Ultrasound has become a useful tool in the workup of pediatric patients because of the highly convenient, cost-effective, and safe nature of the examination. With rapid advancements in anatomic and functional ultrasound techniques over the recent years, the diagnostic and interventional utility of ultrasound has risen tremendously. Advanced ultrasound techniques constitute a suite of new technologies that employ microbubbles to provide contrast and enhance flow visualization, elastography to measure tissue stiffness, ultrafast Doppler to deliver high spatiotemporal resolution of flow, three- and four-dimensional technique to generate accurate spatiotemporal representation of anatomy, and high-frequency imaging to delineate anatomic structures at a resolution down to 30 μm. Application of these techniques can enhance the diagnosis of organ injury, viable tumor, and vascular pathologies at bedside. This has significant clinical implications in pediatric patients who are not easy candidates for lengthy MRI or radiation-requiring examination, and are also in need of a highly sensitive bedside technique for therapeutic guidance. To best use the currently available, advanced ultrasound techniques for pediatric patients, it is necessary to understand the diagnostic utility of each technique. In this review, we will educate the readers of emerging ultrasound techniques and their respective clinical applications.
Ultrasound in which advanced techniques are used can enhance the diagnostic sensitivity of conventional grayscale and color Doppler ultrasound while offering additional functional information. In contrast-enhanced ultrasound (CEUS), intravascular microbubble agents are used to highlight perfusion abnormalities associated with various pathologies, including organ injury and residual tumors, which would otherwise be challenging to identify with conventional ultrasound.1,–3 The enhanced diagnostic sensitivity of CEUS can negate the need for further high-cost, cross-sectional imaging requiring sedation.
Elastography is another functional ultrasound technique that allows for the quantification of tissue stiffness, which reflects tissue composition and/or architecture, edema, injury, and perfusion. The technique provides a quantitative or semiquantitative measure of the tissue evaluated. Two main types of elastography include strain and shear elastography. Strain elastography can produce a semiquantitative measure of tissue stiffness by detecting axial displacements arising from either manual compression or internal physiologic motion (eg, respiration and heartbeat). Shear-wave elastography applies high-intensity pulses to deform the tissue and produce laterally propagating shear waves that can be used to quantify stiffness. Elastography is approved by the Food and Drug Administration (FDA) for the evaluation of all abdominal organs in pediatric patients.
Furthermore, improvements in three-dimensional (3D) ultrasound techniques enable accurate quantification and delineation of anatomic structures for improved diagnosis and surgical guidance. The integration of four-dimensional (4D) ultrasound, with the fourth dimension representing time, allows for 3D depiction of moving objects, such as the heart valves in echocardiography. There is ongoing research to simultaneously scan the whole-organ volume without reconstructive postprocessing, which, if successful, will significantly advance the clinical potential of 3D ultrasound.4
Ultrafast Doppler (UfD) is an advanced Doppler technique with significantly higher temporal resolution than conventional Doppler (up to 100 000 frames per second as opposed to 50 frames per second), offering real-time blood volume changes shown to correlate with neuronal activation.5 Moreover, high-resolution imaging in which a frequency of up to 70 MHz (compared with conventional imaging with a frequency of up to 15 MHz) is used can enhance the diagnostic sensitivity of various dermatologic, neuromuscular, vascular, and other superficial pathologies because of the improved resolution in the region close to the transducer.
In this review, we will highlight recent advancements in anatomic and functional ultrasound techniques that have the potential to significantly improve the diagnostic and therapeutic potential of ultrasound. Our goal for the review is to educate the readers of the availability of these emerging ultrasound techniques and their potential clinical applications.
The ultrasound contrast agents are gas-containing, phospholipid-encapsulated microbubbles of 2 to 3 µm in size (compared with 7–8 µm of red blood cells) that generate an increased ultrasound signal because of a high acoustic impedance mismatch. Lumason (Bracco Diagnostics Inc, Monroe, NJ), sulfur hexafluoride gas-filled microbubbles encapsulated by phospholipids, was approved for characterization of focal liver lesions and evaluation of vesicoureteral reflux by the FDA in 2016.6 The technique requires injection of the manually reconstituted contrast agent into a peripheral vein and detecting the signal reflected from the microbubbles flowing in the vessels. Its safety profile is much superior to computed tomography (CT) and MRI contrast agents.7,8 The contrast agent is primarily exhaled and not renally cleared. Because of the excretion through the lungs, the contrast agent can be safely given to patients with renal insufficiency. In addition, it allows for an ultrasound study with contrast, avoiding the radiation of CT and the sedation needed for MRI. These serve as major advantages in pediatric imaging. CEUS is also lower in cost compared with CT or MRI.
