a b s t r a c t

Introduction: Contrast-enhanced ultrasound (CEUS) using intravascular microbubbles has potential to revolu- tionize Point-of-care ultrasonography by expanding the use of ultrasonography into clinical scenarios previously reserved for computed tomography (CT), magnetic resonance imaging, or angiography.

Methods: We performed a literature search and report clinical experience to provide an introduction to CEUS and describe its current applications for point-of-care indications.

Results: The uses of CEUS include several applications highly relevant for emergency medicine, such as solid-Organ injuries, actively bleeding hematomas, or Abdominal aortic aneurysms. Compared with CT as the preeminent ad- vanced imaging modality in the emergency department, CEUS is low cost, radiation sparing, repeatable, and readily available. It does not require sedation, preprocedural laboratory assessment, or transportation to the radiology suite. Conclusions: CEUS is a promising imaging technique for point-of-care applications in pediatric and adult patients and can be applied for patients with allergy to CT contrast medium or with impaired renal function. More high-quality CEUS research focusing on accuracy, patient safety, health care costs, and throughput times is needed to validate its use in emergency and critical care settings.

(C) 2018

Point-of-care ultrasonography has dramatically changed and im- proved clinical care of many clinical specialties [1-5] in diverse practice environments [6-8]. Simultaneously, computed tomography (CT) utili- zation increased sharply over the past 2 decades [9,10] and continues to increase [11,12]. Care for trauma patients has seen a 3.5-fold increase in CT use from 1995 through 2007, and today almost 1 in 6 patients who present to a US emergency department (ED) with an injury-related con- cern undergoes CT imaging [13]. This trend holds true even for patients with minor trauma, with a nearly 2-fold increase in utilization rates in recent years [14]. Several strategies have been developed to reduce the medical radiation burden of patients. These strategies include clini- cal Decision tools and guidelines for appropriate image use, such as Image Wisely [15] and Image Gently campaigns [16]; advancements

Abbreviations: CEUS, contrast-enhanced ultrasound; CT, computed tomography; ED, emergency department; FAST, Focused assessment with sonography in trauma; FDA, US Food and Drug Administration; ICU, intensive care unit; UCA, ultrasonography contrast agent.

* Corresponding author at: Department of Emergency Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905, United States.

E-mail address: [email protected] (T. Kummer).

in technology, allowing CT dose reduction; and development of alterna- tive imaging modalities.

Point-of-care ultrasonography has distinct advantages over CT in re- gard to portability, cost, lack of ionizing radiation, and improved spatial resolution. Yet, CT has superior diagnostic accuracy in many urgent and emergent conditions. Contrast-enhanced ultrasound (CEUS) using in- travascular microbubbles holds promise to close this diagnostic gap for several clinical applications relevant to emergency medicine practice.

The purpose of this review article is to provide an introduction into CEUS imaging and an overview of relevant applications for point-of- care ultrasonography, as well as current research developments for po- tential future use.

Background

Evolution of CEUS

In the late 1960s, cardiologist Claude Joyner discovered that injec- tion of normal saline can enhance the ultrasound signal greatly during

https://doi.org/10.1016/j.ajem.2018.04.044

0735-6757/(C) 2018

echocardiography because of small air bubbles within the solution [17,18]. Now known as agitated saline, this technique is routinely used in clinical practice to detect right-to-left atrial shunts or to confirm cen- tral line placement [19,20]. Subsequent research succeeded in stabiliz- ing the microbubbles for transpulmonary passage, initially using microbubbles of air within an albumin-containing stabilizing shell [21]. Besides albumin, other substances are highly effective in stabiliza- tion of the air bubble shell, including lipids and synthetic polymers [22]. Modern second-generation ultrasonography Contrast agents (UCAs) use an inert gas as the microsphere core that is surrounded by a stabilizing shell (Fig. 1). These newer agents can be administered in in- travenous Bolus injections or infusions and are detectable by ultraso- nography in the circulation for at least 5 min [23]. The microbubbles of different commercially available contrast agents differ in size but gen- erally have a mean diameter of 1 to 6 um. They have a similar or slightly smaller size than erythrocytes, have similar rheology, and are strictly confined to the intravascular space, unlike other radiologic contrast agents that are small enough to leak through capillary membranes [24,25]. At the end of their lifetime, the microbubbles cavitate and their gas content is exhaled through the lungs while the shell is metab- olized by the liver [26,27]. The contrast agent is rapidly eliminated from

the body after the imaging session is completed.

