altered by advances in medical therapies. However, the effects of long-term alternative therapies and responses to each treatment protocols are not definite. We want to define an IPAH case, which had long-term temporary responses to the conventional therapy plus calcium channel blockers treatment and moreover compared the long-term clinical and physiologic effects of oral sildenafil mono therapy and additional inhaled iloprost therapy. Patients with IPAH may have response to a short-term vasodilatation therapy but they have to follow for the long-term results and may be of benefit from combination treatments.

Topics: Administration, Inhalation; Adult; Diagnosis, Differential; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Iloprost; Male; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension, and consequently right ventricular failure, complicates several congenital heart defects. Although intervention in the prostacyclin-thromboxane ratio is known to improve outcome, the underlying mechanism is not clear. Therefore, effects of acetyl salicylic acid and iloprost are studied in an animal model for flow-associated pulmonary hypertension. Male Wistar rats with flow-associated pulmonary hypertension, an aortocaval shunt in addition to monocrotaline induced pulmonary hypertension, were treated with low-dose aspirin (25 mg/kg/day) or iloprost (72 microg/kg/day). Effects on pulmonary hemodynamics and pulmonary vascular remodeling as well as right ventricular hemodynamics and remodeling were evaluated. Ninety percent (n=7/8) of the untreated pulmonary hypertensive rats developed dyspnea and pleural fluid, whereas this was seen in 50% (n=4/8, ns) and 10% (n=1/8, P<0.05 vs. untreated animals) of the aspirin and iloprost-treated rats, respectively. This could not be attributed to changes in pulmonary artery pressure, wall-lumen ratio of the pulmonary vasculature or right ventricular hypertrophy. However, both therapies restored reduced right ventricular capillary to myocyte ratio in pulmonary hypertensive rats (0.95+/-0.10 in untreated rats vs. 1.38+/-0.18 in control animals; P<0.05, and 1.32+/-0.11 in aspirin-treated and 1.29+/-0.9 in iloprost-treated rats; both P<0.05 vs. non-treated animals), which was associated with improved right ventricular contractility (iloprost). Thus, interventions in the prostacyclin-thromboxane metabolism improve outcome in rats with flow-associated pulmonary hypertension. However, these effects may be attributed to effects on cardiac rather than on pulmonary vascular remodeling.

Topics: Animals; Arachidonic Acid; Aspirin; Blood Pressure; Capillaries; Disease Models, Animal; Echocardiography; Gene Expression; Heart Ventricles; Hypertension, Pulmonary; Iloprost; Lung; Male; Myocardium; Organ Size; Platelet Aggregation Inhibitors; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Wistar; Receptors, Vascular Endothelial Growth Factor; Survival Rate; Vascular Endothelial Growth Factor A; Ventricular Remodeling

Topics: Administration, Inhalation; Adult; Contraindications; Extracorporeal Circulation; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Period; Lung Transplantation; Pulmonary Emphysema; Vascular Resistance; Vasodilator Agents

Aerosolized iloprost has been suggested for selective pulmonary vasodilatation in severe pulmonary hypertension, but its pharmacokinetic profile is largely unknown. In perfused rabbit lungs, continuous infusion of the thromboxane mimetic U46619 was employed for establishing stable pulmonary hypertension. Delivery of a total amount of 75, 300, and 900 ng of iloprost to the bronchoalveolar space by a 10 min-aerosolization maneuver caused a dose-dependent pulmonary vasodilatation. Similarly, dose-dependent appearance of iloprost in the recirculating perfusate was noted, with maximum intravascular concentrations of iloprost ranging at 140, 510, and 1163 pg/mL at the same time period. Comparing pharmacokinetics and pharmacodynamics in a more detailed fashion, the following aspects were of interest. (i) The bioavailability (i.e., the percentage of aerosolized iloprost appearing intravascularly) decreased from 76% at the lowest to 33% at the highest iloprost dosage. (ii) The pulmonary vasodilatory response commenced already during the nebulization maneuver and preceded the perfusate entry of iloprost. (iii) After 3-3.5 h, the pulmonary vasodilatory response to aerosolized iloprost had virtually completely leveled off, whereas approximately two-thirds of the maximum iloprost perfusate levels were still detectable. A corresponding loss of vasodilatory response was also noted in experiments with continuous iloprost perfusion for clamping of the intravascular concentration of this prostanoid. We conclude that aerosolized iloprost causes dose-dependent vasodilatation and iloprost entry into the vascular space in a pulmonary hypertension model. Limited bioavailability in the higher dose range may suggest active prostanoid transport processes, and the early pulmonary vasodilatory response appears to be independent of prostanoid entry into the vessel lumen. Surprisingly, rapid tolerance development to the vasodilatory effect of iloprost is noted, occurring even with fully maintained perfusate levels of this agent.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Drug Tolerance; Epoprostenol; Female; Hypertension, Pulmonary; Iloprost; Lung; Male; Models, Statistical; Nebulizers and Vaporizers; Perfusion; Rabbits; Time Factors; Vasodilator Agents

Topics: Aerosols; Animals; Drug Tolerance; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Lung; Nebulizers and Vaporizers; Perfusion; Rabbits; Vasodilator Agents

Acute pulmonary hypertension with life-threatening right heart failure may complicate the postoperative course following cardiothoracic surgery. Both inhaled nitric oxide and inhaled iloprost, a stable analogue of prostacyclin, have been used frequently for this purpose in acute pulmonary hypertension of various origins. We present a case of a patient with acute pulmonary hypertension and severely impaired gas exchange following pulmonary thrombo-endarterectomy. Therapy with one inhaled vasodilator alone did not satisfactorily abort a postoperative pulmonary hypertensive crisis and low-output syndrome due to right heart failure. Combined inhaled nitric oxide and inhaled iloprost, however, showed additive effects. Hence, the combination of both drugs may be reasonable in cases where the standard therapy fails. The effect has been demonstrated by means of continuous blood gas monitoring.

Topics: Administration, Inhalation; Adult; Drug Therapy, Combination; Endarterectomy; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Male; Nitric Oxide; Pulmonary Embolism; Vasodilator Agents

Iloprost, a prostacyclin analogue with a prolonged plasma half-life has beneficial effects in chronic pulmonary hypertension, whereas the effects in acute lung injury (ALI) are unknown. The present study was performed to evaluate the cardiopulmonary effects of iloprost in experimental ALI. ALI was induced in 18 pigs by repeated lung lavage. Animals were randomised to controls, i.v. or inhaled iloprost for 15 min. Haemodynamics, gas exchange and ventilation-perfusion distribution were measured at the end of iloprost application and after 1 and 2 h. As a short-term effect, both i.v. and inhaled iloprost significantly decreased pulmonary artery pressure without major effects on gas exchange or systemic haemodynamics. After 1 and 2 h, a reduction of pulmonary hypertension was no longer present. As a long-term effect, inhaled, but not i.v., iloprost decreased pulmonary shunt and significantly improved gas exchange after 1 and 2 h. In conclusion, the single application of iloprost revealed short-term pulmonary vasodilation without other major cardiopulmonary effects. However, inhaled iloprost improved gas exchange due to a decrease of pulmonary shunt as a long-term effect, possibly as a result of a reduction of lung oedema formation.

Topics: Acute Disease; Administration, Inhalation; Analysis of Variance; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hemodynamics; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Lung Diseases; Lung Injury; Probability; Pulmonary Circulation; Pulmonary Gas Exchange; Random Allocation; Swine

Iloprost inhalation has recently emerged as an alternative therapy for severe primary pulmonary hypertension. In the studies documenting the effect of iloprost inhalation therapy, hemodynamic variables have been measured invasively. We have followed a patient with primary pulmonary hypertension receiving iloprost inhalation therapy for 5 years using echocardiography to monitor changes in pulmonary artery pressure and right ventricular function. Echocardiography was also used to evaluate the initial response to iloprost inhalation therapy. This case illustrates the feasibility and utility of echocardiography in the testing and follow-up of iloprost inhalation therapy in patients with pulmonary hypertension.

Topics: Adult; Drug Monitoring; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Iloprost; Ultrasonography; Vasodilator Agents; Ventricular Dysfunction, Right

Inhaled iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled iloprost on changes to pulmonary vascular structure that occur in PAH.. The present study was designed to investigate chronic antiremodeling effects of inhaled iloprost in monocrotaline (MCT)-induced PAH in rats.. Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with iloprost at a dose of 6 microg . kg(-1) . day(-1), or underwent sham nebulization with saline.. After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to iloprost. Furthermore, the MCT-induced increase in matrix metalloproteinase-2 and -9 activities and tenascin-C expression was suppressed.. We conclude that the inhalation of iloprost reverses PAH and vascular structural remodeling in MCT-treated rats. This regimen suggests the possibility of an antiremodeling therapy in PAH.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Hypertension, Pulmonary; Iloprost; Monocrotaline; Pulmonary Artery; Rats; Rats, Wistar; Vasodilator Agents; Ventricular Pressure

To describe the long-term clinical efficacy of inhaled iloprost as first-line vasodilator mono-therapy in patients with idiopathic pulmonary arterial hypertension (IPAH).. Seventy-six IPAH patients were prospectively identified and treated with inhaled iloprost. Clinical, haemodynamic, and exercise parameters were obtained at baseline, after 3 and 12 months of therapy and yearly thereafter. Four endpoints were prospectively defined as follows: (i) death, (ii) transplantation, (iii) switch to intravenous (i.v.) therapy, or (iv) addition of or switch to other active oral therapy. During follow-up (535+/-61 days), 11 patients died, six were transplanted, 25 were switched to i.v. prostanoids, 16 received additional or other oral therapy, and 12 patients discontinued iloprost inhalation for other reasons. Event-free survival at 3, 12, 24, 36, 48, and 60 months was 81, 53, 29, 20, 17 and 13%, respectively. Among haemodynamic and exercise parameters, mixed venous oxygen saturation (P<0.001), right atrial pressure (P<0.001), and peak oxygen uptake (P=0.002) were associated with event-free survival.. In this study, only a minority of patients could be stabilized with inhaled iloprost mono-therapy during a follow-up period of up to 5 years. In the presence of multiple treatment options, chronic iloprost inhalation as mono-therapy appears to have a limited role.

