Edited by: Francis Kalemeera, University of Namibia, Namibia
Reviewed by: Joao Massud, Independent Researcher, São Paulo, Brazil; Adina Turcu-Stiolica, University of Medicine and Pharmacy of Craiova, Romania
*Correspondence: Bei Xia,
This article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology
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Contrast-enhanced ultrasound (CEUS) has been widely used in adults. In 2016, it was approved for intravenous use to diagnose liver lesions and intravesical use in children, basing on the big data from studies about safety and feasibility with SonoVue®/Lumason® by the FDA. However, it lacked relevant studies in China. The study was to evaluate the safety and feasibility of intravenous CEUS with SonoVue® in children under 18 years of age.
The study was performed in Shenzhen Children’s Hospital between November 2015 and April 2019. A total of 312 Chinese children were enrolled in clinical trials and 600 intravenous injections were performed. All subjects met the inclusion and exclusion criteria as follows.
Inclusion criteria
Inpatients or outpatients from birth to 18 years old.
Performance of CEUS was needed for diagnosis.
Bedside CEUS for diagnosis instead of CT and MR.
Agreed to be enrolled into the trial and signed the informed consent.
Exclusion criteria
Allergy to sulfur hexafluoride (SF6) or other components of SonoVue®.
Having an allergic history of protein or egg.
Congenital heart disease with right-to-left shunt, severe pulmonary hypertension, or uncontrolled hypertension.
Severe respiratory failure.
Without informed consent.
The prospective study with SonoVue® was approved by the Chinese Ethics Committee (No: 2016[003], ChiCTR-ONh-16009236).
All US examinations, including baseline US and CEUS, were performed with 4.5–9.0-MHz C2-9 convex array probes and 5.0–9.0-MHz 9L linear probes in the US system (LogiQ E9 Ultrasound System; GE Healthcare, Milwaukee, WI). And the mechanical index (MI) during the CEUS examination was lower than 0.2.
The preventive measures for allergy were taken in trials. We weighed all subjects and calculated the doses of anti-allergic medications, including 0.01 mg/kg of 0.1% adrenaline (the maximal dose 0.3 mg) and 1∼2 mg/kg of methylprednisolone, and prepared a rescue equipment with the medications as a routine.
The contrast agent SonoVue® was administered in two different ways: 2.4 ml/time of SonoVue® before June 2016, while 0.03 ml/kg/time between July 2016 and April 2019, according to the recommendation of FDA. The contrast agents were bolus injected through peripheral veins within 3s, and then the irrigation of the catheters with 0.9% of sodium chloride solutions, keeping a velocity of about 2 ml/s, were performed. All subjects underwent different times of CEUS examinations, including 34 cases undergoing one CEUS, 270 cases undergoing two continuous CEUS, 6 cases undergoing three continuous CEUS, and 1 case undergoing four times.
The CEUS examinations and the intravenous bolus injections with SonoVue® were started simultaneously. The views and images of CEUS were acquired and stored until the microbubbles were cleared up, and the wash-in time, time to peak, and wash-out time were recorded in the whole examinations. The heart rate, respiratory rate, oxygen saturation, and blood pressure were observed and recorded respectively at three different times: before administration, immediately after administration, and 15 min after administration. As for awake participants, we inquired and made a record of any discomfort, such as pain, nausea, vomiting, and so on, besides observing the appearance and the rash. The follow-ups, which contained vital sign observation and rash management, were performed within 24 h before CEUS, 24 h after CEUS, and 72 h after CEUS. If it was necessary, for some subjects having a need for more than one intravenous CEUS, especially for the subjects with a diagnostic purpose, the next injections of SonoVue® were performed at least 20 min later.
The images were evaluated for the following: ①hepatic lesions, such as vascular malformation, abscess, hyperplasia, and so on; ②infarction and necrosis in spleen, kidney, and other solid organs; ③distinction between benign and malignant lesions; ④perfusion and blood supply of the mass and guiding the puncture; ⑤active hemorrhage of the site after puncture; ⑥complications after puncture, especially the vascular complications; and ⑦ distinguishing the hematoma from mass.
