Aerosolized Iloprost Therapy Could Not Replace Long-term IV Epoprostenol (Prostacyclin) Administration in Severe Pulmonary Hypertension

doi:10.1378/chest.119.1.296

Chest

Volume 119, Issue 1, January 2001, Pages 296-300

https://doi.org/10.1378/chest.119.1.296 Get rights and content

Objectives:

To switch patients with severe pulmonaryhypertension and previous life-threatening catheter-relatedcomplications from long-term IV epoprostenol therapy to aerosolizediloprost therapy.

Design:

Open, uncontrolledtrial.

Setting:

Medical ICU of a universityhospital.

Patients:

Two patients with primarypulmonary hypertension and one patient with pulmonary hypertensionafter surgical closure of atrial septal defect (mean pulmonary arterypressure ≥ 50 mm Hg). All were classified as New York Heart Association class II under treatment with continuous IV epoprostenolfor 4 years.

Interventions:

Stepwise reduction of IVepoprostenol (1 ng/kg/min steps every 3 to 10 h) during repeatedinhalations of aerosolized iloprost (150 to 300 μg/d with 6 to 18inhalations/d). Continuous pulmonary and systemic arterial monitoringwere performed.

Results:

Aerosolized iloprost reducedpulmonary artery pressure by 49%, 49%, and 45%, respectively, andincreased cardiac output by 70%, 75%, and 41% in the three patients. The effect lasted for 20 min and was similar at different doses of IVepoprostenol. Persistent treatment change to inhaled iloprost could notbe achieved because all patients developed signs of right heartfailure. After termination of iloprost inhalations, return to standardepoprostenol therapy led to clinical and hemodynamic restoration.

Conclusions:

Although aerosolized iloprost demonstratedshort-term hemodynamic effects, it could not be utilized as alternativechronic vasodilator in patients with severe pulmonaryhypertension.

Section snippets

Materials and Methods

The three patients were women, 42, 30, and 49 years old; thefirst two patients had PPH and the third patient suffered fromprogressive pulmonary hypertension after occlusion of an atrialseptal defect.² All had been treated withcontinuous IV epoprostenol and warfarin for 4 years, which had improvedtheir New York Heart Association functional class from III and IV to, II. All three patients had experienced episodes of life-threateningsepsis caused by the catheter (Port-A-Cath; SIMS Deltec; St.

Discussion

Weaning from long-term treatment with continuous IV epoprostenolunder repeated inhalations of aerosolized iloprost was not successfulin the three patients with severe pulmonary hypertension. In patient 1,IV epoprostenol could only be reduced from 13 to 6 ng/kg/min, becauseat this dosage the patient developed acute right heart failure. Inpatient 2, termination of epoprostenol was immediately followed byright heart failure. In patient 3, weaning from epoprostenol seemed tobe successful; however,

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Cited by (41)