Topics: Administration, Inhalation; Adult; Exercise Test; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Proportional Hazards Models; Prospective Studies; Survival Analysis; Vasodilator Agents

Two female patients with pulmonary arterial hypertension and a permanently implanted hemodynamic monitor changed treatment from inhaled iloprost to oral bosentan. The hemodynamic changes were seen very early after the first dose of bosentan and there was no need to re-establish inhaled iloprost.

Topics: Administration, Inhalation; Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Monitoring, Ambulatory; Prostheses and Implants; Sulfonamides

10 years ago a now 49-year-old woman with Render-Osler-Weber disease showed unspecific symptoms of nausea, and general unwellness. Pulmonary manifestation of the disease was accompanied by pulmonary hypertension.. Teleangiectasia of the tongue and pharynx as well as of the mucosa of mouth and nose were observed. Fixed-splitting of the second heart sound with accentuated pulmonary component and a 2/6 systolic murmur over the tricuspid valve were heard. In addition, a murmur was heard dorsal over the right lung's lower lobe. Apart from minor oedema of both ankles, the physical status was not remarkable. Echocardiography showed dilatation of the right ventricle and a minor regurgitation of the tricuspid valve. The computed tomography showed dilatation of the pulmonary arteries as well as an arteriovenous malformation in the right lower lobe. Right-heart catheterisation revealed elevated pulmonary pressure. THERAPY AND FOLLOW-UP: Initial treatment with a calcium channel blocker proved insufficient and was changed to inhalative, and later to oral prostanoids. Under this treatment the cardiopulmonary state was stabilised, but episodes of epistaxis were increased. Two years after readjustment of the medication to a dual endothelin receptor antagonist, the cardiopulmonary state remains stable without significant haemorrhagic complications.. Prostanoid treatment in patients with Render-Osler-Weber disease and additional pulmonary hypertension can lead to an increased risk of haemorrhagic complications. Treatment with newer medications, such as endothelin receptor antagonists, seems indicated as successfully illustrated in our case.

Topics: Anticoagulants; Antihypertensive Agents; Bosentan; Calcium Channel Blockers; Diuretics; Endothelin Receptor Antagonists; Epistaxis; Epoprostenol; Female; Furosemide; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Nifedipine; Pedigree; Phenprocoumon; Pyridines; Sulfonamides; Telangiectasia, Hereditary Hemorrhagic; Treatment Failure; Vasodilator Agents

The last few years have seen significant progress in the treatment of advanced pulmonary arterial hypertension (PAH). The efficacy of new drugs has been proved mainly in idiopathic PAH or PAH associated with connective tissue diseases. As the pathophysiologic patterns are similar, it is reasonable to use these drugs also in Eisenmenger syndrome or in other congenital heart defects with PAH related to initial high pulmonary flow.. To evaluate our early experience with new drugs for PAH in patients with Eisenmenger syndrome.. A retrospective study of five patients, aged 28 to 51 years (39.6 +/- 9.94), four female, with Eisenmenger syndrome due to atrial septal defect (n = 2), patent ductus arteriosus (n = 2) or ventricular septal defect (n = 1), who began therapy with iloprost (n = 4, later associated with sildenafil in one patient) and bosentan (n = 1), between April 2001 and May 2003. The existence of severe and fixed PAH, with predominant right-to-left shunt, was confirmed by hemodynamic study in all cases. The patients were evaluated by clinical examination, Doppler echocardiography and the six-minute walk test before treatment and throughout follow-up (9 to 34 months, 19.8 +/- 9.04). Before treatment two patients were in NYHA class III and three in class III with periods in class IV. By Doppler echocardiography the right ventricle-right atrium (RV-RA) gradient was 74 to 111 mmHg (90.6 +/- 15.73) and the Tei index was 0.53 to 2.05 (1.13 +/- 0.62). In the six-minute walk test the distance was 214 to 500 meters (296.8 +/- 115.27).. All patients improved clinically, though three are still in class III. One patient is in class II and one patient died. At the latest evaluation the RV-RA gradient was 60 to 112 mmHg (84.8 +/- 19.11) and the Tei index was 0.5 to 1.33 (0.85 +/- 80.32). In the six-minute walk test a net increase in the distance covered was evident: 376 to 520 meters (420 +/- 57.89). The treatment was well tolerated in all cases, without serious adverse effects.. Though the number of patients was small, our initial experience with the new specific drugs for PAH in Eisenmenger syndrome showed promising results, with clinical and functional improvement and without adverse effects.

Topics: Adult; Antihypertensive Agents; Bosentan; Eisenmenger Complex; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Retrospective Studies; Sulfonamides; Vasodilator Agents

In patients with pulmonary hypertension, pregnancy is associated with a high risk of maternal death. Such patients are counselled to avoid pregnancy, or if it occurs, are offered early interruption. Some patients, however, decide to continue with their pregnancy and others may present with symptoms for the first time whilst pregnant. Pulmonary vasodilator therapy provides a treatment option for these high-risk patients. The present study describes three patients with pulmonary arterial hypertension of various aetiologies who were treated with the prostacyclin analogue iloprost during pregnancy, and the post-partum period. Nebulised iloprost commenced as early as 8 weeks of gestation and patients were admitted to hospital between 24-36 weeks of gestation. All pregnancies were completed with a duration of between 25-36 weeks and all deliveries were by caesarean section under local anaesthetic. All patients delivered children free from congenital abnormalities, and there was no post-partum maternal or infant mortality. In conclusion, although pregnancy is strongly advised against in those with pulmonary hypertension, the current authors have achieved a successful outcome for mother and foetus with a multidisciplinary approach and targeted pulmonary vascular therapy.

Topics: Administration, Inhalation; Adult; Cesarean Section; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Postpartum Period; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pregnancy Trimester, First; Risk Assessment; Sampling Studies; Severity of Illness Index; Treatment Outcome

Inhaled prostanoids and phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe pulmonary hypertension. In catheterized rabbits with acute pulmonary hypertension induced by continuous infusion of the stable thromboxane analogue U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3 inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure decline, levelling off within <20 min, without significant changes in blood gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and sildenafil caused each a dose-dependent decrease in pulmonary artery pressure, with sildenafil possessing the highest efficacy and at the same time selectivity for the pulmonary circulation. When combining a per se ineffective dose of each PDE inhibitor (200 microg/kg x min 8-Methoxymethyl-IBMX, 1 microg/kg x min sildenafil, 5 microg/kg x min motapizone) with subsequent iloprost nebulization, marked amplification of the prostanoid induced pulmonary vasodilatory response was noted and the area under the curve of PPA reduction was nearly threefold increased with all approaches, as compared to sole iloprost administration. Further amplification was achieved with the combination of inhaled iloprost with sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic hemodynamics and gas exchange were not altered for all combinations. We conclude that co-administration of minute systemic doses of selective PDE inhibitors with inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory response to inhaled iloprost, with maintenance of pulmonary selectivity and ventilation perfusion matching. The prominent effect of sildenafil may be operative via both PDE1 and PDE5, and is further enhanced by co-application of a PDE3 inhibitor.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Drug Combinations; Drug Synergism; Female; Hypertension, Pulmonary; Iloprost; Lung; Male; Phosphodiesterase Inhibitors; Rabbits; Treatment Outcome; Vasodilation

Severe portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis and carries a poor prognosis. In the last years, intravenous (IV) epoprostenol has been suggested to be the optimal medical treatment for PPHTN, and recently oral bosentan has been shown to be efficacious and safe in selected patients with PPHTN. We report a case of PPHTN suffering from recurrent right heart failure while on treatment with IV iloprost, which was successfully managed by combination therapy with IV iloprost plus oral bosentan, providing sustained cardiopulmonary stabilization for at least two years. This report documents the first case of a patient with PPHTN successfully treated with the combination of IV iloprost and oral bosentan over an extended period. Thus, combination therapy with IV iloprost and oral bosentan might be a promising new option for selected patients suffering from PPHTN and recurrent right heart failure.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Liver Cirrhosis, Alcoholic; Male; Recurrence; Sulfonamides; Time Factors

For patients with pulmonary arterial hypertension (PAH) two first line therapies - iloprost inhalation (Ventavis) and bosentan (Tracleer) -- are available in Germany. A third substance, sildenafil, is already approved in the US and will be approved for this indication in the European Union soon. Patients with PAH can be stabilized or improved with a specific mono-therapy for a limited period of time only. Therefore, the question arises when and how to initiate treatment escalation. The available data from controlled clinical trials are insufficient to give a definite answer to these questions. Moreover, it is still unclear which combination of the above mentioned substances may be superior in the treatment of PAH. On the other hand, combination therapy is already reality in clinical practice. Based on this background experts from specialized centers dealing with PAH discussed the scientific basis of the role of combination therapy in PAH patients during a workshop held on April 22/23. 2005 in Wiesbaden. The goal of this workshop was to formulate a common position with regard to combination therapy of PAH on the basis of the available scientific data and clinical experience.

