Elevated Pulmonary Arterial Compliance Is Associated with Survival in Pulmonary Hypertension: Results from a Novel Network Medicine Analysis.

Rationale: Predictors of adverse outcome in pulmonary hypertension (PH) are well established; however, data that inform survival are lacking. Objectives: We aim to identify clinical markers and therapeutic targets that inform the survival in PH. Methods: We included data from patients with elevated mean pulmonary artery pressure (mPAP) diagnosed by right heart catheterization in the U.S. Veterans Affairs system (October 1, 2006-September 30, 2018). Network medicine framework was used to subgroup patients when considering an N of 79 variables per patient. The results informed outcome analyses in the discovery cohort and a sex-balanced validation right heart catheterization cohort from Vanderbilt University (September 24, 1998-December 20, 2013). Measurements and Main Results: From an N of 4,737 complete case patients with mPAP of 19-24 mm Hg, there were 21 distinct subgroups (network modules) (all-cause mortality range = 15.9-61.2% per module). Pulmonary arterial compliance (PAC) drove patient assignment to modules characterized by increased survival. When modeled continuously in patients with mPAP ⩾19 mm Hg (N = 37,744; age, 67.2 yr [range = 61.7-73.8 yr]; 96.7% male; median follow-up time, 1,236 d [range = 570-1,971 d]), the adjusted all-cause mortality hazard ratio was <1.0 beginning at PAC ⩾3.0 ml/mm Hg and decreased progressively to ∼7 ml/mm Hg. A protective association between PAC ⩾3.0 ml/mm Hg and mortality was also observed in the validation cohort (N = 1,514; age, 60.2 yr [range = 49.2-69.1 yr]; 48.0% male; median follow-up time, 2,485 d [range = 671-3,580 d]). The association was strongest in patients with precapillary PH at the time of catheterization, in whom 41% (95% confidence interval, 0.55-0.62; P < 0.001) and 49% (95% confidence interval, 0.38-0.69; P < 0.001) improvements in survival were observed for PAC ⩾3.0 versus <3.0 ml/mm Hg in the discovery and validation cohorts, respectively. Conclusions: These data identify elevated PAC as an important parameter associated with survival in PH. Prospective studies are warranted that consider PAC ⩾3.0 ml/mm Hg as a therapeutic target to achieve through proven interventions.

Cluster analysis identifies novel real-world lung disease-pulmonary hypertension subphenotypes: implications for treatment response.

Background: Clinical trials repurposing pulmonary arterial hypertension (PAH) therapies to patients with lung disease- or hypoxia-pulmonary hypertension (PH) (classified as World Health Organization Group 3 PH) have failed to show a consistent benefit. However, Group 3 PH clinical heterogeneity suggests robust phenotyping may inform detection of treatment-responsive subgroups. We hypothesised that cluster analysis would identify subphenotypes with differential responses to oral PAH therapy. Methods: Two k-means analyses were performed on a national cohort of US veterans with Group 3 PH; an inclusive model (I) of all treated patients (n=196) and a haemodynamic model (H) limited to patients with right heart catheterisations (n=112). The primary outcome was organ failure or all-cause mortality by cluster. An exploratory analysis evaluated within-cluster treatment effects. Results: Three distinct clusters of Group 3 PH patients were identified. In the inclusive model (C1I n=43, 21.9%; C2I n=102, 52.0%; C3I n=51, 26.0%), lung disease and spirometry drove cluster assignment. By contrast, in the haemodynamic model (C1H n=44, 39.3%; C2H n=43, 38.4%; C3H n=25, 22.3%), right heart catheterisation data surpassed the importance of lung disease and spirometry. In the haemodynamic model, compared to C3H, C1H experienced the greatest hazard for respiratory failure or death (HR 6.1, 95% CI 3.2-11.8). In an exploratory analysis, cluster determined treatment response (p=0.006). Conclusions regarding within-cluster treatment responses were limited by significant differences between select variables in the treated and untreated groups. Conclusions: Cluster analysis identifies novel real-world subphenotypes of Group 3 PH patients with distinct clinical trajectories. Future studies may consider this methodological approach to identify subgroups of heterogeneous patients that may be responsive to existing pulmonary vasodilatory therapies.

Organization of pulmonary hypertension care in non-expert care settings: Lessons learned from a multi-site study.

