An expert panel delphi consensus statement on patient selection and management for transitioning between oral and inhaled treprostinil.

Treprostinil, a prostacyclin analogue used in the treatment of pulmonary arterial hypertension (PAH), is available for administration by parenteral, oral, or inhaled routes. Transitioning between routes may be beneficial for appropriate patients; however, there is little published data on transitions between oral and inhaled treprostinil. We used a modified Delphi process to develop expert consensus recommendations on transitions between these formulations. Three questionnaires were used to develop statements about relevant aspects of transition management, which the panelists rated, using a Likert scale, from -5 (strongly disagree) to +5 (strongly agree). Eleven physicians with expertise in PAH treatment modalities, participated in the panel. Of the 492 statements evaluated, consensus was reached on 215 (43.7%). Key consensus recommendations included (1) accurately defining successful transition, as stable or improved PAH with good tolerability and adherence, and (2) patients with stable, low-risk PAH showing insufficient response or tolerability to their existing treprostinil therapy (and due to restrictions in up titration of dosing), as appropriate candidates for transitions between treprostinil formulations. Panelists did not reach consensus for an overall strategy for performing these transitions, mainly because of variability in their practice parameters. Consensus was also achieved on recommendations for adverse event management, including reassurance, administration of oral treprostinil 3 times daily with food, and dosing inhaled treprostinil at intervals ≥3 hours apart. The Delphi process aided in developing expert consensus recommendations that may provide clinically useful guidance for transitioning between treprostinil formulations. However, additional data from centers with high volumes of PAH patients undergoing treprostinil transitions would be optimal for defining more complete and robust strategies to facilitate successful transition.

Recommendations for the use of oral treprostinil in clinical practice: a Delphi consensus project pulmonary circulation.

Oral treprostinil was recently labeled for treatment of pulmonary arterial hypertension. Similar to the period immediately after parenteral treprostinil was approved, there is a significant knowledge gap for practicing physicians who might prescribe oral treprostinil. Despite its oral route of delivery, use of the drug is challenging because of the requirement for careful titration and management of drug-related adverse effects. We aimed to create a consensus document combining available evidence with expert opinion to provide guidance for use of oral treprostinil. Following a methodology commonly used in business and social sciences (the 'Delphi Process'), two investigators from the oral treprostinil (Freedom) studies created a series of statements based on available evidence and the package insert. The set of 'best practice' statements was circulated to nine other Freedom trial investigators. Their comments were incorporated into the document as new line items for further vote and comment. The subsequent document was put to vote line by line (scale of -5 to +5) and a final statement was drafted. Consensus recommendations include initial therapy with 0.125 mg for treatment naÿ patients, three times daily dosing, aggressive use of antidiarrheal medication, and a strong preference for use of the drug in combination with other approved PAH therapies. This process was particularly valuable in providing guidance for the management of adverse events (where essentially no data is available). The Delphi process was useful to codify investigator experience and subsequently develop investigator consensus about practical issues for physicians who may wish to prescribe oral treprostinil.

Exhaled volatile organic compounds in individuals with a history of high altitude pulmonary edema and varying hypoxia-induced responses.

With ascent to altitude, certain individuals are susceptible to high altitude pulmonary edema (HAPE), which in turn can cause disability and even death. The ability to identify individuals at risk of HAPE prior to ascent is poor. The present study examined the profile of volatile organic compounds (VOC) in exhaled breath condensate (EBC) and pulmonary artery systolic pressures (PASP) before and after exposure to normobaric hypoxia (12% O2) in healthy males with and without a history of HAPE (Hx HAPE, n = 5; Control, n = 11). In addition, hypoxic ventilatory response (HVR), and PASP response to normoxic exercise were also measured. Auto-regression/partial least square regression of whole gas chromatography/mass spectrometry (GC/MS) data and binary logistic regression (BLR) of individual GC peaks and physiologic parameters resulted in models that separate individual subjects into their groups with variable success. The result of BLR analysis highlights HVR, PASP response to hypoxia and the amount of benzyl alcohol and dimethylbenzaldehyde dimethyl in expired breath as markers of HAPE history. These findings indicate the utility of EBC VOC analysis to discriminate between individuals with and without a history of HAPE and identified potential novel biomarkers that correlated with physiological responses to hypoxia.

Balloon dilation atrial septostomy for advanced pulmonary hypertension in patients on prostanoid therapy.