Topics: Administration, Inhalation; Antihypertensive Agents; Bosentan; Controlled Clinical Trials as Topic; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones

Topics: Administration, Inhalation; Antihypertensive Agents; Epoprostenol; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Ventilation-Perfusion Ratio

Pulmonary arterial hypertension (PAH) is a recognized complication of congenital heart disease. Despite differences in etiology and pathophysiology, successful therapy for idiopathic PAH may benefit in patients with congenital heart disease. We theorized that combination of oral and aerosolization prostacyclin will benefit this group of patients in long-term.. The study design was single group and open label study with intention to treat for patients with congenital heart disease with pulmonary artery (PA pressure) more than 50% of systemic pressure. All patients were given a combination of orally given beraprost sodium and inhalation of iloprost for 12 months. Data were collected prospectively consisting of functional class, O2 saturation, 6-minute walk test and right ventricular systolic pressure (RVSP).. There were 23 patients with an average right ventricular systolic pressure (+/- SD) of 94.8 +/- 14.5 mmHg and with average age of 27.8 +/- 14.9 years (2.5 to 50 years). The average oxygen saturation was 87.9 +/- 7 %. There were 12 patients with post surgical repair or cardiac catheterization interventional procedure and 11 with and Eisenmenger's syndrome. There were significant improvement of 6-minute-walk test from an average of 268 +/- 70 meters to 308 +/- 57 meters at the end of 12 months. The functional class of patients was also improving. However, there were no significant different in oxygen saturation.. Combination therapy of oral and inhalation of aerosolized vasodilators is a fascinating concept in the therapy of pulmonary hypertension. Treated patients showed an improvement in exercise capacity and right ventricular systolic pressure without a worsening in oxygen saturation.

Topics: Administration, Inhalation; Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Epoprostenol; Exercise Test; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Oxygen; Vasodilator Agents; Ventricular Pressure

The case of a 14 month old girl with primary pulmonary hypertension treated with domiciliary oxygen is described. After invasive evaluation and testing of nitric oxide with very good response, the testing was repeated to study the effect of inhaled iloprost on pulmonary vascular resistance (PVR). An unexpected and severe increase of PVR was observed, rising from 392 dynes x s x cm(-5) with oxygen to a maximum of 1192 dynes x s x cm(-5) with oxygen and iloprost. Underlying ventilatory and technical problems were excluded. While inhaled iloprost has been described to be highly effective in the treatment of primary pulmonary hypertension, the possibility of contrary "paradoxical" reactions in isolated patients is emphasised, with a dramatic increase of PVR and a possible adverse outcome.

Topics: Administration, Inhalation; Blood Pressure; Female; Humans; Hypertension, Pulmonary; Iloprost; Infant; Vascular Resistance; Vasodilator Agents

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Child; Drug Therapy, Combination; Echocardiography; Humans; Hypertension, Pulmonary; Iloprost; Male; Sulfonamides; Vasodilator Agents

Different vasodilators and different routes of application are used for the treatment of primary pulmonary hypertension (PPH). Recently, sildenafil, a phosphodiesterase-V inhibitor, has been shown to have beneficial hemodynamic effects in PPH. However, the hemodynamic effects of sildenafil have not been characterized and compared to other vasodilators such as inhaled nitric oxide (iNO) or iloprost in PPH in the same group of patients.. We investigated prospectively 10 consecutive patients with PPH using iNO, iloprost aerosol, and oral sildenafil to test acute hemodynamic response during right-heart catheterization.. iNO, iloprost aerosol, and sildenafil caused a significant fall of mean pulmonary artery pressure and pulmonary vascular resistance (PVR) [p < 0.05]. Correspondingly, cardiac output and mixed venous saturation increased slightly in all groups. Systemic arterial pressure and vascular resistance were mainly unaltered. Using a PVR reduction of > or =20% to define a significant response, 7 of 10 patients were responders to iloprost aerosol, whereas 4 of 10 patients responded to iNO and oral sildenafil. Improvement of oxygenation as indicated by an increase of arterial oxygen tension was observed with iloprost aerosol (p < 0.01).. All of the three substances, iNO, iloprost aerosol, and oral sildenafil, significantly improved pulmonary hemodynamics in patients with PPH. The most prominent hemodynamic effects and improvement of oxygenation were observed with iloprost aerosol.

Topics: Administration, Inhalation; Administration, Oral; Adult; Cardiac Catheterization; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide; Piperazines; Prospective Studies; Purines; Risk Assessment; Sampling Studies; Severity of Illness Index; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

As antiretroviral therapy has improved life expectancy in human immunodeficiency virus (HIV) infection, the life-limiting complication of HIV-related pulmonary hypertension has come into focus. Inhalation of the stable prostacyclin analogue iloprost is an effective treatment for various forms of precapillary pulmonary hypertension. The main objective of the present study was to evaluate the safety and efficacy of inhaled iloprost in HIV-related pulmonary hypertension. In eight patients with severe pulmonary hypertension related to HIV infection, right heart and femoral artery catheterisation were performed. The acute effect of oxygen, inhaled nitric oxide and aerosolised iloprost was investigated. Four patients underwent long-term treatment with inhaled iloprost. The rank order of pulmonary vasodilatory potency was iloprost>NO>O2, with a maximum reduction (mean +/- SEM) in pulmonary vascular resistance of 30.6 +/- 3.1% (p < 0.001), 5.9 +/- 3.9% and -0.6 +/- 3.9%, respectively. Concomitantly, inhaled iloprost significantly increased the cardiac index and central venous oxygen saturation. Chronic treatment with inhaled iloprost tended to improve the 6 min walking distance and decreased pulmonary vascular resistance in all patients (although not significantly). No serious adverse events and no major interactions with the ongoing antiretroviral therapy were noted. In conclusion, inhaled iloprost is a potent pulmonary vasodilator in human immune deficiency virus-related pulmonary hypertension. Future studies are warranted to confirm the encouraging long-term beneficial results observed in the present limited number of patients.

Topics: Administration, Inhalation; Adult; Cardiac Catheterization; Combined Modality Therapy; Female; HIV Infections; Humans; Hypertension, Pulmonary; Iloprost; Long-Term Care; Male; Middle Aged; Nitric Oxide; Oxygen Inhalation Therapy; Pulmonary Artery; Pulmonary Wedge Pressure; Stroke Volume; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Iloprost is a stable prostacyclin analogue with a pharmacokinetic profile allowing nebulised administration in patients with primary pulmonary hypertension (PPH). Inhaled iloprost is a potent acute pulmonary vasodilator with a duration of action of about 60 minutes. It may exert additional long-term benefit through antiproliferative and antithrombotic effects. Inhaled iloprost 2.5 or 5 microg six or nine times daily for 12 weeks (n = 101) significantly (p < 0.01) improved a combined clinical endpoint of a > or =10% increase in distance walked in 6 minutes and an improvement of > or =1 class in New York Heart Association functional class without clinical deterioration or death (16.8 versus 4.9% of placebo recipients, n = 102) in patients with severe PPH or selected forms of nonprimary pulmonary hypertension. Statistical analysis of the response for the PPH subgroup (20.8 versus 5.5% with placebo; n = 51 and 51) was not reported. Improvements from baseline in exercise capacity and haemodynamic/gas exchange variables have been reported in patients with PPH with continued use of inhaled iloprost. In addition, improvement in preinhalation vascular resistance occurred after 12 weeks of inhaled iloprost (p < 0.01 versus placebo) in a large randomised trial. Increased cough, headache, flushing and an influenza-like syndrome were the most common adverse events in the largest trial of patients receiving inhaled iloprost. Headache, flushing and jaw pain occurred significantly more frequently with inhaled iloprost than with placebo.

Topics: Administration, Inhalation; Clinical Trials as Topic; Drug Administration Schedule; Half-Life; Humans; Hypertension, Pulmonary; Iloprost

Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8+/-2.0 to 62.9+/-3.4 and 70.5+/-7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right heart hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Gelatinases; Hemodynamics; Hypertension, Pulmonary; Hypertrophy; Hypertrophy, Right Ventricular; Iloprost; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Monocrotaline; Muscle, Smooth, Vascular; Naphthyridines; Oxygen; Phosphodiesterase Inhibitors; Pulmonary Artery; Pulmonary Gas Exchange; Pulmonary Heart Disease; Rats; Rats, Sprague-Dawley; Vasodilator Agents; Ventricular Remodeling

Chronic thromboembolic pulmonary hypertension (CTPH) is an uncommon complication of pulmonary embolism. The treatment of choice is thromboendarterectomy, a safe and effective surgical procedure in expert hands. However, a fair number of patients are not considered candidates for thromboendarterectomy or do not accept the risk involved. Such patients may respond well to prostacyclin or its derivatives. In recent years new vasodilator drugs administered by a variety of routes have appeared on the market. These drugs have been studied mainly for their effects on primary pulmonary hypertension or hypertension associated with connective-tissue diseases. Few trials have assessed their efficacy in patients with CTPH, however. We report 2 cases of CTPH in which thromboendarterectomy was rejected. Neither of the patients responded to the conventional treatment of anticoagulants, diuretics, calcium antagonists, and angiotensin-converting enzyme inhibitors, but they did respond very well clinically, hemodynamically, and functionally to an inhaled prostacyclin analog, iloprost. We discuss the effects of iloprost in patients with CTPH, its mechanism of action, and its use as a potential pharmacological alternative to thromboendarterectomy. We also discuss new pulmonary vasodilators in general.

Topics: Aged; Chronic Disease; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Pulmonary Embolism; Vasodilator Agents

We describe a patient with cystic fibrosis, end-stage lung disease, and secondary pulmonary hypertension in whom aerosolized iloprost was effective in lowering pulmonary artery pressure and improving functional status, thus proving successful as a bridge to lung transplantation. Inhaled iloprost may be an efficient and selective approach to treat pulmonary hypertension related to end-stage obstructive pulmonary disease.