Benign Focal Parenchymal Lesions
The main benefit of CEUS in small children is the ability to diagnose certain benign focal lesions, such as hemangioma, focal nodular hyperplasia, or fatty infiltration, obviating the need for expensive radiation or sedation requiring, at times, lengthy cross-sectional imaging. Hemangiomas have a characteristic centripetal pattern of enhancement, with avid peripheral enhancement and progressive mild central enhancement, which can be diagnosed with CEUS alone.9 Grayscale ultrasound and color Doppler findings of these benign focal lesions can be puzzling because the dynamic wash-in and wash-out pattern seen with CEUS cannot be obtained.
We present a challenging case of a large congenital hepatic hemangioma diagnosed with CEUS on initial scanning that would have otherwise been a diagnostic challenge with conventional ultrasound alone (Fig 1). The lesion demonstrated heterogeneous echotexture and an indeterminate color Doppler signal. With a CEUS scan, however, the lesion proved to have avid enhancement in the periphery, to the same degree as the aorta, and partial centripetal filling on day 2 of life (Supplemental Video 1). The diagnosis of hemangioma was made at the time. Subsequent scans obtained monthly until 8 months revealed progressive irregular enhancement of the periphery of the lesion, still enhancing avidly as the aorta, with an increase in the size of the lesion. MRI obtained at 8 months of life revealed the same peripherally avid enhancement pattern seen on CEUS acquired the same month. A biopsy was performed because of the increasing size of the lesion, and the diagnosis of congenital hemangioma was made. Subsequent CEUS of the lesion performed 2 months after the MRI revealed a slight decrease in the size of the lesion and a smoother echotexture and enhancement pattern, most compatible with rapidly involuting congenital hemangioma.
The above case represents an example in which increased CEUS experience and familiarity within the medical community would have prevented a biopsy, which is not without risks, especially because the lesion was seen to regress in size at 10 months of life. Noninvasive monitoring of the lesion with CEUS would have been sufficient. It also highlights the value of CEUS in reducing the number of MRI scans and associated sedation, which has been associated with neurotoxic effects in the developing brain.10,11 Additionally, magnetic resonance contrast administration is posing a challenge because of the gadolinium accumulation in the body. Further benign CEUS enhancement characteristics include well-defined peripheral and/or central vascular pattern (ie, benign lymph nodes, hyperplastic thyroid nodules, focal nodular hyperplasia, and splenic hamartoma), delayed wash out (ie, liver regenerative nodules), and lack of enhancement (ie, hemorrhage, cyst, column of Bertin, and calyceal diverticulum). In summary, CEUS can serve as a diagnostic and/or monitoring tool for many benign lesions without the need for additional imaging and the possibility of a bedside examination.