CEUS principles

Analogous to the basic concept of ultrasonography, the microsphere’s echogenicity is based on the change of acoustic imped- ance between blood and the gas core of the agent [21]. In addition, the nonlinear effect is amplified by the resonance frequency of the UCA, which is determined by its size and fortunately lies within the medical ultrasound range. This increases the signal intensity and greatly im- proves the signal to noise ratio, especially when combined with har- monic imaging and other multipulse techniques [22]. With high- energy ultrasound impulses (ie, high mechanical index), the bubbles burst and emit an even stronger signal. Thus, theoretically, each bubble can be detected [28]. The highly echogenic profile and favorable size allow for detection of contrast medium even in capillaries and therefore are suitable in tissue perfusion measurement [29].

Advantages of CEUS

CEUS can offer several advantages over other imaging modalities in the assessment of an acute care patient. Today’s commercially available UCAs are stable and easy to use compared with earlier agents [30], allowing such studies to be performed at point of care and eliminating the need for critically ill patients to be transported outside the depart- ment or the intensive care unit (ICU) [31]. Because these agents are not cleared renally, no nephrotoxic effects occur. This characteristic en- ables their use without first obtaining laboratory assessment [32,33].

Because of its static nature, CT quality is frequently degraded by

motion-blurring artifacts that can interfere with interpretation [34]. CEUS is a dynamic imaging technique for imaging with patient motion, both voluntary and involuntary. Because CEUS can acquire images over a time period, it allows prolonged or repeated imaging to account for variable Contrast enhancement of tissues that can mimic pathologic characteristics, especially on CT [33-35].

Perhaps one of the more compelling public Health benefits is the lack of ionizing radiation of CEUS studies in an era of increasing CT utilization and concern about medical radiation exposure in adults and pediatric patients [36-38]. A potential advantage of incorporating CEUS more ro- bustly into clinical practice is this lack of ionizing radiation. CEUS may improve imaging of the critically ill and injured patient, beyond the scope of currently used B-mode ultrasonography. Use of CEUS as a pri- mary imaging modality, or as a follow-up study in clinical scenarios where repeat CT now occurs, may reduce medical radiation exposure [39].

Disadvantages of CEUS

Several factors that limit conventional ultrasonography, such as body habitus or shadow from bone or air, also affect CEUS. Optimal visu- alization of second-generation UCAs uses the nonlinear harmonic prop- erties of the microbubbles, which body tissue can also produce [40]. Several techniques have been used to filter out the artifacts arising from tissue, and these techniques, while beneficial to visualization of the contrast agent, decrease the spatial resolution and overall quality of the traditional fundamental B-mode image [41].

Use of UCAs adds several steps to an ultrasonography evaluation, in- cluding placement of peripheral intravenous access [42]. As a special- ized ultrasonography modality, CEUS is operator-dependent and requires supplemental training and expertise [43]. Although still more cost-effective than CT, the contrast agent increases the examination cost. In addition, an upgrade of existing ultrasonography equipment may be needed because the use of UCA requires specific software, and cost may be associated with increased requirements for hospital imag- ing storage space [44].

Safety considerations

UCAs are used worldwide with a low complication rate [33,44-48]. Reported mild adverse events are rare and include headache and nausea in less than 1% of patients [45]. Unusual mouth taste, hyperventilation, and hyperactivity have been reported in children [49,50]. Mild reactions are transient, resolve spontaneously, and do not require treatment [45,47].

Serious adverse reactions to UCAs are anaphylactoid and attributed to complement activation-related pseudoallergy, a variant of type I hy- persensitivity reactions [47,51]. These reactions may occur without prior exposure because they are not mediated by immunoglobulin E. Symptoms range from mild pruritus and urticaria to severe angioede- ma, wheezing, respiratory distress, and anaphylactic shock [45,47]. Most reported serious adverse reactions occurred within 30 min of UCA administration. Studies on adverse effects of UCAs have shown a rate of serious events less than 1:10,000, and adverse effects are thought to be less common than with contrast-medium CT [51,52]. A recent study of 30,222 patients undergoing CEUS examinations over 9 years

Fig. 1. Contrast-enhanced ultrasound microsphere. An ultrasound contrast microsphere consists of an inert gas with a stabilizing lipid shell that allows the bubble to survive transpulmonary passage and extends its lifespan to more than 5 min.

showed that 0.020% had adverse reactions of varying degrees, including 2 patients (0.007%) who had signs of early anaphylactic shock that im- proved after treatment [53]. Previous Allergic reactions to CT or magnet- ic resonance imaging contrast agents do not preclude the use of UCAs [45].

