BREEZE: Open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension.

Inhaled treprostinil is an approved therapy for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease in the United States. Studies have confirmed the robust benefits and safety of nebulized inhaled treprostinil, but it requires a time investment for nebulizer preparation, maintenance, and treatment. A small, portable treprostinil dry powder inhaler has been developed for the treatment of PAH. The primary objective of this study was to evaluate the safety and tolerability of treprostinil inhalation powder (TreT) in patients currently treated with treprostinil inhalation solution. Fifty-one patients on a stable dose of treprostinil inhalation solution enrolled and transitioned to TreT at a corresponding dose. Six-minute walk distance (6MWD), device preference and satisfaction (Preference Questionnaire for Inhaled Treprostinil Devices [PQ-ITD]), PAH Symptoms and Impact (PAH-SYMPACT®) questionnaire, and systemic exposure and pharmacokinetics for up to 5 h were assessed at baseline for treprostinil inhalation solution and at Week 3 for TreT. Adverse events (AEs) were consistent with studies of inhaled treprostinil in patients with PAH, and there were no study drug-related serious AEs. Statistically significant improvements occurred in 6MWD, PQ-ITD, and PAH-SYMPACT. Forty-nine patients completed the 3-week treatment phase and all elected to participate in an optional extension phase. These results demonstrate that, in patients with PAH, transition from treprostinil inhalation solution to TreT is safe, well-tolerated, and accompanied by statistically significant improvements in key clinical assessments and patient-reported outcomes with comparable systemic exposure between the two formulations at evaluated doses (trial registration: clinicaltrials.gov identifier: NCT03950739).

Mesenchymal stem cells-derived extracellular vesicles in acute respiratory distress syndrome: a review of current literature and potential future treatment options.

Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung condition associated with significant morbidity and mortality. Unfortunately, the current treatment for this disease is mainly supportive. Mesenchymal stem cells (MSCs) due to their immunomodulatory properties are increasingly being studied for the treatment of ARDS and have shown promise in multiple animal studies. The therapeutic effects of MSCs are exerted in part in a paracrine manner by releasing extracellular vesicles (EVs), rather than local engraftment. MSC-derived EVs are emerging as potential alternatives to MSC therapy in ARDS. In this review, we will introduce EVs and briefly discuss current data on EVs and MSCs in ARDS. We will discuss current literature on the role of MSC-derived EVs in pathogenesis and treatment of ARDS and their potential as a treatment strategy in the future.

The association between pulmonary hypertension and stroke: A systematic review and meta-analysis.

BACKGROUND: Pulmonary hypertension is associated with atrial fibrillation and paradoxical embolism. Yet, the association between pulmonary hypertension and stroke has not been well studied. METHODS: We reviewed Medline and Embase from inception to December 1, 2018, to identify observational studies reporting prevalence of stroke in adult patients with pulmonary hypertension. We sought studies that included patients with pulmonary hypertension secondary to any etiology except left heart failure, and excluded studies that reported rates of perioperative stroke. We conducted random effects meta-analyses to obtain pooled prevalence of stroke in patients with pulmonary hypertension, and pooled unadjusted odds ratio of stroke in patients with pulmonary hypertension compared to those without. RESULTS: We included 14 studies including 32,523 participants of which 2976 (9.2%) had pulmonary hypertension, and 727 (2.2%) had a stroke. The pooled prevalence of stroke in patients with pulmonary hypertension was 8.0% [95% confidence interval (CI), 5.1%-10.9%, I2 91.9]. The pooled unadjusted odds ratio of stroke in patients with pulmonary hypertension compared to those without was 1.46 (95% CI, 1.07-1.99, I2 55.6, n = 7 studies). CONCLUSION: Stroke is a major non-cardiac morbidity in patients with pulmonary hypertension, requiring further evaluation to determine its etiology, and measures to reduce its risk.

Mortality in Patients With Pulmonary Arterial Hypertension Treated With Continuous Prostanoids.

BACKGROUND: Parenteral prostanoids are considered the treatment of choice for patients with severe pulmonary arterial hypertension (PAH). Prognostic studies for patients treated in the modern era are limited. METHODS: In this retrospective cohort study, patients initiating IV epoprostenol or IV or subcutaneous (SC) treprostinil therapy for PAH from 2007 to 2016 at UT Southwestern and The Ohio State University were included. Transplant-free survival was assessed from the time of IV/SC therapy initiation and from the time of first follow-up. The utility of traditional prognostic measures was assessed by using categories (lower, intermediate, and higher risk) recommended in the 2015 European Society of Cardiology/European Respiratory Society guidelines for functional class, 6-min walk distance, brain natriuretic peptide or N-terminal pro-brain natriuretic peptide level, and hemodynamic results. RESULTS: Patients with group 1 PAH receiving IV epoprostenol (n = 132), IV treprostinil (n = 25), or SC treprostinil (n = 38) were included. Survival from IV/SC prostanoid initiation was 84%, 77%, and 67% at 1, 2, and 3 years. Follow-up assessment was performed after a minimum of 90 days' therapy (mean, 356 ± 247 days) in 163 patients. After treatment with an IV/SC prostanoid, better functional class, 6-min walk distance, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide level, and mixed venous O2 saturation (but not cardiac index) was associated with survival, as was the total number of lower risk and higher risk findings. Having zero lower risk findings or two or more higher risk findings was associated with particularly poor outcomes. CONCLUSIONS: In patients with PAH receiving treatment with a parenteral prostanoid, survival was significantly associated with the number of guideline-recommended lower risk and higher risk criteria achieved at first follow-up.

