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Contrast-Enhanced
Ultrasound in
Pediatric Imaging
Paul S. Sidhu
Maria E. Sellars
Annamaria Deganello
Editors
123
Contrast-Enhanced Ultrasound
in Pediatric Imaging
Paul S. Sidhu • Maria E. Sellars
Annamaria Deganello
Editors
Contrast-Enhanced
Ultrasound in Pediatric
Imaging
Editors
Paul S. Sidhu
Department of Radiology
King’s College Hospital
London
UK
Annamaria Deganello
Department of Radiology
King’s College Hospital
London
UK
Maria E. Sellars
Department of Radiology
King’s College Hospital
London
UK
ISBN 978-3-030-49690-6 ISBN 978-3-030-49691-3 (eBook)
https://doi.org/10.1007/978-3-030-49691-3
© Springer Nature Switzerland AG 2021
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
part of the material is concerned, specically the rights of translation, reprinting, reuse of
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and transmission or information storage and retrieval, electronic adaptation, computer software,
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The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specic statement, that such names are
exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in
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the authors or the editors give a warranty, express or implied, with respect to the material
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neutral with regard to jurisdictional claims in published maps and institutional afliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
This book is dedicated to two pioneers of contrast-enhanced
ultrasound and our colleagues who contributed immensely to
the development of the technique, who both are sadly no longer
with us.
Professor David O.Cosgrove (1938–2017) was the “father
gure” of ultrasound in the United Kingdom, using ultrasound
clinically in the 1970s and embracing the development of
contrast-enhanced ultrasound from the very beginning. An
internationally recognized and respected gure in ultrasound,
mentor, and colleague to all of us.
Professor Martin J.K.Blomley (1959–2006) a respected
colleague, a pioneer in the early days of contrast-enhanced
ultrasound, destined for great things, but a life cruelly cut
short.
A large number of people have helped over the years to
develop the pediatric contrast-enhanced ultrasound service both
in clinical terms and with research, too many to mention, but
contributing to this new area of ultrasound imaging. In addition,
I am grateful for the patience of my family—Monica, Francesca,
and Gianluca who, I believe, continue to support me.
Paul S.Sidhu
To my clinical pediatric colleagues at Kings College Hospital
who have supported us and continue to trust us with their
patients. Also, to my father, Professor Sean Sellars who sadly
passed away last summer, my husband Steve, four children,
Anna, Matthew, Rebecca, and Emily and Emma, all of whose
love and support has been invaluable to me.
Maria E. Sellars
To my husband Tommaso, who is always supportive of my
academic work and keeps me on my toes, and to my children
Marino and Maddalena, my daily reminder of what
unconditional love means. Also, to my parents, Paola and
Vittorio, who are always there for me and have shaped who
Iam today.
Annamaria Deganello
Foreword
In the past two decades, the acoustic microbubble has graduated from a scientic curiosity to a clinical contrast agent that has become an indispensable
part of the ultrasound armamentarium. Injectable microbubbles have been
approved for diagnostic indications in the heart, vascular system, and abdomen in dozens of jurisdictions. Over an estimated 10 million patient studies,
they have proven to be safe and exceptionally well tolerated by patients.
Several generations of guidelines for their clinical use have been published
by both European and World ultrasound federations. Yet none of these guidelines, and until recently none of these approvals, have been for their use in
children. In spite of this, a burgeoning number of pediatric radiologists and
other specialists have been investigating their off-label use for many applications in children, assiduously recording and pooling data on safety and effectiveness. Principal among them have been the authors of this book, who have
both led and brought together many of their international colleagues, all committed to bringing the evident advantages of contrast-enhanced ultrasound to
pediatric diagnosis. The shear breadth of the titles of the contributions here
both testies to their commitment and conrms this book as the most up-todate and comprehensive guide to the use of this new imaging modality in
children.
