The Functional Characterization of Venous Thromboembolic Disease (FUVID) study: rationale, design, and methods of a prospective, observational, multicenter study to evaluate mechanisms of exercise intolerance and dyspnea following pediatric pulmonary embolism

Abstract

Background: To date, the focus of investigation in pediatric pulmonary embolism (PE) has been on PE recurrence and anticoagulant-related bleeding. While highly relevant, these outcomes do not fully capture functional limitations and the psychological impact that comprises post-PE syndrome.

Objectives: The primary objective of the Functional Characterization of Venous Thromboembolic Disease (FUVID) study was to investigate mechanisms of post-PE syndrome in children.

Methods: The ongoing FUVID study will prospectively enroll and systematically follow, over 12 months and with standardized pulmonary, cardiac, and muscle testing, a multicenter prospective cohort of 80 pediatric patients with first-episode PE without comorbidities. FUVID has 2 coprimary outcomes: exercise intolerance and exertional dyspnea. Exercise intolerance will be defined objectively as a percent predicted peak oxygen uptake based on ideal body weight or milliliters per minute per kilogram of lean body mass during cardiopulmonary exercise testing. Dyspnea will be objectively quantified using Borg questionnaires and defined as a mean difference of >1 at the end of the warm-up and submaximal work rates during exercise testing, simulating conditions during daily life that induce dyspnea. Pertinent secondary outcomes include anxiety, depression, and quality of life.

Conclusion: The FUVID study will investigate the relationship between symptoms (exercise intolerance and exertional dyspnea) and multiple mechanisms-hemodynamic, ventilatory, or peripheral/muscle-within the same patient at rest, submaximal exercise (simulating activities of daily living), and maximal exercise using objective measures. It will provide new evidence for selecting patients for long-term follow-up, including psychological sequelae, after PE, the modalities this follow-up should include, and the findings interpreted as indicating functional limitations after PE.

Keywords: children; pediatrics; post–pulmonary embolism syndrome; pulmonary embolism; venous thromboembolism.

Figure 1

The central hypothesis being addressed in the Functional Characterization of Venous Thromboembolic Disease study. Functional Characterization of Venous Thromboembolic Disease study’s overarching hypothesis is that central (cardiac and pulmonary) and peripheral (skeletal muscle) aberrations are associated with exercise intolerance and exertional dyspnea after pulmonary embolism.

Figure 2

Functional Characterization of Venous Thromboembolic Disease study timeline. Visit 1 procedures are completed locally at enrollment sites. Pulmonary embolism (PE) participants travel to the University of Texas Southwestern (UTSW) for visits 2 and 3 research assessments. IRB, institutional review board.

Figure 3

Functional Characterization of Venous Thromboembolic Disease (FUVID) study schema and oversight. Participants are recruited and enrolled nationally at 32 individual centers for pulmonary embolism diagnosis (visit 1). The University of Texas Southwestern multicenter study core serves as the data and clinical coordinating center and coordinates travel to the University of Texas Southwestern at 3 and 12 months after diagnosis, which spans 3 days each, as depicted at visits 2 and 3. cMR, cardiac magnetic resonance imagining; MR, magnetic resonance imagining; PA, pulmonary artery; PRO, patient-reported outcomes; RV, right ventricle.

Figure 4

The study protocol, order of testing, and measurements. ADP, adenosine diphosphate; ASL, arterial spin labeling; ATP, adenosine triphosphate; ATS, American Thoracic Society; BP, blood pressure; CPET, cardiopulmonary exercise testing; DEXA, dual-energy X-ray absorptiometry DLCO, diffusion capacity of carbon monoxide; EKG, electrocardiogram; FEV1, forced expiratory volume; FRC, functional residual capacity; FVC, forced vital capacity; HR, heart rate; MR, magnetic resonance; PA, pulmonary artery; PCr, phosphocreatine; Pi, inorganic phosphate; Q max, maximal mitochondrial oxidative capacity; RV, right ventricle; t 1/2, half-life; TLC, total lung volume; VE, ventilation; VCO2, carbon diaoxide output; VO2, peak oxygen consumption.