Diagnostic management of acute pulmonary embolism: a prediction model based on a patient data meta-analysis.

AIMS: Risk stratification is used for decisions regarding need for imaging in patients with clinically suspected acute pulmonary embolism (PE). The aim was to develop a clinical prediction model that provides an individualized, accurate probability estimate for the presence of acute PE in patients with suspected disease based on readily available clinical items and D-dimer concentrations. METHODS AND RESULTS: An individual patient data meta-analysis was performed based on sixteen cross-sectional or prospective studies with data from 28 305 adult patients with clinically suspected PE from various clinical settings, including primary care, emergency care, hospitalized and nursing home patients. A multilevel logistic regression model was built and validated including ten a priori defined objective candidate predictors to predict objectively confirmed PE at baseline or venous thromboembolism (VTE) during follow-up of 30 to 90 days. Multiple imputation was used for missing data. Backward elimination was performed with a P-value <0.10. Discrimination (c-statistic with 95% confidence intervals [CI] and prediction intervals [PI]) and calibration (outcome:expected [O:E] ratio and calibration plot) were evaluated based on internal-external cross-validation. The accuracy of the model was subsequently compared with algorithms based on the Wells score and D-dimer testing. The final model included age (in years), sex, previous VTE, recent surgery or immobilization, haemoptysis, cancer, clinical signs of deep vein thrombosis, inpatient status, D-dimer (in µg/L), and an interaction term between age and D-dimer. The pooled c-statistic was 0.87 (95% CI, 0.85-0.89; 95% PI, 0.77-0.93) and overall calibration was very good (pooled O:E ratio, 0.99; 95% CI, 0.87-1.14; 95% PI, 0.55-1.79). The model slightly overestimated VTE probability in the lower range of estimated probabilities. Discrimination of the current model in the validation data sets was better than that of the Wells score combined with a D-dimer threshold based on age (c-statistic 0.73; 95% CI, 0.70-0.75) or structured clinical pretest probability (c-statistic 0.79; 95% CI, 0.76-0.81). CONCLUSION: The present model provides an absolute, individualized probability of PE presence in a broad population of patients with suspected PE, with very good discrimination and calibration. Its clinical utility needs to be evaluated in a prospective management or impact study. REGISTRATION: PROSPERO ID 89366.

Pandemic phase-related racial and ethnic disparities in COVID-19 positivity and outcomes among patients presenting to emergency departments during the first two pandemic waves in the USA.

BACKGROUND: In many countries including the USA, the UK and Canada, the impact of COVID-19 on people of colour has been disproportionately high but examination of disparities in patients presenting to ED has been limited. We assessed racial and ethnic differences in COVID-19 positivity and outcomes in patients presenting to EDs in the USA, and the effect of the phase of the pandemic on these outcomes. METHODS: This is a retrospective cohort study of adult patients tested for COVID-19 during, or 14 days prior to, the index ED visit in 2020. Data were obtained from the National Registry of Suspected COVID-19 in Emergency Care network which has data from 155 EDs across 27 US states. Hierarchical models were used to account for clustering by hospital. The outcomes included COVID-19 diagnosis, hospitalisation at index visit, subsequent hospitalisation within 30 days and 30-day mortality. We further stratified the analysis by time period (early phase: March-June 2020; late phase: July-September 2020). RESULTS: Of the 26 111 adult patients, 38% were non-Hispanic White (NHW), 29% Black, 20% Hispanic/Latino, 3% Asian and 10% all others; half were female. The median age was 56 years (IQR 40-69), and 53% were diagnosed with COVID-19; of those, 59% were hospitalised at index visit. Of those discharged from ED, 47% had a subsequent hospitalisation in 30 days. Hispanic/Latino patients had twice (adjusted OR (aOR) 2.3; 95% CI 1.8 to 3.0) the odds of COVID-19 diagnosis than NHW patients, after adjusting for age, sex and comorbidities. Black, Asian and other minority groups also had higher odds of being diagnosed (compared with NHW patients). On stratification, this association was observed in both phases for Hispanic/Latino patients. Hispanic/Latino patients had lower odds of hospitalisation at index visit, but when stratified, this effect was only observed in early phase. Subsequent hospitalisation was more likely in Asian patients (aOR 3.1; 95% CI 1.1 to 8.7) in comparison with NHW patients. Subsequent ED visit was more likely in Blacks and Hispanic/Latino patients in late phase. CONCLUSION: We found significant differences in ED outcomes that are not explained by comorbidity burden. The gap decreased but persisted during the later phase in 2020.

