INTRODUCTION — Contrast echocardiography is a technique for improving echocardiographic resolution and providing real-time assessment of intracardiac blood flow. Agitated saline contrast provides contrast in the right heart and enables detection of right to left shunts. Opacification of the left ventricular (LV) cavity by contrast agents developed to traverse the pulmonary vasculature permits improved endocardial border detection . A 2018 update to the American Society of Echocardiography guidelines proposed ultrasound enhancing agents (UEAs) as an alternative name for echocardiographic contrast agents to help patients and providers distinguish these agents from other iodinated contrast agents and gadolinium .
The only US Food and Drug Administration (FDA)-approved indication for the use of UEAs in cardiac imaging is for LV opacification via an intravenous injection. There are many other off label uses of UEAs, including use during stress echocardiography, enhancement of Doppler signal, as well as assessing myocardial perfusion  and viability . Another off label use is intracoronary injection during alcohol septal ablation for hypertrophic cardiomyopathy patients .
The development and safety of microbubbles for echocardiographic contrast and the optimization of the echocardiographic settings for visualizing contrast will be reviewed here. The current and potential clinical applications of contrast echocardiography are discussed separately. (See "Contrast echocardiography: Clinical applications".)
MICROBUBBLE CONTRAST AGENTS
Mechanism of contrast — As sound travels from one medium to another, the change in density (known as acoustic impedance) at the interface causes the reflection of sound waves . The greater the difference in the media densities, the more echogenic the interface. Gas is an excellent contrast agent since it is 100,000 times less dense than blood.
Agitated saline contrast — Agitated saline solution administered via intravenous injection provides air microbubble contrast in the right heart. The air microbubbles are short-lived and diffuse into the lungs when traversing the pulmonary circulation. Therefore the microbubbles enter the left heart only in the presence of a right to left intracardiac or extracardiac (pulmonary arteriovenous) shunt. Saline microbubbles are therefore helpful in examining the right heart and identifying shunts. (See "Contrast echocardiography: Clinical applications", section on 'Agitated saline contrast' and "Patent foramen ovale", section on 'Ultrasound techniques'.)
Contrast agents for LV opacification — To allow left heart evaluation, an ideal contrast microbubble must be small and durable enough to traverse the pulmonary circulation to pass into the left heart from an intravenous injection. Improvements in contrast agents have resulted from the exploitation of knowledge concerning both the mechanisms of echogenicity and the impediments to transpulmonary passage.
Larger microbubble size enhances durability, which is proportional to the square of the bubble radius . However, a small bubble size (diameter ≤10 micrometers) is required for successful transpulmonary passage .
Contrast agents must meet the following requirements: safe, metabolically inert, long lasting, strong reflector of ultrasound, and small enough to pass through capillaries .
Surrounding the gas bubble in a durable shell enables adequate durability while keeping bubble size small enough to traverse the pulmonary circulation. A number of microbubble capsules have been investigated but produced bubbles that were too large (eg, indocyanine green dye) or too short-lived (eg, polysaccharide or gelatin-encapsulated air) to opacify the left heart . Further stabilization of the microbubble was achieved through the use of a 5 percent human albumin solution, which forms a thin shell of denatured albumin when sonicated ; this led to the development of Albunex as the first FDA-approved myocardial contrast agent. However, the clinical utility of Albunex was limited because microbubble air loss results in large decreases in echogenicity, although it causes only slight decreases in bubble diameter .
Further improvements in microbubble capsules have been incorporated into second-generation agents. Gas diffusion was decreased via the use of inert gases (eg, perfluorocarbons) to form the microbubbles. Improved bubble surface stability was attained through use of innovative colloidal suspensions or emulsions.
Second-generation contrast agents — There are three agents that are commercially available worldwide for cardiac ultrasound imaging :
●Perflutren lipid microspheres (Definity) – A phospholipid shell enclosing octafluoropropane gas (perflutren) [12,15]. This agent is FDA approved and is also available in Europe (known as Lumity), Canada, Australia, and in parts of Asia.
●Sulfur hexafluoride lipid microsphere (Lumason) – A phospholipid shell enclosing sulfur hexafluoride gas. This agent is FDA approved and is available in Canada, Europe, and some Latin American and Asian countries.
Agitated saline safety — Although reports of complications are scant, case reports suggest that agitated saline injection can rarely cause ischemic complications such as stroke or transient ischemic attack. One report compiled five cases of cerebral ischemic events (three ischemic strokes and two transient ischemic attacks) occurring immediately or within five minutes of agitated saline contrast study demonstrating a right-to-left shunt . Available data are not sufficient to estimate the incidence of such events, although such complications appear to be rare.
