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Address correspondence to: Christian Fischer, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany.
Affiliations
Center for Orthopaedics, Trauma Surgery and Spinal Cord Injury, Ultrasound Center, HTRG–Heidelberg Trauma Research Group, Heidelberg University Hospital, Heidelberg, Germany
This World Federation for Ultrasound in Medicine and Biology position paper reviews the diagnostic potential of ultrasound contrast agents for clinical decision-making and provides general advice for optimal contrast-enhanced ultrasound performance in musculoskeletal issues. In this domain, contrast-enhanced ultrasound performance has increasingly been investigated with promising results, but still lacks everyday clinical application and standardized techniques; therefore, experts summarized current knowledge according to published evidence and best personal experience. The goal was to intensify and standardize the use and administration of ultrasound contrast agents to facilitate correct diagnoses and ultimately to improve the management and outcomes of patients.
The use of contrast-enhanced ultrasound (CEUS) for musculoskeletal (MSK) indications has increased significantly over the past year. Unlike conventional imaging tools that rely on mere anatomic characteristics including visible changes in bone structure or signs of soft tissue degeneration, the depiction of local microperfusion via CEUS sheds light on the (patho)physiologic processes in these tissues. Beyond its utility for basic research, this perspective particularly implies being “up to date” in clinical practice, enabling the early detection of peri-operative conditions that require adjustment of planned or initiated treatment, as well as the comprehensive diagnostic workup, of various MSK pathologies. Therefore, while outlining current research topics, these guidelines intend to facilitate and hence promote the further exploration, as well as the implementation, of the MSK approach, providing examples of practical application that have proven their practicability in routine use. The recommendations given are primarily intended to serve as guidance, based on most recent expert opinions and the referenced studies.
The commonly used ultrasound contrast agent (UCA) for MSK imaging, SonoVue (Bracco, Milan, Italy), is a second-generation UCA containing microbubbles with a mean diameter of 1.5–2.5 μm that consist of a sulfur hexafluoride core and a stabilizing phospholipid shell (
Committee for Medicinal Products for Human Use (CHMP). Assessment report EMA/84084/2014. SonoVue. International non-properietary name: sulfur hexafluoride, Procedure No. EMEA/H/C/000303/II/0025. 2014.
). It is the UCA that is the standard used for CEUS examinations in Europe. UCAs have very good safety profiles including SonoVue (Bracco), with a reported rate of serious adverse events of only 0.01%, and there is no need for laboratory tests to assess relevant organ (dys-)functions before examination (
Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver—Update 2012: A WFUMB–EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.
Committee for Medicinal Products for Human Use (CHMP). Assessment report EMA/84084/2014. SonoVue. International non-properietary name: sulfur hexafluoride, Procedure No. EMEA/H/C/000303/II/0025. 2014.
The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
). For further information on SonoVue (Bracco) (e.g., its contraindications) we refer to the manufacturer´s recommendations. As the acquisition and analysis of UCA dynamics differ depending on the information needed, an overview of existing options is introduced first.
UCA dynamics
Qualitative assessment
Outside MSK issues, detection and characterization of lesions and other pathologies are usually realized with qualitative CEUS (
Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver—Update 2012: A WFUMB–EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.
The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
). A single bolus of UCA is injected, and the ultrasound (US) signal is assessed visually. The US transducer may not need to be or even should not be kept at one single position, so that different body regions or views within one examination can be assessed. However, for a semiquantitative evaluation, that is, if scores are to be used to describe the “degree of vascularization” (
Inflammatory low back pain: High negative predictive value of contrast-enhanced color Doppler ultrasound in the detection of inflamed sacroiliac joints.
Contrast enhanced ultrasound with second generation contrast agent for the follow-up of lower-extremity muscle-strain-repairing processes in professional athletes.
). On the other hand, hypo-perfused areas might be of particular interest (e.g., in muscular transplants). A continuous UCA infusion can prolong the duration of the exam, as in the assessment of inflammatory disease of multiple joints (
Because MSK CEUS also addresses questions that are related to critical deviations from physiologic tissue perfusion and is used for monitoring during follow-up, a quantitative analysis of the UCA dynamics providing specific parameters is often required. Thus, objective criteria to assess single measurements (defining terms such as critical and physiologic for one anatomic region in perfusion-related contexts) can be established and sequential examinations can be compared. Considering the sample sizes of the previous studies, multicentric studies on larger patient cohorts are required for the definition of more representative cutoff values and further standardization.
Quantitative analysis of standard time–intensity curves
The quantitative analysis of standard time–intensity curves (TICs) is one central approach. For this, the transducer needs to be maintained at an identical position, and wash-in as well as wash-out dynamics of the UCA after a single bolus injection within certain regions of interest (ROIs) are calculated. The reduced frame rate of the US machine minimizes bubble destruction, and the derived signals need to be linearized. Suitable post-processing solutions (either on the US platform or external) are a prerequisite for quantification of CEUS data. The entire procedure needs to be standardized to obtain data suitable for intra- or inter-individual comparison. For this purpose, detailed examination protocols should be used.
