Unique model of chronic hypoxia in fetal lambs demonstrates abnormal contrast-enhanced ultrasound brain perfusion.

BACKGROUND: Children with congenital heart disease (CHD) demonstrate long-term neurodevelopmental impairments. We investigated contrast-enhanced ultrasound (CEUS) cerebral perfusion in a fetal animal model exposed to sub-physiologic oxygen at equivalent levels observed in human fetuses with CHD. METHODS: Fifteen fetal lambs [hypoxic animals (n = 9) and normoxic controls (n = 6)] maintained in an extrauterine environment underwent periodic brain CEUS. Perfusion parameters including microvascular flow velocity (MFV), transit time, and microvascular blood flow (MBF) were extrapolated from a standardized plane; regions of interest (ROI) included whole brain, central/thalami, and peripheral parenchymal analyses. Daily echocardiographic parameters and middle cerebral artery (MCA) pulsatility indices (PIs) were obtained. RESULTS: Hypoxic lambs demonstrated decreased MFV, increased transit time, and decreased MBF (p = 0.026, p = 0.016, and p < 0.001, respectively) by whole brain analyses. MFV and transit time were relatively preserved in the central/thalami (p = 0.11, p = 0.08, p = 0.012, respectively) with differences in the peripheral parenchyma (all p < 0.001). In general, cardiac variables did not correlate with cerebral CEUS perfusion parameters. Hypoxic animals demonstrated decreased MCA PI compared to controls (0.65 vs. 0.78, respectively; p = 0.027). CONCLUSION: Aberrations in CEUS perfusion parameters suggest that in environments of prolonged hypoxia, there are regional microvascular differences incompletely characterized by MCA interrogation offering insights into fetal conditions which may contribute to patient outcomes. IMPACT: This work utilizes CEUS to study cerebral microvascular perfusion in a unique fetal animal model subjected to chronic hypoxic conditions equal to fetuses with congenital heart disease. CEUS demonstrates altered parameters with regional differences that are incompletely characterized by MCA Doppler values. These findings show that routine MCA Doppler interrogation may be inadequate in assessing microvascular perfusion differences. To our knowledge, this study is the first to utilize CEUS to assess microvascular perfusion in this model. The results offer insight into underlying conditions and physiological changes which may contribute to known neurodevelopmental impairments in those with congenital heart disease.

The Performance of Flash Replenishment Contrast-Enhanced Ultrasound for the Qualitative Assessment of Kidney Lesions in Patients with Chronic Kidney Disease.

We investigated the accuracy of CEUS for characterizing cystic and solid kidney lesions in patients with chronic kidney disease (CKD). Cystic lesions are assessed using Bosniak criteria for computed tomography (CT) and magnetic resonance imaging (MRI); however, in patients with moderate to severe kidney disease, CT and MRI contrast agents may be contraindicated. Contrast-enhanced ultrasound (CEUS) is a safe alternative for characterizing these lesions, but data on its performance among CKD patients are limited. We performed flash replenishment CEUS in 60 CKD patients (73 lesions). Final analysis included 53 patients (63 lesions). Four readers, blinded to true diagnosis, interpreted each lesion. Reader evaluations were compared to true lesion classifications. Performance metrics were calculated to assess malignant and benign diagnoses. Reader agreement was evaluated using Bowker's symmetry test. Combined reader sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignant lesions were 71%, 75%, 45%, and 90%, respectively. Sensitivity (81%) and specificity (83%) were highest in CKD IV/V patients when grouped by CKD stage. Combined reader sensitivity, specificity, PPV, and NPV for diagnosing benign lesions were 70%, 86%, 91%, and 61%, respectively. Again, in CKD IV/V patients, sensitivity (81%), specificity (95%), and PPV (98%) were highest. Inter-reader diagnostic agreement varied from 72% to 90%. In CKD patients, CEUS is a potential low-risk option for screening kidney lesions. CEUS may be particularly beneficial for CKD IV/V patients, where kidney preservation techniques are highly relevant.

Contrast-enhanced subharmonic aided pressure estimation for assessment of intracranial pressure in vivo.

