Massive hemoptysis in Loeys-Dietz syndrome.

We describe four unrelated individuals with Loeys-Dietz syndrome (LDS) who presented with massive hemoptysis of unknown etiology. LDS is an autosomal dominant connective-tissue disorder characterized by altered cardiovascular, craniofacial, and skeletal development that is attributed to mutations in the TGFBR1, TGFBR2, SMAD3, or TGFB2 genes. Massive hemoptysis (MH) is a rare and often fatal pulmonary medical emergency. This is the first report of MH in individuals with LDS and establishes it as part of the LDS spectrum. It compels providers to educate their LDS patients on MH, although much investigation needs to be done to determine etiology and appropriate treatment for this newly described LDS feature.

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.

Prognosis of pulmonary arterial hypertension patients with pericardial effusion before and after initiation of parenteral prostacyclin therapy.

Few studies have evaluated the effects of pulmonary arterial hypertension therapies on pericardial effusion. We evaluated hemodynamics, echocardiograms, and outcomes for 119 parenteral prostanoid-treated patients. We discovered an increased frequency of pericardial effusions posttreatment, and that a moderate-large pericardial effusion at initiation, but not at 1st follow-up, was significantly associated with mortality.

Transitioning Stable Patients with Pulmonary Arterial Hypertension from Parenteral Prostanoids to Oral Selexipag.

Introduction: Parenteral prostanoids are the most potent therapies for pulmonary arterial hypertension (PAH) but are associated with complications and lifestyle limitations. Carefully selected stable patients may be considered for a transition from parenteral prostanoids to a more convenient oral regimen. We present our experience transitioning patients on parenteral prostanoids to selexipag on an outpatient basis. Methods: This was a retrospective cohort study of all group 1 PAH patients on parenteral prostanoids who transitioned to selexipag using a standardized outpatient-based protocol. Hospitalization and routine prognostic data were recorded. Results: Fourteen patients were followed for a median of 1,240 (1,052-1,528) days; all were functional class (FC) II (n = 9) or III (n = 5). Thirteen patients completed the transition, including 11 who underwent catheterization 376 (321-735) days after discontinuing parenteral therapy. Three patients had unfavorable transitions requiring reinitiation of parenteral treatment. Overall, pulmonary vascular resistance increased (3.3-4.5 WU, p = 0.01), cardiac index fell (4.0-2.8 L/min/m2, p = 0.01), N-terminal pro-hormone of brain natriuretic peptide worsened (111-205 pg/dL, p = 0.03), but PAH-related hospitalizations improved (27-8, p = 0.02). Cardiac imaging, FC, and 6-min walk distance (6MWD) were unchanged. Patients who failed were older (64 vs. 56 years old) with shorter 6MWD (274 vs. 392 m) and higher REVEAL 2.0 scores (11 vs. 3). Conclusions: Transition from parenteral prostanoids to oral selexipag in carefully selected low-risk patients was well-tolerated in many patients, with up to 5 years of follow-up. Overall, the hemodynamic response to transition is unpredictable and close monitoring, particularly in the first year of follow-up, is recommended. Additional evaluation of potential predictors of success is necessary.

Prognostic Value of Echocardiographic Variables Prior to and Following Initiation of Parenteral Prostacyclin Therapy: An Observational Study.

BACKGROUND: Echocardiographic parameters are used as prognostic markers in patients with pulmonary arterial hypertension (PAH) receiving parenteral (IV or subcutaneous [IV/SC]) prostacyclin therapy. However, data on how posttreatment echocardiographic results associate with outcomes are limited. RESEARCH QUESTION: Are echocardiographic parameters pre- and post-parenteral prostacyclin therapy in patients with PAH associated with long-term outcomes? STUDY DESIGN AND METHODS: In this retrospective cohort study, patients with PAH initiated on IV epoprostenol or IV/SC treprostinil therapy between 2007 and 2016 were included and followed up through May 31, 2020. Survival free from transplant was assessed from the time of IV/SC prostacyclin therapy initiation and from first follow-up echocardiogram following at least 90 days of therapy. RESULTS: Patients with PAH initiated on IV/SC prostacyclin therapy (N = 118) were followed up for a median of 7.3 years. Survival was 86%, 79%, and 69% at 1, 2, and 3 years, respectively. Follow-up echocardiogram in 101 patients (median, 178 days; interquartile range, 140-273 days) showed improvement in five echocardiographic measures: right ventricular function, right ventricular systolic pressure, right ventricular diastolic diameter, left ventricular diastolic diameter, and tricuspid regurgitation (TR) severity. TR severity and pericardial effusion were associated with survival from IV/SC therapy initiation, whereas right ventricular diastolic diameter, right atrial (RA) size, TR severity, and inferior vena cava characteristics were associated with survival from first follow-up. In a multivariable analysis incorporating other prognostic measures at first follow-up, walk distance, functional class, N-terminal pro-B-type natriuretic peptide, and RA size resulted in the best fit model for survival. INTERPRETATION: Echocardiographic variables improved following IV/SC therapy, and multiple echocardiographic measures associated significantly with survival, particularly when reassessed after at least 90 days of therapy. RA size in particular may be useful in prognostication in follow-up of patients with PAH on IV/SC therapy.

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).

Parenteral prostanoids for severe Group 3 pulmonary hypertension with right ventricular dysfunction.

