Abstract
Contrast-enhanced ultrasound (CEUS) has been increasingly used in pediatric radiology practice worldwide. For nearly two decades, CEUS applications have been performed with the off-label use of gas-containing second-generation ultrasound contrast agents (UCAs). Since 2016, the United States Food and Drug Administration (FDA) has approved the UCA Lumason for three pediatric indications: the evaluation of focal liver lesions and echocardiography via intravenous administration and the assessment of vesicoureteral reflux via intravesical application (contrast-enhanced voiding urosonography, ceVUS). Prior to the FDA approval of Lumason, numerous studies with the use of second-generation UCAs had been conducted in adults and children. Comprehensive protocols for clinical safety evaluations have demonstrated the highly favorable safety profile of UCA for intravenous, intravesical and other intracavitary uses. The safety data on CEUS continue to accumulate as this imaging modality is increasingly utilized in clinical settings worldwide. As of August 2021, 57 pediatric-only original research studies encompassing a total of 4,518 children with 4,906 intravenous CEUS examinations had been published. As in adults, there were a few adverse events; the majority of these were non-serious, although very rarely serious anaphylactic reactions were reported. In the published pediatric-only intravenous CEUS studies included in our analysis, the overall incidence rate of serious adverse events was 0.22% (10/4,518) of children and 0.20% (10/4,906) of all CEUS examinations. Non-serious adverse events from the intravenous CEUS were observed in 1.20% (54/4,518) of children and 1.10% (54/4,906) of CEUS examinations. During the same time period, 31 studies with the intravesical use of UCA were conducted in 12,362 children. A few non-serious adverse events were encountered (0.31%; 38/12,362), but these were most likely attributable to the bladder catheterization rather than the UCA. Other developing clinical applications of UCA in children, including intracavitary and intralymphatic, are ongoing. To date, no serious adverse events have been reported with these applications. This article reviews the existing pediatric CEUS literature and provides an overview of safety-related information reported from UCA uses in children.
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References
Piscaglia F, Bolondi L (2006) The safety of Sonovue in abdominal applications: retrospective analysis of 23,188 investigations. Ultrasound Med Biol 32:1369–1375
Tang C, Fang K, Guo Y et al (2017) Safety of sulfur hexafluoride microbubbles in sonography of abdominal and superficial organs: retrospective analysis of 30,222 cases. J Ultrasound Med 36:531–538
Hu C, Feng Y, Huang P et al (2019) Adverse reactions after the use of SonoVue contrast agent: characteristics and nursing care experience. Medicine 98:e17745
European Medicines Agency (n.d.) SonoVue. Annex 1: summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/sonovue-epar-product-information_en.pdf. Accessed 29 Mar 2021
Dietrich CF, Augustiniene R, Batko T et al (2021) European Federation of Societies for ultrasound in medicine and biology (EFSUMB): an update on the pediatric CEUS registry on behalf of the “EFSUMB pediatric CEUS registry working group.” Ultrasound in Medicine and Biology 42:270–277
Riccabona M (2012) Application of a second-generation US contrast agent in infants and children — a European questionnaire-based survey. Pediatr Radiol 42:1471–1480
Mao M, Xia B, Chen W et al (2019) The safety and effectiveness of intravenous contrast-enhanced sonography in Chinese children — a single center and prospective study in China. Front Pharmacol 10:1447
Yusuf GT, Sellars ME, Deganello A et al (2017) Retrospective analysis of the safety and cost implications of pediatric contrast-enhanced ultrasound at a single center. AJR Am J Roentgenol 208:446–452
Torres A, Koskinen SK, Gjertsen H, Fischler B (2017) Contrast-enhanced ultrasound using sulfur hexafluoride is safe in the pediatric setting. Acta Radiol 58:1395–1399
