Comparison of the New Adult Ventilator-Associated Event Criteria to the Centers for Disease Control and Prevention Pediatric Ventilator-Associated Pneumonia Definition (PNU2) in a Population of Pediatric Traumatic Brain Injury Patients.

OBJECTIVES: The new Centers for Disease Control and Prevention paradigm for ventilator-associated events is intended to simplify surveillance of infectious and noninfectious complications of mechanical ventilation in adults. We assessed the ventilator-associated events algorithm in pediatric patients. DESIGN: A retrospective observational cohort study. SETTING: This single-center study took place in a PICU at an urban academic medical facility. PATIENTS: Pediatric (ages 0-18 yr old) trauma patients with moderate-to-severe traumatic brain injury ventilated for greater than or equal to 2 days. MEASUREMENTS AND MAIN RESULTS: We assessed for pediatric ventilator-associated pneumonia (as defined by current Centers for Disease Control and Prevention PNU2 guidelines), adult ventilator-associated events, and an experimental ventilator-associated events definition modified for pediatric patients. We compared ventilator-associated events to ventilator-associated pneumonia to calculate the test characteristics. Thirty-nine of 119 patients (33%) developed ventilator-associated pneumonia. Sensitivity of the adult ventilator-associated condition definition was 23% (95% CI, 11-39%), which increased to 56% (95% CI, 40-72%) using the modified pediatric ventilator-associated pneumonia criterion. Specificity reached 100% for both original and modified pediatric probable ventilator-associated pneumonia using ventilator-associated events criteria. Children who developed ventilator-associated pneumonia or ventilator-associated condition had similar baseline characteristics: age, mechanism of injury, injury severity scores, and use of an intracranial pressure monitor. Diagnosis of ventilator-associated pneumonia and ventilator-associated condition portended similarly unfavorable outcomes: longer median duration of ventilation, ICU and hospital length of stay, and more discharges to rehabilitation, home health, or nursing care compared with patients with no pulmonary complication. CONCLUSIONS: Both current and modified ventilator-associated events criteria have poor sensitivity but good specificity in identifying pediatric ventilator-associated pneumonia. Despite poor sensitivity, the high specificity of the ventilator-associated events diagnoses does provide a useful and objective metric for interinstitution ICU comparison. Ventilator-associated pneumonia and ventilator-associated condition were both associated with excess morbidity in pediatric traumatic brain injury patients.

Identifying predictors and determining mortality rates of septic cardiomyopathy and sepsis-related cardiogenic shock: A retrospective, observational study.

INTRODUCTION: Septic shock is a severe form of sepsis that has a high mortality rate, and a substantial proportion of these patients will develop cardiac dysfunction, often termed septic cardiomyopathy (SCM). Some SCM patients may develop frank cardiac failure, termed sepsis-related cardiogenic shock (SeRCS). Little is known of SeRCS. This study describes baseline characteristics of patients with SCM and SeRCS compared to patients with septic shock without cardiac dysfunction. We compare clinical outcomes among SCM, SeRCS, and septic shock, and identify risk factors for the development of SCM and SeRCS. METHODS: Septic patients admitted to the ICU with an echocardiogram obtained within 72 hours were included. Left ventricular ejection fraction of ≤55% was used to define SCM, and cardiac index ≤2.1 L/min/m2 among patients with SCM defined SeRCS. Machine learning was used to identify risk factors for development of SCM and SeRCS. Logistic regression was used to compare mortality among groups. RESULTS: Among 1229 patients, 977 patients had septic shock without cardiac dysfunction, 207 had SCM, and 45 had SeRCS. In patients with septic shock, the strongest predictor for developing SCM and SeRCs was a prior history of cardiac dysfunction. Mortality did not significantly differ among the three groups. CONCLUSIONS: SCM and SeRCS affect a minority of patients with septic shock, disproportionately affecting individuals with a history of cardiac disease. We did not identify a mortality difference associated with SCM or SeRCS. Additional work is needed to define further subtypes and treatment options for this patient population.

The association between pulmonary artery enlargement and mortality in an Emergency Department population undergoing computed tomography pulmonary angiography.