OBJECTIVE: To examine how select Veterans Health Administration (VA) sites organized care for patients with pulmonary hypertension (PH), with a focus on describing existing practices and identifying unmet needs within the sites. DATA SOURCES AND STUDY SETTING: Semi-structured interviews across seven diverse VA sites. STUDY DESIGN: Qualitative multiple-site study. DATA COLLECTION/EXTRACTION METHODS: We interviewed 54 key informants including pulmonologists, cardiologists, primary care providers, advanced care practitioners, pharmacists, and clinical leaders to assess the structures and processes of PH care delivery. We analyzed transcripts using directed content analysis and constructed site profiles for each site, comparing profiles to existing guidelines for PH expert centers. PRINCIPAL FINDINGS: Sites varied considerably in how they organized PH care, with wide variation in the availability of structures and processes recommended for expert centers, including availability of PH expertise and PH-specific resources, multidisciplinary approach to care, establishment of clear referral pathways, and presence of PH education. Further, participants identified three areas of unmet need not directly addressed within current guidelines, including better integration of pharmacists into multidisciplinary teams, early and routine involvement of palliative care, and improved care coordination efforts. CONCLUSIONS: The rising prevalence of PH and evolution of treatments for common PH subgroups underscore the need to standardize PH care delivery in non-expert care settings to improve care quality and patient outcomes. The insight gained from this study may inform the development of guidance appropriate for care settings outside of expert centers.

Real-world use of inhaled treprostinil for lung disease-pulmonary hypertension: A protocol for patient evaluation and prescribing.

Inhaled treprostinil was approved recently for interstitial lung disease-pulmonary hypertension; however, efficacy in "real-world" populations is not known. We designed a protocol and report our experience evaluating 10 patients referred for therapy. Misdiagnosis at presentation was common; ultimately, three patients (30%) were prescribed drug. This protocol offers an opportunity to standardize longitudinal assessment of inhaled treprostinil in clinical practice.

Socioeconomically disadvantaged veterans experience treatment delays for pulmonary arterial hypertension.

Prompt initiation of therapy after pulmonary arterial hypertension (PAH) diagnosis is critical to improve outcomes; yet delays in PAH treatment are common. Prior research demonstrates that individuals with PAH belonging to socially disadvantaged groups experience worse clinical outcomes. Whether these poor outcomes are mediated by delays in care or other factors is incompletely understood. We sought to examine the association between race/ethnicity and socioeconomic status and time-to-PAH treatment. We conducted a retrospective cohort study of Veterans diagnosed with incident PAH between 2006 and 2019 and treated with PAH therapy. Our outcome was time-to-PAH treatment. Our primary exposures were race/ethnicity, annual household income, health insurance status, education, and housing insecurity. We calculated time-to-treatment using multivariable mixed-effects Cox proportional hazard models. Of 1827 Veterans with PAH, 27% were Black, 4% were Hispanic, 22.1% had an income < $20,000, 53.3% lacked non-VA insurance, 25.5% had

Hospital Variation in Management and Outcomes of Acute Respiratory Distress Syndrome Due to COVID-19.

OBJECTIVES: To describe hospital variation in use of "guideline-based care" for acute respiratory distress syndrome (ARDS) due to COVID-19. DESIGN: Retrospective, observational study. SETTING: The Society of Critical Care Medicine's Discovery Viral Infection and RESPIRATORY ILLNESS UNIVERSAL STUDY COVID-19 REGISTRY. PATIENTS: Adult patients with ARDS due to COVID-19 between February 15, 2020, and April 12, 2021. INTERVENTIONS: Hospital-level use of "guideline-based care" for ARDS including low-tidal-volume ventilation, plateau pressure less than 30 cm H2O, and prone ventilation for a Pao2/Fio2 ratio less than 100. MEASUREMENTS AND MAIN RESULTS: Among 1,495 adults with COVID-19 ARDS receiving care across 42 hospitals, 50.4% ever received care consistent with ARDS clinical practice guidelines. After adjusting for patient demographics and severity of illness, hospital characteristics, and pandemic timing, hospital of admission contributed to 14% of the risk-adjusted variation in "guideline-based care." A patient treated at a randomly selected hospital with higher use of guideline-based care had a median odds ratio of 2.0 (95% CI, 1.1-3.4) for receipt of "guideline-based care" compared with a patient receiving treatment at a randomly selected hospital with low use of recommended therapies. Median-adjusted inhospital mortality was 53% (interquartile range, 47-62%), with a nonsignificantly decreased risk of mortality for patients admitted to hospitals in the highest use "guideline-based care" quartile (49%) compared with the lowest use quartile (60%) (odds ratio, 0.7; 95% CI, 0.3-1.9; p = 0.49). CONCLUSIONS: During the first year of the COVID-19 pandemic, only half of patients received "guideline-based care" for ARDS management, with wide practice variation across hospitals. Strategies that improve adherence to recommended ARDS management strategies are needed.