Piskunowicz M, Kosiak W, Batko T et al (2015) Safety of intravenous application of second-generation ultrasound contrast agent in children: prospective analysis. Ultrasound Med Biol 41:1095–1099
Torres A, Koskinen SK, Gjertsen H, Fischler B (2018) Contrast-enhanced ultrasound for identifying circulatory complications after liver transplants in children. Pediatr Transplant 23:e13327
Menichini G, Sessa B, Trinci M et al (2015) Accuracy of contrast-enhanced ultrasound (CEUS) in the identification and characterization of traumatic solid organ lesions in children: a retrospective comparison with baseline US and CE-MDCT. Radiol Med 120:989–1001
Knieling F, Strobel D, Rompel O et al (2016) Spectrum, applicability and diagnostic capacity of contrast-enhanced ultrasound in pediatric patients and young adults after intravenous application — a retrospective trial. Ultraschall Med 37:619–626
Di Renzo D, Persico A, Lisi G et al (2020) Contrast-enhanced ultrasonography (CEUS) in the follow-up of pediatric abdominal injuries: value and timing. J Ultrasound 23:151–155
Pschierer K, Grothues D, Rennert J et al (2015) Evaluation of the diagnostic accuracy of CEUS in children with benign and malignant liver lesions and portal vein anomalies. Clin Hemorheol Microcirc 61:333–345
Jacob J, Deganello A, Sellars ME et al (2013) Contrast enhanced ultrasound (CEUS) characterization of grey-scale sonographic indeterminate focal liver lesions in pediatric practice. Ultraschall Med 34:529–540
Stenzel M (2013) Intravenous contrast-enhanced sonography in children and adolescents — a single center experience. J Ultrason 13:133–144
Torres A, Koskinen SK, Gjertsen H et al (2021) Contrast-enhanced ultrasound is useful for the evaluation of focal liver lesions in children. Australas J Ultrasound Med 24:143–150
Karmazyn B, Saglam D, Rao GS et al (2021) Initial experience with contrast-enhanced ultrasound in the first week after liver transplantation in children: a useful adjunct to Doppler ultrasound. Pediatr Radiol 51:248–256
Jung HJ, Choi MH, Pai KS et al (2020) Diagnostic performance of contrast-enhanced ultrasound for acute pyelonephritis in children. Sci Rep 10:10715
Durkin N, Deganello A, Sellars ME et al (2015) Post-traumatic liver and splenic pseudoaneurysms in children: diagnosis, management, and follow-up screening using contrast enhanced ultrasound (CEUS). J Pediatr Surg 51:289–292
Fang C, Bernardo S, Sellars ME et al (2018) Contrast-enhanced ultrasound in the diagnosis of pediatric focal nodular hyperplasia and hepatic adenoma: interobserver reliability. Pediatr Radiol 49:82–90
Bonini G, Pezzotta G, Morzenti C et al (2007) Contrast-enhanced ultrasound with SonoVue in the evaluation of postoperative complications in pediatric liver transplant recipients. J Ultrasound 10:99–106
Valentino M, Serra C, Pavlica P et al (2008) Blunt abdominal trauma: diagnostic performance of contrast-enhanced US in children — initial experience. Radiology 246:903–909
Squires JH, Beluk NH, Lee VK et al (2021) Feasibility and safety of neonatal brain contrast-enhanced ultrasound: a prospective study using MRI as reference standard. AJR Am J Roentgenol. https://doi.org/10.2214/AJR.21.26274
Ponorac S, Gosnak RD, Urlep D et al (2021) Contrast-enhanced ultrasonography in the evaluation of Crohn disease activity in children: comparison with histopathology. Pediatr Radiol 51:410–418
Mudambi K, Sandberg J, Bass D, Rubesova E (2019) Contrast enhanced ultrasound: comparing a novel modality to MRI to assess for bowel disease in pediatric Crohn’s patients. Transl Gastroenterol Hepatol 5:13
Back SJ, Chauvin NA, Ntoulia A et al (2019) Intraoperative contrast-enhanced ultrasound imaging of femoral head perfusion in developmental dysplasia of the hip: a feasibility study. J Ultrasound Med 39:247–257
Kastler A, Manzoni P, Chapuy S et al (2014) Transfontanellar contrast enhanced ultrasound in infants: initial experience. J Neuroradiol 41:251–258
Bowen DK, Back SJ, Van Batavia JP et al (2020) Does contrast-enhanced ultrasound have a role in evaluation and management of pediatric renal trauma? A preliminary experience. J Pediatr Surg 55:2740–2745
