CEUS with SF₆ Microbubbles — Patient Qualification, Safety and Clinical Applications

Korczyk R 11.09.2026

Abstract

Contrast-enhanced ultrasound (CEUS) using intravenous microbubbles containing sulfur hexafluoride (SF₆) is a dynamic method for assessing tissue perfusion and vascularity in real time. In Europe, the most commonly used agent is SonoVue; in the United States, the corresponding product name is Lumason. The current Summary of Product Characteristics (SmPC) and the formulation available in the relevant market should always be verified.

CEUS provides the greatest value when it addresses a precise clinical question that cannot be sufficiently resolved by B-mode or Doppler ultrasound. Its most common applications include the characterization of focal liver lesions, assessment of perfusion, differentiation of cystic and solid lesions, and evaluation of treatment response. CEUS does not automatically replace computed tomography or magnetic resonance imaging, particularly when complete staging, surgical planning, or whole-body assessment is required.

Available data indicate a very favorable safety profile. In large cohorts, adverse events occurred in fewer than 0.1% of patients, while severe reactions were exceptional. This does not eliminate the possibility of anaphylaxis. Safe practice therefore depends on appropriate patient selection, knowledge of the specific product, separate informed consent, direct observation after injection, and readiness to treat anaphylaxis and cardiac arrest.

Keywords

CEUS; sulfur hexafluoride; SF₆; SonoVue; Lumason; microbubbles; safety; anaphylaxis; liver; perfusion.

1. Introduction

CEUS involves the intravenous administration of gas-filled microbubbles and real-time assessment of their behavior within the ultrasound field. Unlike conventional ultrasound, CEUS enables evaluation of contrast arrival, distribution, and washout in real time. The method can assess both macrocirculation and microperfusion patterns without exposure to ionizing radiation [1,2].

In European clinical practice, the most commonly used agent is SonoVue, which contains SF₆ within microbubbles stabilized by a lipid shell. The name Lumason is used primarily in the United States. However, CEUS agents should not be considered interchangeable: their gas, shell, excipients, approved indications, and warnings may differ.

CEUS should be regarded as a question-oriented examination. The mere detection of a lesion on B-mode imaging is not, by itself, sufficient justification for contrast administration. The indication should address whether the CEUS result is expected to change the diagnosis, further diagnostic pathway, treatment eligibility, or assessment of treatment response.

2. Physical and pharmacological principles

Microbubbles used in CEUS typically have a diameter of approximately 1–7 μm, making them comparable in size to erythrocytes or smaller. They therefore remain essentially within the intravascular space and can pass through the microcirculation without typical distribution into the interstitial space [2].

When exposed to ultrasound waves, microbubbles oscillate and generate a strong nonlinear harmonic signal. Resonance frequency is not a single fixed property of all microbubbles; it depends, among other factors, on bubble diameter, gas type, shell characteristics, emitted ultrasound frequency, and acoustic parameters. A range of approximately 2–15 MHz may be a useful educational approximation for microbubbles used in diagnostic ultrasound, but it should not be treated as a universal, unchanging value for every product.

SF₆ is eliminated primarily through the lungs. This distinguishes microbubbles from iodinated contrast agents used in CT and from most contrast agents used in MRI. The favorable renal profile means that chronic kidney disease or reduced glomerular filtration are not automatic contraindications to CEUS [2,3]. This does not remove the need for clinical qualification: the choice of examination still depends on the clinical question, the patient’s condition, the current product information, and local regulations.

In practice, the contrast-enhanced phase usually lasts several minutes to approximately 10–15 minutes. The entire procedure, including preparation, intravenous access, administration, and observation, may take approximately 5–30 minutes, depending on the organ, indication, number of lesions, and need for repeat administration.

3. Contrast-agent generations and terminology

The historical division of contrast agents into generations is educationally useful but is not completely uniform across the literature. First-generation agents, such as Echovist, were characterized by lower stability and a short duration of signal enhancement. Older agents with greater clinical utility included Levovist and Albunex. Contemporary agents, including SonoVue, provide greater microbubble stability, a stronger harmonic response, and real-time low-mechanical-index imaging.