Topics: Administration, Inhalation; Adult; Cystic Fibrosis; Female; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Nitric Oxide; Premedication; Respiratory Insufficiency; Vascular Resistance; Vasodilator Agents

Iloprost, a prostacyclin analogue administered by inhalation, improves hemodynamic and functional class variables in patients with primary pulmonary hypertension. However, repetitive inhalations are required due to its short term effects. One potential approach to prolong and increase the effects of aerosolized iloprost might be to combine its use with phosphodiesterase inhibitors. We report a 36 year old female patient with primary pulmonary hypertension treated with this combination. After 18 months of therapy the patient had an improvement in functional class and in the 6 min walk distance despite persistence of high pulmonary pressures. Our case is in agreement with the reported beneficial effect of the association of sildenafil and iloprost. We postulate that functional improvement in primary pulmonary hypertension is not always related to a decrease in pulmonary artery pressure.

Topics: Adult; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis. Prostanoids have been shown to be effective in the treatment of PPHTN and have been used as a bridge to orthotopic liver transplantation. However, inhibition of platelet aggregation might be a limitation of prostacyclin therapy in patients with end-stage liver disease having an increased risk of bleeding from esophageal varices. The effect of oral bosentan, a dual endothelin-receptor antagonist in the reversal of PPHTN, is still unclear. We report a case of PPHTN (mean pulmonary artery pressure [mPAP] of 51 mmHg) that was successfully switched from inhalative iloprost to oral bosentan therapy. Hemodynamic and symptomatic improvements were maintained after a 12-month long-term treatment with inhalative iloprost as well as after single oral bosentan therapy. This is the first reported case of a successful switch from therapy with an inhalative prostacyclin analogue to oral bosentan in a patient suffering from PPHTN. Thus, oral bosentan therapy might be a promising new option for patients suffering from PPHTN.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Cirrhosis; Liver Transplantation; Middle Aged; Platelet Aggregation Inhibitors; Sulfonamides; Time Factors

Topics: Administration, Inhalation; Adult; Aerosols; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Male; Vasodilator Agents

To directly compare the differential effects of oxygen, prostacyclin and iloprost (aerosolized and intravenous) in primary pulmonary hypertension.. Twenty-one patients with severe primary pulmonary hypertension underwent right heart catheterization following oxygen inhalation, inhalation of aerosolized iloprost, intravenous prostacyclin or intravenous iloprost. The stability of the iloprost solution was tested for up to 4 weeks. Oxygen slightly decreased pulmonary vascular resistance. Intravenous prostacyclin (7.2+/-3.4 ng kg(-1) min(-1)) reduced pulmonary (1772+/-844 vs 1325+/-615 dyn s cm(-5), P<0.001) and systemic vascular resistance, and arterial and right atrial pressure, while cardiac output increased. Iloprost inhalation diminished pulmonary (1813+/-827 vs 1323+/-614 dyn s cm(-5), P<0.001) and systemic vascular resistance, and pulmonary artery (58+/-12 vs 50+/-12 mmHg,P<0.001) and right atrial pressure, while cardiac output increased. With intravenous iloprost (1.2+/-0.5 ng kg(-1) min(-1), n=8) a decrease in pulmonary (2202+/-529 vs 1515+/-356 dyn s cm(-5), P<0.05) and systemic vascular resistance and right a trial pressure occurred while cardiac output increased. Iloprost solution remained stable for 33 days while losing <10% (4 degrees C) of its active drug concentration.Conclusions Intravenous iloprost and prostacyclin have very similar haemodynamic profiles. In contrast, only inhaled iloprost exerted selective pulmonary vasodilation, reducing pulmonary vascular resistance and pulmonary artery pressure without systemic vasodilation. The longer half-life and extended stability despite lower costs render iloprost an attractive alternative to chronic prostacyclin treatment in primary pulmonary hypertension.

Topics: Administration, Inhalation; Adult; Aged; Blood Pressure; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Oxygen; Pulmonary Wedge Pressure; Vascular Resistance; Vasodilator Agents

Topics: Administration, Inhalation; Aerosols; Epoprostenol; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide; Vascular Resistance; Vasodilator Agents

Aerosolized iloprost is used as an alternative to IV prostacyclin in patients with pulmonary hypertension. The desired outcome of this treatment is a reduction of pulmonary pressure, which can be measured by right-heart catheterization or Doppler echocardiography. However, both techniques provide only snapshots of the hemodynamic state.. The aim of our study was to test the usability of an implantable hemodynamic monitor (IHM) [the Chronicle, model 9520; Medtronic Inc; Minneapolis, MN] in patients with pulmonary hypertension. For this purpose, the device was implanted into five patients (mean [+/- SEM] age, 45 +/- 16 years; all women) with pulmonary hypertension who had received long-term treatment with aerosolized iloprost (100 micro g/d). Repeated short-term tests including two standard inhalations of iloprost as well as repeated long-term tests lasting 20 to 26 h, including nighttime, without inhalation were performed on an outpatient basis.. The device provided information that was reproducible and individual for each patient during the entire study period. During short-term tests, pulmonary artery pressure was reduced from a mean (of all patients) of 68 +/- 13 to 49 +/- 11 mm Hg, with a mean total effective treatment time of 49 +/- 8 min. Thereafter, pulmonary pressure returned to preinhalation levels before the next inhalation. Long-term tests showed similar results. During a total recorded time of 15,876 min, the vasodilator effect lasted 2,140 min, corresponding to 13% of the whole time span.. Our study provided new insights into the short-term and long-term effects of treatment with inhaled iloprost in patients with pulmonary hypertension. While there were no signs of tachyphylaxis, the improvement of central hemodynamics was much shorter than expected. Continuous hemodynamic monitoring with the IHM demonstrated the need to improve the treatment modalities of aerosolized iloprost in patients with pulmonary hypertension.

Topics: Administration, Inhalation; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Monitoring, Ambulatory; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Antiretroviral Therapy, Highly Active; Female; HIV; HIV Infections; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Purines; Reverse Transcriptase Inhibitors; Sildenafil Citrate; Sulfones; Time; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterised by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and death. A dysregulation of prostacyclin metabolic pathways has been demonstrated in patients with PAH and in experimental models. Recently, therapy with continuous intravenous prostacyclin (epoprostenol) has been shown to improve symptoms and prognosis in New York Heart Association (NYHA) functional class III and IV patients with different types of PAH. However, epoprostenol administration requires invasive methods with a permanent intravenous catheter and is associated with several side effects and potentially serious complications. Other modes of prostacyclin therapies are being considered using stable prostacyclin analogues administered by inhalation (iloprost), subcutaneously (treprostinil) or orally (beraprost). Over the last years, different multicenter international double-blind trials have demonstrated the efficacy of those novel prostacyclin analogues in PAH compared to conventional therapy promising a better future for these patients.

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

Topics: Administration, Inhalation; Aged; Anesthesia, General; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Echocardiography, Transesophageal; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Complications; Vasodilator Agents

Topics: Administration, Inhalation; Blood Pressure; Cardiac Surgical Procedures; Child, Preschool; Female; Heart Defects, Congenital; Heart Rate; Heart Septal Defects; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Complications; Oxygen; Vasodilator Agents

In primary pulmonary hypertension, aerosolized prostanoids selectively reduce pulmonary vascular resistance and improve right ventricular function. In this study, hemodynamic effects of inhaled iloprost, a stable prostacyclin analogue, were evaluated in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and early after pulmonary thromboendarterctomy (PTE).. Ten patients (mean age 49 years old [32 to 70 years old], New York Heart Association functional class III and IV) received a dose of 33 micro g aerosolized iloprost immediately before surgery (T1), after intensive care unit admission (T2), and 12-hours postoperatively (T3). Effects on pulmonary and systemic hemodynamics and gas exchange were recorded and compared with preinhalation baseline values.. Preoperatively, inhaled iloprost did not significantly change mean pulmonary artery pressure (mPAP), cardiac index (CI), or pulmonary vascular resistance (PVR). Postoperatively, inhaled iloprost induced a significant reduction of mPAP and PVR and a significant increase of CI at T2 and T3. Preinhalation versus postinhalation PVR was as follows: at T1, 847 versus 729 dynes. s. cm(-5), p = 0.45; at T2, 502 versus 316 dynes. s. cm(-5), p = 0.008; and at T3, 299 versus 227 dynes. s. cm(-5), p = 0.004.. In patients with CTEPH, inhalation of iloprost elicits no significant pulmonary vasodilation before surgery, and may have detrimental effects on systemic hemodynamics. Postoperatively, it significantly reduces mPAP and PVR, and enhances CI. Following PTE, inhalation of iloprost is useful to improve early postoperative hemodynamics.

Topics: Administration, Inhalation; Adult; Aged; Chronic Disease; Endarterectomy; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Postoperative Period; Preoperative Care; Pulmonary Embolism; Vasodilator Agents

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Female; Gaucher Disease; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

Topics: Administration, Inhalation; Aged; Female; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Care; Male; Time Factors; Vasodilator Agents

Both aerosolized and intravenous infusion of iloprost caused a significant decrease in mean pulmonary artery pressure and pulmonary vascular resistance. Although intravenous infusion caused a large decrease in mean systemic arterial pressure, this was only slightly affected by aerosolized iloprost. Aerosolized iloprost caused a significant decrease in the pulmonary-to-systemic vascular resistance ratio; however, intravenous infusion did not cause a prominent decrease in this ratio.

