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.

Palliative care referrals in patients with pulmonary arterial hypertension: The Pulmonary Hypertension Association Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a life limiting disease with substantial symptom burden and healthcare utilization. Palliative care alleviates physical and emotional symptoms for patients with serious illness, and has been underutilized for these patients. OBJECTIVE: To characterize patients with PAH referred to palliative care and identify predictors of referral. METHODS: We conducted an observational study of adult patients enrolled in the Pulmonary Hypertension Association Registry from January 2015 through June 2021, performing descriptive statistics on patient characteristics at baseline for all patients and the subset referred to palliative care. These characteristics were modeled in a backwards elimination Cox regression with time to referral to palliative care as the primary outcome. RESULTS: 92 of 1,578 patients were referred to palliative care (5.8%); 43% were referred at their last visit prior to death. Referrals were associated with increasing age per decade (hazard ratio 1.35 [95% confidence interval 1.16-1.58]), lower body mass index (hazard ratio 0.97 [95% confidence interval 0.94-0.998]), supplemental oxygen use (hazard ratio 2.01 [95% confidence interval 1.28-3.16]), parenteral prostanoid use (hazard ratio 2.88 [95% confidence interval 1.84-4.51]), and worse quality of life, measured via lower physical (hazard ratio 0.97 [95% confidence interval 0.95-0.99]) and mental (hazard ratio 0.98 [95% confidence interval 0.96-0.995]) scores on the 12-item Short Form Health Survey. CONCLUSION: Patients with PAH are infrequently referred to palliative care, even at centers of excellence. Referrals occur in sicker patients with lower quality of life scores, often close to the end of life.

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.

Erratum: Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: An analysis of the Pulmonary Hypertension Association Registry.

[This corrects the article DOI: 10.1177/20458940211020913.].

The Operating Room Black Box: Understanding Adherence to Surgical Checklists.

OBJECTIVE: We report for the first time the use of the Operating Room Black Box (ORBB) to track checklist compliance, engagement, and quality. BACKGROUND: Implementation of operative checklists is associated with improved outcomes. Compliance is difficult to monitor. Most studies report either no assessment of checklist compliance or deployed in-person short-term assessment. The ORBB a novel artificially intelligence-driven data analytic platform affords the opportunity to assess checklist compliance without disrupting surgical workflow. METHODS: This was a retrospective review of prospectively collected ORBB data. Operative cases included elective surgery at a quaternary referral center. Cases were analyzed as prepolicy change (first 9 months) or as a postpolicy change (last 9 months). Measures of checklist compliance, engagement, and quality were assessed. RESULTS: There were 3879 cases that were performed and monitored for checklist compliance between August 15, 2020, and February 20, 2022. The overall scores for compliance, engagement, and quality were 81%, 84%, and 67% respectively. When broken down by phase, the scores for time-out were compliance 100%, engagement 98%, and quality 61%. Scores for the debrief phase were 81% for compliance, 98% for engagement, and 66% for quality. After a hospital policy change, the debrief scores improved significantly (85%; P <0.001 for compliance, 88%; P <0.001 for engagement and 71%; P <0.001 for quality). CONCLUSIONS: ORBB provides the unprecedented ability to assess not only compliance with surgical safety checklists but also engagement and quality. Utilization of this technology allows the assessment of compliance in near real time and to accurately address safety threats that may arise from noncompliance.

ISHLT consensus statement: Perioperative management of patients with pulmonary hypertension and right heart failure undergoing surgery.

Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

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.

Aggressive Afterload Lowering to Improve the Right Ventricle: A New Target for Medical Therapy in Pulmonary Arterial Hypertension?

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Health-related quality of life and hospitalizations in chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension: an analysis from the Pulmonary Hypertension Association Registry (PHAR).