The book is particularly timely in view of another, uniquely North
American, story. Microbubble agents were rst approved for abdominal diagnosis in European Union countries in 2002, which were soon joined by China,
Canada, Australasia, and many Asian and south American jurisdictions. But
in spite of continuous efforts by both manufacturers and medical organizations, the United States FDA allowed no approvals outside the heart until
nally, in 2016, they announced acceptance of the same agent and the same
indications that were approved in Europe nearly 15 years previously. However,
when they did so, they extended the approved indications to children. This
was something of a surprise, as it was known that the dossier presented to
them contained no pivotal safety or efcacy studies in this population. It subsequently became clear that they had consulted the data that had been gathered by the authors of this book and their colleagues. While it is notoriously
hazardous to divine the thinking of the FDA, it seems most likely that they
were considering the well-documented overuse of body CT in children in the
United States and the signicant risk of needless radiation exposure to this
radiogenically vulnerable population. That contrast-enhanced ultrasound has
been shown to achieve diagnostic equivalence to CT in detection of liver
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metastases or in the characterization of focal liver lesions in adults suggests
that these might be important applications in children, where there is the
additional hazard of sedation associated with CT and MR examinations, as
well as the nephrotoxic risk of their contrast agents. For those interested in
pursuing contrast-enhanced ultrasound as a means to reduce reliance on contrast CT and MR in children, there is no better starting point than this book.
But microbubbles offer some truly unique properties that allow them to go
further than simple equivalence. They are relatively large, as nearly as big as
red blood cells, so cannot diffuse through vessel walls, as do molecular iodine
and gadolinium compounds. Thus, they have no interstitial phase, and in particular do not leak through hyperpermeable tumor vascular endothelium. In
practice, this means that liver tumor “washout” in the portal phase is a more
reliable sign of malignancy on CT or MR.As a pure blood pool agent, they
provide a direct image of the intravascular volume of an organ or of a tumor,
useful for gauging response to targeted therapies. And uniquely among contrast agents in medical imaging, they can be manipulated by the imaging
process itself. Thus by the press of a key, the bubbles can instantly be eliminated from the imaging plane and their replenishment monitored in real time,
showing vascular morphology and providing a new method to quantitate
ow. The use of such techniques is well documented in the adult radiology
literature and the authors demonstrate in practical detail that almost all are
translatable to the pediatric patient.
The book begins with a description of the principles of contrast imaging:
by now, the techniques employed by the scanners have matured, settling on
one or two contrast-specic modes that are easy to understand. But as with all
ultrasound imaging, understanding is important because the images are produced and interpreted in real time by the operator, and it is essential to understand the effect of the many parameters under his or her control. It is
extraordinary to contemplate that the basis of these methods—that ultrasound
stimulates the bubbles into resonant oscillation so that they ring like microscopic bells—is no more than a serendipity of physics that the size of a bubble determines that their resonance lies in the diagnostic frequency range.
Current machines are so sensitive to this resonance that they can resolve in
real time an individual bubble in a microvessel deep in an adult abdomen, a
feat unmatched by any other clinical modality. A discussion of the excellent
safety prole of ultrasound contrast agents includes summaries of the signicant safety studies published to date in children, whose enrolment will hopefully increase now that post-marketing surveillance of the approved agent is
underway. A chapter on artifacts peculiar to the contrast study follows, written by the principal and most senior author. Novices to the eld may well be
puzzled by the openly competitive enthusiasm shown by experienced sonographers for imaging artifacts; their appreciation is one of the hallmark pleasures of ultrasound imaging. A detailed, step-by-step guide to the performance
of a contrast examination is then provided, from initial planning to nal
reporting.