El-Ali AM, McCormick A, Thakrar D et al (2020) Contrast-enhanced ultrasound of congenital and infantile hemangiomas: preliminary results from a case series. AJR Am J Roentgenol 214:658–664
Deganello A, Rafailidis V, Sellars ME et al (2017) Intravenous and intracavitary use of contrast-enhanced ultrasound in the evaluation and management of complicated pediatric pneumonia. J Ultrasound Med 36:1943–1954
Kapur J, Oscar H (2015) Contrast enhanced ultrasound of kidneys in children with renal failure. J Med Ultrasound 23:86–97
Hwang M, Sridharan A, Darge K et al (2019) Novel quantitative contrast-enhanced ultrasound detection of hypoxic ischemic injury in neonates and infants: pilot study 1. J Ultrasound Med 38:2025–2038
Hains DS, Cohen HL, McCarville MB et al (2017) Elucidation of renal scars in children with vesicoureteral reflux using contrast-enhanced ultrasound: a pilot study. Kidney Int Rep 2:420–424
Sridharan A, Riggs B, Darge K et al (2021) The wash-out of contrast-enhanced ultrasound for evaluation of hypoxic ischemic injury in neonates and infants: preliminary findings. Ultrasound Q. https://doi.org/10.1097/RUQ.0000000000000560
Chan JP, Back SJ, Vatsky S et al (2021) Utility of contrast-enhanced ultrasound for solid mass surveillance and characterization in children with tuberous sclerosis complex: an initial experience. Pediatr Nephrol 36:1775–1784
Svensson JF, Larsson A, Uusijarvi J et al (2008) Oophoropexy, hyperbaric oxygen therapy, and contrast-enhanced ultrasound after asynchronous bilateral ovarian torsion. J Pediatr Surg 43:1380–1384
Rafailidis V, Deganello A, Sellars ME et al (2017) Pediatric adrenal trauma: evaluation and follow-up with contrast-enhanced ultrasound (CEUS). J Ultrasound 20:325–331
Oldenburg A, Hohmann J, Skrok J et al (2004) Imaging of paediatric splenic injury with contrast-enhanced ultrasonography. Pediatr Radiol 34:351–354
Glutig K, Alhussami I, Kruger PC et al (2021) Case report: report of 2 different cases of ovarian teratoma evaluated by dynamic contrast-enhanced ultrasound. Front Pediatr 9:681404
Thimm MA, Cuffari C, Garcia A et al (2019) Contrast-enhanced ultrasound and shear wave elastography evaluation of Crohn’s disease activity in three adolescent patients. Pediatr Gastroenterol Hepatol Nutr 22:282–290
Hwang M, De Jong Jr RM, Herman S et al (2018) Novel contrast-enhanced ultrasound evaluation in neonatal hypoxic ischemic injury: clinical application and future directions. J Ultrasound Med 36:2379–2386
Luo XL, Liu D, Yang JJ et al (2009) Primary gastrointestinal stromal tumor of the liver: a case report. World J Gastroenterol 15:3704–3707
Kljucevsek D, Glusic M, Velikonja O (2021) Clinical value of contrast-enhanced ultrasound in atypical wilms tumor. Indian J Pediatr 88:517–518
Sekej M, Vadnjal Donlagic S, Kljucevsek D (2020) Contrast-enhanced ultrasound for the characterization of infantile hepatic hemangioma in premature neonate. Cureus 12:e9580
Trinci M, Ianniello S, Galluzzo M et al (2019) A rare case of accessory spleen torsion in a child diagnosed by ultrasound (US) and contrast-enhanced ultrasound (CEUS). J Ultrasound 22:99–102
Lorenz N, Schuster F, Steinbach F et al (2019) Segmental testicular infarction after methamphetamine abuse in a 16-year-old — diagnosis by using contrast-enhanced ultrasound (CEUS). Ultraschall Med 40:253–254
Hwang M, Riggs BJ, Saade-Lemus S et al (2018) Bedside contrast-enhanced ultrasound diagnosing cessation of cerebral circulation in a neonate: a novel bedside diagnostic tool. Neuroradiol J 31:578–580
Piorkowska MA, Dezman R, Sellars ME et al (2018) Characterization of a hepatic haemangioma with contrast-enhanced ultrasound in an infant. Ultrasound 26:178–181
Aguirre Pascual E, Fontanilla T, Perez I et al (2017) Wandering spleen torsion — use of contrast-enhanced ultrasound. BJR Case Rep 3:20150342
Al Bunni F, Deganello A, Sellars ME et al (2014) Contrast-enhanced ultrasound (CEUS) appearances of an adrenal phaeochromocytoma in a child with Von Hippel-Lindau disease. J Ultrasound 17:307–311