This standard method of quantitatively analyzing TICs after UCA bolus injection has been applied in various MSK indications such as rheumatology (
Evaluation of finger joint synovial vascularity in patients with rheumatoid arthritis using contrast-enhanced ultrasound with water immersion and a stabilized probe.
Various parameters can be calculated with these linearized TICs and when fitting curves are applied (Fig. 1); they are related to the local blood microperfusion and blood volume, respectively. However, an exact calculation of perfusion or blood volume in absolute values is not possible. Parameters such as “area under the curve” (AUC) values may be related to the total blood volume (mL) in a body area, while time-related parameters such as the slope of the enhancement curve basically depend on the local blood flow (mL/s). Perfusion parameters hence describe the measured blood volume or flow or a combination of the two when they refer to the UCA wash-in or wash-out phase or to the entire enhancement. The most often used TIC parameters as depicted in Figure 1 include peak enhancement (PE in arbitrary units [a.u.]), which relates to the maximum signal intensity of the enhancement curve; area under the curve (AUC [a.u. × s]), the definite integral of the signal intensity against time during wash-in and wash-out; and wash-in rate (WiR [a.u.]), the maximum slope of the signal enhancement curve. Time-dependent parameters include rise time (RT [s]), the wash-in duration of the UCA; time to PE (TPE [s]), the time from UCA application to PE; and mean transit time (MTT [s]), the combined wash-in and wash-out duration of the UCA.
Fig. 1CEUS standard time–intensity curve after UCA bolus injection. Blue dots represent real, linearized values; a fitting curve provides the following CEUS parameters: PE (in a.u.), the maximum signal intensity of the enhancement curve; TPE (s), duration from UCA application to maximum signal; WiR (a.u./s), the maximum slope to peak; RT (s), that is, TPE – time where the maximum slope line originates; AUC (a.u. × s), area under the TIC curve; MTT (s), fitting model dependent. a.u. = arbitrary units; AUC = area under the curve; CEUS = contrast-enhanced ultrasound; MTT = mean transit time; PE = peak enhancement; RT = rise time; TPE = time to peak; UCA = ultrasound contrast agent; WiR = wash-in rate.
These common CEUS parameters are not strictly limited to single perfusion characteristics only; for example, a smaller local blood volume will not only result in a smaller AUC but will also affect the slope. The choice of the most suitable CEUS parameter for perfusion assessment depends on the clinical problem to be addressed.
Quantitative CEUS analysis is an ongoing field of research; further developments have occurred and may further evolve. A pixelwise analysis of TICs has been introduced to characterize arthritis (
). More advanced technical options, which track individual UCA microbubbles and use super-resolution US, may further improve perfusion assessment with CEUS (
An alternative technique is based on flash-replenishment kinetics. Although this method is standard for myocardial perfusion analysis in echocardiography (
), it is less frequently used elsewhere but has been applied in MSK CEUS as well, predominantly in a quantitative manner to evaluate skeletal muscle perfusion (
). After the application of US pulses with high acoustic energy (flash), which destroy the UCA microbubbles inside the ROI, the consecutive refilling from outside is monitored. Different perfusion parameters can be derived from such TICs (Fig. 2).
Fig. 2CEUS time–intensity curve demonstrating flash-replenishment dynamics after the application of a high-energy ultrasonic pulse (flash). Blue dots represent real, linearized values. A fitting curve provides the following CEUS parameters: plateau A (a.u.), the signal after complete refilling indicating local blood volume; slope β (a.u./s), the initial slope of the replenishment indicating local blood flow. According to the fitting model, for example, A × (1 – exp[–βt]). a.u. = arbitrary units; CEUS = contrast-enhanced ultrasound.
Compared with standard TICs, this method provides perfusion parameters that are more directly related to certain vascularization parameters; that is, the slope parameter β is considered to be strictly linear to local blood flow velocity (m/s), while the plateau value A is proportional to local blood volume (mL). For quantitative analysis, it is usually assumed that the UCA signal is in a steady-state situation. Therefore, a continuous infusion of contrast agent is the first option for this method. In the skeletal muscle, relatively high and long-lasting infusion rates are desired to obtain sufficiently high CEUS signals (e.g., ≥1 mL/min for ≥5 min).
Practical implications of skeletal muscle perfusion characteristics
In a skeletal muscle at rest, the blood perfusion and, thus, the detected CEUS signals are generally very low. Moreover, it must be considered that the muscle has a high physiologic variation in its blood supply. Hence, muscle provocation is often performed before the CEUS examination (
Comparison of transient arterial occlusion and muscle exercise provocation for assessment of perfusion reserve in skeletal muscle with real-time contrast-enhanced ultrasound.
Dynamic contrast-enhanced ultrasound for assessment of therapy effects on skeletal muscle microcirculation in peripheral arterial disease: Pilot study.
Preoperative deltoid assessment by contrast-enhanced ultrasound (CEUS) as predictor for shoulder function after reverse shoulder arthroplasty: a prospective pilot study.