ChatGPT and conversational artificial intelligence: Friend, foe, or future of research?

Artificial intelligence (AI) and machine learning are increasingly utilized across healthcare. More recently, there has been a rise in the use AI within research, particularly through novel conversational AI platforms, such as ChatGPT. In this Controversies paper, we discuss the advantages, limitations, and future directions for ChatGPT and other forms of conversational AI in research and scholarly dissemination.

Safety and Efficiency of Diagnostic Strategies for Ruling Out Pulmonary Embolism in Clinically Relevant Patient Subgroups : A Systematic Review and Individual-Patient Data Meta-analysis.

BACKGROUND: How diagnostic strategies for suspected pulmonary embolism (PE) perform in relevant patient subgroups defined by sex, age, cancer, and previous venous thromboembolism (VTE) is unknown. PURPOSE: To evaluate the safety and efficiency of the Wells and revised Geneva scores combined with fixed and adapted D-dimer thresholds, as well as the YEARS algorithm, for ruling out acute PE in these subgroups. DATA SOURCES: MEDLINE from 1 January 1995 until 1 January 2021. STUDY SELECTION: 16 studies assessing at least 1 diagnostic strategy. DATA EXTRACTION: Individual-patient data from 20 553 patients. DATA SYNTHESIS: Safety was defined as the diagnostic failure rate (the predicted 3-month VTE incidence after exclusion of PE without imaging at baseline). Efficiency was defined as the proportion of individuals classified by the strategy as "PE considered excluded" without imaging tests. Across all strategies, efficiency was highest in patients younger than 40 years (47% to 68%) and lowest in patients aged 80 years or older (6.0% to 23%) or patients with cancer (9.6% to 26%). However, efficiency improved considerably in these subgroups when pretest probability-dependent D-dimer thresholds were applied. Predicted failure rates were highest for strategies with adapted D-dimer thresholds, with failure rates varying between 2% and 4% in the predefined patient subgroups. LIMITATIONS: Between-study differences in scoring predictor items and D-dimer assays, as well as the presence of differential verification bias, in particular for classifying fatal events and subsegmental PE cases, all of which may have led to an overestimation of the predicted failure rates of adapted D-dimer thresholds. CONCLUSION: Overall, all strategies showed acceptable safety, with pretest probability-dependent D-dimer thresholds having not only the highest efficiency but also the highest predicted failure rate. From an efficiency perspective, this individual-patient data meta-analysis supports application of adapted D-dimer thresholds. PRIMARY FUNDING SOURCE: Dutch Research Council. (PROSPERO: CRD42018089366).

Database derived from an electronic medical record-based surveillance network of US emergency department patients with acute respiratory illness.

BACKGROUND: For surveillance of episodic illness, the emergency department (ED) represents one of the largest interfaces for generalizable data about segments of the US public experiencing a need for unscheduled care. This protocol manuscript describes the development and operation of a national network linking symptom, clinical, laboratory and disposition data that provides a public database dedicated to the surveillance of acute respiratory infections (ARIs) in EDs. METHODS: The Respiratory Virus Laboratory Emergency Department Network Surveillance (RESP-LENS) network includes 26 academic investigators, from 24 sites, with 91 hospitals, and the Centers for Disease Control and Prevention (CDC) to survey viral infections. All data originate from electronic medical records (EMRs) accessed by structured query language (SQL) coding. Each Tuesday, data are imported into the standard data form for ARI visits that occurred the prior week (termed the index file); outcomes at 30 days and ED volume are also recorded. Up to 325 data fields can be populated for each case. Data are transferred from sites into an encrypted Google Cloud Platform, then programmatically checked for compliance, parsed, and aggregated into a central database housed on a second cloud platform prior to transfer to CDC. RESULTS: As of August, 2023, the network has reported data on over 870,000 ARI cases selected from approximately 5.2 million ED encounters. Post-contracting challenges to network execution have included local shifts in testing policies and platforms, delays in ICD-10 coding to detect ARI cases, and site-level personnel turnover. The network is addressing these challenges and is poised to begin streaming weekly data for dissemination. CONCLUSIONS: The RESP-LENS network provides a weekly updated database that is a public health resource to survey the epidemiology, viral causes, and outcomes of ED patients with acute respiratory infections.