Findings of an enlarged pulmonary artery diameter (PAd) and increased pulmonary artery to ascending aorta ratio (PA:AA) on contrast-enhanced computed tomography pulmonary angiography (CTPA) are associated with increased mortality in particular groups of patients with cardiopulmonary disease. However, the frequency and prognostic significance of these incidental findings has not been studied in unselected patients evaluated in the Emergency Department (ED). This study aims to determine the prevalence and associated prognosis of enlarged pulmonary artery measurements in an ED cohort. We measured PA and AA diameters on 990 CTPA studies performed in the ED. An enlarged PA diameter was defined as >27 mm in females and >29 mm in males, while an increased PA:AA was defined as >0.9. Poisson regression was performed to calculate prevalence ratios for relevant comorbidities, and multivariable Cox regression was performed to calculate hazard ratios (HR) for mortality of patients with enlarged pulmonary artery measurements. An enlarged PAd was observed in 27.9% of 990 patients and was more commonly observed in older patients and in patients with obesity or heart failure. Conversely, PA:AA was increased in 34.2% of subjects, and was more common in younger patients and those with peripheral vascular disease or obesity. After controlling for age, sex, and comorbidities, both enlarged PAd (HR 1.29, 95% CI 1.00-1.68, p = 0.05) and PA:AA (HR 1.70, 95% CI 1.31-2.22 p < 0.01) were independently associated with mortality. In sum, enlarged PAd and increased PA:AA are common in patients undergoing CTPAs in the ED setting and both are independently associated with mortality.

Early Serial Echocardiographic and Ultrasonographic Findings in Critically Ill Patients With COVID-19.

Background: Cardiac function of critically ill patients with COVID-19 generally has been reported from clinically obtained data. Echocardiographic deformation imaging can identify ventricular dysfunction missed by traditional echocardiographic assessment. Research Question: What is the prevalence of ventricular dysfunction and what are its implications for the natural history of critical COVID-19? Study Design and Methods: This is a multicenter prospective cohort of critically ill patients with COVID-19. We performed serial echocardiography and lower extremity vascular ultrasound on hospitalization days 1, 3, and 8. We defined left ventricular (LV) dysfunction as the absolute value of longitudinal strain of < 17% or left ventricle ejection fraction (LVEF) of < 50%. Primary clinical outcome was inpatient survival. Results: We enrolled 110 patients. Thirty-nine (35.5%) died before hospital discharge. LV dysfunction was present at admission in 38 patients (34.5%) and in 21 patients (36.2%) on day 8 (P = .59). Median baseline LVEF was 62% (interquartile range [IQR], 52%-69%), whereas median absolute value of baseline LV strain was 16% (IQR, 14%-19%). Survivors and nonsurvivors did not differ statistically significantly with respect to day 1 LV strain (17.9% vs 14.4%; P = .12) or day 1 LVEF (60.5% vs 65%; P = .06). Nonsurvivors showed worse day 1 right ventricle (RV) strain than survivors (16.3% vs 21.2%; P = .04). Interpretation: Among patients with critical COVID-19, LV and RV dysfunction is common, frequently identified only through deformation imaging, and early (day 1) RV dysfunction may be associated with clinical outcome.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

Analysis of family histories suggests shared genetic risk for chronic thromboembolic pulmonary hypertension and venous thromboembolism.

Chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (PE) are related phenotypes, however, previous reports have suggested that genetic risk factors for CTEPH and PE differ. Here we report that a family history of VTE is equally frequent in individuals with CTEPH and PE, suggesting that shared genetic variants may influence risk of both phenotypes. We also provide the first estimate of the frequency of familial CTEPH, which we identified in 2.2% of CTEPH patients in our cohort.

Frequency of Thrombotic Risk Factors in Patients with Chronic Thromboembolic Pulmonary Hypertension and Acute Pulmonary Embolism: A Case-Control Study.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious complication of acute pulmonary embolism (PE) which remains underdiagnosed. A better understanding of risk factors for CTEPH would improve our ability to predict which PE survivors are at risk. Several medical conditions-including malignancy, splenectomy, thyroid hormone supplementation, the presence of an intravascular device, inflammatory bowel disease, osteomyelitis, and non-O blood group-have been associated with increased risk of CTEPH, primarily in studies comparing patients with CTEPH to individuals with non-thrombotic conditions. Because many of these conditions increase thrombosis risk, it remains unclear whether their association with CTEPH reflects a general effect on thrombosis risk, or a specific effect on the risk of developing CTEPH as an outcome of thrombosis. We performed a case-control study comparing the frequencies of these conditions in patients with CTEPH versus patients with acute PE who did not develop CTEPH. The conditions studied were equally frequent in the CTEPH and PE cohorts, although there was a trend towards an increased frequency of splenectomy and non-O blood group among the CTEPH cohort. Thus, other than the possible exceptions of splenectomy and non-O blood group, the investigated medical conditions do not appear likely to increase the risk of CTEPH as an outcome of acute PE, and thus are unlikely to be useful in predicting CTEPH risk among PE survivors.

Right Ventricular Dysfunction in Early Sepsis and Septic Shock.

