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).

Diagnostic accuracy of echocardiography combined with chest CT in pulmonary hypertension.

BACKGROUND: Transthoracic echocardiography (TTE) and computerized axial tomography (CT) are complementary imaging techniques. It is possible that a combination of the two may offer a better way of identifying pulmonary hypertension (PH) than either one alone. OBJECTIVES: To determine the diagnostic accuracy of TTE combined with chest CT in pulmonary hypertension. METHODS: We performed a retrospective review of consecutive patients who had undergone TTE, CT and right heart catheterization (RHC) between 7/1/2008 and 6/30/2012. PH was defined as systolic pulmonary artery pressure >40 mm Hg or tricuspid regurgitant (TR) jet velocity >2.8m/s on TTE, ratio of diameter of pulmonary artery to ascending aorta (rPA) >1 or diameter of PA (dPA) >30 mm on CT, and mean PAP (mPAP) >25 mm Hg on RHC. RESULTS: There was a total of 87 patients. The mean ± SD age was 54.3 ± 15.9 years and 69 (79%) were female. The prevalence of PH was 75%. The mean ± SD mPAP was 35.8 ± 14.2 mm Hg. The majority of the patients belonged to World Health Organization group I PH. Fifty per cent of the CT scans were done with intravenous contrast dye. The combination of TR jet velocity and rPA provided the best combination of sensitivity (98%) and specificity (70%) with an ROC area under the curve of 0.84. CONCLUSION: The combination of TTE and chest CT is better than either imaging technique alone in identifying patients with PH in a heterogeneous population and may exclude PH.

The safety and tolerability of inhaled treprostinil in patients with pulmonary hypertension and chronic obstructive pulmonary disease.

The primary aim was to explore the safety and tolerability of inhaled treprostinil when used in patients with pulmonary hypertension (PH) with concomitant chronic obstructive pulmonary disease (COPD). Patients with a diagnosis of pre-capillary PH (defined as pulmonary artery mean pressure of ≥ 25 mmHg and pulmonary artery wedge pressure or left ventricular end diastolic pressure of ≤ 15 mmHg) who were being initiated on inhaled treprostinil and had concomitant COPD (defined as FEV1/FVC ratio ≤ 70% with FEV1 ≥ 40% predicted) were considered for inclusion in this pilot study. Assessments included adverse events, physical exam, World Health Organization (WHO) functional class, 6-minute walk test (6MWT), modified Borg dyspnea score, and concomitant medication. At baseline and week 16 St. George's Respiratory Questionnaire (SGRQ), arterial blood gas (ABG), and pulmonary function test (PFT) were assessed. The median age was 65 years (age range, 56-80 years) and five patients (56%) were men. Among the nine patients, a majority had an increase in 6MWT from baseline to week 16 (median change, 19 m). Only three of the nine patients (33%) had an increase in A-a gradient at week 16 (median change, -7). There was no difference in any of the following: arterial blood gases, WHO functional class, 6MWT results, or SGRQ scores from baseline to week 16. There was a statistically significant decline in several of the PFT measures, including FEV1 (median change, -0.18 L; P = 0.004; median change, -7% of predicted; P = 0.016), FVC (median change, -0.23 L; P = 0.027), and diffusion capacity for carbon monoxide (DLCO) (median change, -5% of predicted; P = 0.023). The small number of patients limits firm conclusions; however, inhaled treprostinil did not seem to adversely impact oxygenation in the majority of the study patients with pre-capillary PH and COPD. While there may have an adverse impact on some pulmonary function parameters, the clinical significance is unclear.

Association between aspirin use and deep venous thrombosis in mechanically ventilated ICU patients.