Early detection of right ventricular dysfunction using transthoracic echocardiography in ARDS: a more objective approach.

PURPOSE: Right ventricular (RV) dysfunction is an independent predictor of morbidity and mortality in acute respiratory distress syndrome (ARDS). Our goal was to describe morphologic changes in the RV using objective measures on transthoracic echocardiography (TTE) that occur following ARDS. METHODS: We retrospectively measured changes in the following RV parameters from a pre-ARDS TTE to an ARDS TTE: tricuspid annular plane systolic excursion (TAPSE), myocardial performance index (MPI), fractional area change (FAC), systolic pulmonary artery pressure (SPAP), peak tricuspid regurgitant (TR) velocity, and septal shift. RESULTS: Over 24 months, 14 patients met inclusion/exclusion criteria. Mean TAPSE decreased from 22.4 mm pre-ARDS to 16.3 mm during ARDS, P<.001. Mean MPI increased from 0.19 to 0.38, P=.001. Mean FAC decreased from 60.8% to 41.2%, P=.003. Peak TR velocity increased from 2.67 m/s pre-ARDS to 3.31 m/s during ARDS, P=.02. SPAP and septal shift demonstrated trends but not statistically different between pre-ARDS and ARDS states. TAPSE correlated with ARDS severity (PaO2 /FiO2 ratios), P=.004, and was lower among 30-day nonsurvivors compared with survivors, P=.002. CONCLUSIONS: Mild RV dysfunction is common after ARDS onset. RV morphologic changes coupled with dysfunction can be detected noninvasively through TTE changes with TAPSE, MPI, and FAC. Mild RV dysfunction by TAPSE is associated with ARDS severity and mortality.

Echocardiographic parameters of right ventricular function predict mortality in acute respiratory distress syndrome: a pilot study.

Right ventricular (RV) dysfunction in acute respiratory distress syndrome (ARDS) contributes to increased mortality. Our aim is to identify reproducible transthoracic echocardiography (TTE) parameters of RV dysfunction that can be used to predict outcomes in ARDS. We performed a retrospective single-center cohort pilot study measuring tricuspid annular plane systolic excursion (TAPSE), Tei index, RV-fractional area change (RV-FAC), pulmonary artery systolic pressure (PASP), and septal shift, reevaluated by an independent blinded cardiologist (JK). Thirty-eight patients were included. Patients were divided on the basis of 30-day survival. Thirty-day mortality was 47%. Survivors were younger than nonsurvivors. Survivors had a higher pH, PaO2∶FiO2 ratio, and TAPSE. Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II), and Sequential Organ Failure Assessment (SOFA) scores were lower in survivors. TAPSE has the strongest association with increased 30-day mortality from date of TTE. Accordingly, TAPSE has a strong positive correlation with PaO2∶FiO2 ratios, and Tei index has a strong negative correlation with PaO2∶FiO2 ratios. Septal shift was associated with lower PaO2∶FiO2 ratios. Decrease in TAPSE, increase in Tei index, and septal shift were seen in the severe ARDS group. In multivariate logistic regression models, TAPSE maintained a significant association with mortality independent of age, pH, PaO2∶FiO2 ratios, positive end expiratory pressure, PCO2, serum bicarbonate, plateau pressures, driving pressures, APACHE II, SAPS II, and SOFA scores. In conclusion, TAPSE and other TTE parameters should be used as novel predictive indicators for RV dysfunction in ARDS. These parameters can be used as surrogate noninvasive RV hemodynamic measurements to be manipulated to improve mortality in patients with ARDS and contributory RV dysfunction.

COPD exacerbation care bundle improves standard of care, length of stay, and readmission rates.

INTRODUCTION: COPD is the third leading cause of death in the world. Utilizing care bundles during acute COPD exacerbations results in fewer complications and lower costs. Our aim was to construct a COPD exacerbation care bundle and evaluate the effects on patient care. METHODS: We conducted a prospective analysis of 44 patients admitted with a COPD exacerbation to a single tertiary care facility. Primary outcomes included length of stay, readmission rates, and hospital costs. Secondary outcomes included patient education, pulmonologist follow-up, and timeliness of medication administration. Two cohorts were analyzed: those treated with an electronic COPD care bundle (cases; N=22) versus those treated without the care bundle (controls; N=22). RESULTS: Mean length of stay (51.2 vs 101.1 hours in controls; P-value =0.001), 30-day readmission rates (9.1% vs 54.4% in controls; P-value =0.001), and 60-day readmission rates (22.7% vs 77% in controls; P-value =0.0003) decreased in the care bundle group. Ninety-day hospital costs had a significant difference in the care bundle group (US$7,652 vs US$19,954 in controls; P-value =0.044). Secondary outcomes included a 100% rate of COPD inhaler teaching (vs 27.3% in controls; P-value <0.001), 59.1% rate of pulmonologist follow-up after discharge (vs 18.2% in controls; P-value =0.005), and a mean reduction in time to steroid administration (7.0 hours; P-value =0.015) seen in the care bundle cases. CONCLUSION: Our significant findings coupled with the recent success of standardized algorithms in managing COPD exacerbations stress the importance of enforcing clinical guidelines that can enhance patient care. We demonstrated improved care for COPD exacerbation patients during hospitalizations, thereby decreasing morbidity and the financial burden hospitals face in regard to this increasingly prevalent disease.