It is important to distinguish between products belonging to different families. Sonazoid is a contemporary CEUS agent, but it is not an SF₆-containing product; its pharmacological properties and late-phase imaging result from a different formulation. Sonazoid should therefore not be used as an example of an SF₆ contrast agent, and safety or imaging data from SonoVue/Lumason should not be transferred to it without direct evidence.

4. Main clinical applications

4.1. Liver

The most common application of CEUS is the characterization of focal liver lesions. Analysis of the arterial, portal venous, and late phases can support differentiation between benign and malignant lesions, particularly in patients with cirrhosis, chronic liver disease, or another risk of hepatocellular carcinoma [1,2].

CEUS may help answer the following questions:

• Does the lesion show contrast enhancement?
• What is the enhancement pattern during the arterial phase?
• Is there contrast washout, when does it begin, and how pronounced is it?
• Does a cystic lesion contain an enhancing solid component, mural nodule, or vascularized septum?
• Is viable, vascularized tissue present after ablation, embolization, or another treatment?
• Does an indeterminate area on B-mode imaging represent a true perfusion abnormality?

For assessment after local treatment, CEUS may be useful as a follow-up examination; however, the result should be interpreted in the context of the baseline examination, treatment technique, and other imaging studies.

4.2. Extrahepatic applications

Depending on the experience of the laboratory, equipment availability, and local regulations, CEUS may support the assessment of lesions in the kidneys, spleen, pancreas, vessels, superficial tissues, musculoskeletal system, and pediatric patients [2,5–7].

Potential applications include assessment of renal perfusion, differentiation of cystic and solid lesions, evaluation of ischemia or trauma, analysis of vascularity in superficial lesions, procedural monitoring, and assessment of selected musculoskeletal lesions. The range of indications and regulatory status may differ between countries; in particular, pediatric and intravesical applications may have a different status from intravenous CEUS in adults.

4.3. Situations in which CEUS does not replace CT or MRI

CEUS may be insufficient when assessment of the entire anatomical region, disease extent, structural invasion, metastases, surgical planning, or complete cancer staging is required. Limitations may also include a deeply located lesion, severe obesity, bowel gas, an inadequate acoustic window, multifocal disease, or inability to obtain diagnostically reliable images.

5. Patient qualification

Qualification should address two parallel objectives: determining whether CEUS will answer the clinical question and identifying circumstances requiring increased caution.

Before the examination, information should be obtained regarding:

1. the indication and the expected impact of the result on management;
2. the location, size, and visibility of the lesion on baseline imaging;
3. previous ultrasound, CT, MRI, PET, or CEUS examinations;
4. any previous reaction to a contrast agent, including the product name, time to symptom onset, clinical features, and treatment;
5. severe hypersensitivity to PEG/macrogol or another component of the product;
6. the current cardiovascular and respiratory condition;
7. pregnancy, breastfeeding, and pediatric age;
8. the ability to provide direct observation and emergency treatment.

The phrase “contrast allergy” is imprecise. It may refer to mild nonspecific symptoms such as nausea or warmth, a vasovagal reaction, a rash, or a genuine immediate hypersensitivity reaction. These situations have different implications for repeat qualification.

5.1. Renal impairment

Chronic kidney disease should not automatically be regarded as a contraindication to SF₆ CEUS. The pharmacological properties of microbubbles make the method attractive in patients for whom iodinated or gadolinium-based contrast administration is problematic [2,3]. However, a favorable renal safety profile does not resolve all diagnostic issues: CT or MRI may still be necessary in selected cases.

5.2. Cardiac disease, pulmonary disease, and hemodynamic instability

In patients with stable chronic cardiopulmonary disease, the decision to perform CEUS should be based on an individualized assessment of benefits and risks. Particular caution is required in patients with acute heart failure, hemodynamic instability, worsening hypoxia, severe respiratory failure, shock, or a need for intensive inotropic treatment.

Stable heart failure or pulmonary hypertension should not automatically be considered an absolute contraindication. However, a planned examination should be deferred when stabilization of a life-threatening condition is the priority. Data concerning critically ill patients suggest good tolerance in many circumstances, but they are partly based on post-marketing data and do not replace individualized clinical judgment [3,4].

5.3. Children

Available pediatric data are generally reassuring but limited in size. In an intravenous study of patients younger than 18 years, no immediate adverse events were recorded [5]. Intravenous CEUS must be distinguished from voiding urosonography, in which the agent is administered intravesically. In a prospective observation of 531 children, no acute severe reactions were identified after intravesical administration, but these results cannot be directly extrapolated to intravenous CEUS [6].