Safety in children

Available published data are limited about the safety of UCAs in pe- diatric patients. The largest case series to date reports 1 anaphylactoid reaction among 167 examinations [50]. Therefore, the same safety re- cord in adults cannot be assumed in children. Current studies have small sample sizes, and in the few centers where they are performed, parental consent is required for UCA administration. Investigators have concluded that a paucity of uniform guidelines for monitoring and dosing and of large multicenter studies involving intravenous UCAs and pediatric patients contribute to the current lack of an accepted safety profile of UCA use for children [49,50].

This uncertain safety profile of UCAs must be balanced with the po-

tential to offset other risks related to current imaging modalities avail- able for pediatric patients. This potential includes benefits of CEUS in reductions to exposure to ionizing radiation, need for sedation, and pa- tient transport to other areas of the hospital.

Pregnancy and breastfeeding

UCAs are classified as category B (sulfur hexafluoride lipid-type A microspheres [Lumason] and perflutren lipid microspheres [Definity]) or category C (perflutren protein-type A microspheres [Optison]) re- garding use during pregnancy. Category B agents should be used in pregnancy only when absolutely needed [47,54]. Little is known about breast milk and UCAs. Women who are breastfeeding and require UCAs should consider pumping breast milk and disposing of it in the first 24 h following UCA administration [54].

Other considerations

All 3 UCAs approved by the US Food and Drug Administration have a black box warning stating that uncommonly serious cardiopul- monary reactions have been reported. Since 2008, the FDA has downgraded the warnings and contraindications. Prior concerns about risks for patients with Intracardiac shunts and other cardiorespiratory conditions (eg, chronic obstructive pulmonary disease, pulmonary hy- pertension) and the need for enhanced monitoring have not been sub- stantiated [55] and therefore were progressively removed from the warning.

Bioeffects

The potential for bioeffects related to UCAs was suggested after in vitro cell observations of sonoporation, hemolysis, and cell death [44]. In vivo significance lies in the changes that resulted from interac- tions between gas bodies and cells. Hemorrhagic effects-in the glomer-

Cardiac imaging

Cardiac imaging has distinctive challenges in the ED and ICU. The ability to obtain optimal images for cardiac assessment is affected by re- stricted patient position, lung expansion with positive pressure ventila- tion, and wound dressings. In these clinical settings, UCAs can greatly improve the visualization of cardiac structures (Fig. 2). Reilly et al. [56] showed that left ventricular ejection fraction could be assessed with reasonable certainty in only 56% of ICU patients and could not be assessed at all in 23%. Addition of contrast agent allowed for assessment of the ejection fraction for all patients, with 91% read with surety. An- other study in various hospital settings showed the most dramatic im- provement in the surgical ICU, where Image quality improved from 0%, 75%, and 25% (i.e., adequate, technically difficult, and uninterpret- able) to 78%, 21%, and 1%, respectively [57]. In that study, improvement in image quality had an important effect on patient treatment, leading to decreasED resource utilization and cost savings. In addition, regional function and myocardial perfusion assessment with use of UCAs have incremental Diagnostic and prognostic value in the rapid assessment of acute myocardial ischemia. This value is realized in the ED for treat- ment of patients presenting with a history concerning for acute coro- nary syndrome but with a nondiagnostic electrocardiography study [58,59].

Abdominal trauma

Adult patients

One of the primary potential applications of CEUS at point of care is evaluation of a patient presenting after blunt abdominal trauma. While conventional ultrasonography can miss important solid-organ injury in the absence of hemoperitoneum, use of a contrast medium greatly im- proves visualization of injuries to kidney, liver, and spleen. In a 2009 multicenter study of 156 patients, Catalano et al. [60] observed that con- trast medium improved the sensitivity and specificity of renal trauma seen on conventional ultrasonography from 36% and 98% to 69% and 99%. For Liver trauma, UCAs improved the sensitivity and specificity from 68% and 97% to 84% and 99%. For splenic trauma, the sensitivity

and specificity improved from 77% and 96% to 93% and 99%. In short, CEUS was shown to be clearly superior to conventional ultrasonogra- phy. Although false-negative results occurred with CEUS in this study, only minor injuries were missed that did not require surgical intervention.