BACKGROUND: Intracranial pressure (ICP) monitoring in children currently requires invasive techniques. Subharmonic aided pressure estimation (SHAPE) uses contrast-enhanced ultrasound (CEUS) to measure intravascular and interstitial pressure, but utility in ICP measurements has yet to be explored. OBJECTIVE: The objective of this study was to investigate SHAPE as a novel tool for noninvasive ICP measurements in fetal lambs. MATERIALS AND METHODS: Eighteen fetal lambs at 107-139 days gestational age (term = 145 days) underwent subdural ICP catheter placement. The brain was imaged in the coronal plane in CEUS mode optimized for SHAPE, while infusing an US contrast agent into the fetal circulation. After SHAPE calibration, saline was infused via the subdural catheter to increase ICP. Five-second SHAPE cine clips were obtained at various ICPs. Subharmonic intensity values of the whole brain and thalami were correlated with ICP values using mixed effects linear regression analyses and the strength of the relationship was evaluated by Spearman's rank-order correlation. RESULTS: Forty-nine experiments produced 723 datapoints, including SHAPE intensity values and mean ICP measurements. There was a statistically significant inverse relationship between SHAPE intensity values and ICP measurements in the whole brain and thalami (median rho value - 0.58 and - 0.56, respectively). CONCLUSION: SHAPE intensity values of the brain demonstrate an inverse and statistically significant correlation with in vivo ICP measurements in an animal model.

Brain Targeted Xenon Protects Cerebral Vasculature After Traumatic Brain Injury.

Abstract Cerebrovascular dysfunction following traumatic brain injury (TBI) is a well-characterized phenomenon. Given the therapeutic potential of xenon, we aimed to study its effects after localized delivery to the brain using microbubbles. We designed xenon-containing microbubbles stabilized by dibehenoylphosphatidylcholine (DBPC) and polyethylene glycol (PEG) attached to saturated phospholipid (DPSE-PEG5000). Using a pig model of TBI, these microbubbles were intravenously injected, and ultrasound was used to release xenon at the level of the carotid artery. The control group received perfluorobutane containing microbubbles. Diffusion tensor imaging (DTI) showed areas of higher fractional anisotropy for pigs receiving xenon microbubbles compared to the control group at 1 day after injury. Radial diffusivity analysis showed that this effect was mainly the result of acute edema. Pigs were euthanized at 5 days, and the brain tissues of xenon-treated animals showed reduction of perivascular inflammation and blood-brain barrier disruption. Endothelial cell culture experiments showed that glutamate reduces tight junction protein zona occludens-1 (ZO-1), but treatment with xenon microbubbles attenuates this effect. Xenon treatment protects cerebrovasculature and reduces astroglial reactivity after TBI. Further, these data support the future use of localized delivery of various therapeutic agents for brain injury using microbubbles in order to limit systemic side effects and reduce costs.

Transtemporal brain contrast-enhanced ultrasound in children: preliminary experience in patients without neurological disorders.

AIM: To evaluate the use of transtemporal brain contrast-enhanced ultrasound (CEUS) to assess cerebral blood perfusion in a cohort of children without neurological disorders. METHODS: We included pediatric patients who were undergoing a clinically-indicated CEUS study. Brain scans were performed with a Siemens Sequoia scanner and a 4V1 transducer, that was placed on the left transtemporal bone. Brain scans were performed simultaneously with the images of the clinically-indicated organ of interest. Qualitative and quantitative analysis was performed to evaluate the hemispherical blood flow at the level of the midbrain during the wash-in and wash-out phases of the time-intensity curve. Clinical charts were reviewed to evaluate post-CEUS adverse events. RESULTS: Five patients were evaluated (mean age 5.8 ± 5.1 years). Qualitatively, more avid enhancement in the midbrain than the cortex was observed. Structures depicted ranged between the centrum semiovale at the level of the lateral ventricles and the midbrain. A quantitative analysis conducted on four patients demonstrated less avid perfusion on the contralateral (i.e. right) side, with a mean left/right ratio ranging between 1.51 and 4.07. In general, there was a steep positive wash-in slope starting at approximately 10 s after contrast injection, reaching a peak intensity around 15-26 s on the left side, and 17-29 s on the right side. No adverse events were reported. CONCLUSION: Transtemporal brain CEUS is feasible and safe in the pediatric population and allows qualitative and quantitative assessment of cerebral perfusion.