Topics: Administration, Inhalation; Adolescent; Aerosols; Child; Child, Preschool; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Hypotension; Iloprost; Infant; Infusions, Intravenous; Pulmonary Wedge Pressure; Vascular Resistance; Vasodilator Agents

To determine the prevalence of systemic sclerosis associated pulmonary arterial hypertension (SScPAH), evaluate outcome, and identify predictors of mortality in a large patient cohort.. A prospective four year follow up study of 794 patients (722 from our own unit and 72 referrals). All patients screened for PAH using a combination of echocardiography, lung function testing, and clinical assessment. Patients with suspected raised pulmonary artery systolic pressures of >35 mm Hg, carbon monoxide transfer factor (TLCO) <50% predicted, or a precipitous fall in TLCO >20% over a one year period with no pulmonary fibrosis, and patients with SSc with breathlessness with no pulmonary fibrosis found were investigated with right heart catheterisation. All patients with SScPAH were treated in accordance with current best practice.. The prevalence of PAH was 12% (89/722) by right heart catheter. The survival was 81%, 63%, and 56% at 1, 2, and 3 years from the diagnosis (in 89 patients from our own cohort and 59/72 referrals). Haemodynamic indices of right ventricular failure--raised mRAP (hazard ratio 21), raised mPAP (hazard ratio 20), and low CI (hazard ratio 11) predicted an adverse outcome There was no significant difference in survival between patients with SScPAH with (n=40) and without (n=108) pulmonary fibrosis (p=0.3).. The prevalence of SScPAH in this cohort was similar to that of other catheter based studies and lower than that of previous echo based studies. The 148 patients with SScPAH actively treated had comparable outcomes to those of the cohorts with primary pulmonary hypertension. A high mRAP was the strongest haemodynamic predictor of mortality. To improve prognosis, future treatments need to be implemented at an earlier disease stage to prevent right ventricular decompensation.

Topics: Aged; Cardiac Catheterization; Echocardiography; Epidemiologic Methods; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pulmonary Wedge Pressure; Registries; Scleroderma, Systemic; Vasodilator Agents; Ventricular Dysfunction, Right

Polymorphonuclear neutrophils (PMN) have been implicated in various vascular inflammatory processes. We isolated PMN from venous blood samples of 10 patients with severe primary pulmonary arterial hypertension (PPH), 7 patients with pulmonary hypertension secondary to chronic thromboembolism (CTEPH), and 12 healthy controls. When stimulated with the calcium-ionophore A23187, platelet activating factor (PAF) or the microbial agent n-formyl-Methionyl-Leucyl-Phenylalanine (fMLP), significantly increased release of elastase and superoxide anion was noted in both groups with pulmonary hypertension. Moreover, the neutrophils of CTEPH patients responded with an enhanced liberation of leukotriene (LT) B(4) and 5-hydroxyeicosatetraenoic acid (5-HETE). Inhalation of aerosolized iloprost (5 microg) caused a rapid decline in pulmonary vascular resistance, in both PPH and CTEPH. This hemodynamic response was paralleled by a significant suppression of ionophore- and ligand-induced elastase and superoxide release, as well as LTB(4) and 5-HETE formation. The neutrophil inhibitory effect of the inhalation maneuver was fully reproduced by in vitro incubation of neutrophils with 1-10 pg/ml iloprost for 2 hours. This is the first study to demonstrate that circulating neutrophils from patients with PPH and CTEPH possess an enhanced readiness to respond with inflammatory mediator generation to different stimulatory agents ex-vivo, and that PMN respiratory burst, elastase secretion and leukotriene generation are promptly reduced by an iloprost inhalation maneuver. Neutrophils might participate in the inflammatory processes in pulmonary arterial hypertension.

Topics: Administration, Inhalation; Case-Control Studies; Humans; Hydroxyeicosatetraenoic Acids; Hypertension, Pulmonary; Iloprost; Inflammation Mediators; Leukocyte Elastase; Leukotrienes; Neutrophils; Pulmonary Circulation; Respiratory Burst; Superoxides; Thromboembolism; Vascular Resistance

Iloprost is useful in the short-term treatment of severe Raynaud's phenomenon and ischaemic ulcers in patients with systemic sclerosis (SSc), but its long-term effects are largely unknown. The aim of this study was to report long-term outcome (median follow-up 36 months) in a prospective observational study of a cohort of 30 consecutive patients with SSc who received iloprost therapy with maintenance infusions every 3 weeks after an initial cycle of 5 consecutive days. At the end of the observation, compared to the pretreatment point, we observed complete healing of digital ulcers in 19/21 patients (90%), a decrease of the Raynaud's phenomenon visual analogue score from 10/10 (25th-75th percentile 7-10) to 5/10 (4-6.75) ( P <0.001) and, in patients with diffuse cutaneous involvement, of the modified Rodnan skin thickness score from 25.5 (16.5-31.5) to 16 (13.5-20) ( P = 0.02), minimal improvement of the Health Assessment Questionnaire from 0.87 (0.68-1.37) to 0.75 (0.62-1.25), which was neither statistically nor clinically significant. The forced vital capacity was not significantly changed, but the diffusion capacity corrected for the alveolar volume decreased from 71% (54-76.7) of the expected value to 62% (51.5-71) ( P = 0.02). In one patient with limited SSc a positive effect on pulmonary hypertension was observed. Six patients, after a median of 25 months of treatment and healing of digital ulcers, discontinued the therapy; after a median of 10 months ulcers did not recur in five of these six. Other reasons for discontinuation were: tolerability (1), disease progression (normotensive renal crisis: 1), and death due to intracranial haemorrhage (1). This same patient had previously suffered a central retinal vein thrombosis. In conclusion, long-term therapy with iloprost in patients with SSc has a durable effectiveness on ischaemic ulcers and Raynaud's phenomenon, but it is not possible to conclude that the natural history of the disease was modified.

Topics: Adult; Aged; Cohort Studies; Female; Fingers; Humans; Hypertension, Pulmonary; Iloprost; Ischemia; Longitudinal Studies; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Raynaud Disease; Respiratory Function Tests; Scleroderma, Systemic; Skin; Ulcer; Vasodilator Agents

Topics: Administration, Inhalation; Child, Preschool; Humans; Hypertension, Pulmonary; Iloprost; Male; Radiography; Vasodilator Agents

Pulmonary hypertension (PH) is a rare disease of the pulmonary vasculature with diverse pathogenetic mechanisms. Vasoactive substances such as endothelin A receptor (ET(A)) antagonists and prostanoids have been used to improve haemodynamics and clinical outcome. We compared the hemodynamic response to BQ-123 (an ET(A) receptor antagonist) and prostacyclin or its analogue iloprost in ten patients (four men) with a mean age of 35.9+/-15.6 years. Seven patients had primary PH and three had PH owing to connective tissue disease. Patients underwent haemodynamic evaluation before and after administration of intra-atrial BQ-123 (200 mmol/min for 60 min), intravenous prostacyclin (3 ng x kg(-1) x min(-1) for 4 h) or iloprost as an aerosol (100 microg over 24 h). Response to vasodilator administration was defined as >15% decrease in pulmonary vascular resistance index (PVRI). Of the ten patients, five showed a response to BQ-123 and eight responded to prostanoids. Four patients were responders and one patient was a non-responder to both agents. PVRI decreased by 16.6+/-13.4% with BQ-123, and 24.4+/-15.7% with prostanoids (not statistically significant). The aetiology of PH did not affect the response to either drug. In conclusion, response to ET(A) antagonist or prostanoid administration can be achieved in a large group of patients with severe PH, however few patients respond identically to both agents. These findings are consistent with a multifactorial mechanism involved in this disease.

Topics: Adolescent; Adult; Aged; Endothelin Receptor Antagonists; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Peptides, Cyclic; Receptor, Endothelin A; Vascular Resistance; Vasodilator Agents

Treatment with aerosolised iloprost, a prostacyclin analogue, has beneficial effects in patients with pulmonary arterial hypertension (PAH). It is unclear if patients, whose clinical condition deteriorates under treatment with aerosolised iloprost, benefit from switching to continuous intravenous iloprost. The current authors report on 16 patients with severe PAH who received continuous intravenous iloprost after primary or secondary failure of treatment with aerosolised iloprost. Determinants of efficacy were survival, New York Heart Association (NYHA) class, and walking distance in the 6-min walk test. Of 93 patients with PAH treated with aerosolised iloprost, 16 required switching to intravenous iloprost for clinical deterioration. These patients had severe right heart failure with a cardiac index of 1.6+/-0.2 L x min(-1) x m(-2) and a mixed-venous oxygen saturation of 52+/-6%. Five of these patients showed no improvement and eventually died. Three patients had further deterioration in NYHA class and exercise capacity; two of them underwent lung transplantation; the third patient is still alive. Eight patients showed marked clinical improvement; one underwent lung transplantation and the others are currently alive and stable. In the latter group of patients, the walking distance in the 6-min walk test increased from 205+/-94 to 329+/-59 m. It was not possible to identify clinical or haemodynamic factors that would predict whether switching from inhaled to intravenous iloprost would have a beneficial effect. In patients with pulmonary arterial hypertension who deteriorated while being treated with aerosolised iloprost, switching to continuous intravenous iloprost caused substantial improvement in exercise capacity in eight of 16 patients but could not prevent progression of pulmonary hypertension in the remaining eight patients. Since it was impossible to predict the individual effects of this approach, intravenous prostaglandin treatment should be considered in pulmonary arterial hypertension patients who deteriorate while receiving iloprost aerosol.

Topics: Administration, Inhalation; Adult; Aged; Exercise Test; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Retreatment; Retrospective Studies; Severity of Illness Index; Survival Rate; Treatment Failure; Vasodilator Agents

Significant pulmonary hypertension is a predictor of postoperative right heart insufficiency and increased mortality in patients undergoing orthotopic heart transplantation. Since the use of iv vasodilators is limited by their systemic effects, we evaluated the pulmonary and systemic hemodynamic effects of inhaled aerosolized iloprost (IP) in heart transplant candidates with elevated pulmonary vascular resistance (PVR).. Twenty-nine male heart transplant candidates because of dilated or ischemic cardiomyopathy with elevated PVR were included in the study. After assessing baseline hemodynamics, 50 micro g aerosolized IP were administered by inhalation.. Inhalation of iloprost reduced PVR index (PVRI; 416 +/- 180 vs 349 +/- 173 dyn x sec(-1) x m(-2) x cm(-5); P < 0.01) and mean pulmonary artery pressure (MPAP; 28.6 +/- 9 vs 24.2 +/- 9.1 mmHg; P < 0.01), but did not affect blood pressure or systemic vascular resistance. An additional improvement of ventricular performance with an increase of cardiac index (CI; 2.8 +/- 0.7 vs 2.6 +/- 0.7 L x min(-1) x m(-2); P < 0.05) and a decrease of pulmonary capillary wedge pressure (PCWP; 15.6 +/- 6.8 vs 12.8 +/- 7.1 mmHg; P < 0.01) was observed after inhalation of IP.. Inhaled aerosolized iloprost effectively reduces MPAP and is accompanied by an increase in CI and stroke index. Further advantages of iloprost inhalation are the lack of adverse reactions and ease of administration. Iloprost may be a useful drug to screen for vascular reactivity in cardiac transplantation patients.