Similarly, Valentino et al. [61] showed that CEUS identified 81 of 84 traumatic lesions seen on CT. It missed only 2 injuries, which were treat- ed nonoperatively: a grade 1 kidney lesion and an adrenal hematoma. CEUS had 1 false-positive result, an ischemic lesion viewed on CT. Com- pared with nonenhanced CT in characterization of focal liver, kidney, and peritoneal pathologic characteristics, CEUS is the superior modality

Table 1

Selected indications for point-of-care contrast medium-enhanced ultrasonography.

Organ system Potential indications

Cardiac LV visualization, myocardial ischemia

ular capillary, for example-were noted in animals, mainly at higher mechanical index settings than typically used for CEUS. In preclinical

abdominal aorta

AAA rupture, aortic dissection, endoleak detection

cardiac imaging studies, ventricular ectopic beats have been observed, but this observation has not been shown to be a clinically relevant prob- lem in extensive clinical use [33,44].

Applications

CEUS offers several potential applications relevant in emergency medicine (Table 1). Herein is an overview of its most promising indications.

Venous Improved visualization of deep Venous system Lung Differentiation between pneumonia and infarction

Kidney Lacerations, hematoma, abscess, infarction, renal perfusion Liver and biliary Lacerations, hematoma, acute cholecystitis

Spleen Lacerations, hematoma, infarction GI tract inflammatory bowel disease activity

Scrotum testicular torsion and infarction, infectious processes,

hematoma

Musculoskeletal Actively bleeding hematomas, muscle perfusion in compartment syndrome

Abbreviations: AAA, abdominal aorta aneurysm; GI, gastrointestinal; LV, left ventricle.

[62]. This may be of medical significance for patients who cannot toler- ate CT contrast medium because of allergy or renal insufficiency.

In CEUS, enhancement of abdominal solid organs varies and depends on the vascularization of the interrogated organ [63]. Kidney enhance- ment is rapid and intense; each kidney is examined in a separate bolus, along with other solid organs on the ipsilateral side. Enhance- ment occurs in 3 phases: early arterial, venous, and rapid loss of en- hancement. The optimal period to examine the kidney is within the first 2 min of an examination with CEUS focused assessment with so- nography in trauma (FAST) [63,64]. Injuries to the kidney capsule are seen in the early arterial pHase, which enhances the cortex; vascular de- fects of parenchyma are visualized in the venous pHase [63]. Subcapsu- lar hematoma appears as a nonhomogeneous collection and laceration appears as a clear hypoechoic band. If the patient has an avulsion injury at the renal hilum, no enhancement is seen in the renal parenchyma. Al- though CEUS improves the sensitivity of conventional ultrasonography for Renal injuries, an injury involving the excretory tract may be missed because microbubbles are not excreted in urine [65].

In the liver, because of dual vascular supply, the phases are arterial, portal (40-120 s after injection), and sinusoidal or late (lasting 120-300 s after injection) [66]. Hepatic lacerations are most easily seen in the venous phase [63]. In a CEUS FAST protocol, the liver is ex- amined in 2 to 5 min postinjection, after examination of the ipsilateral kidney. Hepatic lacerations and hematomas appear as hypoechoic areas; contusions are less well defined.

The spleen is the most commonly injured organ in blunt abdominal trauma [67]. During the initial Arterial phase postinjection, enhance- ment is nonhomogeneous in a zebralike pattern because of different perfusion rates between red and white pulp [35,63]. This observation can be mistaken as an injury pattern, but the pattern disappears 60 s postinjection. Later, enhancement is homogeneous and the late phase of enhancement lasts more than 5 min. At 2 to 3 min, veins become an- echoic and can be mistaken for lacerations; reinjection of a small amount of contrast medium can clarify whether an injury exists [63]. The splenic vein also can be differentiated from a laceration through the presence of branching vessels and microbubbles in the lumen [39]. In the CEUS FAST protocol, the spleen also is examined in 2 to 5 min postinjection, after the ipsilateral kidney is examined in the first 2 min. Signs of splenic injury include free fluid, subcapsular splenic he- matoma, parenchymal injury, and pseudoaneurysm (Fig. 3). Splenic he- matomas appear as subcapsular or intraparenchymal nonhomogeneous collections; contusions are more subtle [68]. In a 2015 study by Sessa et al. [69], CEUS identified 34 of 35 splenic injuries in 256 patients with history of low-energy blunt trauma.

Pancreatic injuries occur in less than 2% of blunt abdominal trauma. In a 2014 study by Lv et al. [70], 21 of 22 patients with blunt pancreatic

trauma seen with CT had injury identified on CEUS (detection rate, 95.5%).