Second-generation contrast safety — The FDA approved perflutren protein type A (Optison) and perflutren lipid microspheres (Definity) for cardiac indications after clinical trial experience, including detailed safety evaluations [14,15]. Sulfur hexafluoride lipid microsphere (Lumason) was approved by the FDA for cardiac imaging in adults in 2014 and, subsequently, was approved for use in cardiac imaging in pediatric patients in 2019.
Initial postmarketing approval surveillance over five years and in greater than one million patients demonstrated no medically significant risks other than rare allergic events at a rate of approximately 1 per 10,000 [1,2].
The rare severe allergic reactions are thought to be a variant of the type I hypersensitivity reaction known as Complement Activation Related Pseudo Allergy (CARPA). These are not immunoglobulin E (IgE)-mediated. There is a higher rate of reaction in women and atopic individuals. CARPA reactions may be mild to moderate (eg, urticaria, pruritus, tingling, sneezing) or severe (eg, wheezing, angioedema, cyanosis, anaphylactic shock) [17,18]. All personnel utilizing these agents should be trained in recognizing and treating these reactions.
Central nervous system reactions have also rarely been reported and may or may not be associated with hypersensitivity reactions. Reported adverse events are generally infrequent and mild and may include headache, weakness, fatigue, palpitations, nausea, dizziness, dry mouth, altered sense of smell or taste, dyspnea, urticaria, pruritus, back pain, chest pain, or rash.
Definity, Optison, and Lumason are not recommended for use at mechanical indices greater than 0.8. A high ultrasound mechanical index value may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. In addition, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias [19-21].
In 2011, the FDA removed the previously mandated 30-minute monitoring period after contrast administration in patients with pulmonary hypertension or unstable cardiopulmonary conditions. The revised labeling of all contrast agents now lists an acknowledgment that serious cardiopulmonary reactions after contrast administration are rare and typically occur within 30 minutes. All personnel utilizing these agents should be trained in recognizing these reactions, and resuscitative equipment should be readily available for use by trained individuals.
In late 2016 and early 2017, the FDA removed the contraindication for administration of perflutren protein type A (Optison), sulfur hexafluoride lipid microsphere (Lumason), and perflutren lipid microspheres (Definity) in patients with intracardiac shunts. This was based on a number of studies that demonstrated the safety of these agents in patients with known shunts .
In late 2021, the FDA removed the contraindication for hypersensitivity to blood and blood products from the labeling for Optison [20,23].
In 2021, MedWatch, the FDA's product safety reporting system, announced that there were 11 cases of anaphylaxis, including two deaths, in patients with a known polyethylene glycol (PEG) hypersensitivity who had received a lipid-based UEA. This led to updated labeling of Definity and Lumason to list PEG allergy or hypersensitivity as a contraindication to the administration of their agents in those patients who have a known allergy or hypersensitivity to PEG, also known as macrogol or polyoxyethylene. Many products contain PEG, such as some laxatives, bowel preparations used prior to colonoscopy, cosmetics, mRNA vaccines, and other household products. The American Society of Echocardiography (ASE) recently published an expert consensus statement acknowledging this issue, and recommended that sonographers inquire about PEG allergy prior to the administration of lipid-based UEAs . The overall incidence of adverse reactions (including PEG hypersensitivity) to UEAs is low (1:10,000), and no additional changes to lab protocols were recommended.
Contrast agents can be used in LV assist devices (LVADs)  and extracorporeal membrane oxygenator (ECMO), though care must be taken to avoid ECMO circuit shutdown due to bubble sensing safety systems [26,27].
The current contraindications to the use of UEAs include:
●For perflutren lipid microspheres (Definity), known or suspected hypersensitivity to perflutren or PEG.
●For perflutren protein type A (Optison), known or suspected hypersensitivity to perflutren, blood, blood products, or albumin.
●For sulfur hexafluoride lipid microsphere (Lumason), known hypersensitivity to sulfur hexafluoride, the inactive components of the contrast agent, or PEG.
Limited data suggest that second-generation contrast agents also appear safe for off-label use in children and adolescents [28,29]. In a single-center retrospective review of 113 patients between ages 5 and 21 years (mean age 17.8 years) who received perflutren lipid microspheres (Definity) between 2005 and 2014, 13 patients (12 percent) reported a variety of symptoms (eg, chest pain, fatigue, back/neck pain, headache, dizziness, or shortness of breath) lasting less than 60 seconds during contrast administration, and none of the 113 patients were found to have had an adverse event within 24 hours of perflutren lipid microsphere (Definity) administration . Another study included 20 patients (ages 9 to 18 years) who underwent transthoracic echocardiography with perflutren protein type A (Optison) echocontrast. There were no adverse hemodynamic effects, changes in taste, or flushing episodes. Three patients experienced transient headaches .