Malignant Focal Lesions
CEUS permits real-time imaging of dynamic perfusion with high temporal resolution and quantitative analysis of in flow and out flow of the microbubbles through the vessels and within the lesion. Because the vascularization pattern of benign and malignant lesions is different, CEUS can be a useful tool in distinguishing the 2.12 On CEUS, most malignant lesions reveal fast arrival of the contrast agent (wash in) during the arterial phase followed by rapid wash out. The quick wash-out phenomenon is one of the most characteristic features of a malignant lesion because of a nearly complete arterial blood supply and abnormal arterio-venous shunts. Accurate assessment of tumor vascularity is possible because of retention of microbubbles within the intravascular space in contrary to increased permeability of iodinated and gadolinium-based contrast agents.13,–15
The potential spectrum of the clinical application of CEUS in pediatric oncology is broad. Immediate exclusion of malignancy without the need to wait for further imaging studies substantially reduces the stress for parents and their child. In terms of biopsy guidance, CEUS could identify areas of a necrotic versus viable tumor so as not to result in false-negative results (Fig 2). With the technique, serial quantitative estimation of tumor vasculature is feasible for assessment of response to anticancer treatment (Fig 3). Lastly, CEUS could reduce a number of oncologic follow-up examinations with the use of ionizing radiation and/or general anesthesia. In a study in which the authors evaluated the utility of CEUS in children, it was shown that CEUS substantially decreased the need for further evaluation with MRI or CT.16
The degree of microbubble enhancement is reflective of organ perfusion and viability, and CEUS may be used for diagnosis of organ ischemia, injury, or death. CEUS can depict varying degrees of brain injury, as can be seen with postinjury hyperperfusion, and the evolution of reperfusion response has important prognostic implications (Fig 4, Supplemental Video 2). For infants who are critically ill with significant brain injury, timely performance of either 4-vessel cerebral angiography or radionuclide cerebral blood flow studies for diagnosis of brain death is not easy. If further validated against the gold standard examinations, CEUS has the potential to serve as an alternate tool for diagnosis of brain death.17 Moreover, the bedside use of CEUS for diagnosis of trauma has shown much potential because of the portability and repeatability of the examination combined with superior diagnostic sensitivity compared with conventional ultrasound.18,19 In the case of necrotizing enterocolitis, CEUS can serve as a complementary tool for assessing bowel perfusion and identifying bowel ischemia, the diagnosis of which would otherwise be delayed because of the presence of an oscillator causing a false color Doppler signal or the absence of flow in the bowel wall misconstrued as technical limitations of color Doppler (Fig 4, Supplemental Video 3).
In addition, CEUS can be used to assess the degree of inflammation or fibrosis and/or scarring. In Crohn disease, the discernment of fibrotic versus inflammatory bowel strictures has important clinical implications. Inflammatory bowel strictures respond better to anti-inflammatory medications, whereas fibrotic strictures may benefit from surgical resection. Although MRI should be the gold standard for the diagnosis of Crohn disease, its use for routine monitoring of the diseased bowel segment is limited in children because of high cost and sedation needs. In this setting, CEUS may be used for serial monitoring of therapeutic response and evolution of the disease during clinic visits and potentially serve as a comparable tool to MRI by providing a quantifiable dynamic perfusion pattern of the diseased bowel segment. If combined with elastography, an advanced ultrasound technique that can assess tissue stiffness, CEUS may improve our understanding and management of diseased bowel segments with varying degrees of fibrosis and inflammation.20,21
In the 1990s, contrast-enhanced voiding urosonography (ceVUS) was introduced as a safe, radiation-free alternative to voiding cystourethrography (VCUG) in children. The technique consists of administration of microbubbles through a urinary catheter and evaluation for vesicoureteral reflux with ultrasound (Fig 5). Since then, thousands of children have been evaluated with ceVUS for vesicoureteral reflux, with a favorable safety profile. In a study of 1010 children ages 15 days to 17.6 years evaluated with ceVUS, no serious adverse event occurred, and only a few minor events occurred, likely because of catheterization.22 More recent prospective clinical trials in which the authors compared the diagnostic sensitivity of VCUG and ceVUS revealed comparable23 or superior24 diagnostic sensitivity of ceVUS in comparison with the conventional VCUG. The higher sensitivity of ceVUS in the detection of vesicoureteral reflux and the ability to conduct a detailed evaluation of the urethra have enabled ceVUS to replace VCUG.
Ultrasound elastography is a functional imaging technique in which tissue stiffness can be inferred and quantified by studying the alterations in speed of traveling ultrasound waves. The stiffer the tissue, the faster a wave travels. Ultrasound elastography was initially developed by the food industry to evaluate the stiffness, or maturity, of cheeses.25 Since its introduction in 2002 for assessment of liver fibrosis,26 rapid improvements in the technique has resulted in the ability to accurately identify different stages of liver fibrosis for application in a variety of disorders, including nonalcoholic fatty liver disease and metabolic, autoimmune, and veno-occlusive diseases.27,–36
In brief, there are 2 main types of ultrasound elastographies: shear-wave and strain elastography (Fig 6). The former is used to quantify absolute tissue stiffness by applying high-intensity pulses and detecting laterally propagating waves as a result of tissue deformation. The latter is a semiquantitative technique in which manual compression or internal physiologic motion, such as the heartbeat, results in axial displacements reflective of tissue stiffness. The strain elastography is semiquantitative because the exact force used to generate tissue displacement is unknown, but relative tissue stiffness (ie, stiffness of a lesion compared with the surrounding area) can be obtained in the interrogated region of interest.