CEUS also outperforms conventional ultrasonography in the identifi- cation of active bleeding, which is recognized in contrast medium pooling or jet outside blood vessels [64]. In a 2011 study by Lv et al. [71], 392 patients with Hepatic injury or trauma, or both, underwent CEUS examination following CT. CEUS detected contrast medium ex- travasation or pooling in 16% of patients; detection of extravasation was not significantly different from contrast medium-enhanced CT with sensitivity of 72% vs 81%. Lv et al. noted that active bleeding could be represented as either a hyperechoic or an isoechoic region de- pending on whether the organ was interrogated during the arterial or late parenchymal phase (hyperechoic appearance) or the early paren- chymal phase (isoechoic appearance).

CEUS can be used to grade injury according to the organ injury scale of the American Association for the Surgery of Trauma [65]. In 2014, Lv et al. [72] demonstrated that 2 radiologists were able to classify contrast medium-enhanced abdominal images of 306 patients into groups with mild, moderate, and severe injury with high interreader agreement (?, 0.973). Moreover, the CEUS-based classification and clinical outcomes were highly correlated, suggestive that CEUS may be useful in surgical management decisions.

Pediatric patients

In a 2017 study, Holmes et al. [73] concluded that when convention- al ultrasonography is used for a hemodynamically stable pediatric pa- tient with blunt torso trauma, it does not improve clinical care, resource use, ED length of stay, missed Intra-abdominal injuries, or hos- pital charges. The addition of contrast medium, however, has been shown to improve the sensitivity and specificity of conventional ultra- sonography in the evaluation of solid-organ injury. In a 2017 study by Armstrong et al. [74], 18 children with CT-diagnosed abdominal solid- organ injury were examined with conventional ultrasonography and CEUS. The investigators observed that addition of contrast medium im- proved the sensitivity of ultrasonography from 45.2% to 85.7% and the specificity from 96.4% to 98.6%. After the exclusion of a 100-kg patient from the data, the sensitivity and specificity improved to 94.5% and 99.2%. Menichini et al. [75] demonstrated in a 2015 study a sensitivity and a specificity of 100% in the detection of abdominal solid-organ inju- ry with CEUS for 73 pediatric patients. In 2008, Valentino et al. [76] demonstrated that CEUS provided a sensitivity of 92% and specificity of 100% in 27 pediatric patients.

CEUS may be used for hemodynamically stable trauma patients to enhance conventional ultrasonography or in the follow-up of patients with conservative management of abdominal trauma. CEUS is excellent for detecting injuries to solid organs. However, similar to conventional

Fig. 2. Unenhanced and enhanced echocardiography. A, a 4-chamber cardiac view at baseline. B, a 4-chamber cardiac view after intravenous injection of contrast agent.

Fig. 3. Splenic Injury of a 34-year-old man who presented with left-sided flank pain after a motor vehicle crash. A, contrast medium-enhanced ultrasonography shows a filling defect (arrows) in proximity of the splenic hilum. B, filling defect cannot be visualized with traditional B-mode ultrasonography. C, the same defect is apparent with computed tomography.

ultrasonography, it has limited ability to detect injury to the diaphragm, the bowel, and the mesentery and damage to bile ducts and renal collecting system injuries [65,77]. CEUS is also an operator- and patient-dependent technology; patients who are obese or have large amounts of bowel gas may have suboptimal images. While CT continues to be the gold standard for blunt abdominal trauma, the CEUS modality-especially for pediatric patients and women of reproductive age-is a promising alternative.

Other applications

In the United States, second-generation UCAs are FDA approved only for cardiac and liver imaging and for evaluation of pediatric vesicoureteral reflux. However, several off-label applications have also been described (Table 1) [44].

CEUS can be used to evaluate abdominal aortic aneurysm rupture, with the ability to evaluate both intrathrombus hemorrhage and aortic rupture through Contrast medium extravasation [43]. Not only does this extravasated contrast pattern allow clinicians to differentiate stable from ruptured aneurysms, it also can be used to distinguish the true extraparenchymal aneurysm bleeding of an aortic aneurysm rupture (which results in jetlike extravasation) from the less serious intraparenchymal bleeding from other abdominal injuries (which leads to pooling of contrast medium) [78].