Subsequent chapters are devoted to a comprehensive description of a
series of key clinical applications of contrast in pediatric diagnosis, including
focal liver lesions, organ transplantation, abdominal trauma, the kidneys,
Foreword
Foreword
ix
spleen, and scrotum; in pneumonia, inammatory bowel, oncology, and specialist applications in interventional radiology, intraoperative neuroimaging,
and in the neonatal nursery. Each chapter is written by experts in the eld, in
many cases those with the most experience worldwide, beginning with practical basics and progressing to the limit of current knowledge. Additional chapters give the clinician’s perspective, in the liver and from the trauma room. An
important chapter is included on the principal extravascular indication for
ultrasound contrast (also approved by the FDA), of vesicoureteral reux. It is
written by one of the originators of the method and presents convincing arguments for its use over X-ray and radionuclide alternatives. Finally, an analysis
of cost-effectiveness of contrast-enhanced ultrasound in children comes from
the academic medical center of the main authors, and though inevitably
linked to the particulars of their own healthcare system, nonetheless provides
a prima facie case for any healthcare administrator to support its use.
As these applications continue to nd their place, research propels the
acoustic bubble in new directions. Those currently approved are designed to
circulate passively within the vascular system; new ones have surface ligands
that attach to endothelial cells expressing VEGF, indicative of vascular proliferation, or VCAMs, associated with inammation. Disrupting them in situ
allows measure of expression of these molecules. As alluded to in Chap. 2,
bubbles in oscillation near cell membranes can permeabilize them, allowing
the selective enhancement of drug delivery under ultrasound guidance.
Bubbles can even open the blood–brain barrier in regions selected by an
ultrasound beam through the skull or into the spinal cord. And liquid nanodroplets can act as precursors of bubbles, diffusing into tissue and transforming into bubbles under the ultrasound beam, releasing drugs or providing a
diagnostic beacon. Exciting and original though the benets derived by pediatric patients from the applications described in this book may be, they surely
are just the beginning.
PeterN.Burns
University of Toronto
Toronto, ON, Canada
Sunnybrook Research Institute
Toronto, ON, Canada
Preface
There has been a wealth of experience accumulated over the last 25 years
with regard to the application of contrast-enhanced ultrasound in adult practice. From the initial stages of the application of early ultrasound contrast
agents for “Doppler rescue” to the science of gene and drug delivery therapy,
the eld has been constantly changing, improving, and most importantly
remaining innovative. Initially, this was mostly driven by practitioners in
Europe, exploring clinical applications outside the few licenced uses, constantly discovering new areas, and extending the usefulness of this novel
extension of the ultrasound examination.
The ultrasound physicists made enormous advances in the understanding
of the interaction of the microbubble in an acoustic eld, opening up tremendous opportunity to image right down to the capillary level, reecting the
unique intravascular nature of the microbbuble contrast agent. Multiple
advances in numerous areas made the development of the technique a fascinating journey for those involved in the evolutionary process.
We as a team here at King’s College Hospital evolved with this unfolding
scenario, “tagging” along with the many greats of the eld, experimenting
and innovating as much as we could, dragged along by the momentum generated by enthusiastic and skilled practitioners. The developments, particularly
on the technical aspects, rapidly advanced with usefulness of the technique so
blatantly obvious to the enthusiast.
Around the early part of this century, we were approached by our pediatric
clinical colleagues to help with reducing the amount of imaging they were
obliged to request when incidental abnormalities in the liver were picked up
on our ultrasound imaging. The hospital serves as a large tertiary referral for
chronic pediatric liver disease, with children on surveillance ultrasound at
regular intervals, with new focal liver lesions needing workup with computed
tomography and magnetic resonance imaging, often nearly always benign.
This additional “imaging” demands all those aspects that you should avoid in
children; sedation, general anesthesia, radiation, potentially harmful contrast
agents, which ultrasound avoids.
We had already an established adult liver contrast-enhanced ultrasound
service, and without hesitation we embarked on expanding pediatric applications into our contrast-enhanced ultrasound practice. We targeted the focal
liver lesions in these children, but we had previously been using contrastenhanced ultrasound following liver transplantation in both adults and children, in pursuit of the elusive hepatic artery. This initiative proved to be
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