BACKGROUND: Prostanoid therapy improves quality of life and may increase survival in patients with advanced pulmonary hypertension (PH). Balloon dilated atrial septostomy (BDAS) can palliate or bridge to transplantation for patients resistant to medical therapy. The safety and efficacy of BDAS in the prostanoid era has not previously been reported. METHODS: All patients had progressive symptoms despite prostanoid therapy at the time of their first BDAS. Sixteen patients who underwent a total of 23 septostomies between 2004 and 2014 were included in this retrospective case series. RESULTS: Patients were aged 47.6 years ± 11.3 with 12/16 women. Etiologies included idiopathic (7), methamphetamine (6), scleroderma (1), and anorexigen (2). One patient died within 24 hr post-procedure. Thirty-day and 1-year survival were 75% and 64%, respectively. Six of the septostomies were revisions, including two which were ultimately stented. Three subjects were successfully bridged to transplant. Pulmonary capillary wedge pressure (PCWP) increased from a mean of 13 to 17 mm Hg, cardiac index increased from 2.1 to 2.4 L/min/m(2) , and arterial saturation decreased from 90.7 ± 4.3 to 82.5 ± 5.6%. All non-survivors at 30 days were male and had higher baseline serum creatinine, mean RAP, right ventricular end diastolic pressure (RVEDP), and left ventricle (LV) filling pressures, and lower right ventricle (RV) ejection fraction. Mortality was associated with unchanged post-septostomy cardiac output despite an increase in left ventricular end diastolic pressure (LVEDP). CONCLUSIONS: BDAS may be an alternate therapy for select PH patients who have symptomatic progression despite prostanoid therapy. Survival is comparable to prior reports of BDAS in the pre-prostanoid era.

Diverse forms of pulmonary hypertension remodel the arterial tree to a high shear phenotype.

Pulmonary hypertension (PH) is associated with progressive changes in arterial network complexity. An allometric model is derived that integrates diameter branching complexity between pulmonary arterioles of generation n and the main pulmonary artery (MPA) via a power-law exponent (X) in dn = dMPA2(-n/X) and the arterial area ratio ß = 2(1-2/X). Our hypothesis is that diverse forms of PH demonstrate early decrements in X independent of etiology and pathogenesis, which alters the arteriolar shear stress load from a low-shear stress (X > 2, ß > 1) to a high-shear stress phenotype (X < 2, ß < 1). Model assessment was accomplished by comparing theoretical predictions to retrospective morphometric and hemodynamic measurements made available from a total of 221 PH-free and PH subjects diagnosed with diverse forms (World Health Organization; WHO groups I-IV) of PH: mitral stenosis, congenital heart disease, chronic obstructive pulmonary lung disease, chronic thromboembolism, idiopathic pulmonary arterial hypertension (IPAH), familial (FPAH), collagen vascular disease, and methamphetamine exposure. X was calculated from pulmonary artery pressure (PPA), cardiac output (Q) and body weight (M), utilizing an allometric power-law prediction of X relative to a PH-free state. Comparisons of X between PAH-free and PAH subjects indicates a characteristic reduction in area that elevates arteriolar shear stress, which may contribute to mechanisms of endothelial dysfunction and injury before clinically defined thresholds of pulmonary vascular resistance and PH. We conclude that the evaluation of X may be of use in identifying reversible and irreversible phases of PH in the early course of the disease process.

Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial.

BACKGROUND: Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor. METHODS: A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score. RESULTS: Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m). CONCLUSIONS: The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

6.6-hour inhalation of ozone concentrations from 60 to 87 parts per billion in healthy humans.

RATIONALE: Identification of the minimal ozone (O(3)) concentration and/or dose that induces measurable lung function decrements in humans is considered in the risk assessment leading to establishing an appropriate National Ambient Air Quality Standard for O(3) that protects public health. OBJECTIVES: To identify and/or predict the minimal mean O(3) concentration that produces a decrement in FEV(1) and symptoms in healthy individuals completing 6.6-hour exposure protocols. METHODS: Pulmonary function and subjective symptoms were measured in 31 healthy adults (18-25 yr, male and female, nonsmokers) who completed five 6.6-hour chamber exposures: filtered air and four variable hourly patterns with mean O(3) concentrations of 60, 70, 80, and 87 parts per billion (ppb). MEASUREMENTS AND MAIN RESULTS: Compared with filtered air, statistically significant decrements in FEV(1) and increases in total subjective symptoms scores (P < 0.05) were measured after exposure to mean concentrations of 70, 80, and 87 ppb O(3). The mean percent change in FEV(1) (+/-standard error) at the end of each protocol was 0.80 +/- 0.90, -2.72 +/- 1.48, -5.34 +/- 1.42, -7.02 +/- 1.60, and -11.42 +/- 2.20% for exposure to filtered air and 60, 70, 80, and 87 ppb O(3), respectively. CONCLUSIONS: Inhalation of 70 ppb O(3) for 6.6 hours, a concentration below the current 8-hour National Ambient Air Quality Standard of 75 ppb, is sufficient to induce statistically significant decrements in FEV(1) in healthy young adults.