). Consequently, muscle microperfusion considerably increases, which may also reveal pathologic perfusion patterns (well known from stress myocardial perfusion imaging).
Provocation by muscle exercise can be either dynamic or isometric (
Comparison of transient arterial occlusion and muscle exercise provocation for assessment of perfusion reserve in skeletal muscle with real-time contrast-enhanced ultrasound.
). Another option that has been used is transient arterial occlusion using specific cuffs with pressures above arterial occlusion pressure and an automated plethysmograph to simplify the application (
Comparison of transient arterial occlusion and muscle exercise provocation for assessment of perfusion reserve in skeletal muscle with real-time contrast-enhanced ultrasound.
Dynamic contrast-enhanced ultrasound for assessment of therapy effects on skeletal muscle microcirculation in peripheral arterial disease: Pilot study.
), with intra- and inter-individual variation. Furthermore, other factors influence the detected US signal, such as the local acoustic conditions or the general blood circulation, which may differ between patients. For such reasons, the use of relative instead of absolute CEUS values is generally less vulnerable to variations. Relative means perfusion parameters of the affected tissue referenced to defined adjacent tissue (
). To minimize methodologically-caused variations when measuring muscular microperfusion, a strict examination algorithm, including the provocation method, correct timing of contrast agent application and exact transducer adjustment according to appropriate reference landmarks are paramount (
. With respect to muscular exercise as a provocation method, provocation dynamometers that guide and monitor the degree of force can support standardization. For transducer adjustment, it should be noted that in the case of quantitative CEUS applications, defined landmarks have to be assessed for sufficient sectional plane reproducibility by testing the intra-/inter-observer reliability of measurements in advance (
In muscle perfusion evaluation, measurement with CEUS is not only feasible after a standardized provocation, but also before, during and immediately after. Such assessments may be particularly useful in evaluating therapeutic effects on perfusion reserve or in better understanding training effects in sports medicine.
The UCA signals should be in a steady state before provocation, so a continuous infusion of UCA is needed. In combination with low values of the mechanical index (MI), this enables continuous real-time evaluation of rapid provocation-related changes in signal intensity (
). Compared with analogous parameters derived from standard quantitative TICs, the parameters derived from such TICs always have to be considered in terms of these special conditions of acquisition (Fig. 3). Another simplified, special type of quantitative UCA dynamics analysis is to measure arrival times of a contrast bolus. In MSK CEUS this can be used in peripheral muscles for evaluation of peripheral arterial disease or the presence of collaterals in this disease (
Fig. 3CEUS time–intensity curve during ultrasound contrast agent infusion and muscle provocation. CEUS signal during provocation may vary (here continuous decrease in signal), followed by a rapid increase after provocation cessation and subsequent recovery. Blue dots represent real, linearized values. A fitting curve provides the following CEUS parameters: PE (a.u.) after cessation of provocation; TPE (s); maximum slope (a.u./s) after provocation; AUC (a.u. × s) after provocation cessation. a.u. = arbitrary units; AUC = area under the curve; CEUS = contrast-enhanced ultrasound; TPE = time to peak; UCA = ultrasound contrast agent.
Guidelines and recommendations on hepatic and non-hepatic use of CEUS have recently been published, including detailed information on the injection process, the video recording and general technical aspects (
The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
), and those involved should be familiar with them.
Technical aspects
Technical settings derived for the following MSK applications should cover key features such as “a wide dynamic range,” gain “slightly above the noise floor,” “a low mechanical index (MI)” and “the use of a dual-image display format” (
The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
). The depth is chosen based on the principle “as little as possible, as much as required,” meaning that on the one hand, the target structure (e.g., the fracture gap) should be displayed in large size, but on the other hand, it should be small enough to position the focus adequately (
To obtain the best contrast agent resonance (fundamental stimulating frequency at about 3.5 MHz), broadband linear probes with low frequencies or suitable lower-frequency transducers are preferably used at all relevant resonance frequencies (subharmonic, fundamental, ultraharmonic and second harmonic resonances) for up-to-date second-generation contrast agents are lower than 8 MHz for low-MI imaging. In this context, only applications with highly specific demands on resolution, for example, examination of the finger joints, may justify the use of higher frequencies. For larger or deeper-lying structures, the use of curved probes can be helpful in better depicting the structure at better contrast agent utilization with less resolution.
Preparation and performance of a CEUS procedure
The exact positioning of the patient depends on the region to be examined. In general, we recommend a stable supine or lateral position, which can be easily maintained during the entire measurement to avoid movement artifacts, which impede qualitative and quantitative perfusion assessment. When another setting is more suitable for specific applications, a detailed description is given separately. Afterward, pre-assessment via unenhanced US modalities is focused on, which is reasonable before adjusting the primary scan plane for CEUS. To reproduce this scan plane when performing sequential examinations, the exact position and orientation of the transducer have to be documented, particularly in those applications for which no standardized anatomic landmarks are available for orientation. This can be realized with position markers on stored images in B-mode preceding CEUS, supplemented by annotations in the corresponding examination report. The same technical settings should be used to re-examine the patient.
