Contrast-enhanced ultrasound detects changes in microvascular blood flow in adults with sickle cell disease

Jonathan R Lindner,Todd Belcik,Joshua J Field,Nancy J Wandersee,Leanne M Harmann,Joel Linden,Maneka Puligandla,Matthew S Karafin,Michael Widlansky,Donna Neuberg,Wei-Ning Lee

doi:10.1371/journal.pone.0218783

Abstract

In patients with sickle cell disease (SCD), poor outcome measures compromise the potential success of clinical trials. Contrast-enhanced ultrasound (CEUS) is a technique that can non-invasively quantify deep tissue microvascular blood flow. We tested the hypothesis that CEUS of forearm skeletal muscle could be used to: 1) assess microvascular abnormalities that occur during vaso-occlusive crisis; and 2) test new therapies for SCD that are targeted to improving the status of the microcirculation. We performed a prospective study, CEUS perfusion imaging of resting forearm muscle was performed in adults with SCD: 1) during and after a pain episode, and 2) before, during, and after a 24-hour infusion of the investigative agent, regadenoson, an adenosine A2A agonist. CEUS destruction-replenishment time-intensity data were analyzed to measure microvascular blood flow, as well as its components, microvascular blood volume and flux rate. Serial CEUS measurements were obtained in 32 adults with SCD. For the studies during crisis, there was a 30% reduction in microvascular blood flow compared to steady-state (p = 0.031), a reduction that was largely due to microvascular flux rate. For the regadenoson group, a non-significant 25% increase in flux rate and 9% increase in microvascular blood flow compared to baseline were detected during infusion. In a study of adults with SCD, CEUS detected changes in microvascular blood flow associated with vaso-occlusive crises. No changes were found during an infusion of the adenosine A2A agonist, regadenoson. This study provides preliminary evidence that CEUS could detect blood flow changes consistent with SCD physiology.

Highlights

Sickle cell disease (SCD) is a group of inherited hemoglobinopathies that are characterized by red cell sickling
We extend findings by members of our research team that previously demonstrated the ability of CEUS to detect an increase in microvascular blood flow (MBF) between SCD patients treated with hydroxyurea compared to those without hydroxyurea [16]
We evaluated the ability of CEUS to detect changes in MBF in forearm skeletal muscle: 1) in SCD patients during vaso-occlusive crisis and after recovery, as a proof-of-concept to demonstrate the ability to detect dynamic perfusion abnormalities; and 2) sequentially in subjects undergoing an infusion of regadenoson, an adenosine A2A agonist that has been investigated as a therapy for SCD

Summary

Introduction

Sickle cell disease (SCD) is a group of inherited hemoglobinopathies that are characterized by red cell sickling. Vaso-occlusion in the bone marrow and lungs, the most commonly affected sites, produce episodes of pain and acute chest syndrome, which are leading causes of death [2,3,4]. These acute complications, as well as chronic end-organ damage, reduce the lifespan of patients with SCD to about 50 years [2]. The complex pathophysiology of the disease itself is the most significant barrier to the development of new therapies, another critical impediment is reliable outcome measures Clinical outcome measures, such as frequency or duration of pain crises, or amount of opioids used, are subjective and vary from patient to patient [4,9,12]. Imaging MBF in the bone marrow, the main site of vaso-occlusion, is challenging and there is no blood flow measure that is commonly used in SCD clinical trials

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