BACKGROUND: Sepsis is a frequently lethal state, commonly associated with left ventricular (LV) dysfunction. Right ventricular (RV) dysfunction in sepsis is less well understood. RESEARCH QUESTION: In septic patients, how common is RV dysfunction, and is it associated with worse outcomes? STUDY DESIGN AND METHODS: We measured echocardiographic parameters on critically ill patients with severe sepsis or septic shock within the first 24 hours of ICU admission. We defined RV dysfunction as fractional area change (FAC) less than 35% or tricuspid annulus systolic plane excursion (TAPSE) less than 1.6 cm. We defined LV systolic dysfunction as ejection fraction (EF) less than 45% or longitudinal strain greater than -19%. Using logistic regression, we assessed the relationship between 28-day mortality and presence of RV dysfunction and LV systolic dysfunction, controlling for receipt of vasopressors, receipt of fluid, mechanical ventilation, and the acute physiology and chronic health evaluation (APACHE II) score. RESULTS: We studied 393 patients. RV and LV dysfunction were common (48% and 63%, respectively). Mean echocardiographic values were: RV end-diastolic area, 22.4 ± 7.0 cm2; RV end-systolic area, 14.2 ± 6.0 cm2; RV FAC, 38 ± 11%; TAPSE, 1.8 ± .06 cm; RV longitudinal strain, -15.3 ± 6.5%; LV EF, 60% ± 14%; LV longitudinal strain, -16.5% ± 6.0%. Patients with RV dysfunction had higher 28-day mortality (31% vs 16%, P = .001). In our multivariable regression model, RV dysfunction was associated with increased mortality (OR, 3.4; CI, 1.7-6.8; P = .001), and LV systolic dysfunction was not (OR, 0.63; CI, 0.3 -1.2; P = .32) INTERPRETATION: Right ventricular dysfunction is present in nearly half of studied septic patients and is associated with over threefold higher 28-day mortality.

At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension.

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.

Clinical, Bronchoscopic, and Imaging Findings of e-Cigarette, or Vaping, Product Use-Associated Lung Injury Among Patients Treated at an Academic Medical Center.

Importance: e-Cigarette, or vaping, product use-associated lung injury (EVALI) has caused more than 2800 illnesses and 68 deaths in the United States. Better characterization of this novel illness is needed to inform diagnosis and management. Objective: To describe the clinical features, bronchoscopic findings, imaging patterns, and outcomes of EVALI. Design, Setting, and Participants: This case series of 31 adult patients diagnosed with EVALI between June 24 and December 10, 2019, took place at an academic medical center in Salt Lake City, Utah. Exposures: e-Cigarette use, also known as vaping. Main Outcomes and Measures: Symptoms, laboratory findings, bronchoscopic results, imaging patterns, and clinical outcomes. Results: Data from 31 patients (median [interquartile range] age, 24 [21-31] years) were included in the study. Patients were primarily men (24 [77%]) and White individuals (27 [87%]) who used e-cigarette products containing tetrahydrocannabinol (THC) (29 [94%]). Patients presented with respiratory (30 [97%]), constitutional (28 [90%]), and gastrointestinal (28 [90%]) symptoms. Serum inflammatory markers were elevated in all patients. Bronchoscopy was performed in 23 of 28 inpatients (82%) and bronchoalveolar lavage (BAL) revealed the presence of lipid-laden macrophages (LLMs) in 22 of 24 cases (91%). BAL samples tested positive for Pneumocystis jirovecii (3 patients [13%]), rhinovirus (2 patients [8%]), human metapneumovirus and Aspergillus (1 patient each [4%]); all except human metapneumovirus were determined to be false-positives or clinically inconsequential. The exclusive or dominant computed tomography (CT) pattern was organizing pneumonia in 23 of 26 cases (89%). Patients received antibiotics (26 [84%]) and corticosteroids (24 [77%]), and all survived; 20 patients (65%) seen in follow-up showed marked improvement, but residual symptoms (13 [65%]), radiographic opacities (8 [40%]), and abnormal pulmonary function tests (8 of 18 [44%]) were common. Conclusions and Relevance: In this case series, patients with EVALI characteristically presented with a flu-like illness with elevated inflammatory markers, LLMs on BAL samples, and an organizing pneumonia pattern on CT imaging. Bronchoscopic testing for infection had a high incidence of false-positive results. Patients had substantial residual abnormal results at early follow-up. These data suggest a limited role for bronchoscopy in typical presentations of EVALI without risk factors for alternative diagnoses and the need for careful longitudinal follow-up.

Acute vasodilator testing: An opportunity to advance the precision care of pulmonary hypertension.

The pulmonary arterial pressure of a child with severe pulmonary arterial hypertension immediately normalized while breathing nitric oxide during heart catheterization at 8 years of age. Her acute pulmonary vascular response to nitric oxide has persisted throughout her life. Her acute response to other medications has been similar to her long-term response to medications in the same class. Acute vasodilator testing with inhaled nitric oxide and other medications may be an opportunity to refine study design and advance precision care for patients with pulmonary hypertension.