A novel quantitative approach to evaluate femoral head perfusion by contrast-enhanced ultrasound: A pilot study in infants with developmental dysplasia of the hip.

Avascular necrosis (AVN) is a major morbidity that can occur after surgical reduction of a hip with developmental dysplasia. Early detection of changes in femoral head perfusion during surgery may help detect a hip at risk for AVN and guide intraoperative management. Contrast-enhanced ultrasound (CEUS) can be employed for visualization of femoral head perfusion. In this study we evaluate a quantitative CEUS technique to assess femoral head perfusion pre- and post-surgical reduction. CEUS images were obtained following a bolus injection of an ultrasound contrast agent, prior to and again following surgical reduction and casting. An image processing technique called delta projection was used to quantify hip perfusion, measuring peak enhancement (PE) and perfusion index (PI). We analyzed CEUS images of the hips of eight patients, including seven females, whose ages ranged from 4 months to 1 year. In five hips, perfusion increased following surgery, with a mean pre-surgery PE of 6.7 ±2.5(± SE) and PI of 10.5 ±6.3; and a post-reduction PE of 13.1±6.1 (p=0.07) and PI of 14.2 ±6.2 (p=0.008). The change in contrast visualization was observed to be greater within the central aspect of the cartilaginous femoral epiphysis. The proposed technique can quantify pre- and post-surgical perfusion changes on CEUS images in patients with developmental dysplasia. This quantitative technique may provide a more objective and accurate assessment of changes in femoral head perfusion that may have the potential to be indicative of the risk of developing AVN.

Association of Contrast-Enhanced Ultrasound-Derived Kidney Cortical Microvascular Perfusion with Kidney Function.

Background: Individuals with chronic kidney disease (CKD) have decreased kidney cortical microvascular perfusion, which may lead to worsening kidney function over time, but methods to quantify kidney cortical microvascular perfusion are not feasible to incorporate into clinical practice. Contrast-enhanced ultrasound (CEUS) may quantify kidney cortical microvascular perfusion, which requires further investigation in individuals across the spectrum of kidney function. Methods: We performed CEUS on a native kidney of 83 individuals across the spectrum of kidney function and calculated quantitative CEUS-derived kidney cortical microvascular perfusion biomarkers. Participants had a continuous infusion of the microbubble contrast agent (Definity) with a flash-replenishment sequence during their CEUS scan. Lower values of the microbubble velocity (ß) and perfusion index (ß×A) may represent lower kidney cortical microvascular perfusion. Multivariable linear regression models tested the associations of the microbubble velocity (ß) and perfusion index (ß×A) with estimated glomerular filtration rate (eGFR). Results: Thirty-eight individuals with CKD (mean age±SD 65.2±12.6 years, median [IQR] eGFR 31.5 [18.9-41.5] ml/min per 1.73 m2), 37 individuals with end stage kidney disease (ESKD; age 54.8±12.3 years), and eight healthy volunteers (age 44.1±15.0 years, eGFR 117 [106-120] ml/min per 1.73 m2) underwent CEUS without side effects. Individuals with ESKD had the lowest microbubble velocity (ß) and perfusion index (ß×A) compared with individuals with CKD and healthy volunteers. The microbubble velocity (ß) and perfusion index (ß×A) had moderate positive correlations with eGFR (ß: rs=0.44, P<0.001; ß×A: rs=0.50, P<0.001). After multivariable adjustment, microbubble velocity (ß) and perfusion index (ß×A) remained significantly associated with eGFR (change in natural log transformed eGFR per 1 unit increase in natural log transformed biomarker: ß, 0.38 [95%, CI 0.17 to 0.59]; ß×A, 0.79 [95% CI, 0.45 to 1.13]). Conclusions: CEUS-derived kidney cortical microvascular perfusion biomarkers are associated with eGFR. Future studies are needed to determine if CEUS-derived kidney cortical microvascular perfusion biomarkers have prognostic value.

Can Ultrasound-Guided Xenon Delivery Provide Neuroprotection in Traumatic Brain Injury?

