Abstract
Objectives
We aimed to evaluate the safety of the ultrasound contrast agent sulfur hexafluoride microbubbles in a large group of patients referred for routine contrast-enhanced ultrasound (CEUS).
Methods
A retrospective assessment was made of all patients that received sulfur hexafluoride microbubbles intravenously for CEUS at 24 centers between January 2006 and April 2019. Patient demographic details, examination type, and the dose of sulfur hexafluoride microbubbles administered were recorded with specific adverse events (AEs) documentation tools at each center. All AEs were recorded as serious or non-serious. Non-serious AEs were classified by intensity as mild, moderate, or severe according to ACR criteria. The frequencies of AEs across patient subgroups were compared using the chi-square test.
Results
A total of 463,434 examinations were evaluated. Overall, 157 AEs (153 [0.033%] non-serious; 4 [0.001%] serious) were reported after sulfur hexafluoride microbubbles administration, giving an AE frequency of 0.034% (157/463,434). Among the non-serious AEs, 66 (0.014%) were mild, 70 (0.015%) moderate, and 17 (0.004%) severe in intensity. The liver was the most common examination site, presenting an AE frequency of 0.026%. The highest AE frequency (0.092%) was for patients undergoing CEUS for vascular disease. There were no significant gender differences in either the total number or the severity of non-serious AEs (chi-square = 2.497, p = 0.287). The onset of AEs occurred within 30 min of sulfur hexafluoride microbubbles administration in 91% of cases.
Conclusion
The frequency of AEs to sulfur hexafluoride microbubbles is very low and severe reactions are rare, confirming that sulfur hexafluoride microbubbles are appropriate for routine CEUS applications.
Key Point
• The frequency of AEs to sulfur hexafluoride microbubbles is very low and severe reactions are rare.
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Abbreviations
- ACR:
-
American College of Radiology
- AEs:
-
adverse events
- CEUS:
-
Contrast-Enhanced Ultrasound
- UEAs:
-
Ultrasound Enhancing Agents
References
Pang EHT, Chan A, Ho SG, Harris AC (2018) Contrast-enhanced ultrasound of the liver: optimizing technique and clinical applications. AJR Am J Roentgenol 210:320–332
Choi JH, Seo DW (2017) Applications of contrast-enhanced harmonic endoscopic ultrasound on biliary, focal liver lesions and vascular diseases. Endosc Ultrasound 6:21–24
Wang DC, Jang HJ, Kim TK (2020) Characterization of indeterminate liver lesions on CT and MRI with contrast-enhanced ultrasound: what Is the evidence? AJR Am J Roentgenol 214:1295–1304
Wang JY, Feng SY, Yi AJ et al (2020) Comparison of contrast-enhanced ultrasound versus contrast-enhanced magnetic resonance imaging for the diagnosis of focal liver lesions using the liver imaging reporting and data system. Ultrasound Med Biol 46:1216–1223
Sidhu PS, Cantisani V, Dietrich CF et al (2018) The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: update 2017 (short version). Ultraschall Med 39:154–180
Piscaglia F, Wilson SR, Lyshchik A et al (2017) American College of Radiology Contrast Enhanced Ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS) for the diagnosis of hepatocellular carcinoma: a pictorial essay. Ultraschall Med 38:320–324
Greis C (2004) Technology overview: SonoVue (Bracco, Milan). Eur Radiol 14(Suppl 8):P11–P15
Hoffmann R, von Bardeleben S, ten Cate F et al (2005) Assessment of systolic left ventricular function: a multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography. Eur Heart J 26:607–616
Kamińska M, Sobkowicz B, Sawicki R et al (2015) Is real time contrast echocardiography useful for assessment of the right ventricular morphology, function, and perfusion? Echocardiography 32:1080–1086
van den Oord SC, ten Kate GL, Sijbrands EJ, van der Steen AF, Schinkel AF (2013) Effect of carotid plaque screening using contrast-enhanced ultrasound on cardiovascular risk stratification. Am J Cardiol 111:754–759
Sporea I, Badea R, Popescu A et al (2014) Contrast-enhanced ultrasound (CEUS) for the evaluation of focal liver lesions - a prospective multicenter study of its usefulness in clinical practice. Ultraschall Med 35:259–266