5.4. Pregnancy and breastfeeding

Clinical data on intravenous SF₆ CEUS during pregnancy remain limited. The examination should be considered only when the expected diagnostic benefit is clinically important and cannot be obtained by a method that does not require contrast. The decision should be documented and based on the current SmPC for the specific product and local recommendations. Data relating to one product should not automatically be extrapolated to all contrast agents.

5.5. PEG/macrogol and excipients

Hypersensitivity may involve the active agent, the microbubble shell, or another excipient in the formulation. For some products and in certain markets, PEG/macrogol may be clinically relevant. The composition of the specific product should be checked in the current product information, because the presence of PEG cannot automatically be assumed for every SF₆-containing agent.

Cases of severe reactions after SonoVue have been described in which macrogol 4000 was suspected to contribute, including a case involving anaphylaxis and cardiac arrest [9]. This is an important clinical signal, but a single case cannot define the risk for all formulations and all patients. SF₆ gas itself should not automatically be considered the allergen.

6. Safety — clinical data

In a retrospective analysis of 49,100 patients who received Lumason/SonoVue, 43 adverse events were recorded, corresponding to 0.088% of patients. Mild, moderate, and severe reactions occurred in 0.047%, 0.026%, and 0.014% of patients, respectively; no deaths were reported in this cohort [10].

In an older large safety analysis of SonoVue including 23,188 examinations, 29 adverse events were reported, including two serious events, with no deaths. The reported frequency of serious adverse events was 0.0086% [2]. In another retrospective series of 34,478 cases, 40 reactions were reported, corresponding to approximately 0.12%; three cases were described as anaphylactic shock. However, the definitions and confirmation methods were not fully standardized [11].

These data should be interpreted in light of several limitations: retrospective study design, differences between patient-level and examination-level denominators, inconsistent severity definitions, possible under-reporting, and lack of complete adjudication of all reactions. Post-marketing data and passive reporting systems also include reports of anaphylaxis, hypotension, dyspnea, cardiac arrest, and death, but they lack a reliable exposure denominator and cannot establish incidence or definite causality [12].

7. Severe reactions and hypersensitivity

Severe hypersensitivity reactions, including anaphylaxis, are rare but represent the most important procedural risk. Case reports confirm the possibility of anaphylaxis, shock, and, in isolated situations, cardiac arrest after SonoVue/Lumason administration [3,8,9]. Case reports demonstrate that the event is possible but cannot determine its incidence.

Time to onset has practical importance. In the analysis of 49,100 patients, the mean time to onset of severe adverse events was 1.89 ± 1.21 minutes after injection. The mean time was longer for mild and moderate reactions, approximately 14.5 and 15.75 minutes, respectively [10]. The highest level of vigilance is therefore required immediately after administration, although observation should account for the possibility of later symptom onset.

Warning signs include generalized urticaria, rapidly progressive pruritus, swelling of the lips or tongue, dyspnea, wheezing, stridor, hypoxia, hypotension, pallor, sweating, syncope, chest pain, arrhythmia, sudden altered mental status, or loss of consciousness.

8. Organizational requirements for a safe CEUS laboratory

A CEUS laboratory should have:

• staff trained to recognize and treat anaphylaxis;
• access to oxygen, vital-sign monitoring, and equipment for airway management;
• an emergency kit, including adrenaline/epinephrine according to the local protocol;
• an effective method for calling the resuscitation team;
• a procedure for documenting the product name, dose, time of administration, and any reaction;
• the ability to observe the patient directly after injection;
• access to the current SmPC and a hypersensitivity-management procedure.

Before each administration, separate, explicit, informed, and voluntary consent should be obtained from the patient or legal representative in accordance with applicable law and the healthcare institution’s procedures. Consent to the ultrasound examination itself should not automatically be treated as consent to contrast administration.