BACKGROUND: Group 3 pulmonary hypertension (PH) is a common complication in patients with lung diseases but there are currently no FDA-approved therapies. The data is conflicting, but a few small studies suggest potential benefits in using Group 1 PH therapies in these patients, particularly in severe PH with right ventricular (RV) dysfunction. METHODS: A retrospective cohort study of patients with severe Group 3 PH with RV dysfunction who received parenteral prostanoids from 2007-2018 at our institution was undertaken. Severe PH was defined as mean pulmonary arterial pressure (mPAP) ≥35 mmHg or mPAP 25-34 with cardiac index (CI) <2.4 L/min/m2. Routine prognostic studies including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), WHO Functional Class assessment, oxygen requirement, arterial oxygen saturation, right ventricular systolic pressure (RVSP) and right heart catheterization (RHC) pressures, were obtained before initiation of parenteral therapy and at first clinical follow-up. RESULTS: Nine patients were included. Five were female (55.6%) with a median [interquartile range (IQR)] of 69 [54-71] years. Median CI was 1.8 (1.6-2.4) L/min/m2 and median pulmonary vascular resistance (PVR) was 14.7 (10.7-17.1) Wood units (WU). We found no statistically significant improvement in NT-proBNP levels, exercise capacity, or functional class. Resting oxygen requirement worsened from 4 to 6 L/min (P=0.04) and exertional oxygen saturation nadir worsened from 90% to 83% (P=0.01) despite the increase in FiO2 with exertion. Overall results were heterogenous: several patients demonstrated clinical stabilization, with two undergoing lung transplantation and one showing long-term stability with medical therapy. Symptoms remained severe for most: three patients discontinued prostanoid therapy, choosing to pursue hospice care. CONCLUSIONS: We found no statistically significant improvement in NT-proBNP levels, exercise capacity, or functional class, while oxygen requirement at rest and oxygen saturation during exertion significantly worsened. Our results suggest that parenteral prostanoids should not generally be considered in the treatment of Group 3 PH patients.

Variable Creatinine Levels in Critical Care Patients: A Concerning Knowledge Gap.

An accurate creatinine (Cr) estimate is pivotal for the assessment of renal function. Both patient- and practice-spawned factors palliate the test accuracy of serum creatinine (sCr) and can erratically represent actual kidney function. This study evaluated the caregivers' awareness of enzymatic serum creatinine (E-sCr) assay interfering in dopamine/dobutamine (DD)-infused patient samples and the frequency of such interference in a critical care setting. We conducted an sCr awareness survey among UT Southwestern physicians, nurses, and pharmacists. We then performed a cross-sectional E-sCr comparison against the kinetic Jaffe method using the DD-infused patient samples collected from central venous catheters (CVC), peripherally inserted central catheter (PICC) lines, and the peripheral vein (PV). We retrospectively compared the longitudinal E-sCr results of the CVC/PICC draws with the corresponding blood urea nitrogen (BUN) levels. The survey results show a significant lack of awareness among caregivers about the negative interference of DD infusions on E-sCr. Cross-sectional E-sCr assessment relative to the Jaffe method displayed a negative interference in 12% of CVC/PICC line samples (7/57 DD-infused patients) compared to none in the PV draws. A longitudinal assessment of E-sCr, BUN, and potassium (K) levels from CVC/PICC line samples further confirmed a spurious decrease for E-sCr in about 12/50 (24%) patients who did not show a concurrent BUN or K decrease. The results suggest that a direct PV sampling accompanied by clinical laboratory-directed proactive discussion/activities can foster awareness among caregivers and eschew the false E-sCr estimates in DD-infused patients.

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.

Alk5/Runx1 signaling mediated by extracellular vesicles promotes vascular repair in acute respiratory distress syndrome.

BACKGROUND: Pulmonary endothelial cells' (ECs) injury and apoptotic death are necessary and sufficient for the pathogenesis of the acute respiratory distress syndrome (ARDS), regardless of epithelial damage. Interaction of dysfunctional ECs with circulatory extracellular vesicles (EVs) holds therapeutic promise in ARDS. However, the presence in the blood of long-term ARDS survivors of EVs with a distinct phenotype compared to the EVs of non-surviving patients is not reported. With a multidisciplinary translational approach, we studied EVs from the blood of 33 patients with moderate-to-severe ARDS. RESULTS: The EVs were isolated from the blood of ARDS and control subjects. Immunoblotting and magnetic beads immunoisolation complemented by standardized flow cytometry and nanoparticles tracking analyses identified in the ARDS patients a subset of EVs with mesenchymal stem cell (MSC) origin (CD73+CD105+Cd34-CD45-). These EVs have 4.7-fold greater counts compared to controls and comprise the transforming growth factor-beta receptor I (TßRI)/Alk5 and the Runx1 transcription factor. Time course analyses showed that the expression pattern of two Runx1 isoforms is critical for ARDS outcome: the p52 isoform shows a continuous expression, while the p66 is short-lived. A high ratio Runx1p66/p52 provided a survival advantage, regardless of age, sex, disease severity or length of stay in the intensive care unit. Moreover, the Runx1p66 isoform is transiently expressed by cultured human bone marrow-derived MSCs, it is released in the EVs recoverable from the conditioned media and stimulates the proliferation of lipopolysaccharide (LPS)-treated ECs. The findings are consistent with a causal effect of Runx1p66 expression on EC proliferation. Furthermore, morphological and functional assays showed that the EVs bearing the Runx1p66 enhanced junctional integrity of LPS-injured ECs and decreased lung histological severity in the LPS-treated mice. CONCLUSIONS: The expression pattern of Runx1 isoforms might be a reliable circulatory biomarker of ARDS activity and a novel determinant of the molecular mechanism for lung vascular/tissue repair and recovery after severe injury.

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.

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.