Yusuf GT, Sellars ME, Huang DY et al (2013) Cortical necrosis secondary to trauma in a child: contrast-enhanced ultrasound comparable to magnetic resonance imaging. Pediatr Radiol 44:484–487
Mandry D, Bressenot A, Galloy MA et al (2007) Contrast-enhanced ultrasound in fibro-lamellar hepatocellular carcinoma: a case report. Ultraschall Med 28:547–552
Valentino M, Galloni SS, Rimondi MR et al (2006) Contrast-enhanced ultrasound in non-operative management of pancreatic injury in childhood. Pediatr Radiol 36:558–560
Coleman JL, Navid F, Furman WL et al (2014) Safety of ultrasound contrast agents in the pediatric oncologic population: a single-institution experience. AJR Am J Roentgenol 202:966–970
McCarville MB, Coleman JL, Guo J et al (2016) Use of quantitative dynamic contrast-enhanced ultrasound to assess response to antiangiogenic therapy in children and adolescents with solid malignancies: a pilot study. AJR Am J Roentgenol 206:933–939
McMahon CJ, Ayres NA, Bezold LI et al (2005) Safety and efficacy of intravenous contrast imaging in pediatric echocardiography. Pediatr Cardiol 26:413–417
McCarville MB, Kaste SC, Hoffer FA et al (2012) Contrast-enhanced sonography of malignant pediatric abdominal and pelvic solid tumors: preliminary safety and feasibility data. Pediatr Radiol 42:824–833
Armstrong LB, Mooney DP, Paltiel H et al (2017) Contrast enhanced ultrasound for the evaluation of blunt pediatric abdominal trauma. J Pediatr Surg 53:548–552
Kutty S, Xiao Y, Olson J et al (2016) Safety and efficacy of cardiac ultrasound contrast in children and adolescents for resting and stress echocardiography. J Am Soc Echocardiogr 29:655–662
Cvitkovic-Roic A, Turudic D, Milosevic D et al (2021) Contrast-enhanced voiding urosonography in the diagnosis of intrarenal reflux. J Ultrasound. https://doi.org/10.1007/s40477-021-00568-w
Papadopoulou F, Ntoulia A, Siomou E et al (2014) Contrast-enhanced voiding urosonography with intravesical administration of a second-generation ultrasound contrast agent for diagnosis of vesicoureteral reflux: prospective evaluation of contrast safety in 1,010 children. Pediatr Radiol 44:719–728
Papadopoulou F, Anthopoulou A, Siomou E et al (2009) Harmonic voiding urosonography with a second-generation contrast agent for the diagnosis of vesicoureteral reflux. Pediatr Radiol 39:239–244
Duran C, del Riego J, Riera L et al (2012) Voiding urosonography including urethrosonography: high-quality examinations with an optimised procedure using a second-generation US contrast agent. Pediatr Radiol 42:660–667
Kis E, Nyitrai A, Varkonyi I et al (2010) Voiding urosonography with second-generation contrast agent versus voiding cystourethrography. Pediatr Nephrol 25:2289–2293
Woźniak MM, Osemlak P, Ntoulia A et al (2018) 3D/4D contrast-enhanced urosonography (ceVUS) in children — is it superior to the 2D technique? J Ultrason 18:120–125
Piskunowicz M, Swieton D, Rybczynska D et al (2016) Premature destruction of microbubbles during voiding urosonography in children and possible underlying mechanisms: post hoc analysis from the prospective study. Biomed Res Int 2016:1764692
Battelino N, Kljucevsek D, Tomazic M et al (2016) Vesicoureteral refux detection in children: a comparison of the midline-to-orifice distance measurement by ultrasound and voiding urosonography. Pediatr Nephrol 31:957–964
Ključevšek D, Pecanac O, Tomazic M et al (2019) Potential causes of insufficient bladder contrast opacification and premature microbubble destruction during contrast-enhanced voiding urosonography in children. J Clin Ultrasound 47:36–41
Zhang W, Cai B, Zhang X et al (2018) Contrast-enhanced voiding urosonography with intravesical administration of ultrasound contrast agent for the diagnosis of pediatric vesicoureteral reflux. Exp Ther Med 16:4546–4552
Ascenti G, Zimbaro G, Mazziotti S et al (2004) Harmonic US imaging of vesicoureteric reflux in children: usefulness of a second generation US contrast agent. Pediatr Radiol 34:481–487