Deep venous thrombosis (DVT) is common in intensive care unit (ICU) patients. It is often silent and may be complicated by pulmonary embolism and death. Thromboprophylaxis with heparin does not always prevent venous thromboembolism (VTE). Aspirin (ASA) reduces the risk of VTE in surgical and high-risk medical patients but it is unknown if ASA may prevent DVT in mechanically ventilated ICU patients. We performed a retrospective chart review of critically ill patients who received mechanical ventilation for >72 h and underwent venous ultrasonography for suspected DVT between Jan 2012 and Dec 2013. We excluded patients who were on therapeutic doses of anticoagulation or had coagulopathy. We used multivariable logistic regression to evaluate association between aspirin use and DVT during hospitalization. There were 193 patients. The mean ± SD age was 58 ± 15.7 years. Half were male. DVT was found in 49 (25.4%). DVT was found in the first 15 days of hospitalization in 67.3% of the patients. The majority (82.8%) received thromboprophylaxis with unfractionated or low molecular weight heparin. Fifty-six (29%) were on ASA. On multivariable regression analysis, ASA use was associated with a significant reduction in the odds of finding DVT (OR 0.39, 95% CI 0.16-0.94; p = 0.036). DVT is common in mechanically ventilated ICU patients despite the use of thromboprophylaxis. Aspirin may prevent DVT in such patients.

Operator dependent factors implicated in failure of non-invasive positive pressure ventilation (NIPPV) for respiratory failure.

BACKGROUND: Non-invasive Positive Pressure Ventilation (NIPPV) is employed for the management of acute respiratory failure and studies have shown that it can prevent the need for endotracheal intubation, mechanical ventilation and associated complications. Given limited studies evaluating the factors, other than those related patient or underlying disease severity, that may lead to NIPPV failure, we performed this study to gain insight into current practices in terms of utilization of NIPPV and operator dependent factors that may possibly contribute to failure of NIPPV. METHOD: After institutional board review approval a retrospective chart review was performed of consecutive patients who were initiated on and failed NIPPV between January 2009 and December 2009. Data was recorded regarding baseline demographics, admission diagnosis, indications for NIPPV, presence of contraindications, type of NIPPV and initial settings, ABG analysis before and after initiation, whether a titration of the settings was performed or not, operator related factors that may have contributed to failure of NIPPV and clinical outcomes. RESULTS: Among 1095 patients screened, 111 failed NIPPV. The mean age was 60 years with 59% males. The most frequent indication for initiating NIPPV was COPD exacerbation (N = 27) followed by pneumonia (N = 26). CPAP was used in 5(6%) patients. Median inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) setting were 10 and 5 cm of H2 O respectively. Three most common reasons for failure were an inappropriate indication (33%), Progression of underlying disease (30%) and lack of titration (23%). Overall mortality was 22%. Mortality was higher when NIPPV failure was seen among patients with an inappropriate indication or an overlooked contraindication compared to those with an appropriate indication (27% vs 17%). CONCLUSIONS: Excluding progression of underlying disease, operator dependent factors linked to NIPPV failure are; inappropriate indication, lack of adequate titration and an overlooked contraindication. Inappropriate utilization of NIPPV in respiratory failure is associated with higher mortality.

Severe Pulmonary Arterial Hypertension: Comprehensive Evaluation by Magnetic Resonance Imaging.

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery (PA) pressure, which negatively affects the right ventricular (RV) function. This report shows a patient with severe PAH, on whom a comprehensive MRI exam was performed to evaluate both PA and RV. New imaging sequences were implemented for obtaining additional parameters about the patient's condition. The results show the capabilities of the developed exam of providing complete picture of the cardiovascular system in PAH, which helps the physician optimize treatment.

Is There Any Association between PEEP and Upper Extremity DVT?