Ruling out pulmonary embolism across different healthcare settings: A systematic review and individual patient data meta-analysis.

BACKGROUND: The challenging clinical dilemma of detecting pulmonary embolism (PE) in suspected patients is encountered in a variety of healthcare settings. We hypothesized that the optimal diagnostic approach to detect these patients in terms of safety and efficiency depends on underlying PE prevalence, case mix, and physician experience, overall reflected by the type of setting where patients are initially assessed. The objective of this study was to assess the capability of ruling out PE by available diagnostic strategies across all possible settings. METHODS AND FINDINGS: We performed a literature search (MEDLINE) followed by an individual patient data (IPD) meta-analysis (MA; 23 studies), including patients from self-referral emergency care (n = 12,612), primary healthcare clinics (n = 3,174), referred secondary care (n = 17,052), and hospitalized or nursing home patients (n = 2,410). Multilevel logistic regression was performed to evaluate diagnostic performance of the Wells and revised Geneva rules, both using fixed and adapted D-dimer thresholds to age or pretest probability (PTP), for the YEARS algorithm and for the Pulmonary Embolism Rule-out Criteria (PERC). All strategies were tested separately in each healthcare setting. Following studies done in this field, the primary diagnostic metrices estimated from the models were the "failure rate" of each strategy-i.e., the proportion of missed PE among patients categorized as "PE excluded" and "efficiency"-defined as the proportion of patients categorized as "PE excluded" among all patients. In self-referral emergency care, the PERC algorithm excludes PE in 21% of suspected patients at a failure rate of 1.12% (95% confidence interval [CI] 0.74 to 1.70), whereas this increases to 6.01% (4.09 to 8.75) in referred patients to secondary care at an efficiency of 10%. In patients from primary healthcare and those referred to secondary care, strategies adjusting D-dimer to PTP are the most efficient (range: 43% to 62%) at a failure rate ranging between 0.25% and 3.06%, with higher failure rates observed in patients referred to secondary care. For this latter setting, strategies adjusting D-dimer to age are associated with a lower failure rate ranging between 0.65% and 0.81%, yet are also less efficient (range: 33% and 35%). For all strategies, failure rates are highest in hospitalized or nursing home patients, ranging between 1.68% and 5.13%, at an efficiency ranging between 15% and 30%. The main limitation of the primary analyses was that the diagnostic performance of each strategy was compared in different sets of studies since the availability of items used in each diagnostic strategy differed across included studies; however, sensitivity analyses suggested that the findings were robust. CONCLUSIONS: The capability of safely and efficiently ruling out PE of available diagnostic strategies differs for different healthcare settings. The findings of this IPD MA help in determining the optimum diagnostic strategies for ruling out PE per healthcare setting, balancing the trade-off between failure rate and efficiency of each strategy.

An adaptive clinical trial design to identify the target dose of tenecteplase for treatment of acute pulmonary embolism.

BACKGROUND/AIMS: Fibrinolytic therapy with tenecteplase has been proposed for patients with pulmonary embolism but the optimal dose is unknown. Higher-than-necessary dosing is likely to cause excess bleeding. We designed an adaptive clinical trial to identify the minimum and assumed safest dose of tenecteplase that maintains efficacy. METHODS: We propose a Bayesian adaptive, placebo-controlled, group-sequential dose-finding trial using response-adaptive randomization to preferentially allocate subjects to the most promising doses, dual analyses strategies (continuous and dichotomized) using a gatekeeping approach to maximize clinical impact, and interim stopping rules to efficiently address competing trial objectives. The operating characteristics of the proposed design were evaluated using Monte Carlo simulation across multiple hypothetical efficacy scenarios. RESULTS: Simulation demonstrated response-adaptive randomization can preferentially allocate subjects to doses which appear to be performing well based on interim data. Interim decision-making, including the interim evaluation of both analysis strategies with gatekeeping, allows the trial to continue enrollment when success with the dichotomized analysis strategy appears sufficiently likely and to stop enrollment and declare superiority based on the continuous analysis strategy when there is little chance of ultimately declaring superiority with the dichotomized analysis. CONCLUSION: The proposed design allows evaluation of a greater number of dose levels than would be possible with a non-adaptive design and avoids the need to choose either the continuous or the dichotomized analysis strategy for the primary endpoint.