Do airway metallic stents for benign lesions confer too costly a benefit?

BACKGROUND: The use of self-expanding metallic stents (SEMAS) in the treatment benign airway obstruction is controversial. METHODS: To evaluate the safety and efficacy of SEMAS for this indication, we conducted a 10-year retrospective review at our tertiary medical centre. RESULTS: Using flexible bronchoscopy, 82 SEMAS (67% Ultraflex, 33% Wallstent) were placed in 35 patients with inoperable lesions, many with significant medical comorbidities (88%). 68% of stents were tracheal, and 83% of patients showed immediate symptomatic improvement. Reversible complications developed in 9% of patients within 24 hrs of stent placement. Late complications (>24 hrs) occurred in 77% of patients, of which 37% were clinically significant or required an interventional procedure. These were mainly due to stent migration (12.2%), fracture (19.5%), or obstructive granulomas (24.4%). The overall granuloma rate of 57% was higher at tracheal sites (59%) than bronchial ones (34%), but not significantly different between Ultraflex and Wallstents. Nevertheless, Wallstents were associated with higher rates of bleeding (5% vs. 30%, p = 0.005) and migration (7% vs. 26%, p = 0.026). Of 10 SEMAS removed using flexible bronchoscopy, only one was associated with incomplete removal of fractured stent wire. Median survival was 3.6 +/- 2.7 years. CONCLUSION: Ill patients with inoperable lesions may be considered for treatment with SEMAS.

Transition from IV epoprostenol to subcutaneous treprostinil in pulmonary arterial hypertension: a controlled trial.

BACKGROUND: We determined the relative efficacy of subcutaneous (SC) treprostinil in stable World Health Organization class II and III patients transitioned from IV epoprostenol. METHODS: This was an 8-week, multicenter, randomized study in which patients were transitioned from IV epoprostenol to SC treprostinil or placebo over a period of up to 14 days and monitored carefully during and after the transition period for signs of deterioration. Patients with clinical deterioration were returned promptly to epoprostenol. Placebo or SC treprostinil doses were titrated in response to symptoms. Time to adjudicated clinical deterioration was compared between treatment groups, and exercise capacity, symptoms of disease, and safety were assessed throughout the study. RESULTS: Twenty-two patients were enrolled and completed the study. Seven of 8 patients (88%) [corrected] withdrawn to placebo had clinical deterioration, while only 1 of 14 patients (7%) [corrected] withdrawn to SC treprostinil had clinical deterioration (p = 0.00023 based on a treatment comparison of time to deterioration). Analyses of exercise capacity and symptoms strongly supported the efficacy of SC treprostinil in epoprostenol-treated patients. Adverse events consisted of painful infusion site reactions and anticipated prostacyclin side effects. CONCLUSIONS: SC treprostinil is effective in pulmonary arterial hypertension and prevents clinical deterioration and maintains functional status in patients transitioned from epoprostenol.

Advances in the management of endobronchial lung malignancies.

The effective palliation of endobronchial malignancies often involves the use of multiple modalities including surgery, external beam radiation, chemotherapy, or a variety of interventional bronchoscopic techniques. The authors discuss in detail recent advances in interventional bronchoscopy that enhance local tumor control. An integrated and individualized approach to the use of these complementary modalities can provide rapid palliation and may improve survival in a subset of patients.

Bronchiolitis obliterans.

Bronchiolitis obliterans (BO) is a disease of small airways that results in progressive dyspnea and airflow limitation. It is a common sequela of bone marrow, lung, and heart-lung transplantation, but can also occur as a complication of certain pulmonary infections, adverse drug reaction, toxic inhalation, and autoimmune disorders. Non-transplant-related BO is rare and can mimic asthma and chronic obstructive pulmonary disease (COPD). In transplant-related BO, the diagnosis can be suggested by obstructive changes in serial pulmonary function testings, while open lung biopsy is usually required in non-transplant cases. High-resolution computerized tomography (HRCT) is also a helpful tool to diagnose and assess the severity of BO. The treatment of BO, regarding of the cause, is usually disappointing. Systemic corticosteroid immunosuppression and retransplantation have been described with variable success.