One of the major benefits of elastography is the reduced need for an invasive liver biopsy, which oftentimes requires moderate sedation to general anesthesia in small children and is associated with a 6% complication risk (up to 0.1% life-threatening).37 Although a biopsy is accepted as the gold standard, it has its own limitations, including sampling error and substantial variability in the staging of histopathologic fibrosis of up to 33% in previous literature.38 There is also no validated histologic scoring system of liver fibrosis for the pediatric population.
Although further research is needed, elastography may be used to diagnosis other pathologies, including severe brain injury,39 fibrotic bowel segment,21,40 and renal fibrosis.41 Noninvasive inference of the severity of brain injury is of clinical importance because invasive intracranial pressure measurements are not without risks. Severe anoxic brain injury can be quantitatively detected by elastography as an increase in stiffness due to brain edema, although the exact biochemical and physiologic basis of such elasticity change in the affected tissue warrants further research.39 Close monitoring of brain injury also permits timely institution of neuroprotective and/or adjunct therapies for improved outcome. In the setting of Crohn disease, in which distinction between fibrosis and inflammation is critical to determining a surgical versus anti-inflammatory medical approach, elastography may be of importance in the diagnosis of inflammatory and/or fibrotic bowel strictures. In patients with chronic kidney disease, elastography may be of prognostic value in identifying those at risk for renal function deterioration.41
UfD is an advanced Doppler technique with a high temporal resolution of >100 000 frames per second compared with the typical 50 frames per second used in conventional color Doppler imaging (Fig 7).42 The technique sends out a plane wave to simultaneous scan a whole field of view rather than transmitting focused beams, as in traditional Doppler techniques. The high-frame rate permits up to a 50-fold increase in sensitivity for blood flow changes in the human brain, which correlate neuronal activity as assessed by EEG.5 In preclinical imaging, cerebral blood volume changes seen on UfD highly correlated with neuronal activity, with a high spatiotemporal resolution of ∼100 mm and 1 millisecond.43,44 Improved sensitivity for slow-flow and smaller vessels is particularly important in rheumatology,42,45 brain vascular imaging,46,47 and carotid flow velocity estimation.48,–50
Note that the super high temporal resolution of UfD surpasses that of functional MRI (fMRI). The high temporal resolution of up to 1 millisecond contrasts with that of traditional fMRI, which is at best 1 second. This has important clinical implications in the neonatal and infant population as fMRI is not routinely performed because of the complexity of the examination, including sedation, transportation, and high cost. It is also highly convenient for intraoperative use and for continuous, noninvasive monitoring of cerebral function during surgeries. Close bedside monitoring of perfusion changes associated with brain injury and/or seizure activity for children of all ages may be feasible with this technique, although further research is required in this regard. Further studies will be needed, however, to understand the potential correlation between fMRI and UfD because the former measures oxygenated blood whereas the latter measures both oxygenated and deoxygenated blood, technically different physiologic parameters. UfD on the other hand is low cost, portable, and easily repeatable without the need for sedation.
3D and 4D Ultrasound
Although 3D ultrasound suffered from long image-processing times during its infancy, current computer technology allows for high speed of image acquisition and reconstruction. In the 3D technology, positional information gained from the transducer or external positional devices is used to reconstruct 3D images from two-dimensional (2D) images. In the case of hydrocephalus, the traditionally used manual quantification of the ventricular size on a 2D plane is more cumbersome and less accurate than the volumetric reconstruction of the ventricular system (Fig 8).52,–57 The 3D technique is also useful in generating accurate organ or tumor volume.58 The 4D technology allows for the incorporation of time dimension into 3D imaging, which can be useful in the imaging of moving objects, such as the heart valves. The 3D-4D technique overcomes the limitations of a 2D technique, namely lengthy acquisition times, operator dependence during multiple sweeps, and mental integration of 2D-acquired images. With further developments of 3D-4D technology, simultaneous acquisition of whole-organ perfusion with UfD or CEUS may be possible, which will drastically change the way in which ultrasound is used in the clinical setting. Further improvements will be needed to minimize artifacts associated with 3D-4D technology59 that may cause diagnostic challenges.