Variation in Use of High-Flow Nasal Cannula and Noninvasive Ventilation Among Patients With COVID-19.

BACKGROUND: The use of high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) for hypoxemic respiratory failure secondary to COVID-19 are recommended by critical-care guidelines; however, apprehension about viral particle aerosolization and patient self-inflicted lung injury may have limited use. We aimed to describe hospital variation in the use and clinical outcomes of HFNC and NIV for the management of COVID-19. METHODS: This was a retrospective observational study of adults hospitalized with COVID-19 who received supplemental oxygen between February 15, 2020, and April 12, 2021, across 102 international and United States hospitals by using the COVID-19 Registry. Associations of HFNC and NIV use with clinical outcomes were evaluated by using multivariable adjusted hierarchical random-effects logistic regression models. Hospital variation was characterized by using intraclass correlation and the median odds ratio. RESULTS: Among 13,454 adults with COVID-19 who received supplemental oxygen, 8,143 (60%) received nasal cannula/face mask only, 2,859 (21%) received HFNC, 878 (7%) received NIV, 1,574 (12%) received both HFNC and NIV, with 3,640 subjects (27%) progressing to invasive ventilation. The hospital of admission contributed to 24% of the risk-adjusted variation in HFNC and 30% of the risk-adjusted variation in NIV. The median odds ratio for hospital variation of HFNC was 2.6 (95% CI 1.4-4.9) and of NIV was 3.1 (95% CI 1.2-8.1). Among 5,311 subjects who received HFNC and/or NIV, 2,772 (52%) did not receive invasive ventilation and survived to hospital discharge. Hospital-level use of HFNC or NIV were not associated with the rates of invasive ventilation or mortality. CONCLUSIONS: Hospital variation in the use of HFNC and NIV for acute respiratory failure secondary to COVID-19 was great but was not associated with intubation or mortality. The wide variation and relatively low use of HFNC/NIV observed within our study signaled that implementation of increased HFNC/NIV use in patients with COVID-19 will require changes to current care delivery practices. (ClinicalTrials.gov registration NCT04323787.).

Polymicrobial empyema; a novel case of Actinomyces turicensis.

Empyema or infection of the pleural space is a well described complication of pneumonia, however knowledge of culprit pathogens is still evolving. We report a novel case of empyema due to Actinomyces turicensis, a commensal of the oropharynx and female urogenital tract but previously undescribed cause of empyema. We additionally review general pathogenesis of Actinomyces species within the pleural space. Familiarity with this unique pleural infection pathogen is important for selection of adequate antimicrobial therapy given the propensity of anaerobes such as Actinomyces species to disobey anatomic boundaries and recrudescence of infection in the absence of appropriate therapy.

Variation in Use of Repurposed Medications Among Patients With Coronavirus Disease 2019. From The Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 Registry Investigator Group.

IMPORTANCE: At the start of the coronavirus disease 2019 pandemic, medications repurposed for management of coronavirus disease 2019 were used in the absence of clinical trial evidence. OBJECTIVES: To describe the variation and evolution in use of repurposed medications for coronavirus disease 2019. DESIGN SETTING AND PARTICIPANTS: Observational cohort study of adults hospitalized with coronavirus disease 2019 between February 15, 2020, and April 12, 2021, across 76 United States and international hospitals within the Society of Critical Care Medicine's Discovery Viral Infection and Respiratory Illness Universal Study coronavirus disease 2019 registry. MAIN OUTCOMES AND MEASURES: Hospital variation was quantified using multivariable adjusted random effects logistic regression models and unsupervised clustering. Repurposed medications included antivirals, corticosteroids, hydroxychloroquine, immunomodulators, and therapeutic dose anticoagulants. RESULTS: Among 7,069 adults hospitalized with coronavirus disease 2019, 1,979 (28%) received antivirals, 2,876 (41%) received corticosteroids, 1,779 (25%) received hydroxychloroquine, 620 (9%) received immunomodulators, and 2,154 (31%) received therapeutic dose anticoagulants. Contribution of hospital site to risk-adjusted variation was 46% for antivirals, 30% for corticosteroids, 48% for hydroxychloroquine, 46% for immunomodulators, and 52% for therapeutic dose anticoagulants. Compared with the early pandemic, the later pandemic practice phenotypes converged with increased use of antivirals (odds ratio, 3.14; 95% CI, 2.40-4.10) and corticosteroids (odds ratio, 5.43; 95% CI, 4.23-6.97), with decreased use of hydroxychloroquine (odds ratio, 0.02; 95% CI, 0.01-0.04) and immunomodulators (odds ratio, 0.49; 95% CI, 0.34-0.70). There was no clinically significant change in the use of therapeutic dose anticoagulants (odds ratio, 1.01; 95% CI, 1.01-1.02). There were no differences in risk-adjusted mortality between hospitals with high rates of repurposed medication use compared with hospitals with low rates of use. CONCLUSIONS AND RELEVANCE: Hospital variation in the use of repurposed medications varied widely across hospitals early in the pandemic and later converged with the emergence of randomized clinical trials. Platforms developed for rapid activation and enrollment in clinical trials of repurposed medications are needed prior to the next pandemic to expedite effective, evidence-based practice.