Generally, there are different doses of SonoVue (Bracco) in clinical use, ranging from 1–4.8 mL. For each introduced MSK application, we recommend the most effective UCA dose based on our previous experience in clinical practice. Nevertheless, a final standardization has to be conducted depending on the device used, referred to the anatomic region that is focused by MSK CEUS (
If MSK CEUS is performed in a potential multicenter setup requiring the comparison of quantified TIC values, standardization of all described settings is vital and should also include the interval between UCA application and the start of the video, which is best realized instantaneously. The duration of the recorded video depends on the tissue examined and the capability of local storage capacities for large files. Yet, it will generally be shorter than, for example, in liver diagnostics, as there is no late “portal” phase and the wash-in parameters are usually of most interest. If qualitative instead of quantitative assessment is primary, initial video clips can be recorded during the wash-in phase followed by sequential snapshots at determined intervals.
During measurement, holding the transducer stable with both hands is another key factor in avoiding motion, but at the same time the operator should keep in mind the need to reduce transducer pressure to a negligible level to avoid the risk of small vessel compression.
All examples of the standardized CEUS procedure presented in these guidelines follow the approach to UCA bolus injection and analysis of standard time–intensity curves in case of quantitative evaluation.
Peri-operative diagnostics
Fractures and non-unions
Background
Osseous perfusion is an essential quality of bone metabolism and regeneration (
). Given a cortical gap permitting US beam penetration, CEUS allows the visualization of osseous microcirculation and, thus, its use as novel diagnostic approach complementing conventional modalities of fracture and non-union diagnostics. Compared with healing tibial fractures, aseptic tibial non-unions have been reported to suffer impaired microcirculation, whereas infected tibial non-unions exhibited excessive perfusion (
), suggesting that the physiologic process of bone healing is reflected by a specific level of osseous perfusion. Moreover, further evidence of the diagnostic value of osseous CEUS can be found in the field of non-union revision surgery, where perfusion measurement is performed at different peri-operative stages.
In a pilot study examining the microperfusion of non-union tissue 12 wk after revision surgery, sufficient perfusion was favorable, as it predicted successful eventual consolidation (
). This finding is the subject of further research, while current clinical interest focuses on osseous CEUS application before revision surgery. CEUS hyperperfusion of a non-union pre-operatively indicates infection is an underlying condition (Fig. 4), which is particularly valuable because of the low diagnostic accuracy of clinical, radiologic and laboratory tests (
Fig. 4Time–intensity curves of infected (red) and aseptic (blue) tibial non-unions before revision surgery. (a, c, e) Corresponding ultrasound images with the non-union gap in B-mode (a) and in contrast mode before (c) and after (e) contrast agent inflow in case of infection. (b, d, f) Corresponding ultrasound images with the non-union gap in B-mode (b) and in contrast mode before (d) and after (f) contrast agent inflow in the case of an aseptic non-union. Informed patient consent for publication available. a.u. = arbitrary units.
Derived from the largest patient cohort with lower-extremity non-unions examined to date, CEUS can detect infections with a sensitivity and specificity of 85.1% and 88.7%, respectively, based on P (cutoff value = 81.2 a.u.) (
The AMANDUS Project—Advanced Microperfusion Assessed Non-Union Diagnostics with Contrast-Enhanced Ultrasound (CEUS) for the Detection of Infected Lower Extremity Non-Unions.
Adequate evaluation of osseous perfusion via CEUS initially requires identification of the widest visible bone gap in B-mode (Fig. 5), while the transducer basically is oriented in-line with the long bone axis. The primary scan plane for CEUS measurement (Fig. 6) includes an osseous gap that is (i) clearly defined by cortical bone on each side and (ii) well visible without being overlapped by implant material or cortical displacement.
Fig. 5Adjustment of the primary scan plane preceding CEUS examination of a tibial non-union.
Fig. 6Primary scan plane for contrast-enhanced ultrasound examination of a tibial non-union. (a) Transducer orientation in-line with the long bone axis. (b) Clearly depicted non-union gap on corresponding B-mode ultrasound without overlapping material, surrounded by intact cortical bone. Informed patient consent for publication available.
After pre-assessment of the bone gap in B-mode, a bolus of 2.4 mL of UCA is administered. To record subsequent contrast agent flow, a 90-s video clip is adequate, beginning with injection. Contrast-specific signals can already be assessed qualitatively during the examination with respect to the visual kinetics of the contrast agent inflow, but the overall evaluation of CEUS sequences is based mainly on the quantitative features of an ROI placed inside the bone gap.
Tissue transplants
Background
Complications rates after free flap transplantation still amount to 10% (
), with free flap loss from vascular compromise remaining a serious complication. It has been reported that large numbers of the failing flaps could be successfully salvaged after early detection of vascular compromise and immediate intervention (
Dynamic CEUS has become an important imaging method yielding information on tissue perfusion of the cutaneous, subcutaneous and deeper layers of free flaps in a hitherto unparalleled feasible and comprehensive way (
Preoperative imaging for thoracic branch of supraclavicular artery flap: A comparative study of contrast-enhanced ultrasound with three-dimensional reconstruction and color duplex ultrasound.