Simicic Majce A, Arapovic A, Saraga-Babic M et al (2021) Intrarenal reflux in the light of contrast-enhanced voiding urosonography. Front Pediatr 9:642077
Woźniak MM, Wieczorek AP, Pawelec A et al (2016) Two-dimensional (2D), three-dimensional static (3D) and real-time (4D) contrast enhanced voiding urosonography (ceVUS) versus voiding cystourethrography (VCUG) in children with vesicoureteral reflux. Eur J Radiol 85:1238–1245
Kljucevsek D, Battelino N, Tomazic M et al (2012) A comparison of echo-enhanced voiding urosonography with X-ray voiding cystourethrography in the first year of life. Acta Paediatr 101:e235–e239
Siomou E, Giapros V, Serbis A et al (2020) Voiding urosonography and voiding cystourethrography in primary vesicoureteral reflux associated with mild prenatal hydronephrosis: a comparative study. Pediatr Radiol 50:1271–1276
Giordano M, Marzolla R, Puteo F et al (2007) Voiding urosonography as first step in the diagnosis of vesicoureteral reflux in children: a clinical experience. Pediatr Radiol 37:674–677
Fernandez-Ibieta M, Parrondo-Muinos C, Fernandez-Masaguer LC et al (2016) Voiding urosonography with second-generation contrast as a main tool for examining the upper and lower urinary tract in children. Pilot study. Actas Urol Esp 40:183–189
Velasquez M, Emerson MG, Diaz E et al (2019) The learning curve of contrast-enhanced 'microbubble' voiding urosonography — validation study. J Pediatr Urol 15:385.e1–385.e6
Marschner CA, Schwarze V, Stredele R et al (2021) Safety assessment and diagnostic evaluation of patients undergoing contrast-enhanced urosonography in the setting of vesicoureteral reflux confirmation. Clin Hemorheol Microcirc. https://doi.org/10.3233/CH-219110
Benya EC, Prendergast FM, Liu DB et al (2021) Assessment of distal ureteral and ureterovesical junction visualization on contrast-enhanced voiding urosonography. Pediatr Radiol 51:1406–1411
Kim D, Choi YH, Choi G et al (2021) Contrast-enhanced voiding urosonography for the diagnosis of vesicoureteral reflux and intrarenal reflux: a comparison of diagnostic performance with fluoroscopic voiding cystourethrography. Ultrasonography 40:530–537
Kuzmanovska D, Risteski A, Kambovska M et al (2017) Voiding urosonography with second-generation ultrasound contrast agent for diagnosis of vesicoureteric reflux: first local pilot study. Open Access Maced J Med Sci 5:215–221
Wong LS, Tse KS, Fan TW et al (2014) Voiding urosonography with second-generation ultrasound contrast versus micturating cystourethrography in the diagnosis of vesicoureteric reflux. Eur J Pediatr 173:1095–1101
Mane N, Sharma A, Patil A et al (2018) Comparison of contrast-enhanced voiding urosonography with voiding cystourethrography in pediatric vesicoureteral reflux. Turk J Urol 44:261–267
Ntoulia A, Back SJ, Shellikeri S et al (2018) Contrast-enhanced voiding urosonography (ceVUS) with the intravesical administration of the ultrasound contrast agent Optison for vesicoureteral reflux detection in children: a prospective clinical trial. Pediatr Radiol 48:216–226
Faizah MZ, Hamzaini AH, Kanaheswari Y et al (2015) Contrast enhanced voiding urosonography (ce-VUS) as a radiation-free technique in the diagnosis of vesicoureteric reflux: our early experience. Med J Malaysia 70:269–272
Woźniak MM, Osemlak P, Pawelec A et al (2014) Intraoperative contrast-enhanced urosonography during endoscopic treatment of vesicoureteral reflux in children. Pediatr Radiol 44:1093–1100
Colleran GC, Paltiel HJ, Barnewolt CE et al (2016) Residual intravesical iodinated contrast: a potential cause of false-negative reflux study at contrast-enhanced voiding urosonography. Pediatr Radiol 46:1614–1617
Babu R, Gopinath V, Sai V (2015) Voiding urosonography: contrast-enhanced ultrasound cystography to diagnose vesico-ureteric reflux: a pilot study. J Indian Assoc Pediatr Surg 20:40–41
Colleran GC, Barnewolt CE, Chow JS et al (2016) Intrarenal reflux: diagnosis at contrast-enhanced voiding urosonography. J Ultrasound Med 35:1811–1819
Chow JS, Paltiel HJ, Padua HM et al (2019) Contrast-enhanced colosonography for the evaluation of children with an imperforate anus. J Ultrasound Med 38:2777–2783