Primer on Logistic Regression for Emergency Care Researchers.

BACKGROUND: Logistic regression plays a fundamental role in the production of decision rules, risk assessment, and in establishing cause and effect relationships. This primer is aimed at novice researchers with minimal statistical expertise. OBJECTIVE: Introduce the logit equation and provide a hands-on example to facilitate understanding of its benefits and limitations. DISCUSSION: This primer reviews the mathematical basis of a logit equation by comparing and contrasting it with the simple straight-line (linear) equation. After gaining an understanding of the meaning of beta coefficients, readers are encouraged to download a free statistical program and database to produce a logistic regression analysis. Using this example, the narrative then discusses commonly used methods to describe model fitness, including the C-statistic, chi square, Akaike and Bayesian Information Criteria, McFadden's pseudo R2, and the Hosmer-Lemeshow test. The authors provide a how-to discussion for variable selection and estimate of sample size. However, logistic regression alone can seldom establish causal inference without further steps to explore the often complex relationship amongst variables and outcomes, such as with the use of a directed acyclic graphs. We present key elements that generally should be considered when appraising an article that uses logistic regression. This primer provides a basic understanding of the theory, hands-on construction, model analysis, and limitations of logistic regression in emergency care research. CONCLUSIONS: Logistic regression can provide information about the association of independent variables with important clinical outcomes, which can be the first step to show predictiveness or causation of variables on the outcomes of interest. © 2022 Elsevier Inc.

SARS-CoV-2 Positivity in Ambulatory Symptomatic Patients Is Not Associated With Increased Venous or Arterial Thrombotic Events in the Subsequent 30 Days.

BACKGROUND: COVID-19 has been associated with increased risk of thromboembolism in critically ill patients. OBJECTIVE: We sought to examine the association of SARS-CoV-2 test positivity and subsequent acute vascular thrombosis, including venous thromboembolism (VTE) or arterial thrombosis (AT), in a large nationwide registry of emergency department (ED) patients tested with a nucleic acid test for suspected SARS-CoV-2. METHODS: The RECOVER (Registry of Potential COVID-19 in Emergency Care) registry includes 155 EDs across the United States. We performed a retrospective cohort study to produce odds ratios (ORs) for COVID-19-positive vs. COVID-19-negative status as a predictor of 30-day VTE or AT, adjusting for age, sex, active cancer, intubation, hospital length of stay, and intensive care unit (ICU) care. RESULTS: Comparing 14,056 COVID-19-positive patients with 12,995 COVID-19-negative patients, the overall 30-day prevalence of VTE events was 1.4% vs. 1.3%, respectively (p = 0.44, χ2). Multivariable analysis identified that testing positive for SARS-CoV-2 status was negatively associated with both VTE (OR 0.76; 95% confidence interval [CI] 0.61-0.94) and AT (OR 0.51; 95% CI 0.32-0.80), whereas intubation, ICU care, and age 50 years or older were positively associated with both VTE and AT. CONCLUSIONS: In contrast to other reports, results from this large, hetereogenous national sample of ED patients tested for SARS-CoV-2, showed no association between vascular thrombosis and COVID-19 test positivity.

Synergistic effects of emergency physician empathy and burnout on patient satisfaction: a prospective observational study.