9. Documentation and reporting of the examination

The CEUS report should allow the diagnostic reasoning to be reconstructed. It should include:

• lesion location and size on B-mode imaging;
• the name and dose of the contrast agent;
• image quality and technical limitations;
• the enhancement pattern during the arterial phase;
• findings during the portal venous and late phases;
• the presence, onset, and intensity of washout;
• the presence of viable tissue after treatment;
• the most likely diagnosis or a justified differential diagnosis;
• a recommendation for further diagnostic evaluation when the result is not conclusive;
• any adverse event, its time of onset, and treatment provided.

10. Practical conclusions

1. SF₆ microbubble CEUS is an intravascular perfusion-imaging method that is particularly useful for characterizing focal liver lesions and assessing treatment response.
2. The favorable renal profile of SF₆ does not mean that CEUS replaces CT or MRI in every clinical situation.
3. Qualification should be based on a specific clinical question, the patient’s current condition, the history of reactions to contrast agents, and the composition of the specific product.
4. In large cohorts, adverse events occurred in fewer than 1 in 1,000 patients, while severe reactions were exceptional [10,11].
5. Anaphylaxis is rare but possible and often begins within the first minutes after injection.
6. PEG/macrogol is relevant only when present in the specific formulation; reactions should not automatically be attributed to SF₆ gas.
7. Stable cardiac or pulmonary disease requires individualized assessment, whereas hemodynamic instability and active respiratory failure support postponement of a planned examination until stabilization.
8. A safe CEUS laboratory must be prepared for immediate recognition and treatment of anaphylaxis.

References:

1. Dietrich CF, Nolsøe CP, Barr RG, Berzigotti A, Burns PN, Cantisani V, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver—update 2020: WFUMB in cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med Biol. 2020;46(10):2579-2604. doi:10.1016/j.ultrasmedbio.2020.04.030. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8354100/
2. Piscaglia F, Bolondi L; Italian Society for Ultrasound in Medicine and Biology (SIUMB) Study Group on Ultrasound Contrast Agents. The safety of SonoVue in abdominal applications. Eur J Radiol. 2006;60(1):5-13. PMID:16965977. Available from: https://pubmed.ncbi.nlm.nih.gov/16965977/
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4. Piscaglia F, et al. Clinical safety of SonoVue, a new contrast agent for ultrasound imaging. Eur J Radiol. 2001. PMID:11224758. Available from: https://pubmed.ncbi.nlm.nih.gov/11224758/
5. Lerchbaumer MH, et al. Contrast-enhanced ultrasound using sulfur hexafluoride is safe in patients aged under 18 years. 2017. PMID:28173725. Available from: https://pubmed.ncbi.nlm.nih.gov/28173725/
6. Darge K, et al. Off-label-use of sulfur-hexafluoride in voiding urosonography for vesicoureteral reflux: a prospective two-centre survey on adverse events in children. Pediatr Radiol. 2017. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5296630/
7. Gorenoi V, et al. Safety profile of musculoskeletal contrast-enhanced ultrasound using sulfur hexafluoride microbubbles. Ther Clin Risk Manag. 2020;16:269-280. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7166060/
8. Anaphylaxis after SonoVue: a case report and a literature review. 2024. PMID:39274231. Available from: https://pubmed.ncbi.nlm.nih.gov/39274231/
9. Anaphylactic shock and cardiac arrest after intravenous injection of SonoVue. 2024. PMID:39613417; PMCID:PMC11605675. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11605675/
10. Liu YK, et al. Safety analysis of adverse events of ultrasound contrast agent Lumason/SonoVue in 49,100 patients. Ultrasound Med Biol. 2023. PMID:36357252. Available from: https://pubmed.ncbi.nlm.nih.gov/36357252/
11. Wang L, et al. Adverse reactions after the use of SonoVue contrast agent: characteristics and nursing care experience. Medicine (Baltimore). 2019. PMCID:PMC6946512. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6946512/
12. Patil A, et al. Safety of the contrast enhancement agent sulfur hexafluoride in endoscopic ultrasound: analysis of a US national adverse-event database. 2024/2025. PMID:40386454; PMCID:PMC12080674. Available from: https://pubmed.ncbi.nlm.nih.gov/40386454/

Methodological note: This is a narrative expert synthesis based on the provided lecture notes, guidelines, and selected publications. It is not a complete PRISMA systematic review. Before using it in a publication, hospital protocol, or educational material, verify the completeness of the bibliographic data, the current SmPC for the specific contrast agent, and applicable local regulations.