Room for improvement in pulmonary capillary wedge pressure reporting: a review of hemodynamic tracings at a large academic medical center.

To describe the frequency with which pulmonary capillary wedge pressure measurements, obtained during right heart catheterization, are falsely elevated and to educate operators on techniques to improve accuracy of pulmonary capillary wedge pressure reporting. Failure to completely occlude pulmonary artery branch vessels during balloon inflation can lead to falsely elevated, "incomplete" pulmonary capillary wedge pressures. Balloon deflation prior to catheter retraction may result in catheter advancement into smaller branch vessels, yielding an inadvertent but more accurate alternative pulmonary capillary wedge pressure. We hypothesized that this phenomenon can be identified on retrospective review of right heart catheterization tracings, which occurs commonly and goes unrecognized by operators. We conducted a retrospective study of patients undergoing right heart catheterization or right heart catheterization and left heart catheterization with computer-generated pulmonary capillary wedge pressure ≥20 from January 2015 to June 2017. Alternative pulmonary capillary wedge pressures were defined as a pulmonary capillary wedge pressure trace during balloon deflation ≥3 mmHg lower than the reported pulmonary capillary wedge pressure. Inter-rater reliability of tracing reviewers was also evaluated. Results showed that, of the 182 tracings reviewed, an alternative pulmonary capillary wedge pressure was identified in 26 or 14.3% of cases. Eleven of these alternative pulmonary capillary wedge pressures were ≤15 mmHg with a calculated pulmonary vascular resistance ≥3 Wood units in 10 patients, re-classifying the etiology of pulmonary hypertension from post-capillary to pre-capillary in 38.5% of cases. For the eight patients for whom left heart catheterization data were available, left ventricular end-diastolic pressure aligned with the alternative pulmonary capillary wedge pressure. In conclusion, inadvertently obtained, but likely more accurate, alternative pulmonary capillary wedge pressures were identified in almost 15% of procedures reviewed from a busy academic institution. As wedge pressures often drive diagnosis and treatment decisions for patients with cardiac and pulmonary pathology, operators should be attuned to balloon deflation as a time when alternative pulmonary capillary wedge pressures may be identified as they are likely more reflective of left ventricular end-diastolic pressure. Additional tools to ensure accuracy of pulmonary capillary wedge pressure reporting are reviewed.

Spontaneous coronary artery dissection masquerading as Takotsubo cardiomyopathy: a case report.

BACKGROUND: Although obstructive coronary artery disease (CAD) is the most likely cause of acute coronary syndromes (ACS), nearly one in 20 individuals with clinical myocardial infarction (MI) do not have obstructive CAD. For many such individuals, presentation of Takotsubo cardiomyopathy frequently mimics presentation of MI, though spontaneous coronary artery dissection (SCAD) is an increasingly recognized aetiology of MI in women. CASE SUMMARY: This case report describes a woman with chest pain, found to have non-obstructive CAD on angiogram and left ventricular apical dysfunction on echocardiogram raising suspicion for Takotsubo cardiomyopathy. Additional suspicion for SCAD led to coronary CT angiogram (CCTA) which ultimately confirmed this diagnosis. DISCUSSION: Familiarity with a differential diagnosis for non-obstructive CAD is less common than that for obstructive coronary disease. This case emphasizes the clinical features that should raise suspicion for SCAD when Takotsubo is presumed and outlines the clinical utility of CCTA in making this diagnosis when angiography is unrevealing.