BACKGROUND: Physician empathy and burnout have been shown to be independently associated with patient satisfaction. However, their correlations were uncertain in previous studies. We aimed to determine correlations among empathy, burnout, and patient satisfaction, and further analyse interactions among these factors. METHOD: A single centre prospective observational study was conducted from December 2018 to August 2019 at JPS Health Network, USA. Emergency physician (EP) self-assessed empathy and burnout were measured by the Jefferson Scale of Empathy (JSE) and the Copenhagen Burnout Inventory (CBI) separately. We assessed patient perception of physician empathy and patient satisfaction with their treating physician by the Jefferson Scale of Patient Perception of Physician Empathy and a patient assessed satisfaction survey. Spearman's correlation was used to determine associations among JSE, patient assessed physician empathy, CBI and patient satisfaction. Additionally, JSE, patient assessed physician empathy and CBI predictive of patient satisfaction were measured by multivariate logistic regression analysis. RESULTS: A total of 28 EPs and 423 patients were enrolled. Patient satisfaction had a weak correlation with JSE (ρ=0.11) but showed a strong correlation with patient assessed physician empathy (ρ=0.60). CBI showed no correlation with patient satisfaction (ρ<0.1). However, when JSE, patient assessed physician empathy and CBI were analysed together in relation to patient satisfaction, adjusted odds ratios (AOR) was 3.85 (95% CI 1.36 to 10.88) with high patient assessed physician empathy alone; AOR was 7.17 (2.62-19.67) when high patient assessed physician empathy was combined with low CBI; and AOR was 8.37 (3.07-22.83) when high patient assessed physician empathy, low CBI and high JSE were combined. CONCLUSION: Patient assessed physician empathy had a strong positive correlation with patient satisfaction. Moreover, higher patient satisfaction was achieved from EPs of high patient assessed physician empathy, low CBI and high JSE, indicating a positive synergistic effect. These findings suggest different interventions might be applied to EPs of different wellness features to maximise patient satisfaction.

Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism.

BACKGROUND: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE). METHODS: Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation. RESULTS: Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysate sGC activity was increased with PE compared with controls. CONCLUSIONS: In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target.

Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study.

BACKGROUND: Studies examining the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes have reported conflicting results. Our objective was to test the hypothesis that early postresuscitation hyperoxia is associated with poor neurological outcome. METHODS: This was a multicenter prospective cohort study. We included adult patients with cardiac arrest who were mechanically ventilated and received targeted temperature management after return of spontaneous circulation. We excluded patients with cardiac arrest caused by trauma or sepsis. Per protocol, partial pressure of arterial oxygen (Pao2) was measured at 1 and 6 hours after return of spontaneous circulation. Hyperoxia was defined as a Pao2 >300 mm Hg during the initial 6 hours after return of spontaneous circulation. The primary outcome was poor neurological function at hospital discharge, defined as a modified Rankin Scale score >3. Multivariable generalized linear regression with a log link was used to test the association between Pao2 and poor neurological outcome. To assess whether there was an association between other supranormal Pao2 levels and poor neurological outcome, we used other Pao2 cut points to define hyperoxia (ie, 100, 150, 200, 250, 350, 400 mm Hg). RESULTS: Of the 280 patients included, 105 (38%) had exposure to hyperoxia. Poor neurological function at hospital discharge occurred in 70% of patients in the entire cohort and in 77% versus 65% among patients with versus without exposure to hyperoxia respectively (absolute risk difference, 12%; 95% confidence interval, 1-23). Hyperoxia was independently associated with poor neurological function (relative risk, 1.23; 95% confidence interval, 1.11-1.35). On multivariable analysis, a 1-hour-longer duration of hyperoxia exposure was associated with a 3% increase in risk of poor neurological outcome (relative risk, 1.03; 95% confidence interval, 1.02-1.05). We found that the association with poor neurological outcome began at ≥300 mm Hg. CONCLUSIONS: Early hyperoxia exposure after resuscitation from cardiac arrest was independently associated with poor neurological function at hospital discharge.

Association Between Elevated Mean Arterial Blood Pressure and Neurologic Outcome After Resuscitation From Cardiac Arrest: Results From a Multicenter Prospective Cohort Study.