Wang YM, Fan W, Zhang K, Zhang L, Tan Z, Ma R (2016) Comparison of transducers with different frequencies in breast contrast-enhanced ultrasound (CEUS) using SonoVue as contrast agent. Br J Radiol 89:20151050
Piscaglia F, Bolondi L (2006) The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol 32:1369–1375
Tang C, Fang K, Guo Y et al (2017) Safety of sulfur hexafluoride microbubbles in sonography of abdominal and superficial organs: retrospective analysis of 30,222 Cases. J Ultrasound Med 36:531–538
ACR Committee on Drugs and Contrast Media (2017) ACR Manual on Contrast Media, Version 10.3. American College of Radiology. Available via https://www.acr.org/Clinical-Resources/Contrast-Manual. Accessed 31 May 2017
Jakobsen JA, Oyen R, Thomsen HS, Morcos SK (2005) Safety of ultrasound contrast agents. Eur Radiol 15:941–945
McDonald JS, Hunt CH, Kolbe AB et al (2019) Acute adverse events following gadolinium-based contrast agent administration: a single-center retrospective study of 281 945 injections. Radiology 292:620–627
Park SJ, Kang DY, Sohn KH et al (2018) Immediate mild reactions to CT with iodinated contrast media: strategy of contrast media readministration without corticosteroids. Radiology 288:710–716
Cha MJ, Kang DY, Lee W et al (2019) Hypersensitivity reactions to iodinated contrast media: a multicenter study of 196 081 patients. Radiology 293:117–124
Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K (1990) Adverse reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology 175:621–628
Behzadi AH, Zhao Y, Farooq Z, Prince MR (2018) Immediate allergic reactions to gadolinium-based contrast agents: a systematic review and meta-analysis. Radiology 286:471–482
Kanal E (2016) Gadolinium based contrast agents (GBCA): Safety overview after 3 decades of clinical experience. Magn Reson Imaging 34:1341–1345
McDonald RJ, Levine D, Weinreb J et al (2018) Gadolinium retention: a research roadmap from the 2018 NIH/ACR/RSNA workshop on gadolinium chelates. Radiology 289:517–534
Porter TR, Mulvagh SL, Abdelmoneim SS et al (2018) Clinical applications of ultrasonic enhancing agents in echocardiography: 2018 American Society of Echocardiography Guidelines Update. J Am Soc Echocardiogr 31:241–274
Porter TR, Abdelmoneim S, Belcik JT et al (2014) Guidelines for the cardiac sonographer in the performance of contrast echocardiography: a focused update from the American Society of Echocardiography. J Am Soc Echocardiogr 27:797–810
Funding
This study has received funding from the International Science & Technology Cooperation Program of China (No. 2015DFA30920), the National Natural Science Foundation of China (No. 81771856), and the Major Field Technical Innovation Program Project of the Affiliated Hospital of Army Medical University (No. SWH2016ZDCX4101).
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The scientific guarantor of this publication is Yanli Guo M.D. (Department of Ultrasound, Southwest Hospital, Army Medical University, Chongqing, 400038, China) and Wen He M.D. (Department of Ultrasound, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China).
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The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.
Statistics and biometry
No complex statistical methods were necessary for this paper.
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Written informed consent was waived by the Institutional Review Board.
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Institutional Review Board approval was obtained.
Study subjects or cohorts overlap
Some study subjects or cohorts have been previously reported in J Ultrasound Med. In the prior study, we reported on 30 222 patients included in the current study. The prior report evaluated the rate of adverse reactions. The current study expands on this by having a larger patient number and a multicenter study.
Methodology
• retrospective
• observational
• multicenter study
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Shang, Y., Xie, X., Luo, Y. et al. Safety findings after intravenous administration of sulfur hexafluoride microbubbles to 463,434 examinations at 24 centers. Eur Radiol 33, 988–995 (2023). https://doi.org/10.1007/s00330-022-09108-4
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DOI: https://doi.org/10.1007/s00330-022-09108-4