Postoperative control of functional muscle flaps for facial palsy reconstruction: Ultrasound guided tissue monitoring using contrast enhanced ultrasound (CEUS) and ultrasound elastography.
Contrast-enhanced ultrasonography as a new method for assessing autonomization of pedicled and microvascular free flaps in head and neck reconstructive surgery.
The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
For surgical planning, knowledge of the flow parameter and the number and exact course of the involved vessels is essential, though challenging to acquire because the small diameters of the vessels (in raised free flaps at most 1–2 mm) (
The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
). With its high temporal and spatial resolution, CEUS improves such pre-operative assessment. Also in case of perforator mapping, which is important because of the considerable anatomic variations, CEUS had high accuracy (
Preoperative imaging for thoracic branch of supraclavicular artery flap: A comparative study of contrast-enhanced ultrasound with three-dimensional reconstruction and color duplex ultrasound.
). Thus, CEUS may facilitate the intervention and, in particular, enable a more accurate estimation of the flap size with sufficient blood supply.
The feeding vessels, the optional connection to a bypass, the anastomosis and the transplant's own vessels can also be examined post-operatively. CEUS provides valuable information on vascular compromises (thrombosis, embolism, twisting, kinking or compression), enabling timely surgical revision. Also, in deeply buried flaps, the entire flap tissue can be evaluated for perfusion abnormalities down to the microcirculatory level (
Postoperative control of functional muscle flaps for facial palsy reconstruction: Ultrasound guided tissue monitoring using contrast enhanced ultrasound (CEUS) and ultrasound elastography.
The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version).
). Critical microperfusion of free flaps means a significant difference between compromised flaps and physiologically vascularized soft tissue. It can well be detected using time to peak (TTP) and regional blood volume (RBV) as CEUS quantification parameters. TTP and RBV appear to be the most precise perfusion parameters available, and first critical thresholds of sufficient flap perfusion could empirically be set for both (
Distinct areas with disturbed microperfusion can be detected early with CEUS, independent of the composition of the free flap, so that the identification and characterization (e.g., the exact extent) of hematomas, seromas or partial flap necrosis become possible (
Initially, the whole flap is examined to determine if there are any morphologic abnormalities (e.g., fluid collections). Additionally, the surrounding vessels up to the anastomosis should be delineated for color-coded Doppler sonography (CCDS) and power Doppler-based flow evaluation, which may already identify hemodynamically relevant arterial stenosis or venous thrombosis. To adjust the primary scan plane for CEUS measurement, meaning a representative US slice of the respective flap tissue, the transducer is positioned in the center of the flap.
CEUS procedure
The standardized step-by-step approach that has been applied in this field starts with a bolus injection of 1–2.4 mL of UCA, followed by continuous recording of contrast-specific signaling for 1 min, with the transducer stabilized in the primary scan plane for subsequent quantitative evaluation of a critical flap perfusion level.
The remainder of the procedure focuses on distinct regions with contrast enhancement indicating abnormal local microcirculation, based on reduced signal intensity and/or altered UCA kinetics. For this purpose, the scanning is continued by sweeping from the primary scan plane over the whole flap and the margins to the normal tissue while CEUS data are digitally stored up to 3 min after the initial injection.
If there are any abnormalities, the respective area is selectively scanned after another bolus injection according to the first part of the examination, but now with the transducer stabilized in the conspicuous plane and for more than 1 min. This separate sequence allows for a detailed qualitative evaluation, the findings of which can additionally be quantified by comparing the TIC analyses of contrast-deficient and surrounding tissue.
Muscular determinants of shoulder surgery outcome
Supraspinatus muscle tissue
Background
Considering the notable re-tear rate and variability of functional outcomes after rotator cuff repair (
), the issue of identifying a given predisposition to failure appears to be particularly relevant to choosing adequate treatment strategies in this field. Looking beyond common morphologic criteria by revealing muscular microperfusion, which is accessible via CEUS as a surrogate marker of supraspinatus muscle vitality and function (
b), pre-operative quantification of microperfusion of the supraspinatus muscle tissue could predict the risk of a re-tear within the first 6 mo after repair and correlate it significantly to functional outcome; thus, the latter approach is superior to the use of fatty infiltration and tendon retraction (in magnetic resonance imaging [MRI]) with respect to their predictive potential. In the future, in addition to the intra-individual monitoring of muscle vitality during rehabilitation, CEUS might become useful in routine pre-operative diagnostics when planning rotator cuff surgery. It may optimize the selection of patients who are not likely to benefit from supraspinatus tendon repair but require alternative treatment.
Setting
Seated patients place their arm in neutral position keeping the extended elbow close to the body, while the operator sits behind the shoulder to be examined, with both the patient's and operator's view focused on the US device. The described setting provides easy access to the supraspinatus muscle tissue and enables patients to follow gradual adjustment of different scan planes on the screen as well as to move their arm freely during pre-contrast exercise.