Traumatic brain injury (TBI) is associated with high mortality and morbidity in children and adults. Unfortunately, there is no effective management for TBI in the acute setting. Rodent studies have shown that xenon, a well-known anesthetic gas, can be neuroprotective when administered post-TBI. Gas inhalation therapy, however, the approach typically used for administering xenon, is expensive, inconvenient, and fraught with systemic side effects. Therapeutic delivery to the brain is minimal, with much of the inhaled gas cleared by the lungs. To bridge major gaps in clinical care and enhance cerebral delivery of xenon, this study introduces a novel xenon delivery technique, utilizing microbubbles, in which a high impulse ultrasound signal is used for targeted cerebral release of xenon. Briefly, an ultrasound pulse is applied along the carotid artery at the level of the neck on intravenous injection of xenon microbubbles (XeMBs) resulting in release of xenon from microbubbles into the brain. This delivery technique employs a hand-held, portable ultrasound system that could be adopted in resource-limited environments. Using a high-fidelity porcine model, this study demonstrates the neuroprotective efficacy of xenon microbubbles in TBI for the first time.

The fetal lamb model of congenital diaphragmatic hernia shows altered cerebral perfusion using contrast enhanced ultrasound.

BACKGROUND: Neurodevelopmental impairment is common in survivors of congenital diaphragmatic hernia (CDH). Altered cerebral perfusion in utero may contribute to abnormal brain development in CDH patients. METHODS: 5 fetal lambs with surgical left-CDH and 5 controls underwent transuterine cranial Doppler and contrast enhanced ultrasound (CEUS). Global and regional perfusion metrics were obtained. Biometric and perfusion data were compared between groups via nonparametric Mann Whitney U test and Spearman's rank order correlation. RESULTS: No significant differences in cerebral Doppler measurements were identified between groups. By CEUS, CDH animals demonstrated significantly decreased global brain perfusion and increased transit time. With focal regions-of-interest (ROIs), there was a tendency towards decreased perfusion in the central/thalamic region in CDH but not in the peripheral brain parenchyma. Transit time was significantly increased in both ROIs in CDH, whereas flux rate was decreased in the central/thalamic region but not the peripheral brain parenchyma. Biometric CDH severity was correlated to perfusion deficit. There was no difference in cardiomyocyte histology. CONCLUSION: The fetal lamb model of CDH shows altered cerebral perfusion as measured by CEUS, correlating to disease severity. This suggests a physiological abnormality in fetal cerebrovascular perfusion that may contribute to abnormal brain development and neurodevelopmental impairment in survivors.

Contrast-Enhanced Ultrasound of Brain Perfusion in Cardiopulmonary Resuscitation.

ABSTRACT: To evaluate the feasibility and potential utility of contrast-enhanced ultrasound for real-time imaging of whole-brain perfusion during cardiopulmonary resuscitation (CPR), cardiac arrest was induced in 8- to 7-week-old 10-kg piglets ( Sus scrofa domesticus ). Contrast-enhanced ultrasound was performed through a parietal cranial window in the coronal plane visualizing the thalami during hemodynamic-directed CPR. Whole-brain mean and maximum pixel intensities in each slice during resuscitation were calculated. Piglets were monitored for 24 hours postarrest. Seven piglets achieved return of spontaneous circulation and 6 survived to 24 hours. Of the 6 surviving piglets, 2 piglets demonstrated greater intra-CPR brain enhancement at maximum 73.2% and 42.1% and mean 36.7% and 31.9% enhancement above background, respectively, compared with maximum 5.8%, 22.9%, 6.0%, and 26.6% and mean 5.1%, 8.9%, 2.9%, and 6.6% above background, respectively, in the other 4. Intra-CPR average mean arterial pressures were similar between all 6 surviving piglets. One piglet achieved return of spontaneous circulation but expired 10 minutes later with enhancement maximum 45.2% and mean 18.9% enhancement above background. The final piglet did not achieve return of spontaneous circulation and exhibited minimal enhancement at maximum 2.8% and mean 0.9% enhancement above background. Contrast-enhanced ultrasound can detect brain perfusion during CPR, identifying a spectrum of cerebral blood flow responses in the brain despite similar systemic hemodynamics. This novel application can form the basis for future large animal model studies and eventually human clinical studies to further explore the neurologic implications of cerebral blood flow responses during resuscitation and stimulate novel strategies for optimizing brain perfusion restoration.