Transitioning from parenteral to inhaled prostacyclin therapy in pulmonary arterial hypertension
2016, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Only one patient failed inhaled therapy necessitating transition back to intravenous epoprostenol. Limited data exists supporting the transition of patients from parenteral epoprostenol therapy to parenteral treprostinil [12–15], inhaled iloprost [16,17], and inhaled treprostinil [10,11]. Currently, there is an ongoing prospective trial evaluating the transition of patients from parenteral to inhaled prostacyclins (NCT01268553).
Parenteral prostacyclin therapy for PAH has allowed for improvements in functional status, quality of life and mortality. Parenteral therapies however carry an increased risk of line-associated complications. Inhaled prostacyclins are an attractive alternative therapy; however, limited data exists supporting the safety and outcomes after transition.
We describe a retrospective observational analysis of adults with PAH who were transitioned from a parenteral prostacyclin to inhaled treprostinil at our institution. Endpoints include duration of transition, hospital length of stay, adverse effects during transition, and cardiopulmonary function post transition.
Eight patients were included, all of which were on triple therapy. Seven patients receiving intravenous prostacyclin therapy were transitioned in an ICU setting, while one patient was transitioned from subcutaneous treprostinil as an outpatient. The average ICU and hospital length of stay was 4.1 ± 0.7 days. Patient preference was the most common reason for transition (n = 5), followed by line complication (n = 2), and intolerance to parenteral therapy (n = 1). One adverse event was observed while initiating inhaled treprostinil that only required slowing of the transition process. On follow-up (19.6 ± 11.1 months) functional class did not change, and non-parametric test showed no change in 6MWD after transition (p = 0.62). One patient failed inhaled therapy necessitating transition back to intravenous therapy.
Transitioning patients from parenteral to inhaled prostacyclin therapy can be safely accomplished in specialized centers over a 48–72 h period. Patient preference was overwhelming the most prevalent reason for transition.
Hemodynamic Stability After Transitioning Between Endothelin Receptor Antagonists in Patients With Pulmonary Arterial Hypertension
2013, Canadian Journal of Cardiology
Maintenance of a favourable hemodynamic profile is central to therapeutic success in pulmonary arterial hypertension (PAH). There is little information about the safety of transitioning patients between oral therapies for PAH. Endothelin receptor antagonists (ERAs) have been a therapeutic mainstay in PAH, providing benefit to many patients. Three ERAs, bosentan, sitaxsentan, and ambrisentan have been approved for clinical use. Sitaxsentan was voluntarily withdrawn from the market in late 2010 resulting in the need to quickly transition a large number of stable patients.
We transitioned 30 clinically stable patients to either ambrisentan or bosentan. Patients underwent a right heart catheterization, measurement of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and assessment of functional class before changing ERA and again 4 months later. We present a retrospective analysis of those data.
Of the 30 patients transitioned (15 to ambrisentan, 15 to bosentan), 23 had complete hemodynamic data. No significant change was observed in the groups in right atrial, mean pulmonary artery, and pulmonary artery wedge pressures, or in cardiac output, pulmonary vascular resistance, or NT-proBNP levels. There was no change in World Health Organization functional class. Four ambrisentan and 2 bosentan-treated patients reported fluid retention, and 3 bosentan-treated patients had elevation of hepatic transaminases. Two of the patients had a right atrial pressure increase of ≥5 mm Hg, and 4 had pulmonary artery wedge pressure increase of ≥5 mm Hg.
Transitioning between ERAs in stable PAH patients does not result in hemodynamic or clinical deterioration during the first 4 months posttransition. A minority of patients have developed increased cardiac filling pressures.
Le maintien d'un profil hémodynamique favorable est essentiel au succès thérapeutique de l'hypertension artérielle pulmonaire (HAP). Peu d'informations existent sur l'innocuité de la transition vers les différents traitements oraux de l'HAP chez les patients. Les antagonistes des récepteurs de l'endothéline (ARE) ont été un pilier thérapeutique de l'HAP s'avérant un avantage chez plusieurs patients. Trois (3) ARE, le bosentan, le sitaxsentan et l'ambrisentan ont été approuvés pour utilisation clinique. Le sitaxsentan a été volontairement retiré du marché à la fin de 2010, ce qui a entraîné la nécessité d'une transition rapide chez un grand nombre de patients stables.
Nous avons assuré la transition vers l'ambrisentan ou le bosentan chez 30 patients cliniquement stables. Les patients ont subi un cathétérisme cardiaque droit, une mesure de la concentration sérique du propeptide natriurétique de type B N-terminal (NT-proBNP : N-terminal pro-brain natriuretic peptide) et une évaluation de la classe fonctionnelle avant le changement d'ARE ainsi que 4 mois plus tard. Nous présentons une analyse rétrospective de ces données.
Parmi ces 30 patients ayant effectué la transition (15 à l'ambrisentan, 15 au bosentan), 23 avaient des données hémodynamiques complètes. Dans les groupes, aucun changement significatif n'a été observé dans la pression auriculaire droite, la pression artérielle pulmonaire moyenne et la pression capillaire pulmonaire, ni dans le débit cardiaque, la résistance vasculaire pulmonaire ou les concentrations de NT-proBNP. Il n'y a eu aucun changement dans la classe fonctionnelle de l'Organisation mondiale de la santé. Quatre (4) patients traités à l'ambrisentan et 2 traités au bosentan ont rapporté une rétention hydrique, et 3 patients traités au bosentan ont eu une augmentation des transaminases hépatiques. Deux (2) des patients ont eu une augmentation de la pression auriculaire droite ≥5 mm Hg, et 4 ont eu une augmentation de la pression capillaire pulmonaire ≥5 mm Hg.