OBJECTIVES: Laboratory studies suggest elevated blood pressure after resuscitation from cardiac arrest may be protective; however, clinical data are limited. We sought to test the hypothesis that elevated postresuscitation mean arterial blood pressure is associated with neurologic outcome. DESIGN: Preplanned analysis of a prospective cohort study. SETTING: Six academic hospitals in the United States. PATIENTS: Adult, nontraumatic cardiac arrest patients treated with targeted temperature management after return of spontaneous circulation. INTERVENTIONS: Mean arterial blood pressure was measured noninvasively after return of spontaneous circulation and every hour during the initial 6 hours after return of spontaneous circulation. MEASURES AND MAIN RESULTS: We calculated the mean arterial blood pressure and a priori dichotomized subjects into two groups: mean arterial blood pressure 70-90 and greater than 90 mm Hg. The primary outcome was good neurologic function, defined as a modified Rankin Scale less than or equal to 3. The modified Rankin Scale was prospectively determined at hospital discharge. Of the 269 patients included, 159 (59%) had a mean arterial blood pressure greater than 90 mm Hg. Good neurologic function at hospital discharge occurred in 30% of patients in the entire cohort and was significantly higher in patients with a mean arterial blood pressure greater than 90 mm Hg (42%) as compared with mean arterial blood pressure 70-90 mm Hg (15%) (absolute risk difference, 27%; 95% CI, 17-37%). In a multivariable Poisson regression model adjusting for potential confounders, mean arterial blood pressure greater than 90 mm Hg was associated with good neurologic function (adjusted relative risk, 2.46; 95% CI; 2.09-2.88). Over ascending ranges of mean arterial blood pressure, there was a dose-response increase in probability of good neurologic outcome, with mean arterial blood pressure greater than 110 mm Hg having the strongest association (adjusted relative risk, 2.97; 95% CI, 1.86-4.76). CONCLUSIONS: Elevated blood pressure during the initial 6 hours after resuscitation from cardiac arrest was independently associated with good neurologic function at hospital discharge. Further investigation is warranted to determine if targeting an elevated mean arterial blood pressure would improve neurologic outcome after cardiac arrest.

Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial.

OBJECTIVE: To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE. METHODS: This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 h. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL. The secondary endpoint required a blood brain natriuretic peptide concentration <90 pg/mL and a Borg dyspnea score ≤ 2. The sample size of N = 76 tested if 30% more patients treated with NO would achieve the primary endpoint with 80% power and alpha = 5%. RESULTS: We randomized 78 patients and after two withdrawals, 38 were treated per protocol in each group. Patients were well matched for baseline conditions. At 24 h, 5/38 (13%) of patients treated with placebo and 9/38 (24%) of patients treated with NO reached the primary endpoint (P = 0.375). The secondary endpoint was reached in 34% with placebo and 13% of the NO (P = 0.11). In a pre-planned post-hoc analysis, we examined how many patients with RV hypokinesis or dilation at enrollment resolved these abnormalities; 29% more patients treated with NO resolved both abnormalities at 24 h (P = 0.010, Cochrane's Q test). CONCLUSIONS: In patients with severe submassive PE, inhaled nitric oxide failed to increase the proportion of patients with a normal troponin and echocardiogram but increased the probability of eliminating RV hypokinesis and dilation on echocardiography. CLINICAL TRIAL REGISTRATION: NCT01939301.

Assessment of Right Ventricular Function in the Research Setting: Knowledge Gaps and Pathways Forward. An Official American Thoracic Society Research Statement.

BACKGROUND: Right ventricular (RV) adaptation to acute and chronic pulmonary hypertensive syndromes is a significant determinant of short- and long-term outcomes. Although remarkable progress has been made in the understanding of RV function and failure since the meeting of the NIH Working Group on Cellular and Molecular Mechanisms of Right Heart Failure in 2005, significant gaps remain at many levels in the understanding of cellular and molecular mechanisms of RV responses to pressure and volume overload, in the validation of diagnostic modalities, and in the development of evidence-based therapies. METHODS: A multidisciplinary working group of 20 international experts from the American Thoracic Society Assemblies on Pulmonary Circulation and Critical Care, as well as external content experts, reviewed the literature, identified important knowledge gaps, and provided recommendations. RESULTS: This document reviews the knowledge in the field of RV failure, identifies and prioritizes the most pertinent research gaps, and provides a prioritized pathway for addressing these preclinical and clinical questions. The group identified knowledge gaps and research opportunities in three major topic areas: 1) optimizing the methodology to assess RV function in acute and chronic conditions in preclinical models, human studies, and clinical trials; 2) analyzing advanced RV hemodynamic parameters at rest and in response to exercise; and 3) deciphering the underlying molecular and pathogenic mechanisms of RV function and failure in diverse pulmonary hypertension syndromes. CONCLUSIONS: This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.

Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition.

Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.

High rate of isolated right ventricular dysfunction in patients with non-significant CT pulmonary angiography.