Pre-assessment and primary scan plane
CEUS of the supraspinatus muscle is performed within the area of its maximum cross section, taking advantage of the high muscle/tendon ratio. This requires standardized adjustment of an oblique sagittal plane perpendicular to the muscle's long axis at the suprascapular notch (Fig. 7) (
). For CEUS-based evaluation of supraspinatus muscle perfusion, a slightly modified approach is used under consideration of the following criteria (Fig. 8):
1.
Apparent delineation of the supraspinatus muscle tissue from the overlying trapezius reference muscle, presenting as hyper-echoic line. This might increase the accuracy of placing an ROI within each muscle during the subsequent quantification process.
2.
A distinct osseous boundary (given by the supraspinatus fossa and the scapular spine)
Fig. 7Adjustment of the primary scan plane preceding contrast-enhanced ultrasound examination of the supraspinatus muscle tissue.
Fig. 8Primary scan plane for contrast-enhanced ultrasound examination of the supraspinatus muscle tissue. (a) Transducer positioning in an oblique sagittal plane at the suprascapular notch. (b) Corresponding B-mode and contrast mode ultrasound images; focus and depth settings optimally adapted. Informed patient consent for publication available.
To activate the supraspinatus muscle, the specific pre-contrast exercise consists of 120 s of repeated arm raising up to 90° in the plane of the scapula (frequency of direction change = 1 Hz), with the thumb directed downward in full pronation. After exercise, the patient returns to neutral position and CEUS is started immediately with a bolus injection of 4.8 mL UCA. The corresponding 90-s video clip is analyzed quantitatively.
Deltoid muscle tissue
Background
Muscular CEUS has also shown its diagnostic value when quantifying deltoid muscle microperfusion to peri-operatively assess functional deltoid properties. In an initial study comparing the outcome after open and minimally invasive locked plating of proximal humerus fractures, CEUS was a feasible method to analyze relevant differences in post-operative muscle vitality and soft tissue damage (
). After RSA, the operated shoulders had reduced perfusion kinetics compared with the contralateral side, which significantly correlated with clinical outcome. Moreover, the measured microperfusion reflected the functional difference between patient groups with above-average and below-average outcomes, thereby revealing its potential as a surrogate marker for deltoid function.
On the basis of these findings, a prospective study on dynamic deltoid perfusion before RSA indicated that pre-operative CEUS assessment was highly predictive of deltoid outcome (r = 0.84, p = 0.0004) and revealed patient subgroups with a particular need for individually adapted center of rotation positioning (
Preoperative deltoid assessment by contrast-enhanced ultrasound (CEUS) as predictor for shoulder function after reverse shoulder arthroplasty: a prospective pilot study.
The basic setting for CEUS of the deltoid muscle corresponds to that described for the peri-operative assessment of supraspinatus muscle tissue, but with the patient's palm on his or her thigh. Thus, optimal exposure of the muscle area to be scanned is achieved while fixing the examined arm, which itself is relaxed, as “counterbearing” for transducer stabilization from (postero-)lateral.
Pre-assessment and primary scan plane
To evaluate deltoid microperfusion, we recommend longitudinal adjustment of the acromial portion at its posterior part (transition zone to the spinal portion) (Fig. 9). This area combines, to a certain extent, the acromial portion's property of contributing significantly to deltoid abductor function (
) with the anatomic condition of crossing structures that can be easily used for orientation (teres minor muscle) and quantification (posterior humeral circumflex artery). Finally, the adjusted scan plane visualizes (Fig. 10) the following:
1.
The posterior humeral circumflex artery, which as a standardized reference for quantification has been found to be more feasible than the teres minor muscle, which was initially intended for this purpose (
The surgical neck of the humerus, forming a trough with the humeral shaft that comprises the cross section of the teres minor muscle (now serving primarily as a landmark for transducer positioning besides the bony structures)
3.
An apparent delineation of the deltoid muscle tissue by its fasciae, complying with the criteria for CEUS assessment of the supraspinatus muscle tissue.
Fig. 9Adjustment of the primary scan plane preceding contrast-enhanced ultrasound examination of the deltoid muscle tissue.
Fig. 10Primary scan plane for contrast-enhanced ultrasound examination of the deltoid muscle tissue. (a) Longitudinal transducer orientation at the transition between the acromial and spinal portion of the muscle. (b) Corresponding B-mode and contrast mode ultrasound images; focus and depth settings optimally adapted. Informed patient consent for publication available.
Similar to activation of the supraspinatus muscle, the patient is instructed to repeatedly abduct the extended arm up to 90° for a period of 120 s (frequency of direction change = 1 Hz), but in the coronal plane with neutral rotation of the arm. Afterward, the patient rests her or his palm on the thigh and CEUS is started immediately after bolus injection of 2.4 mL of UCA. Finally, quantitative analysis of the resulting 90-s video clip is performed.