In addition, CEUS has shown potential as an adjunct to non-CEUS in the diagnosis of deep venous thrombosis. Duplex ultrasonography is the modality of choice for deep venous thrombosis detection. However, sensitivity of non-CEUS decreases with detection of distal lower- extremity vessels and for patients with obesity or lower-extremity swelling from congestive heart failure [79]. CEUS can help improve the visualization of lower-extremity venous structures distal to the common femoral vein [80]. Investigators have demonstrated that CEUS also improves the visibility of more proximal veins such as the in- ferior vena cava thrombosis compared with Doppler ultrasonography [81].

When used in the ultrasonographic diagnosis of pneumonia, CEUS in most cases shows a rapid homogeneous contrast medium enhancement throughout the identified lesion [82]. By comparison, pulmonary embo- lism lesions are characterized by absent or inhomogeneous contrast medium enhancement [83,84]. Although inhomogeneous enhancement can be present in pneumonia as well, demonstration of absent or rapid

homogeneous enhancement can help distinguish an infectious cause from an embolic cause for sonographic lesions that might otherwise be very similar (Fig. 4).

For patients with traumatic or nontraumatic soft-tissue hematomas, CEUS has the potential to replace CT in assessment for active bleeding [85]. The bleeding can be seen as pooling of contrast medium within the hematoma.

Besides its use for trauma patients, the applications of CEUS are an- ticipated to expand into evaluation of other disease processes. It can be used to assess various structures, including gallbladder, kidney, and testes, in the ED [86]. CEUS can potentially help diagnose intermittent testicular or Ovarian torsion, incomplete torsion, and segmental infarct by detecting subtle perfusion abnormalities not identified by conven- tional ultrasonography [64].

Future directions and research

Application of CEUS is evolving continuously, and wider adoption of this technique is expected, especially with the predicted refine- ment and enhancement of this imaging modality [87]. In addition to the more established indications described above, CEUS can pro- vide new insights into renal perfusion and pathogenesis of acute kid- ney injury for patients in the ED or ICU and potentially help physicians identify patients at risk for renal failure and aid early in- tervention to prevent acute kidney injury [88]. Future applications of CEUS also can be expanded to assess perfusion of the extremities in vascular emergencies (e.g., ischemia, thrombosis, embolism, oc- clusion, pseudoaneurysm) at bedside [89].

Development of a CEUS program in the ED can be rewarding. Yet, several barriers to CEUS need to be addressed before it can be used rou- tinely as an adjunct in the ED. Ultrasonography equipment needs to be optimized for the use of contrast medium. Contrast medium-specific software needs to be available on all point-of-care ultrasonography sys- tems. Specific training recommendations and guidelines need to be de- veloped for use of CEUS in the ED. Training pathways need to be created for emergency medicine physicians to develop competency in this ap- plication. In addition, physicians need to ensure that a sufficient number of CEUS examinations are performed in the ED to confirm that skills are maintained.

The use of a contrast agent may require approval from the local hos- pital or institutional committees on safety, pharmacology, and

therapeutics. Collaboration with other specialties, competition with other imaging modalities, and lack of FDA approval of UCAs for different emergency applications are further challenges to overcome before CEUS can become a mainstream tool for ED use. Building collaborations with other departments, such as departments of radiology and trauma sur- gery, is crucial for conquering some of these challenges. Given that there are limited current procedural terminology codes for CEUS of the abdomen, payers may not reimburse for contrast agent administra- tion. These reimbursement issues need to be solved.

As CEUS moves forward in the ED setting, more high-quality re- search in this setting is needed to validate its utility. Several develop- ments need to occur to ensure CEUS can influence patient care by increasing accuracy and influence patient safety by decreasing health care costs and throughput times. Future studies focused on patient out- comes are crucial for advancement of CEUS use in the point-of-care era. Research is needed that specifically addresses physician training, as well as CEUS accuracy in the hands of emergency medicine physicians and the feasibility of CEUS program implementation in the ED. Novel appli- cations of CEUS need to be studied regarding evaluation of conditions other than trauma. Multicenter studies producing a higher level of evi- dence will allow for continued growth and appropriate use of CEUS in the care of patients in EDs.

Conclusions

CEUS overcomes many limitations of traditional ultrasonography and allows expansion of ultrasonography into areas previously reserved for other Advanced imaging modalities that have a favorable safety pro- file. The portability of ultrasonography systems can bring these ad- vanced diagnostic capabilities to remote sites. Numerous clinical applications highly relevant to emergency medicine and critical care have been developed or are undergoing intense research efforts currently.

Additional research, training, and validation are needed before CEUS can be incorporated routinely into clinical practice. Yet, its future holds great promise and excitement for use in emergency and critical care applications.

Conflict of interest

None.

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