Topics: Administration, Inhalation; Adult; Aerosols; Aged; Chronic Disease; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Nitric Oxide

Topics: Adolescent; Aerosols; Heart Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Male; Nitric Oxide; Vasodilator Agents

To switch patients with severe pulmonary hypertension and previous life-threatening catheter-related complications from long-term IV epoprostenol therapy to aerosolized iloprost therapy.. Open, uncontrolled trial.. Medical ICU of a university hospital.. Two patients with primary pulmonary hypertension and one patient with pulmonary hypertension after surgical closure of atrial septal defect (mean pulmonary artery pressure > or =50 mm Hg). All were classified as New York Heart Association class II under treatment with continuous IV epoprostenol for 4 years.. Stepwise reduction of IV epoprostenol (1 ng/kg/min steps every 3 to 10 h) during repeated inhalations of aerosolized iloprost (150 to 300 microg/d with 6 to 18 inhalations/d). Continuous pulmonary and systemic arterial monitoring were performed.. Aerosolized iloprost reduced pulmonary artery pressure by 49%, 49%, and 45%, respectively, and increased cardiac output by 70%, 75%, and 41% in the three patients. The effect lasted for 20 min and was similar at different doses of IV epoprostenol. Persistent treatment change to inhaled iloprost could not be achieved because all patients developed signs of right heart failure. After termination of iloprost inhalations, return to standard epoprostenol therapy led to clinical and hemodynamic restoration.. Although aerosolized iloprost demonstrated short-term hemodynamic effects, it could not be utilized as alternative chronic vasodilator in patients with severe pulmonary hypertension.

Topics: Administration, Inhalation; Adult; Aerosols; Cardiac Output; Critical Care; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Long-Term Care; Middle Aged; Pulmonary Wedge Pressure; Treatment Failure; Treatment Outcome

Continuous intravenous infusion of prostacyclin is an effective treatment for primary pulmonary hypertension. This approach, however, requires the insertion of a permanent central venous catheter with the potential risk of serious complications. Recently, administration of aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension.. We evaluated the effects of treatment with aerosolized iloprost over a one-year period on exercise capacity and hemodynamic variables in patients with primary pulmonary hypertension.. Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a cumulative daily dose of 100 to 150 micrograms for at least one year. The mean (+/- SD) walking distance in the 6-min-walk test increased from 278 +/- 96 meters at base line to 363 +/- 135 meters after 12 months (P < 0.0001). During the same period, the mean pulmonary artery pressure declined from 59 +/- 10 mmHg to 52 +/- 15 mmHg (P = 0.006), the cardiac output increased from 3.8 +/- 1.4 l/min to 4.4 +/- 1.3 l/min (P = 0.02), and the pulmonary vascular resistance declined from 1.205 +/- 467 dynes.s.cm-5 to 925 +/- 469 dynes.s.cm-5 (P = 0.0003). Treatment was generally well tolerated and except for mild coughing, minor headache and jaw pain in some patients, no side effects occurred.. Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.

Topics: Administration, Inhalation; Adult; Aged; Exercise Test; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Long-Term Care; Male; Middle Aged

Preexisting pulmonary hypertension in pediatric patients is associated with poor outcome after cardiac transplantation because of donor right ventricular dysfunction. To avoid a combined heart-lung transplantation in a 17-year-old patient, we used an intensified pretreatment with intravenous prostacyclin and dobutamine combined with an inhalative therapy with the aerosolized prostacyclin-analog Iloprost. With this regimen, the patient was hemodynamically stabilized for the waiting period of 21 days after which an uneventful cardiac transplantation was performed.

Topics: Adolescent; Aerosols; Cardiovascular Agents; Heart Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Male; Preoperative Care; Severity of Illness Index

Topics: Clinical Trials, Phase III as Topic; Controlled Clinical Trials as Topic; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

Topics: Administration, Inhalation; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

Vasodilative therapy in the form of calcium channel blockers and, recently, continuous intravenous prostacyclin has improved exercise capacity and reduced mortality in primary pulmonary hypertension. Their clinical value is limited by either low rate of response or serious side effects. These shortcomings could be overcome by the use of iloprost, a stable prostacyclin analogue. Administering it by inhalation, we assessed its short-term efficacy in patients with primary and secondary pulmonary hypertension.. We studied six patients with primary and six with secondary pulmonary hypertension, all with New York Heart Association functional class III or IV symptoms of congestive heart failure. Iloprost was nebulised with 8 l/min of oxygen and administered in increasing doses from 10 to 40 micrograms via a facemask. The haemodynamic effects of iloprost was assessed by right-heart catheterisation.. Inhalation of iloprost was well tolerated, and produced a median reduction in mean pulmonary artery pressure from 52 (42-63) to 41 (35-56) mm Hg (p < 0.05). Cardiac output increased from 3.5 (2.8-4.3) to 4.1 (3.1-5.1) l/min (p < 0.05) and pulmonary vascular resistance decreased from 1036 (722-1526) to 753 (446-1107) dyn.sek.cm-5 (p < 0.01). No changes occurred in heart rate, systemic blood pressure or pulmonary wedge pressure.. Drug testing with inhalation of iloprost is safe and causes beneficial haemodynamic changes with selective pulmonary vasodilatation. Since the long-term effect of medical intervention is based on the degree of acute pulmonary vascular reactivity, inhalation of iloprost may be a new therapeutic option for severe pulmonary hypertension.

Topics: Administration, Inhalation; Adult; Aged; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Platelet Aggregation Inhibitors; Vasodilator Agents

Topics: Administration, Inhalation; Aerosols; Humans; Hypertension, Pulmonary; Iloprost; Long-Term Care; Treatment Failure

Topics: Aerosols; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypertension, Pulmonary; Iloprost; Long-Term Care; Treatment Failure; Vasodilator Agents

Primary pulmonary hypertension is a rare disease in childhood associated with a poor prognosis. However, during the past 10 years, pulmonary vasodilator treatment has somewhat improved its prognosis. Long term continuous infusion of prostacyclin (epoprostenol) has been shown to improve physical capacity and to reduce mortality in primary and secondary pulmonary hypertension. It has been reported in adults that daily repetitive inhalation of iloprost, a prostacyclin analogue, seems also suitable for long term therapy of pulmonary hypertension. Repetitive inhalation of iloprost was administered to a 5 year old boy with severe primary pulmonary hypertension. He showed continuous clinical improvement without any side effects over the three years of treatment. This treatment may offer an alternative to continuous intravenous prostacyclin infusion and obviates the need for a permanent central venous catheter.

Topics: Administration, Inhalation; Child, Preschool; Humans; Hypertension, Pulmonary; Iloprost; Male; Vasodilator Agents

Continuous intravenous treatment with epoprostenol significantly improves pulmonary haemodynamics and survival in patients with primary pulmonary hypertension (PPH). Its beneficial effect, however, may be blunted due to adverse effects such as catheter sepsis and systemic hypotension. Recent investigations have shown that inhaled iloprost is effective in the treatment of PPH. Based on their different pharmacokinetics, we hypothesised that the combination of intravenous epoprostenol and inhaled iloprost would be more efficacious than epoprostenol alone during acute testing in patients with PPH.. The effect of a single dose of inhaled iloprost (30 microg total over 15 minutes) on pulmonary haemodynamics was examined in eight patients with PPH (initial non-responders to nitric oxide) who had considerable adverse effects during treatment with epoprostenol.. The combination of inhaled iloprost and intravenous epoprostenol significantly improved mean pulmonary artery pressure (MPAP), cardiac index (CI), mixed venous oxygen saturation (SvO2), and systemic arterial oxygen pressure (PaO2) compared with epoprostenol treatment alone. Mean systemic arterial pressure (MSAP) and pulmonary capillary wedge pressure (PCWP) remained unchanged.. The pulmonary vasoreactivity shown by additional iloprost inhalation during effective epoprostenol treatment suggests that an improvement of treatment for pulmonary hypertension may be possible by combining vasoactive substances.