Chow JS, Paltiel HJ, Padua HM et al (2019) Case series: comparison of contrast-enhanced genitosonography (ceGS) to fluoroscopy and cone-beam computed tomography in patients with urogenital sinus and the cloacal malformation. Clin Imaging 60:204–208
Seranio N, Darge K, Canning DA et al (2018) Contrast enhanced genitosonography (CEGS) of urogenital sinus: a case of improved conspicuity with image inversion. Radiol Case Rep 13:652–654
Cahill AM, Escobar F, Acord MR (2021) Central venous catheter fracture leading to TPN extravasation and abdominal compartment syndrome diagnosed with bedside contrast-enhanced ultrasound. Pediatr Radiol 51:307–310
Gokli A, Pinto E, Escobar FA et al (2020) Contrast-enhanced ultrasound: use in the management of lymphorrhea in generalized lymphatic anomaly. J Vasc Interv Radiol 31:1511–1513
Mejia EJ, Otero HJ, Smith CL et al (2020) Use of contrast-enhanced ultrasound to determine thoracic duct patency. J Vasc Interv Radiol 31:1670–1674
Tirrell TF, Demehri FR, McNamara ER et al (2021) Contrast enhanced colostography: new applications in preoperative evaluation of anorectal malformations. J Pediatr Surg 56:192–195
Dillman JR, Strouse PJ, Ellis JH et al (2007) Incidence and severity of acute allergic-like reactions to i.v. nonionic iodinated contrast material in children. AJR Am J Roentgenol 188:1643–1647
Dillman JR, Ellis JH, Cohan RH et al (2007) Frequency and severity of acute allergic-like reactions to gadolinium-containing i.v. contrast media in children and adults. AJR Am J Roentgenol 189:1533–1538
Davenport MS, Dillman JR, Cohan RH et al (2013) Effect of abrupt substitution of gadobenate dimeglumine for gadopentetate dimeglumine on rate of allergic-like reactions. Radiology 266:773–782
United States Food and Drug Administration (2020) CFR - code of federal regulations title 21. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm. Accessed 17 Sep 2021
World Health Organization (WHO) (2002) Safety of medicines: a guide to detecting and reporting adverse drug reactions. http://apps.who.int/iris/bitstream/handle/10665/67378/WHO_EDM_QSM_2002.2.pdf;jsessionid=1FE3E8E1B813999C2EB895BCB7E4787B?sequence=1. Accessed 17 Sep 2021
Management Sciences for Health, World Health Organization (2007) Drug and therapeutics committee training course. U.S. Agency for International Development by the Rational Pharmaceutical Management Plus Program. Management Sciences for Health, Arlington
United States Food and Drug Administration (1994) E2A clinical safety data management: definitions and standards for expedited reporting. Presented at the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (2017) Division of AIDS (DAIDS) table for grading the severity of adult and pediatric adverse events. Corrected version 2.1. https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. Accessed 17 Sep 2021
Hoigne R, Jaeger MD, Wymann R et al (1990) Time pattern of allergic reactions to drugs. Agents Actions Suppl 29:39–58
United States Food and Drug Administration (2016) Determining the extent of safety data collection needed in late-stage premarket and postapproval clinical investigations; guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/determining-extent-safety-data-collection-needed-late-stage-premarket-and-postapproval-clinical. Accessed 17 Sep 2021
Johansson SG, Hourihane JO, Bousquet J et al (2001) A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 56:813–824
Simons FE, Ardusso LR, Bilo MB et al (2014) International consensus on (ICON) anaphylaxis. World Allergy Organ J 7:9
Simons FE, Ardusso LR, Bilo MB et al (2011) World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 4:13–37
Zerin JM, Shulkin BL (1992) Postprocedural symptoms in children who undergo imaging studies of the urinary tract: is it the contrast material or the catheter? Radiology 182:727–730
Lindner JR, Belcik T, Main ML et al (2021) Expert consensus statement from the American Society of Echocardiography on hypersensitivity reactions to ultrasound enhancing agents in patients with allergy to polyethylene glycol. J Am Soc Echocardiogr 34:707–708