BACKGROUND: Right ventricular (RV) dysfunction and pulmonary hypertension (PH) are commonly unrecognized in the emergency department (ED), but are associated with poor outcomes. Prior research has found a 30% prevalence of isolated RV dysfunction in ED patients after non-significant computed tomographic pulmonary angiography (CTPA). We aimed to prospectively define the prevalence of RV dysfunction and/or PH in short of breath ED patients, and assess outcomes. METHODS: Prospective observational study of patients with a non-significant CTPA. Isolated RV dysfunction and/or PH was defined as normal left ventricular function plus RV dilation, moderate to severe tricuspid regurgitation or RV systolic pressure>40mmHg on comprehensive echocardiography. RESULTS: Of 83 patients, 20 (24%, 95% [confidence interval] CI: 16-34%) had isolated RV dysfunction and/or PH. These patients had 40% ED recidivism and 30% hospital readmission at 30-days. When compared to patients with normal echocardiographic function, they had significantly longer intensive care unit and hospital length of stays. CONCLUSIONS: In a prospective cohort of ED patients, we found a high prevalence of isolated RV dysfunction and/or PH after a non-significant CTPA. These patients had high rates of recidivism and hospital readmission. This data supports a continued need for ED based screening and specialty referral.

Anxiety about anxiety: a survey of emergency department provider beliefs and practices regarding anxiety-associated low risk chest pain.

BACKGROUND: Approximately 80% of patients presenting to emergency departments (ED) with chest pain do not have any true cardiopulmonary emergency such as acute coronary syndrome (ACS). However, psychological contributors such as anxiety are thought to be present in up to 58%, but often remain undiagnosed leading to chronic chest pain and ED recidivism. METHODS: To evaluate ED provider beliefs and their usual practices regarding the approach and disposition of patients with low risk chest pain associated with anxiety, we constructed a 22-item survey using a modified Delphi technique. The survey was administered to a convenience sample of ED providers attending the 2016 American College of Emergency Physicians Scientific Assembly in Las Vegas. RESULTS: Surveys were completed by 409 emergency medicine providers from 46 states and 7 countries with a wide range of years of experience and primary practice environment (academic versus community centers). Respondents estimated that 30% of patients presenting to the ED with chest pain thought to be low risk for ACS have anxiety or panic as the primary cause but they directly communicate this belief to only 42% of these patients and provide discharge instructions to 48%. Only 39% of respondents reported adequate hospital resources to ensure follow-up. Community-based providers reported more adequate follow-up for these patients than their academic center colleagues (46% vs. 34%; p = 0.015). Most providers (82%) indicated that they wanted to have referral resources available to a specific clinic for further outpatient evaluation. CONCLUSION: Emergency Department providers believe approximately 30% of patients seeking emergency care for chest pain at low risk for ACS have anxiety as a primary problem, yet fewer than half discuss this concern or provide information to help the patient manage anxiety. This highlights an opportunity for patient centered communication.

Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism: The iNOPE trial.

BACKGROUND: The study hypothesis is that administration of inhaled nitric oxide (NO) plus oxygen to subjects with submassive pulmonary embolism (PE) will improve right ventricular (RV) systolic function and reduce RV strain and necrosis, while improving patient dyspnea, more than treatment with oxygen alone. METHODS: This article describes the rationale and protocol for a registered (NCT01939301), nearly completed phase II, 3-center, randomized, double-blind, controlled trial. Eligible patients have pulmonary imaging-proven acute PE. Subjects must be normotensive, and have RV dysfunction on echocardiography or elevated troponin or brain natriuretic peptide and no fibrinolytics. Subjects receive NO plus oxygen or placebo for 24 hours (±3 hours) with blood sampling before and after treatment, and mandatory echocardiography and high-sensitivity troponin posttreatment to assess the composite primary end point. The sample size of N=78 was predicated on 30% more NO-treated patients having a normal high-sensitivity troponin (<14 pg/mL) and a normal RV on echocardiography at 24 hours with α=.05 and ß=.20. Safety was ensured by continuous spectrophotometric monitoring of percentage of methemoglobinemia and a predefined protocol to respond to emergent changes in condition. Blinding was ensured by identical tanks, software, and physical shielding of the device display and query of the clinical care team to assess blinding efficacy. RESULTS: We have enrolled 78 patients over a 31-month period. No patient has been withdrawn as a result of a safety concern, and no patient has had a serious adverse event related to NO. CONCLUSIONS: We present methods and a protocol for the first double-blinded, randomized trial of inhaled NO to treat PE.