Topics: Administration, Inhalation; Antihypertensive Agents; Blood Pressure; Epoprostenol; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Middle Aged; Pulmonary Circulation; Vasodilator Agents

The goal of this study was to assess atrial natriuretic peptide (ANP) levels during inhalation of iloprost in severe primary (PPH) and nonprimary pulmonary hypertension (NPPH).. The ANP system is activated in pulmonary hypertension and may help protect from right ventricular (RV) decompensation. It is unknown if ANP regulation is the same in severe PPH and NPPH and if the dynamic regulation is intact in a highly activated ANP system.. In 11 patients with PPH and seven patients with NPPH, right heart catheter investigations were performed. Pulmonary and systemic artery ANP and cyclic guanosine monophosphate (cGMP) levels as well as hemodynamics were measured before and after iloprost inhalation.. The baseline hemodynamics of patients with PPH and patients with NPPH were comparable (mean pulmonary artery pressure [mPAP]: 61 +/- 5 mm Hg vs. 52 +/- 5 mm Hg, pulmonary vascular resistance [PVR]: 1,504 +/- 153 dyne.s.cm(-5) vs. 1,219 +/- 270 dyne.s.cm(-5). Atrial natriuretic peptide and cGMP levels were increased about tenfold and fivefold compared with controls in both PPH and NPPH. Iloprost inhalation significantly decreased mPAP (-9.1 +/- 2.5 mm Hg vs. -7.9 +/- 1.5 mm Hg), PVR (-453 +/- 103 dyne.s.cm(-5) vs. -381 +/- 114 dyne.s.cm(-5)), ANP (-99 +/- 63 pg/ml vs. -108 +/- 47 pg/ml) and cGMP (-4.6 +/- 0.9 nM vs. -4.2 +/- 1.6 nM). Baseline ANP including all patients significantly correlated with PVR, right atrial pressure, cardiac index, RV ejection fraction, mixed venous oxygen saturation and cGMP.. The ANP system is highly activated in patients with severe PPH and NPPH. Atrial natriuretic peptide levels are significantly correlated with parameters of RV function and pre- and afterload. Iloprost inhalation causes a rapid decrease in ANP and cGMP in parallel with pulmonary vasodilation and hemodynamic improvement.

Topics: Administration, Inhalation; Adult; Atrial Natriuretic Factor; Cardiac Catheterization; Cyclic GMP; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Male; Vasodilator Agents

Inhalation of aerosolized iloprost, a stable prostacyclin analog, has been suggested for treatment of primary and secondary pulmonary hypertension, but demands multiple daily inhalation maneuvers because of the short-term effect of this approach. In intact rabbits, pulmonary hypertension was induced by continuous infusion of the stable thromboxane mimetic U46619. Thereafter, the influence of aerosolized iloprost on pulmonary and systemic hemodynamics and gas exchange was investigated in the presence and absence of phosphodiesterase (PDE) inhibitors for stabilization of the second-messenger cAMP. First, dose-effect curves for pulmonary artery pressure (Ppa) decline were established for the nonspecific PDE inhibitors pentoxifylline and dipyridamole and for the dual-selective PDE3/4 inhibitor tolafentrine when being applied as sole agent, either via the intravenous or the inhalative route. Subthreshold doses for each agent and each route of administration were then combined with a standardized iloprost aerosolization maneuver, which resulted in a substantial prolongation, but not augmentation, of the lung vasodilatory response for the prostanoid. Next, higher doses of each PDE inhibitor were employed for nebulization, causing per se some pulmonary vasodilative effect, in the absence of arterial pressure decrease or impairment of gas exchange. Coaerosolization of these PDE inhibitor doses with standardized iloprost caused approximate doubling of the immediate pulmonary vasodilator response, marked prolongation of the pressure relief overtime, and a 2- to 4-fold increase in the area under the curve of pulmonary vasodilation (efficacy tolafentrine > dipyridamole > pentoxifylline). Still, systemic arterial pressure was not suppressed and gas exchange was fully maintained. We conclude that coadministration of PDE inhibitors with inhaled iloprost markedly enhances the prostanoid-induced pulmonary artery pressure decrease while maintaining the lung selectivity of the vasodilatory response, and that coaerosolization is a particularly suitable route of administration. Even nonselective clinically approved PDE inhibitors may be employed for this purpose.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aerosols; Animals; Dipyridamole; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemodynamics; Hypertension, Pulmonary; Iloprost; Naphthyridines; Pentoxifylline; Phosphodiesterase Inhibitors; Rabbits; Vasodilation; Vasodilator Agents

The treatment of chronic pulmonary hypertension with prostacyclin in children is prone to severe complications due to mandatory long-term venous therapy. Inhaled iloprost has been evaluated in adult patients with good preliminary results.. We report our experience of the use of aerosolized iloprost in an infant treated for pulmonary hypertension associated to a right ventricular failure, which occurred after a neonatal arterial switch operation for transposition of the great arteries. For nine months, hemodynamic and functional status improved and the quality of life was satisfactory at home.. If further experiences and studies support this observation, aerosolized iloprost could be an alternative to prostacyclin venous therapy in treating children with chronic pulmonary hypertension.

Topics: Administration, Inhalation; Cardiovascular Surgical Procedures; Chronic Disease; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Male; Transposition of Great Vessels; Vasodilator Agents

Topics: Administration, Inhalation; Cardiac Output; Humans; Hypertension, Pulmonary; Iloprost; Models, Theoretical; Nebulizers and Vaporizers; Nitric Oxide; Prognosis; Vascular Resistance

Undifferentiated connective tissue disease with secondary antiphospholipid syndrome was diagnosed in a 33 year old woman after recurrent arterial thromboses, two miscarriages and myocarditis. Despite effective immunosuppression and anticoagulation her initially mild precapillary pulmonary hypertension progressed in the absence of thromboembolic events, cardiopulmonary disease or other systemic disorders. With continuous i.v. iloprost in a dosage of up to 4.5 ng/kg/min for a total of 15 months, her 6 min walking-distance improved from 210 to 315 m, the pulmonary vascular resistance decreased from 1710 to 1111 dyn x s x cm-5 and the mean pulmonary arterial pressure decreased from 64 to 54 mmHg. This partial success of conservative treatment enabled a reassessment of the necessity for heart and lung transplantation.

Topics: Adult; Antiphospholipid Syndrome; Catheterization, Central Venous; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Long-Term Care; Treatment Outcome

We assessed the effect of oxygen, nitric oxide (NO) and prostanoids (prostacyclin and iloprost) on pulmonary hemodynamics and plasma levels of vasoactive mediators in children with pulmonary hypertension (PH). It is not known whether the hemodynamic response during acute vasodilator testing correlates with changes in plasma levels of endothelin-1 (ET-1), cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). In this retrospective analysis 14 children at a median age of 4 years and 3 months [1.8 months-13 years] with a median pulmonary resistance to perfusion of 10.1 [2.1-37.7]. Wood-Units x m2 were studied. Diagnoses included PH due to congenital heart disease (AVSD n = 5; VSD n = 2; PDA n = 1) or unknown causes (n = 6). The ratios of pulmonary/systemic pressure (Pp/Ps) and of pulmonary/systemic resistance (Rp/Rs) were recorded a) at baseline, b) during oxygen (FiO2 = 1.0) and c) while on NO (80 ppm max., at FiO2 = 0.23). In 13 out of 14 children prostanoids were given additionally: 7 received prostacyclin (i.v.) and 6 were given iloprost which was nebulized. ET-1, cGMP and cAMP were measured in blood samples taken from the pulmonary vein or left ventricle at baseline, during increased FiO2, during NO inhalation and while on prostanoids. Pulmonary vasodilation in response to oxygen was found in 2/14 patients. 4/14 patients responded to NO and 2/7 to prostacyclin i.v. Increased FiO2 was not associated with changes in plasma concentrations of ET-1, cGMP or cAMP. NO inhalation was followed by an increase in cGMP levels from 10.9 [5.5-55.4] nM/L to 21.3 [6.4-76.3] nM/L independent from the individual hemodynamic response. Oxygen and NO identify most children with reactive pulmonary vasculature. cGMP plasma levels do not correlate with individual hemodynamic responses to NO.

Topics: Adolescent; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Iloprost; Infant; Male; Nitric Oxide; Oxygen Inhalation Therapy; Retrospective Studies; Vasodilation

Topics: Administration, Inhalation; Aerosols; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Severity of Illness Index; Vascular Resistance; Vasodilator Agents

Pulmonary hypertension (PHT) associated with systemic lupus erythematosus (SLE) has a dismal prognosis. Vasodilators and immunosuppressive therapy have been tried over the years with discouraging results. Prostacyclin (PGI2) which has potent vasodilatatory and anti-platelet effects has been demonstrated to significantly decrease pulmonary arterial pressure and pulmonary vascular resistance during acute infusion. Satisfactory response has been reported in SLE patients with PHT treated with short-term intravenous continuous PGI2 infusion. We report here a 48-month experience of the use of monthly low dose infusion of a PGI2 analogue, iloprost, in a SLE patient with pulmonary hypertension in New York Heart Association functional Class III. There was an initial haemodynamic response to an acute infusion of iloprost. Repeated infusions were followed by marked improvement in her functional status and her mean pulmonary arterial pressure dropped from 80 mmHg in the first few months and remained static at around 55 mmHg for the subsequent years.

Topics: Adult; Disease Progression; Female; Humans; Hypertension, Pulmonary; Iloprost; Lupus Erythematosus, Systemic; Pulmonary Wedge Pressure; Treatment Outcome; Vasodilator Agents

Topics: Administration, Inhalation; Adult; Aerosols; Antihypertensive Agents; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Lung; Male; Middle Aged; Vasodilator Agents

Topics: Administration, Inhalation; Breath Tests; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Nitric Oxide; Scleroderma, Systemic; Vasodilator Agents

The treatment of decompensated right ventricular failure with vasodilators is difficult due to reduced systemic pressure and/or ventilation/perfusion (V/Q) mismatch with hypoxemia. In a recent study we demonstrated that inhaled vasodilatory prostanoids may offer a new strategy to achieve pulmonary selective vasodilatation and improvement of right ventricular function. We applied this new approach to a patient with circulatory shock due to primary pulmonary hypertension (PPH), complicated by a pulmonary infiltrate, who did not tolerate intravenous prostacyclin.. Case report.. Intensive Care Unit (ICU), Medizinische Klinik Giessen, Germany.. A 45-year-old woman with PPH presenting with decompensated right heart failure (ascites, pleural effusion), circulatory shock and commencing renal and hepatic failure, despite maximum therapy including the use of catecholamines.. Intermittent inhalation of aerosolized iloprost, the stable analogue of prostacyclin, and comparison to inhaled nitric oxide (NO). Subsequent long-term therapy with aerosolized iloprost, 150 microg/day.. In response to inhaled iloprost, pulmonary arterial pressure (PAP) decreased from 65 to 61 mmHg, cardiac index (CI) increased from 1.25 to 1.85 l/min per m2, and pulmonary vascular resistance (PVR) decreased from 2416 to 1549 dyn/s per cm5 while inhaled NO decreased the PVR from 2280 to 1920 dyn/s per cm5 without a decrease in PAP. Both of these interventions increased the arterial pO2 but did not change the systemic arterial pressure. In contrast, intravenous prostacyclin was not tolerated, due to systemic side effects. During repeated inhalations with iloprost, the baseline hemodynamics and gas exchange improved dramatically and renal and liver functions normalized. During 1 year of continued therapy, the clinical status improved very much, concomitant with improved hemodynamics, and the patient has been taken off the transplantation list.. Inhalation of aerosolized iloprost may offer a new life-saving strategy in near desperate cases of pulmonary hypertension in which intravenous prostacyclin cannot be applied due to severe side effects.