Stempniak M (2021) FDA warns providers after 2 patients die from ultrasound contrast-agent reactions. Radiology Business. https://www.radiologybusiness.com/topics/policy/fda-warns-die-ultrasound-contrast-agent-reactions. Accessed 17 Sep 2021
Wenande E, Garvey LH (2016) Immediate-type hypersensitivity to polyethylene glycols: a review. Clin Exp Allergy 46:907–922
Sellaturay P, Nasser S, Ewan P (2021) Polyethylene glycol-induced systemic allergic reactions (anaphylaxis). J Allergy Clin Immunol Pract 9:670–675
International Contrast Ultrasound Society (2021) International Contrast Ultrasound Society (ICUS) policy statement supporting established safety record of ultrasound contrast agents and continued use where medically appropriate. ICUS News release. http://icus-society.org/international-contrast-ultrasound-society-icus-policy-statement-supporting-established-safety-record-of-ultrasound-contrast-agents-and-continued-use-where-medically-appropriate/. Accessed 17 Sep 2021
United States Food and Drug Administration (2016) Lumason prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203684s009lbl.pdf. Accessed 17 Sep 2021
United States Food and Drug Administration (2016) Optison prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020899s018s019lbl.pdf. Accessed 17 Sep 2021
United States Food and Drug Administration (2011) Definity prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021064s025s029lbl.pdf. Accessed 17 Sep 2021
Darge K, Back SJ, Bulas DI et al (2021) Pediatric contrast ultrasound: shedding light on the pursuit of approval in the United States. Pediatr Radiol. https://doi.org/10.1007/s00247-021-05102-y
Miller DL, Averkiou MA, Brayman AA et al (2008) Bioeffects considerations for diagnostic ultrasound contrast agents. J Ultrasound Med 27:611–632
Church CC (2002) Spontaneous homogeneous nucleation, inertial cavitation and the safety of diagnostic ultrasound. Ultrasound Med Biol 28:1349–1364
Miller DL (2007) Overview of experimental studies of biological effects of medical ultrasound caused by gas body activation and inertial cavitation. Prog Biophys Mol Biol 93:314–330
Nyborg W (2007) WFUMB safety symposium on echo-contrast agents: mechanisms for the interaction of ultrasound. Ultrasound Med Biol 33:224–232
Miller DL, Quddus J (2000) Diagnostic ultrasound activation of contrast agent gas bodies induces capillary rupture in mice. Proc Natl Acad Sci U S A 97:10179–10184
van Der Wouw PA, Brauns AC, Bailey SE et al (2000) Premature ventricular contractions during triggered imaging with ultrasound contrast. J Am Soc Echocardiogr 13:288–294
Li P, Armstrong WF, Miller DL (2004) Impact of myocardial contrast echocardiography on vascular permeability: comparison of three different contrast agents. Ultrasound Med Biol 30:83–91
Ay T, Havaux X, Van Camp G et al (2001) Destruction of contrast microbubbles by ultrasound: effects on myocardial function, coronary perfusion pressure, and microvascular integrity. Circulation 104:461–466
Chen S, Kroll MH, Shohet RV et al (2002) Bioeffects of myocardial contrast microbubble destruction by echocardiography. Echocardiography 19:495–500
Fowlkes JB, Bioeffects Committee of the American Institute of Ultrasound in Medicine (2008) American Institute of Ultrasound in Medicine consensus report on potential bioeffects of diagnostic ultrasound: executive summary. J Ultrasound Med 27:503–515
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Dr. Maciej Piskunowicz was supported by the Kosciuszko Foundation.
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Drs. Back and Darge have received an educational grant from Bracco Diagnostics Inc.
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Ntoulia, A., Anupindi, S.A., Back, S.J. et al. Contrast-enhanced ultrasound: a comprehensive review of safety in children. Pediatr Radiol 51, 2161–2180 (2021). https://doi.org/10.1007/s00247-021-05223-4
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DOI: https://doi.org/10.1007/s00247-021-05223-4