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, morbid, potentially curable subtype of pulmonary hypertension that negatively impacts health-related quality of life (HRQoL). Little is known about differences in HRQoL and hospitalization between CTEPH patients and idiopathic pulmonary arterial hypertension (IPAH) patients. Using multivariable linear regression and mixed effects models, we examined differences in HRQoL assessed by emPHasis-10 (E10) and SF-12 between CTEPH and IPAH patients in the Pulmonary Hypertension Association Registry, a prospective multicenter cohort of patients newly evaluated at a Pulmonary Hypertension Care Center. Multivariable negative binomial regression models were used to estimate incidence rate ratios (IRR) for hospitalization amongst the two groups. We included 461 IPAH patients and 169 CTEPH patients. Twenty-one percent of CTEPH patients underwent pulmonary thromboendarterectomy (PTE) before the end of follow-up. At baseline, patients with CTEPH had significantly worse HRQoL (higher E10 scores) (ß 2.83, SE 1.11, p = 0.01); however, differences did not persist over time. CTEPH patients had higher rates of hospitalization (excluding the hospitalization for PTE) compared to IPAH patients after adjusting for age, sex, body mass index, WHO functional class and six-minute walk distance (IRR 1.66, 95%CI 1.04-2.65, p = 0.03). CTEPH patients who underwent PTE had improved HRQoL as compared to those who were medically managed, but patients who underwent PTE were younger, had higher cardiac outputs and greater six-minute walk distances. In this large, prospective, multicenter cohort, CTEPH patients had significantly worse baseline HRQoL and higher rates of hospitalizations than those with IPAH. CTEPH patients who underwent PTE had significant improvements in HRQoL.

Health disparities and treatment approaches in portopulmonary hypertension and idiopathic pulmonary arterial hypertension: an analysis of the Pulmonary Hypertension Association Registry.

Compared to idiopathic pulmonary arterial hypertension (IPAH), patients with portopulmonary hypertension (POPH) have worse survival. Health disparities may contribute to these differences but have not been studied. We sought to compare socioeconomic factors in patients with POPH and IPAH and to determine whether socioeconomic status and/or POPH diagnosis were associated with treatment and health-care utilization. We performed a cross-sectional study of adults enrolled in the Pulmonary Hypertension Association Registry. Patients with IPAH (n = 344) and POPH (n = 57) were compared. Compared with IPAH, patients with POPH were less likely to be college graduates (19.6% vs. 34.9%, p = 0.02) and more likely to be unemployed (54.7% vs. 30.5%, p < 0.001) and have an annual household income below poverty level (45.7% vs. 19.0%, p < 0.001). Patients with POPH had similar functional class, quality of life, 6-min walk distance, and mean pulmonary arterial pressure with a higher cardiac index. Compared with IPAH, patients with POPH were less likely to receive combination therapy (46.4% vs. 62.2%, p = 0.03) and endothelin receptor antagonists (28.6% vs. 55.1%, p < 0.001) at enrollment with similar treatment at follow-up. Patients with POPH had more emergency department visits (1.7 ± 2.1 vs. 0.9 ± 1.2, p = 0.009) and hospitalizations in the six months preceding enrollment (1.5 ± 2.1 vs. 0.8 ± 1.1, p = 0.02). Both POPH diagnosis and lower education level were independently associated with a higher number of emergency department visits. Compared to IPAH, patients with POPH have lower socioeconomic status, are less likely to receive initial combination therapy and endothelin receptor antagonists but have similar treatment at follow-up, and have increased health-care utilization.

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.

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Long-term outcomes in pulmonary arterial hypertension by functional class: a meta-analysis of randomized controlled trials and observational registries.

Limited data about the long-term prognosis and response to therapy in pulmonary arterial hypertension patients with World Health Organization functional class I/II symptoms are available. PubMed and Embase were searched for publications of observational registries and randomized, controlled trials in pulmonary arterial hypertension patients published between January 2001 and January 2018. Eligible registries enrolled pulmonary arterial hypertension patients ≥18 years, N > 30, and reported survival by functional class. Randomized, controlled trial inclusion criteria were pulmonary arterial hypertension patients ≥18 years, ≥6 months of treatment, and morbidity, mortality, or time to worsening as end points reported by functional class. The primary outcomes were survival for registries and clinical event rates for randomized, controlled trials. Separate random effects models were calculated for registries and randomized, controlled trials. Four randomized, controlled trials (n = 2482) and 10 registries (n = 6580) were included. Registries enrolled 9%-47% functional class I/II patients (the vast majority being functional class II) with various pulmonary arterial hypertension etiologies. Survival rates for functional class I/II patients at one, two, and three years were 93% (95% confidence interval (CI): 91%-95%), 86% (95% CI: 82%-89%), and 78% (95% CI: 73%-83%), respectively. The hazard ratio for the treatment effect in randomized, controlled trials overall was 0.61 (95% CI: 0.51-0.74) and 0.60 (95% CI: 0.44-0.82) for functional class I/II patients and 0.62 (95% CI: 0.49-0.78) for functional class III/IV. The calculated risk of death of 22% within three years for functional class I/II patients underlines the need for careful assessment and optimal treatment of patients with functional class I/II disease. The randomized, controlled trial analysis demonstrates that current medical therapies have a beneficial treatment effect in this population.