Inflammatory, degenerative and neoplastic MSK pathologies
Inflammatory rheumatic diseases
In the case of inflammatory activity within joints and synovia, it is important to differentiate between active and inactive disease. CEUS techniques have been analyzed for these purposes in a number of regions among patients with inflammatory disorders (
Power Doppler sonography with and without echo-enhancing contrast agent and contrast-enhanced MRI for the evaluation of rheumatoid arthritis of the shoulder joint: Differentiation between synovitis and joint effusion.
A comparison of clinical vs ultrasound determined synovitis in rheumatoid arthritis utilizing gray-scale, power Doppler and the intravenous microbubble contrast agent ‘Sono-Vue’.
Knee osteoarthritis. Efficacy of a new method of contrast-enhanced musculoskeletal ultrasonography in detection of synovitis in patients with knee osteoarthritis in comparison with magnetic resonance imaging.
), predominantly to estimate synovial hypervascularity caused by angiogenesis, which is believed to contribute to articular destruction and erosion (Fig. 11). Some applications focused even further on detectable changes during therapeutic follow-up or the evaluation of soft tissue involvement (
Fig. 11Contrast-enhanced ultrasound pannus hyperperfusion in a patient with clinically active rheumatoid arthritis. Longitudinal dorsal wrist with high-grade enhancement in the synovial proliferation (arrows) after ultrasound contrast agent injection (right side) indicating active joint inflammation. MC = metacarpus; R = radius. Informed patient consent for publication available.
A comparison of clinical vs ultrasound determined synovitis in rheumatoid arthritis utilizing gray-scale, power Doppler and the intravenous microbubble contrast agent ‘Sono-Vue’.
, synovial samples of patients with psoriatic arthritis confirmed the association of CEUS perfusion kinetics with histopathological and immunohistochemical signs of microvascular proliferation, suggesting CEUS is a valid method for assessing synovial hypervascularity (
). However, the exact clinical relevance still needs to be clarified.
Another focus of research is inflammatory myopathies. In this context, CEUS was proposed as an adjuvant method for the detection of acute myositis via muscular hyperperfusion (
) after patients with histologically confirmed dermatomyositis or polymyositis had manifested significantly higher local muscle perfusion in the affected muscles than patients without these diseases (
In chronic tendinopathy, specific histopathological changes in tendon constituents occur, with localized tendon widening, irregular appearance of fiber structure and hypo-echoic areas as common ultrasonographic correlates (
Is vasculo-neural ingrowth the cause of pain in chronic Achilles tendinosis? An investigation using ultrasonography and colour Doppler, immunohistochemistry, and diagnostic injections.
). Moreover, the neovascularization in association with neural ingrowth seen is hypothesized to play a causal role in the presence of pain among affected patients (
Is vasculo-neural ingrowth the cause of pain in chronic Achilles tendinosis? An investigation using ultrasonography and colour Doppler, immunohistochemistry, and diagnostic injections.
Considering the growing interest in sonographic visualization of such neovascularity, CEUS techniques have been found to be favorable according to previous studies on Achilles tendinopathy. While having higher sensitivity than conventional US modalities, they further contributed to the ongoing debate on the clinical value of neovessel detection and proved promising for tendinopathy research (
Soft tissue masses (STMs) are frequently encountered in everyday practice at a relatively high incidence, but still pose a significant challenge because of their imaging features often overlap between those of benign and malignant lesions. Malignant soft tissue sarcomas (STSs) are rare, with an estimated incidence of 1% of overall STMs (
Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978–2001: An analysis of 26,758 cases.
). The foremost aim in the evaluation of such lesions ought to be a rapid radiologic workup and the differentiation of malignant entities from their benign counterparts, as delay in diagnosis and treatment can worsen the prognosis because of greater local complications, metastases and larger surgical resections (
Diagnostic hierarchy of radiological features in soft tissue tumours and proposition of a simple diagnostic algorithm to estimate malignant potential of an unknown mass.
). Despite significant progress in diagnostic imaging, correct classification of malignant soft tissue tumors is rarely achieved based on imaging alone; a guided or open surgical biopsy is usually mandatory.
Various studies based their evaluation of STMs on morphologic features and tumor vascularity using CCDS (
). These proved to be helpful in the differentiation between malignant and benign STMs; however, the high degree of uncertainty remaining does not allow for further therapeutic triage.
CEUS has become a helpful adjunct in the radiologic workup and stratification of STMs: vessels with a diameter as small as 40 µm (
), corresponding to the pre- and post-capillary systems, can be visualized. Contrary to other contrast agents used in MRI, the strictly intravascular microbubble UCA with no relevant interstitial phase can depict actual tumor angiogenesis. This enables the definition of four different perfusion patterns as described by
, which allows for a differentiation of STMs beyond the scope of gray-scale and Doppler/Duplex US as follows (Fig. 12): P1 = non-enhancing STM; P2 = peripherally enhancing STM with central non-enhancing region; P3 = diffusely enhancing STM with patchy non-enhancing areas; P4 = completely homogeneously enhancing STM.