La transition vers les différents ARE chez les patients ayant une HAP stable n'entraînait pas de détérioration hémodynamique ou clinique au cours des 4 premiers mois suivant la transition. Une augmentation des pressions de remplissage cardiaque est apparue chez une minorité de patients.
Safety and efficacy of transition from systemic prostanoids to inhaled treprostinil in pulmonary arterial hypertension
2012, American Journal of Cardiology
Citation Excerpt :
One study described the attempt to transition 3 inpatients from IV epoprostenol to iloprost by making a rapid stepwise decrease of IV epoprostenol (1-ng/kg/min steps every 3 to 10 hours) concurrent with repeated inhalations of aerosolized iloprost (150 to 300 μg/day with 6 to 18 inhalations per day). Despite using high doses of iloprost all patients in this particular study developed signs consistent with decompensated right heart failure that corrected after reinitiating epoprostenol.15 Another group reported successful transition from IV epoprostenol (baseline dose 24 ng/kg/min) to iloprost in a patient with portopulmonary hypertension using a more conservative approach by starting inhalations of iloprost 2.5 μg every 2 hours and rapidly titrating to 5 μg and the epoprostenol dose was simultaneously decreased from 24 to 5 ng/kg/min at a rate of 1 ng/kg/min per day as an outpatient after which the patient was admitted to the hospital to finish weaning the epoprostenol.13
Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ± 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation.
Pulmonary hypertension
2012, Revue des Maladies Respiratoires Actualites
L’hypertension pulmonaire (HTP) est une pathologie complexe de pronostic sombre. Selon la recommandation actuelle, l’HTP est classée en cinq groupes et un sous groupe. Dans le groupe 3, l’HTP associée à la broncho-pneumopathie chronique obstructive (BPCO) est une forme fréquente. Elle est associée à un taux élevé de mortalité dû au dysfonctionnement ventriculaire droit. Le traitement pharmacologique spécifique est principalement proposé aux patients du groupe 1. Dans la prise en charge de l’HTP, la réalisation d’un registre national, le diagnostic précoce et l’amélioration de la classe fonctionnelle sont les principaux objectifs. Pendant le Congrès de l’European Respiratory Society à Amsterdam en 2011, plusieurs communications ont traité de ce thème.
Pulmonary hypertension (PH) is a complex disease with poor prognosis. In current recommendations, PH is classified in five groups and one subgroup. In group 3, PH associated with chronic obstructive pulmonary disease (COPD) is a common form. It is associated with a high mortality due to right ventricular dysfunction. The specific pharmacological treatment is proposed principally to patients in group 1. In the treatment of PH, inclusion in registries, early diagnosis and improved functional class are the main objectives. During the European Respiratory Society Congress in Amsterdam in 2011, this topic has been discussed via several communications.
Rebound effect after prostacyclin inhalation in pulmonary hypertension [3]
2007, Medicina Clinica
Perfusion lung scan as a prognostic indicator of response to beraprost sodium in idiopathic pulmonary arterial hypertension
2006, Pulmonary Pharmacology and Therapeutics
To study whether there is any difference in thfe clinical characteristics between the two patterns of perfusion lung scan of idiopathic pulmonary arterial hypertension (normal vs. diffuse, multiple ill-defined defects) and whether the perfusion lung scan patterns of these patients would predict the effect of long-term use of beraprost sodium.
We evaluated 27 patients who used beraprost sodium for over 3 months, and noted a diffuse patchy pattern in 13 cases and a normal pattern in the remaining 14 cases. We judged that beraprost sodium was effective when at least two of the following conditions were met: improvement in symptom of dyspnea, more than 10% decrease in peak velocity of tricuspid valve regurgitation by echocardiography (V_max), or more than 10% increase in 6-min walking distance.
At baseline there was no difference between the two groups in dyspnea, hemodynamic parameters, and 6-min walking distance. After the use of beraprost sodium, the normal group showed improvement in dyspnea, 6-min walking distance, and V_max. But the diffuse patchy group showed no improvement. The use of beraprost sodium in the normal group was effective in 10 out of 14 cases, but was effective in only two out of 13 cases in the diffuse patchy group.
Perfusion lung scan pattern in patients with idiopathic pulmonary arterial hypertension is a useful prognostic indicator of the response to beraprost sodium.

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Selected ReportsAerosolized Iloprost Therapy Could Not Replace Long-term IV Epoprostenol (Prostacyclin) Administration in Severe Pulmonary Hypertension

Objectives:

Design:

Setting:

Patients:

Interventions:

Results:

Conclusions:

Section snippets

Materials and Methods

Discussion

Prog Cardiovasc Dis

Chest

Lancet

Reversibility of primary pulmonary hypertension during six years of treatment with oral diazoxide

Br Heart J

The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension

N Engl J Med

The place of prostacyclin in the clinical management of primary pulmonary hypertension

Am Rev Respir Dis

A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group

N Engl J Med

Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin

Ann Intern Med

Selected Reports
Aerosolized Iloprost Therapy Could Not Replace Long-term IV Epoprostenol (Prostacyclin) Administration in Severe Pulmonary Hypertension