Topics: Administration, Inhalation; Aerosols; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Nitric Oxide; Oxygen; Shock; Vasodilator Agents; Ventricular Dysfunction, Right

To investigate the relation between the severity of pulmonary hypertension and the outcome of medical treatment.. 98 patients with primary pulmonary hypertension--nine (6%) with systemic disease and pulmonary hypertension and 39 (27%) with thromboembolic pulmonary hypertension--received medical treatment and were followed between 1982 and 1995. They were given long term intravenous prostaglandin treatment (either epoprostenol (n = 61) or iloprost (n = 13)) or conventional treatment with oral anticoagulants (n = 24) with or without calcium channel blockers. Event-free survival was measured to death or transplant surgery, or pulmonary thromboendarterectomy.. Prognosis (hazard ratio) was affected by: New York Heart Association grade, 1.52 (95% confidence interval 1.11 to 2.09); mixed venous oxygen saturation (SvO2%), 0.97 (0.95 to 0.98); cardiac index, 0.72 (0.49 to 1.06); mean right atrial pressure, 1.04 (1.01 to 1.07); and pulmonary vascular resistance, 1.02 (1.00 to 1.04). The median event-free survival time of patients with SvO2 < 60% was 239 days (0 to 502) on conventional treatment (n = 22) and 585 days (300 to 870) on prostaglandin treatment (n = 42). No difference was seen in patients with SvO2 > or = 60% between conventional treatment and prostaglandin treatment, survival being 1275 days (732 to 1818; (n = 48)) and 986 days (541 to 1431; n = 30)), respectively. Capacity for pulmonary vasodilatation did not predict outcome of treatment.. Continuous intravenous prostaglandins were more effective than anticoagulants, with or without calcium channel blockers, in prolonging survival in patients with right heart failure. In these patients a capacity to vasodilate did not predict outcome from medical treatment.

Topics: Adult; Analysis of Variance; Anticoagulants; Calcium Channel Blockers; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Platelet Aggregation Inhibitors; Prognosis; Retrospective Studies; Statistics, Nonparametric; Survival Analysis; Treatment Outcome

To compare the effects of aerosolization of prostacyclin and its stable analog iloprost with those of nasal oxygen, inhaled nitric oxide, and intravenous prostacyclin on hemodynamics and gas exchange in patients with severe pulmonary hypertension.. Open uncontrolled trial.. Justus-Liebig-University, Giessen Germany.. 4 patients with primary pulmonary hypertension and 2 patients with severe pulmonary hypertension associated with calcinosis, the Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia (the CREST syndrome). All were classified as New York Heart Association class III or class IV.. Short-term applications of O2, inhaled nitric oxide, intravenous prostacyclin, aerosolized prostacyclin, and aerosolized iloprost during repeated catheter investigation of the right side of the heart within a 1-month period. One patient had long-term therapy with inhaled iloprost.. Aerosolized prostacyclin decreased pulmonary artery pressure in 6 patients from (mean +/- SE) 62.3 +/- 4.1 mm Hg to 50.8 +/- 5.5 mm Hg and reduced pulmonary vascular resistance from 1721 +/- 253 dyne/s cm-5 to 1019 +/- 203 dyne/s cm-5, and it increased cardiac output from 2.75 +/- 0.21 L/min to 4.11 +/- 0.54 L/min, mixed venous oxygen saturation from 51.1% +/- 3/4% to 66.3% +/- 4.1% and arterial oxygen saturation from 90.6% +/- 2.7% to 93.8% +/- 23% (P<0.05 for all changes). Mean systemic arterial pressure was only slightly affected. The responses lasted for 10 to 30 minutes after inhalation was terminated. Aerosolized iloprost had an identical efficacy profile but was associated with a longer duration of the pulmonary vasodilatory effect (60 min to 120 min). In comparison, intravenous prostacyclin reduced pulmonary vascular resistance with corresponding efficacy but produced a more pronounced decline in systemic artery pressure and no clinically significant decrease in pulmonary artery pressure. Nitric oxide and O2 were less potent pulmonary vasodilators in these patients. In one patient, 1 year of therapy with aerosolized iloprost (100 microgram/d in six aerosol doses) resulted in sustained efficacy of the inhaled vasodilator regimen and clinical improvement.. Aerosolization of prostacyclin or its stable analog iloprost causes selective pulmonary vasodilatation, increases cardiac output, and improves venous and arterial oxygenation in patients with severe pulmonary hypertension. Thus, it may offer a new strategy for treatment of this disease.

Topics: Adult; Aerosols; Antihypertensive Agents; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Middle Aged; Nitric Oxide; Oxygen Inhalation Therapy; Vasodilator Agents

We have studied the effect of combining inhaled nitric oxide (NO) with an i.v. vasodilator agent, nitroglycerin, or ciloprost, a prostacyclin analogue, during acute pulmonary hypertension in pigs, induced by continuous infusion of a thromboxane analogue (U46619), adjusted to maintain mean pulmonary artery pressure (MPAP) at 40 mm Hg. The effects of the different treatments on MPAP and pulmonary resistances were determined. In the first part of the study, we determined the dose-response to increased NO concentrations from 5 to 40 ppm. This showed a maximum pulmonary effect with NO 5 ppm, but with no systemic effects. The effect of NO 10 ppm was then compared with two i.v. drugs. Nitroglycerin was less effective than NO on pulmonary vessels but induced significant arterial hypotension. Pulmonary vasodilatation induced by ciloprost was greater than that by NO but with the same side effects as nitroglycerin on systemic variables. We also found that the combination of NO and nitroglycerin had the same pulmonary effects as NO 10 ppm but that adding ciloprost to NO decreased pulmonary pressures significantly more than either drug used alone. We conclude that inhaled NO may be usefully combined with i.v. ciloprost but not with i.v. nitroglycerin.

Topics: Administration, Inhalation; Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Nitric Oxide; Nitroglycerin; Swine; Vasodilator Agents

Topics: Female; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intra-Arterial; Male; Pilot Projects; Scleroderma, Systemic; Time Factors; Vasodilator Agents

We report the hemodynamic and clinical effects of acute and chronic administration of iloprost in two patients with severe pulmonary hypertension caused by toxic oil syndrome. We tested the acute effect of progressive increments of iloprost, followed by long-term infusion of the drug during 14 days. The acute response produced an increase in cardiac output and moderate reduction in pulmonary vascular resistance, with no change in pulmonary artery pressure. Nevertheless, a maintained reduction in pulmonary artery pressure and resistance, as well as clinical improvement, was observed after chronic infusion. We conclude that (1) the acute effect of iloprost does not necessarily predict long-term hemodynamic response, and (2) iloprost given in long-term infusion seems to have been an efficacious and safe drug in our two patients, and it opens a new line of treatment.

Topics: Adult; Brassica; Fatty Acids, Monounsaturated; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Male; Plant Oils; Rapeseed Oil; Time Factors

Vasodilator therapy in pulmonary hypertension is limited by the lack of an agent selective for the pulmonary circulation. The effects of intravenous prostacyclin and two stable prostaglandin analogs, ZK 36-374 and CL 115,347, were assessed on the preconstricted pulmonary vasculature of the anesthetized dog. During hypoxic vasoconstriction ZK 36-374 (0.4 micrograms/kg per min) markedly reduced pulmonary artery pressure (26 +/- 3 to 13 +/- 1 mm Hg) (p less than 0.05) and pulmonary vascular resistance (6.2 +/- 1.1 to 2.8 +/- 0.2 mm Hg/liter per min) (p less than 0.01). There was no significant effect on cardiac output, aortic pressure or arterial blood gases. Pulmonary vasoconstriction induced by prostaglandin F2 alpha was similarly affected by ZK 36-374, and in this instance the aortic pressure was also reduced (158 +/- 11 to 129 +/- 11 mm Hg) (p less than 0.01). ZK 36-374 (0.2 micrograms/kg per min) was more effective in lowering hypoxic pulmonary vascular resistance (from 6.5 +/- 0.6 to 3.0 +/- 0.3 mm Hg/liter per min) than was prostacyclin (0.75 micrograms/kg per min) (from 6.3 +/- 0.6 to 4.2 +/- 0.4 mm Hg/liter per min) (p less than 0.05) and resulted in a smaller fall in aortic pressure (p less than 0.05). CL 115,347 (1.0 micrograms/kg per min) had no effect on the pulmonary vasculature during normoxia or when preconstricted by prostaglandin F2 alpha or hypoxia, but reduced aortic pressure and total systemic resistance (p less than 0.05). It appears to be a selective systemic vasodilator with no pulmonary vascular activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cardiovascular Agents; Dinoprost; Dogs; Drug Evaluation, Preclinical; Epoprostenol; Female; Hypertension, Pulmonary; Hypoxia; Iloprost; Male; Prostaglandins F; Pulmonary Circulation; Vascular Resistance