Background. We hypothesized that positive end-exploratory pressure (PEEP) may promote venous stasis in the upper extremities and predispose to upper extremity deep vein thrombosis (UEDVT). Methods. We performed a retrospective case control study of medical intensive care unit patients who required mechanical ventilation (MV) for >72 hours and underwent duplex ultrasound of their upper veins for suspected DVT between January 2011 and December 2013. Results. UEDVT was found in 32 (28.5%) of 112 patients. Nineteen (67.8%) had a central venous catheter on the same side. The mean ± SD duration of MV was 13.2 ± 9.5 days. Average PEEP was 7.13 ± 2.97 cm H2O. Average PEEP was ≥10 cm H2O in 23 (20.5%) patients. Congestive heart failure (CHF) significantly increased the odds of UEDVT (OR 4.53, 95% CI 1.13-18.11; P = 0.03) whereas longer duration of MV (≥13 vs. <13 days) significantly reduced it (OR 0.29, 95% CI 0.11-0.8; P = 0.02). Morbid obesity showed a trend towards significance (OR 3.82, 95% CI 0.95-15.4; P = 0.06). Neither PEEP nor any of the other analyzed predictors was associated with UEDVT. Conclusions. There is no association between PEEP and UEDVT. CHF may predispose to UEDVT whereas the risk of UEDVT declines with longer duration of MV.

The relationship of intravenous fluid chloride content to kidney function in patients with severe sepsis or septic shock.

BACKGROUND: Previous studies suggest a relationship between chloride-rich intravenous fluids and acute kidney injury in critically ill patients. OBJECTIVES: The aim of this study was to evaluate the relationship of intravenous fluid chloride content to kidney function in patients with severe sepsis or septic shock. METHODS: A retrospective chart review was performed to determine (1) quantity and type of bolus intravenous fluids, (2) serum creatinine (Cr) at presentation and upon discharge, and (3) need for emergent hemodialysis (HD) or renal replacement therapy (RRT). Linear regression was used for continuous outcomes, and logistic regression was used for binary outcomes and results were controlled for initial Cr. The primary outcome was change in Cr from admission to discharge. Secondary outcomes were need for HD/RRT, length of stay (LOS), mortality, and organ dysfunction. RESULTS: There were 95 patients included in the final analysis; 48% (46) of patients presented with acute kidney injury, 8% (8) required first-time HD or RRT, 61% (58) were culture positive, 55% (52) were in shock, and overall mortality was 20% (19). There was no significant relationship between quantity of chloride administered in the first 24 hours with change in Cr (ß = -0.0001, t = -0.86, R(2) = 0.92, P = .39), need for HD or RRT (odds ratio [OR] = 0.999; 95% confidence interval [CI], 0.999-1.000; P = .77), LOS >14 days (OR = 1.000; 95% CI, 0.999-1.000; P = .68), mortality (OR = 0.999; 95% CI, 0.999-1.000; P = .88), or any type of organ dysfunction. CONCLUSION: Chloride administered in the first 24 hours did not influence kidney function in this cohort with severe sepsis or septic shock.

Use of pulmonary arterial hypertension-specific therapy in non-WHO group I pulmonary hypertension.

OBJECTIVES: The development of pulmonary hypertension (PH) in non-World Health Organization group I PH adversely affects exercise capacity. It is unclear whether pulmonary artery hypertension (PAH)-specific drugs improve pulmonary hemodynamics and exercise capacity in such patients. METHODS: We performed a retrospective chart review of consecutive patients with non-World Health Organization group I PH treated with PAH-specific therapy. RESULTS: We identified 24 patients. The mean (standard deviation) age was 48 (14.8) years. Seventeen (71%) patients were women. The 6-minute walk distance improved significantly for the whole group in an initial follow-up period of 4.6 (2.3) months; however, the improvement was seen only in patients with obstructive sleep apnea (OSA) or severe PH and it was not sustained during a longer follow-up period of 11.5 (4.1) months, except in patients with OSA. PH was treated with a variety of PAH-specific drugs, including combination therapy in five patients. CONCLUSIONS: The use of PAH-specific therapy in selected patients with PH secondary to lung diseases, OSA, or sarcoidosis may result in significant improvement in 6-minute walk distance, particularly in patients with OSA or severe PH.