Sulfur hexafluoride lipid microsphere (Lumason) was initially FDA approved for noncardiac imaging in pediatric patients (eg, liver imaging and evaluation of vesicoureteral reflux). The FDA has also approved the use of sulfur hexafluoride lipid microsphere (Lumason) for cardiac imaging in pediatric patients using a weight-based dose . This is based on a study of 12 pediatric patients (ages 9 to 17 years) with suspected cardiac disease and suboptimal noncontrast echocardiography who received Lumason in one prospective multicenter clinical trial, as well as extrapolation from prior data on pediatric use in liver imaging and adult use in cardiac imaging. No major adverse effects were reported in the 12 pediatric patients who received Lumason in the cardiac study. Of note, patients with intracardiac shunts were excluded from this trial, as this was a contraindication at the time the study commenced.
There are no studies on the safety of UEAs in children under the age of five years . There are no data on the safety of contrast agents in pregnancy or lactation.
OPTIMAL ECHOCARDIOGRAPHIC SETTINGS — Contrast agent durability is dependent upon both bubble composition and ultrasonic characteristics. Alterations in the echocardiographic settings can therefore optimize both microbubble durability and contrast intensity. Guidelines for equipment setup and contrast agent administration are included in the 2008 American Society of Echocardiography consensus statement on contrast agents in echocardiography .
Harmonic detection — Second harmonic detection systems improve the signal-to-noise ratio of contrast images [31,32].
Microbubbles resonate (shake) with exposure to ultrasound energy at frequencies that are multiples of the ultrasound frequency emitted from the transducer. This results in the emission of fundamentals (same frequency) and harmonics (multiples) of the frequency to which they are exposed . By setting the imaging frequency of the echo system to a harmonic of the emitted frequency, the system "filters" out all returning fundamental frequencies from the myocardium and enhances the microbubble signal.
The contrast intensity improves two to three times using second harmonics . Other advantages to harmonic imaging include decreased artifact and shadowing, as well as enhanced contrast detection in areas of low microbubble concentration .
Harmonic imaging also improves endocardial tracking even without echocardiographic contrast (see "Echocardiography essentials: Physics and instrumentation", section on 'Second harmonic imaging'). However, the ejection fraction obtained by harmonic imaging along with contrast echocardiography provides the closest correlation with the radionuclide ejection fraction .
Intermittent or transient imaging — When a sound wave interacts with a microbubble, some of the energy is reflected, but a portion actively destroys the microbubbles. As a result, continuous ultrasound imaging results in depletion of the microbubble population, giving a suboptimal signal-to-noise ratio .
Increased microbubble durability may be accomplished with intermittent or transient response imaging . Ultrasound that is emitted only once per cardiac cycle, or as infrequently as every 5 to 10 beats, improves microbubble contrast intensity inversely with bubble transit velocity . Controversy exists as to which part of the cardiac cycle should be imaged; however, either systolic or diastolic imaging appears to improve the contrast effect .
Low mechanical index imaging — Another technique to decrease the destruction of microbubbles is low mechanical index imaging. If a very low acoustic power is transmitted, fewer bubbles will be destroyed even with continuous imaging. Commercial echocardiographic machines now have this "real-time" contrast imaging and studies assessing its utility are ongoing.
Mode of contrast injection — The mode of contrast injection can affect image quality. Steady state infusions offer an advantage over single or multiple bolus injections of agents by allowing titration to an optimal and uniform image and extending the duration of LV opacification, allowing for time to assess multiple anatomic views [42,43].
SUMMARY AND RECOMMENDATIONS
●Contrast echocardiography is a technique for improving echocardiographic resolution and providing real-time assessment of intracardiac blood flow using ultrasound enhancing agents (UEAs). (See 'Introduction' above.)
●Second-generation contrast agents surrounding the gas bubble in a durable shell enable adequate durability while keeping bubble size small enough to traverse the pulmonary circulation and enhance the LV cavity, improving endocardial border delineation. (See 'Microbubble contrast agents' above.)
●Several studies have demonstrated the safety of these second-generation contrast agents. (See 'Safety' above.)
Contraindications to the use of UEAs include:
•For perflutren lipid microspheres (Definity), known or suspected hypersensitivity to perflutren or polyethylene glycol (PEG).
•For perflutren protein type A (Optison), known or suspected hypersensitivity to perflutren or albumin.
•For sulfur hexafluoride lipid microsphere (Lumason), known hypersensitivity to sulfur hexafluoride, the inactive components of the contrast agent, or PEG.
●Contrast agents require different echocardiography machine settings to enhance their utility. (See 'Optimal echocardiographic settings' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Neil J Weissman, MD, who contributed to an earlier version of this topic review.
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