Cerebral microcirculation mapped by echo particle tracking velocimetry quantifies the intracranial pressure and detects ischemia.

Affecting 1.1‰ of infants, hydrocephalus involves abnormal accumulation of cerebrospinal fluid, resulting in elevated intracranial pressure (ICP). It is the leading cause for brain surgery in newborns, often causing long-term neurologic disabilities or even death. Since conventional invasive ICP monitoring is risky, early neurosurgical interventions could benefit from noninvasive techniques. Here we use clinical contrast-enhanced ultrasound (CEUS) imaging and intravascular microbubble tracking algorithms to map the cerebral blood flow in hydrocephalic pediatric porcine models. Regional microvascular perfusions are quantified by the cerebral microcirculation (CMC) parameter, which accounts for the concentration of micro-vessels and flow velocity in them. Combining CMC with hemodynamic parameters yields functional relationships between cortical micro-perfusion and ICP, with correlation coefficients exceeding 0.85. For cerebral ischemia cases, the nondimensionalized cortical micro-perfusion decreases by an order of magnitude when ICP exceeds 50% of the MAP. These findings suggest that CEUS-based CMC measurement is a plausible noninvasive method for assessing the ICP and detecting ischemia.

3D Harmonic and Subharmonic Imaging for Characterizing Breast Lesions: A Multi-Center Clinical Trial.

OBJECTIVE: Breast cancer is the most frequent type of cancer among women. This multi-center study assessed the ability of 3D contrast-enhanced ultrasound to characterize suspicious breast lesions using clinical assessments and quantitative parameters. METHODS: Women with suspicious breast lesions scheduled for biopsy were enrolled in this prospective, study. Following 2D grayscale ultrasound and power Doppler imaging (PDI), a contrast agent (Definity; Lantheus) was administrated. Contrast-enhanced 3D harmonic imaging (HI; transmitting/receiving at 5.0/10.0 MHz), as well as 3D subharmonic imaging (SHI; transmitting/receiving at 5.8/2.9 MHz), were performed using a modified Logiq 9 scanner (GE Healthcare). Five radiologists independently scored the imaging modes (including standard-of-care imaging) using a 7-point BIRADS scale as well as lesion vascularity and diagnostic confidence. Parametric volumes were constructed from time-intensity curves for vascular heterogeneity, perfusion, and area under the curve. Diagnostic accuracy was determined relative to pathology using receiver operating characteristic (ROC) and reverse, step-wise logistical regression analyses. The κ-statistic was calculated for inter-reader agreement. RESULTS: Data were successfully acquired in 219 cases and biopsies indicated 164 (75%) benign and 55 (25%) malignant lesions. SHI depicted more anastomoses and vascularity than HI (P < .021), but there were no differences by pathology (P > .27). Ultrasound achieved accuracies of 82 to 85%, which was significantly better than standard-of-care imaging (72%; P < .03). SHI increased diagnostic confidence by 3 to 6% (P < .05), but inter-reader agreements were medium to low (κ < 0.52). The best regression model achieved 97% accuracy by combining clinical reads and parametric SHI. CONCLUSIONS: Combining quantitative 3D SHI parameters and clinical assessments improves the characterization of suspicious breast lesions.

Intracranial Pressure and Cerebral Hemodynamic Monitoring After Cardiac Arrest in Pediatric Pigs Using Contrast Ultrasound-Derived Parameters.

