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      Safety Profile of Musculoskeletal Contrast-Enhanced Ultrasound with Sulfur Hexafluoride Contrast Agent

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          Muscle, bone and tendon regeneration depend on the microperfusion of the corresponding tissue which can be quantified with contrast-enhanced ultrasound (CEUS) using sulfur hexafluoride contrast agent (SonoVue ®). This study investigated the incidence of adverse events (AEs) in musculoskeletal patients and gives an overview of musculoskeletal CEUS applications.

          Patients and Methods

          Based on 13 studies in a standardized monocentric setting, a total of 2268 CEUS examinations in 764 patients were performed and AEs due to the administration of sulfur hexafluoride contrast agent were classified as either mild, moderate or severe.


          No fatal events occurred. AEs were reported in three cases, of which only one was classified as severe and two as mild. The total rate of all AEs was 0.13% and 0.04% for severe AEs.


          The present analysis confirms the safety of musculoskeletal CEUS using sulfur hexafluoride contrast agent with a lower rate of AEs than that reported for other contrast agents even in elderly patients with concomitant diseases.

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          Most cited references 30

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          The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Long Version).

          The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.
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            Ultrasound contrast agents: an overview.

            With the introduction of microbubble contrast agents, diagnostic ultrasound has entered a new era that allows the dynamic detection of tissue flow of both the macro and microvasculature. Underpinning this development is the fact that gases are compressible, and thus the microbubbles expand and contract in the alternating pressure waves of the ultrasound beam, while tissue is almost incompressible. Special software using multiple pulse sequences separates these signals from those of tissue and displays them as an overlay or on a split screen. This can be done at low acoustic pressures (MI<0.3) so that the microbubbles are not destroyed and scanning can continue in real time. The clinical roles of contrast enhanced ultrasound scanning are expanding rapidly. They are established in echocardiography to improve endocardial border detection and are being developed for myocardial perfusion. In radiology, the most important application is the liver, especially for focal disease. The approach parallels that of dynamic CT or MRI but ultrasound has the advantages of high spatial and temporal resolution. Thus, small lesions that can be indeterminate on CT can often be studied with ultrasound, and situations where the flow is very rapid (e.g., focal nodular hyperplasia where the first few seconds of arterial perfusion may be critical to making the diagnosis) are readily studied. Microbubbles linger in the extensive sinusoidal space of normal liver for several minutes whereas they wash out rapidly from metastases, which have a low vascular volume and thus appear as filling defects. The method has been shown to be as sensitive as three-phase CT. Microbubbles have clinical uses in many other applications where knowledge of the microcirculation is important (the macrocirculation can usually be assessed adequately using conventional Doppler though there are a few important situations where the signal boost given by microbubbles is useful, e.g., transcranial Doppler for evaluating vasospasm after subarachnoid haemorrhage). An important situation where demonstrating tissue devitalisation is important is in interstitial ablation of focal liver lesions: using microbubble contrast agents at the end of a procedure allows immediate evaluation of the adequacy of the ablation which can be extended if needed; this is much more convenient and cost-saving than moving the patient to CT and perhaps needing an additional ablation session at a later date. Similar considerations suggest that contrast-enhanced ultrasound might have a role in abdominal trauma: injury to the liver, spleen and kidneys can be assessed rapidly and repeatedly if necessary. Its role here alongside dynamic CT remains to be evaluated. Infarcts or ischaemia and regions of abnormal vascularity, especially in malignancies, in the kidneys and spleen seem to be useful and improved detection of the neovascularisation of ovarian carcinomas is promising. Similar benefits in the head-and-neck and in the skin while the demonstration of the neovascularisation of atheromatous plaques and of aggressive joint inflammation offer interesting potentials.
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              Incidence of immediate gadolinium contrast media reactions.

              Our objective was to determine the incidence of immediate adverse events for gadolinium-based contrast agents. All gadolinium-based contrast agent adverse events reported to radiology quality assurance committees were graded according to American College of Radiology criteria and divided by the total number of injections to determine incidence during the past 10 years. For each event, an age- and examination-matched control patient was identified to compare sex, weight, creatinine, eosinophil count, allergic history and gadolinium-based contrast agent dose differences. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database was analyzed to compare local experience to national trends. Abdominal MRI had the highest rates of adverse events, 0.013% compared with brain (0.0045%, p < 0.001) or spine (0.0034%, p < 0.001). Adverse events were more likely in women, with a female to male ratio of 3.3, and in patients with history of prior allergic reactions (p < 0.001). Immediate adverse events rates were 0.2, 0.5, 1.2, and 3.3 per 1,000 injections for gadodiamide, gadopentetate dimeglumine, gadobenate dimeglumine, and gadoteridol, respectively. Gadobenate dimeglumine had more severe patient reactions, including three patients who arrested (defined as the patient becoming unresponsive and the code team being called), one of whom died. From 2004 to 2009, the FDA received reports on 40 gadolinium-based contrast agent U.S. deaths unrelated to nephrogenic systemic fibrosis, with an incidence per million doses of 0.15, 0.19, 0.97, 2.7, and 0.7 for gadodiamide, gadoversetimide, gadopentetate dimeglumine, gadobenate dimeglumine, and gadoteridol, respectively. This limited retrospective analysis shows that gadolinium-based contrast agents are very safe, with only rare reports of death, and raises the possibility that nonionic linear gadolinium-based contrast agents and gadopentetate dimeglumine may have fewer severe immediate adverse events compared with gadobenate dimeglumine.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                14 April 2020
                : 16
                : 269-280
                [1 ]Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Ultrasound Center, HTRG - Heidelberg Trauma Research Group, Heidelberg University Hospital , Heidelberg 69118, Germany
                [2 ]Institute of Diagnostic and Interventional Radiology, Pediatric Radiology and Neuroradiology, University Medical Center Rostock , Rostock 18057, Germany
                Author notes
                Correspondence: Julian Doll Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Ultrasound Center HTRG – Heidelberg Trauma Research Group Heidelberg University Hospital , Schlierbacher Landstrasse 200a, Heidelberg69118, GermanyTel +49 6221 5636388Fax +49 6221 5629213 Email julian.doll@med.uni-heidelberg.de

                These authors contributed equally to this work

                © 2020 Fischer et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 3, Tables: 5, References: 37, Pages: 12
                Original Research


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