Fig. 12Contrast-enhanced ultrasound perfusion patterns in the diagnostic workup of soft tissue masses. P1 = no enhancement; P2 = peripheral enhancement with central non-enhancing region; P3 = diffuse enhancement with patchy non-enhancing areas; P4 = completely homogeneous enhancement. It has been reported that the majority of soft tissue sarcomas exhibit a P2 or P3 perfusion pattern in contrast to benign soft tissue masses, which usually exhibit a P1 or P4 perfusion pattern (
). This can be explained by analyzing the pathophysiology of STMs: malignant STMs manifest rapid cell proliferation and thus develop a much higher interstitial pressure compared with benign lesions (
). This leads to a central underperfusion, which eventually results, together with pathologic tumor vessels, in areas with necrosis (non-enhancing areas: P2 or P3 pattern). In contrast, benign lesions, which do not outgrow their vital blood supply, are non-enhancing (“pseudotumors”) or exhibit a regular, hierarchic and thus stable angiogenesis (
In evaluation of an STM, radiographic and some known MRI features should be taken into account, in addition to morphologic parameters such as configuration, location, gray-scale and Doppler features (
Diagnostic hierarchy of radiological features in soft tissue tumours and proposition of a simple diagnostic algorithm to estimate malignant potential of an unknown mass.
). All available parameters combined with CEUS can be decisive in a holistic patient workup. Moreover, the definition of vital neoplasm can be depicted via CEUS, and if a subsequent US-guided biopsy is needed, the needle can “target” these areas to minimize the rate of inconclusive histology resulting from biopsy of necrotic tumor areas (
An initial gray-scale and Doppler US is performed to assess the dimensions of the STM and to evaluate the surrounding tissue and intended needle path for a subsequent US-guided biopsy. For CEUS, the probe is placed primarily with its orientation in line with the greatest diameter of the STM.
CEUS procedure
Usually, a single injection of 2.4 mL of UCA is used. Because of the often “multicomponent” tissue texture of STMs (and, thus, acoustic signal loss), it might be necessary to escalate the volume administered (as recommended by the vendor) up to 4.8 mL to optimize the visibility of the CEUS texture of the tumor. After contrast injection, continuous digital cine loops as long as 3 min are acquired. During contrast enhancement, the probe (adjustment unchanged) is moved to both sides along an imaginary axis orthogonal to the primary scan plane so that the whole STM is addressed. Afterward, qualitative assessment of the STM contrast enhancement pattern is performed, enabling the definition of a target area for subsequent US-guided biopsy if requested (Fig. 13).
Fig. 13Ultrasonographic depiction of a histologically verified clear cell sarcoma on the left lower leg of a 47-y-old male patient. (a) B-Mode scan. (b) Power Doppler scan revealing inhomogeneous, mostly peripheral tumour vessels. (c) Contrast-enhanced ultrasound image revealing a P3 perfusion pattern highly suspicious for malignancy. Definition of a target area (red dotted line) for the subsequent ultrasound-guided biopsy. (d) Ultrasound-guided biopsy from the pre-defined region (red dotted line). Informed patient consent for publication available.
Through review of the acquired cine loops, the area with the most pronounced enhancement is defined and correlated with the gray-scale images (some US vendors even provide tools for image superimposition). The probe position is marked on the skin, and biopsy is performed using standardized procedures.
Basic research on muscle perfusion physiology
Apart from the primarily clinical focus on patients who suffer from severe, often chronic conditions, there has been emerging CEUS research on characteristic muscle physiology, which is particularly relevant for healthy and active individuals because of the possible use in sports science/sports medicine.
Early studies on muscular CEUS with high-MI techniques have reported that local blood volume measurements correlated with aerobic capacity (VO2max) and capillary fiber contacts in histology. A great variability in muscle microcirculation at rest was observed, with the highest values for people practicing endurance sports (
Another possibility to investigate muscle perfusion physiology was provided through the application of low-MI CEUS techniques in combination with a continuous infusion of UCA.
During different levels of isometric exercise this method revealed a lower or a higher local blood volume according to
, reflecting the effect of the complex relationship between muscle perfusion regulation and local tissue pressure on UCA signals. CEUS detects not only arterial blood flow but also venous blood flow, and the latter can be reduced during muscle exercise, depending on the individual's fitness level.
Current applied research used CEUS to increase accuracy in the ultrasonographic diagnosis of low-grade muscle lesions (
Contrast-enhanced ultrasound as a new investigative tool in diagnostic imaging of muscle injuries—A pilot study evaluating conventional ultrasound, CEUS, and findings in MRI.
Contrast enhanced ultrasound with second generation contrast agent for the follow-up of lower-extremity muscle-strain-repairing processes in professional athletes.
reported significantly increased PE and wash-in area under the curve parameters for gastrocnemius muscle perfusion compared with baseline in a delayed-onset muscle soreness model, suggesting CEUS is a feasible diagnostic tool even for ultrastructural muscle lesions, with the potential to evaluate relevant preventative and recovery strategies.
Conflict of interest disclosure
The authors declare no competing interests.
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