OBJECTIVES: We explore the correlation of contrast-enhanced ultrasound (CEUS) parameters to intracranial pressure (ICP) in a porcine experimental model of pediatric cardiac arrest. METHODS: Eleven pediatric pigs underwent electrically induced cardiac arrest followed by cardiopulmonary resuscitation. ICP was measured using intracranial bolt monitor and CEUS was monitored through a cranial window. Various CEUS parameters were monitored at baseline, immediately post return of spontaneous circulation (ROSC), 1 hour-post ROSC, and 3 hours post-ROSC. RESULTS: There was significant ICP correlation with wash-out slope assessed by CEUS time intensity curve analysis at immediate post-ROSC. At 3 hours post-ROSC there was also significant negative correlation between ICP and peak enhancement which may be due to the evolution of anoxic injury. CONCLUSION: The use of CEUS in assessing disruption of cerebral hemodynamics and ICP post cardiac arrest will need future validation and comparison to other imaging modalities. The correlation between CEUS parameters and ICP may be due to the alterations in cerebral autoregulation that result from anoxic brain injury.

Advanced Ultrasound Techniques for Differentiation of Benign Versus Malignant Thyroid Nodules: A Review.

ABSTRACT: Grayscale ultrasound (US) is decisive in stratifying which thyroid nodules benefit from fine-needle aspiration to evaluate for malignancy. Unfortunately, a significant percentage of nodules remain indeterminate.Herein, we review the clinical considerations and diagnostic accuracy of advanced US, Doppler US, contrast-enhanced US, and US elastography techniques in the evaluation of indeterminate nodules.We conclude that these techniques may be used in combination with grayscale US to improve the assessment of lesion vascularity and tissue property.

Ultrasound contrast agents: microbubbles made simple for the pediatric radiologist.

The ability to provide prompt, real-time, easily accessible and radiation-free diagnostic assessments makes ultrasound (US) one of the most versatile imaging modalities. The introduction and development of stable microbubble-based ultrasound contrast agents (UCAs) in the early 1990s improved visualization of complex vascular structures, overcoming some of the limitations of B-mode and Doppler imaging. UCAs have been used extensively in the adult population to visualize vasculature and to evaluate perfusion and blood flow dynamics in organs and lesions. Since the first observations that air bubbles within a liquid can generate a strong echogenic effect, to the early makeshift approaches with agitated saline, and later to the development of industrially produced and federally approved UCAs, these agents have evolved to become both clinically and commercially viable. Perhaps the most exciting potential of UCAs is being uncovered by current research that explores the use of these agents for molecular imaging and therapeutic applications. As contrast-enhanced ultrasound (CEUS) becomes more widely available, it is important for pediatric radiologists to understand the physics of the interaction between the US signal and the microbubbles in order to properly utilize them for the highest level of diagnostic imaging and interventions. In this article we introduce the composition of UCAs and the physics of their behavior in US, and we offer a brief history of their development over the last decades.

Translational research in pediatric contrast-enhanced ultrasound.

The role of contrast-enhanced ultrasound (CEUS) imaging is being widely explored by various groups for its use in the pediatric population. Clinical implementation of new diagnostic or therapeutic techniques requires extensive and meticulous preclinical testing and evaluation. The impact of CEUS will be determined in part by the extent to which studies are oriented specifically toward a pediatric population. Rather than simply applying principles and techniques used in the adult population, these studies are expected to advance and augment preexisting knowledge with pediatric-specific information. To further develop this imaging modality for use in children, pediatric-focused preclinical research is essential. In this paper we describe the development and implementation of the pediatric-specific preclinical animal and phantom models that are being used to evaluate CEUS with the goal of clinical translation to children.

The Wash-Out of Contrast-Enhanced Ultrasound for Evaluation of Hypoxic Ischemic Injury in Neonates and Infants: Preliminary Findings.

ABSTRACT: We evaluated the use of quantitative contrast-enhanced ultrasound (CEUS) to study wash-out behavior of ultrasound contrast agents in the pediatric brain in cases of hypoxic ischemic injury (HII). Six neonates and young infants were imaged using CEUS for suspected HII in the Neonatal Intensive Care Unit/Pediatric Intensive Care Unit. After receiving a bolus of ultrasound contrast agent Lumason (Bracco Diagnostics Inc.), analysis was performed in the whole brain, cortex, cortical/subcortical gray and white matter and central gray nuclei to quantify wash-out metrics and ratios. On magnetic resonance imaging clinical imaging findings, 3 children were classified as unaffected and 3 with classical imaging findings consistent with HII. A lower wash-out rate was found in the case of HII compared with the unaffected cases. Here, we present initial work exploring the wash-out behavior for differentiation between unaffected and HII in the brain. These preliminary findings are indicative of altered hemodynamics in HII and are promising for the potential use of CEUS to quantitatively differentiate between the unaffected and HII brain. Little is known about the CEUS wash-out dynamics, especially in the setting of the pediatric brain injury. Our preliminary findings are encouraging and warrant further investigation into the mechanisms behind delayed clearance of the ultrasound contrast agent in the setting of HII.