The frequency range of medical ultrasound systems for most scanners is from 2 to 20 MHz. Recently, ultrasound systems of much higher frequency ranges have been introduced to the clinical setting, permitting a significant increase in resolution. VisualSonics ultrahigh-resolution ultrasound systems (FUJIFILM VisualSonics, Inc, Toronto, Canada), used for preclinical studies for the past 10 years, are now FDA approved for clinical applications. Note that the higher frequency peak of up to 70 MHz provides a tremendous increase in resolution compared with that of conventional ultrasound systems, permitting resolution down to 30 μm. Such resolution surpasses that of CT or MRI. Note that an increased frequency results in an increase in ultrasound attenuation in tissues, which means that the use of the system is limited to the first 3 cm of the body. Such resolution can be used to depict single hair follicles growing out of the skin.
The best applications of the high-resolution ultrasound system are neonatology, neuromusculoskeletal, dermatology, lymphatic, vascular, thyroid, and other small-part imaging.60,–66 Further neuromusculoskeletal application of this technique would be helpful for guided superficial nerve blocks or reconstructive surgeries. Higher resolution imaging of the subungual space, moreover, can help assess the integrity of the subungual vessels (terminal branches of the proper digital artery) in the setting of trauma or help characterize various types of benign and malignant tumors affecting the subungual space (Fig 9). A variety of pediatric venous diseases leading to the formation of debris or thrombus in the superficial and deep veins can be evaluated with high-resolution ultrasound. Other applications include improved characterization of nerve fascicles, large- and small-vessel intima-media thickness, internal contents of peripheral veins, and salivary glands (Fig 10). Thyroid nodules, superficial vascular anomalies, and ocular pathology, especially in small children, would also be better evaluated with high-resolution imaging.
It is important to note that for evaluation of superficial soft-tissue abnormalities in small children, ultrasound provides higher spatial resolution than MRI. The spatial resolution of a high-resolution ultrasound scanner is in micrometers, whereas that of MRI is in millimeters. With the availability of FDA-approved ultrasound contrast, ultrasound can now provide dynamic enhancement information similar to multiphase contrast-enhanced MRI. Moreover, sedation required for MRI of most small children is not without risks. Although the diagnostic benefits of MRI should be acknowledged, the awareness that, in some circumstances, advanced ultrasound techniques can provide the necessary diagnostic information is worth noting. In referral of pediatric patients to radiologic exams, such knowledge would be beneficial.
Conclusions and Future Directions
Rapid advancements in ultrasound techniques are changing the role of ultrasound in the management of a pediatric patient. Ultrasound is not merely a screening tool that precedes cross-sectional examinations; it is a critical tool in disease diagnosis and monitoring as well as therapeutic guidance, including as a point-of-care modality. The aforementioned techniques now offer functional information, including dynamic perfusion, tissue stiffness, and hemodynamic changes at the spatiotemporal resolution surpassing that of MRI. Improved 3D-4D and high-resolution techniques additionally serve to enhance the diagnostic potential of ultrasound. Combined with portability, low cost, lack of the need for radiation and sedation, and safety, ultrasound in which advanced techniques are used can serve as a useful clinical tool in the management of pediatric patients.
Further research in validating the emerging ultrasound techniques is ongoing. CEUS, for instance, is increasingly being explored for novel applications besides focal liver lesions and vesicoureteral reflux. In the case of elastography, the exact histopathologic and physiologic mechanisms behind changes in quantitatively measured tissue stiffness warrant further study. The continued work in this regard will improve our understanding of the parameters measured with advanced ultrasound techniques and help generate standardized guidelines to help discern healthy from diseased and/or injured organs.
Dr Hwang conceptualized and wrote the manuscript; Drs Piskunowicz and Darge contributed to the writing and image acquisition; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
This trial has been registered at www.clinicaltrials.gov (identifiers NCT03549507 and NCT03549520).
FUNDING: Funded by the National Institutes of Health KL2 award and Radiological Society of North America Research Scholar Grant (Dr Hwang) and National Science Center grant DEC-2012/05/B/NZ5/01554 (Dr Piskunowicz). Funded by the National Institutes of Health (NIH).
contrast-enhanced voiding urosonography
Food and Drug Administration
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: Dr Hwang has received funding from the National Institutes of Health KL2 award. Dr Piskunowicz has received funding from National Science Center grant DEC-2012/05/B/NZ5/01554. Dr Darge has financial relationships with Bracco Diagnostics Inc, Lantheus Medical Imaging, Philips Healthcare, and Siemens Healthineers.