Hemodynamic effects of fluoxetine in pulmonary arterial hypertension: an open label pilot study.

In order to evaluate the therapeutic potential of fluoxetine in pulmonary arterial hypertension, 13 patients with pulmonary arterial hypertension underwent catheterization before and after 12 (N = 5) or 24 (N = 8) weeks fluoxetine therapy. No change was seen in the primary endpoint of pulmonary vascular resistance, other hemodynamic values, or any secondary endpoints.

Ambrisentan in portopulmonary hypertension: A multicenter, open-label trial.

BACKGROUND: Ambrisentan has shown effectiveness in the treatment of Group 1 pulmonary arterial hypertension (PAH). Although portopulmonary hypertension (PoPH) is a subset of Group 1 PAH, few clinical trials have been testing PAH therapies in patients with PoPH. The objective of this study is to evaluate the efficacy and safety of ambrisentan in PoPH. METHODS: This study is a prospective, multicenter, open-label trial in which treatment-naive patients with PoPH with Child-Pugh class A/B were administered with ambrisentan for 24 weeks, followed by a long-term extension (24-28 weeks). The primary end-points were change in pulmonary vascular resistance (PVR) and 6-minutes walk distance (6MWD) at 24 weeks, whereas secondary end-points included safety, World Health Organization (WHO) functional class (FC) and echocardiographic assessments. RESULTS: Of the 31 patients, 23 finished 24 weeks of ambrisentan therapy and 19 finished the extension. PVR decreased significantly (mean ± SD) (7.1 ± 5 vs 3.8 ± 1.8 Wood units, p < 0.001), whereas 6MWD remained unchanged (314 ± 94 vs 336 ± 108 m). Other hemodynamic parameters such as right atrial pressure (13 ± 8 vs 9 ± 4 mm Hg, p < 0.05), mean pulmonary arterial pressure (46 ± 13 vs. 38 ± 8 mm Hg, p < 0.01), cardiac index (2.6 ± 0.6 vs. 3.5 ± 0.7 liter/min/m2, p < 0.001) showed improvement, whereas pulmonary capillary wedge pressure remained unchanged. Of the 22 patients with WHO FC assessments at baseline and 24 weeks, WHO FC improved significantly (p = 0.005). Most frequent drug-related adverse events were edema (38.7%) and headache (22.5%). One episode of leg edema resulted into the permanent discontinuation of ambrisentan. CONCLUSIONS: Ambrisentan monotherapy in PoPH improves hemodynamics and FC at 24 weeks; however, it did not show any improvement in 6MWD. These preliminary outcomes should be interpreted with caution (Clinicaltrials.Gov:NCT01224210).

Portopulmonary Hypertension: A Survey of Practice Patterns and Provider Attitudes.

BACKGROUND: The role of liver transplantation (LT) in the management of portopulmonary hypertension (POPH) is poorly understood. The aim of this study was to better understand provider attitudes and practice patterns regarding the management of patients with POPH and to assess the concordance between clinical practice and current guidelines. METHODS: We performed a multicenter survey study of hepatologists and pulmonary hypertension (PH) physicians at US LT centers that performed >50 transplants per year. Survey responses are summarized as number (%). Associations were assessed using a Wilcoxon-rank sum, chi-square, or Fisher exact test, as appropriate. RESULTS: Seventy-four providers from 35 centers were included. There was marked variability regarding screening practices, management, and attitudes. Forty-two percent responded that POPH nearly always or often improves with LT, and 15.5% reported that POPH rarely or never improves. In contrast to current guidelines, 50.7% agreed that treated POPH should be an indication for LT in patients with compensated cirrhosis. Hepatologists were more likely than PH physicians to agree that POPH should be an indication for LT (P = 0.02). Forty-nine percent of respondents thought that the current POPH Model for End-stage Liver Disease exception criteria should be modified, and management of patients with an elevated mean pulmonary arterial pressure and normal pulmonary vascular resistance differed from current policies. CONCLUSIONS: There is marked variability in provider attitudes and practice patterns regarding the management of POPH. This study highlights the need for prospective studies to inform practice and for improved implementation of practice guidelines in order to standardize care.