Emerging contrast-enhanced ultrasound applications in children.

Ultrasound contrast agent (UCA) use in radiology is expanding beyond traditional applications such as evaluation of liver lesions, vesicoureteral reflux and echocardiography. Among emerging techniques, 3-D and 4-D contrast-enhanced ultrasound (CEUS) imaging have demonstrated potential in enhancing the accuracy of voiding urosonography and are ready for wider clinical adoption. US contrast-based lymphatic imaging has been implemented for guiding needle placement in MR lymphangiography in children. In adults, intraoperative CEUS imaging has improved diagnosis and assisted surgical management in tumor resection, and its translation to pediatric brain tumor surgery is imminent. Because of growing interest in precision medicine, targeted US molecular imaging is a topic of active preclinical research and early stage clinical translation. Finally, an exciting new development in the application of UCA is in the field of localized drug delivery and release, with a particular emphasis on treating aggressive brain tumors. Under the appropriate acoustic settings, UCA can reversibly open the blood-brain barrier, allowing drug delivery into the brain. The aim of this article is to review the emerging CEUS applications and provide evidence regarding the feasibility of these applications for clinical implementation.

Utility of contrast-enhanced ultrasound for solid mass surveillance and characterization in children with tuberous sclerosis complex: an initial experience.

BACKGROUND: Patients with tuberous sclerosis complex (TSC) can develop solid kidney masses from childhood. Imaging surveillance is done to detect renal cell carcinoma (RCC) and angiomyolipomas (AML), including AMLs at risk for hemorrhage. Intravenous contrast-enhanced ultrasound (CEUS) may be useful for screening as ultrasound is well tolerated by children and ultrasound contrast agents (UCA) are not nephrotoxic. METHODS: Retrospective review of kidney CEUS exams of pediatric TSC patients. Qualitative CEUS analysis by consensus of 3 radiologists assessed rate, intensity, and pattern of lesion enhancement. Quantitative CEUS analysis was performed using Vuebox®. Where available, abdominal MRI was analyzed qualitatively for the same features and quantitatively by in-house-developed software. Time-intensity curves were generated from both CEUS and MRI where possible. Appearance of lesions were compared between CEUS and MRI and histology where available. RESULTS: Nine masses in 5 patients included one histologically proven RCC and 8 AMLs diagnosed by imaging. Quantitative CEUS of RCC showed malignant features including increased peak enhancement 162%, rapid wash-in rate 162%, and elevated washout rate 156% compared to normal kidney tissue; versus AML which was 68%, 105%, and 125%, respectively. All masses were hypoenhancing on MRI compared to normal kidney tissue; MR dynamic contrast study offered no distinction between RCC and AML. The only MRI feature differentiating RCC from AML was absence of fat. CONCLUSION: Temporal resolution afforded by CEUS was useful to distinguish malignant from benign kidney masses. CEUS may prove useful for screening, characterizing, and follow-up of kidney lesions in pediatric TSC patients.

Contrast-enhanced ultrasound of the pediatric brain.

Brain contrast-enhanced ultrasound (CEUS) is an emerging application that can complement gray-scale US and yield additional insights into cerebral flow dynamics. CEUS uses intravenous injection of ultrasound contrast agents (UCAs) to highlight tissue perfusion and thus more clearly delineate cerebral pathologies including stroke, hypoxic-ischemic injury and focal lesions such as tumors and vascular malformations. It can be applied not only in infants with open fontanelles but also in older children and adults via a transtemporal window or surgically created acoustic window. Advancements in CEUS technology and post-processing methods for quantitative analysis of UCA kinetics further elucidate cerebral microcirculation. In this review article we discuss the CEUS examination protocol for brain imaging in children, current clinical applications and future directions for research and clinical uses of brain CEUS.