Pathophysiology, incidence, management, and consequences of cardiac arrhythmia in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Arrhythmias are increasingly recognized as serious, end-stage complications of pre-capillary pulmonary hypertension, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Although arrhythmias contribute to symptoms, morbidity, in-hospital mortality, and possibly sudden death in PAH/CTEPH, there remains a paucity of epidemiologic, pathophysiologic, and outcome data to guide management of these patients. This review summarizes the most current evidence on the topic: from the molecular mechanisms driving arrhythmia in the hypertrophied or failing right heart, to the clinical aspects of epidemiology, diagnosis, and management.

The peripheral blood transcriptome in septic cardiomyopathy: an observational, pilot study.

BACKGROUND: Septic cardiomyopathy (SCM) is common in sepsis and associated with increased morbidity and mortality. Left ventricular global longitudinal strain (LV GLS), measured by speckle tracking echocardiography, allows improved identification of impaired cardiac contractility. The peripheral blood transcriptome may be an important window into SCM pathophysiology. We therefore studied the peripheral blood transcriptome and LV GLS in a prospective cohort of patients with sepsis. RESULTS: In this single-center observational pilot study, we enrolled adult patients (age > 18) with sepsis within 48 h of admission to the ICU. SCM was defined as LV GLS > - 17% based on echocardiograms performed within 72 h of admission. We enrolled 27 patients, 24 of whom had high-quality RNA results; 18 (75%) of 24 had SCM. The group was 50% female and had a median (IQR) age of 59.5 (48.5-67.0) years and admission APACHE II score of 21.0 (16.0-32.3). Forty-six percent had septic shock. After filtering for low-expression and non-coding genes, 15,418 protein coding genes were expressed and 73 had significantly different expression between patients with vs. without SCM. In patients with SCM, 43 genes were upregulated and 30 were downregulated. Pathway analysis identified enrichment in type 1 interferon signaling (adjusted p < 10-5). CONCLUSIONS: In this hypothesis-generating study, SCM was associated with upregulation of genes in the type 1 interferon signaling pathway. Interferons are cytokines that stimulate the innate and adaptive immune response and are implicated in the early proinflammatory and delayed immunosuppression phases of sepsis. While type 1 interferons have not been implicated previously in SCM, interferon therapy (for viral hepatitis and Kaposi sarcoma) has been associated with reversible cardiomyopathy, perhaps suggesting a role for interferon signaling in SCM.

Right-to-left ventricular end diastolic diameter ratio in severe sepsis and septic shock.

PURPOSE: The ratio of right ventricular end-diastolic diameter (EDD) to left ventricular EDD (RV/LV) is a measure predictive of right ventricular failure. We hypothesized that an increase in RV/LV would be associated with poor prognosis in severe sepsis and septic shock. MATERIALS AND METHODS: This is a retrospective chart review of patients with severe sepsis and septic shock admitted to a medical intensive care unit (ICU) at a single tertiary care hospital. Patients were identified by ICD-9 codes: 995.92 for severe sepsis and 785.52 for septic shock; and had to have an echocardiogram within 48 h of ICU admission. Increased RV/LV was defined as RV/LV ≥ 0.9. Left and right-sided chamber dimensions were measured according to American Society of Echocardiography guidelines. RESULTS: We included 146 consecutive ICU patients admitted with septic shock (72) or severe sepsis (74). There was no significant difference in ICU mortality in patients with RV/LV ≥ 0.9 versus RV/LV < 0.9 (p = .49). CONCLUSIONS: An increased RV/LV does not predict mortality in severe sepsis or septic shock.

Where do we go from here? Reappraising the data on anticoagulation in pulmonary arterial hypertension.

The use of anticoagulation as part of the treatment regimen in pulmonary arterial hypertension (PAH) remains a topic of debate. A recently published analysis of anticoagulation use in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) study offers conflicting conclusions regarding the benefit of this therapeutic strategy. There remains no robust randomized trial in PAH weighing the risks versus benefits of including anticoagulation in treatment regimens, leaving clinicians to surmise value in individual patients. Reexamination of available data may help to provide guidance on this controversial topic in the absence of future dedicated investigations.

Pulmonary arterial hypertension in primary amyloidosis.

Amyloidosis involves extravascular deposition of fibrillar proteins within tissues and organs. Primary light chain amyloidosis represents the most common form of systemic amyloidosis involving deposition of monoclonal immunoglobulin light chains. Although pulmonary amyloid deposition is common in primary amyloidosis, clinically significant pulmonary amyloidosis is uncommon, and elevated pulmonary artery pressures are rarely observed in the absence of other underlying etiologies for pulmonary hypertension, such as elevated filling pressures secondary to cardiac amyloid. In this case report, we present a patient with primary light chain amyloidosis and pulmonary arterial hypertension in the setting of pulmonary vascular and right ventricular myocardial amyloid deposition.