The SPSS software (SPSS, version 21.0, IBM) was employed for statistical analysis. Means and standard deviations were used to summarize continuous data for descriptive statistics purposes. The patients’ characteristics were evaluated by using
Among 312 participants, 179 were male and 133 were female. The median age was 7.08 years old (from 5 days to 14.5 years) and the median weight was 23 kg (3.7–65.0 kg). 287 cases had complete records of vital sign, including heart rate (HR), respiration rate (RR), oxygen saturation (SO2), systolic blood pressure (SBP), and diastolic blood pressure (DBP), before and after administration. Ten cases of the records were shown as follows (
Ten cases of the records before and after administration.
Case number | Gender | Age | Weight | Condition | Before administration | After administration | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
HR (/min) | RR (/min) | SO2 (%) | SBP (mmHg) | DBP (mmHg) | HR (/min) | RR (/min) | SO2 (%) | SBP (mmHg) | DBP (mmHg) | |||||
Case 1 | male | 3y3m | 15.3 | combined anesthesia | 125 | 30 | 100 | 96 | 53 | 117 | 30 | 100 | 95 | 49 |
Case 2 | male | 3y1m | 15 | combined anesthesia | 116 | 19 | 98 | 88 | 51 | 122 | 20 | 97 | 84 | 52 |
Case 3 | male | 9y3m | 32 | combined anesthesia | 111 | 30 | 98 | 87 | 51 | 113 | 30 | 98 | 88 | 53 |
Case 4 | female | 13y6m | 46.3 | combined anesthesia | 111 | 25 | 98 | 102 | 71 | 114 | 24 | 99 | 107 | 72 |
Case 5 | male | 10m | 10.6 | combined anesthesia | 108 | 24 | 100 | 132 | 60 | 105 | 24 | 100 | 105 | 61 |
Case 6 | female | 5y8m | 17 | awake | 116 | 18 | 97 | 80 | 42 | 115 | 20 | 97 | 79 | 40 |
Case 7 | male | 14y4m | 57 | awake | 79 | 28 | 100 | 116 | 72 | 78 | 28 | 100 | 121 | 67 |
Case 8 | female | 5y6m | 19 | awake | 110 | 30 | 99 | 98 | 72 | 112 | 30 | 99 | 98 | 68 |
Case 9 | male | 4m | 7.2 | sedation | 128 | 20 | 99 | 125 | 78 | 134 | 20 | 99 | 125 | 78 |
Case 10 | male | 5y | 18 | coma | 78 | 30 | 100 | 136 | 79 | 80 | 30 | 100 | 135 | 80 |
All the 312 participants underwent CEUS successfully. They included: 228 cases in combined anesthesia, 63 cases in awake state, 18 cases in sedation with chloral hydrate, 3 cases in coma. Comparing the vital signs after administration with that before administration in both combined anesthetic and awake participants, there was a statistically significant difference (
The vital signs of the combined anesthetic participants.
Subjects (n = 228) | Heart rate (/min) | Respiration rate (/min) | Oxygen saturation (%) | Systolic blood pressure (mmHg) | Diastolic blood pressure (mmHg) |
---|---|---|---|---|---|
Before administration | 108.79 ± 18.33 | 22.83 ± 3.84 | 98.80 ± 1.82 | 101.78 ± 15.24 | 60.03 ± 13.23 |
After administration | 108.16 ± 17.44 | 22.80 ± 3.68 | 98.95 ± 1.36 | 99.69 ± 14.87 | 57.92 ± 13.24 |
|
0.834 | 0.329 | −1.388 | 3.829 | 5.086 |
|
0.408 | 0.743 | 0.167 | <0.001* | <0.001* |
*The significance was set at a p-value < 0.05 in the study.
The vital signs of the awake participants.
Subjects (n = 63) | Heart rate (/min) | Respiration rate (/min) | Oxygen saturation (%) | Systolic blood pressure (mmHg) | Diastolic blood pressure (mmHg) |
---|---|---|---|---|---|
Before administration | 102.14 ± 22.00 | 23.68 ± 4.56 | 99.43 ± 1.17 | 104.94 ± 15.92 | 65.05 ± 10.81 |
After administration | 100.27 ± 21.37 | 24.11 ± 5.08 | 99.48 ± 1.06 | 104.79 ± 14.04 | 65.68 ± 11.28 |
|
1.699 | −1.989 | −0.554 | 0.148 | −0.704 |
|
0.094 | 0.051 | 0.582 | 0.883 | 0.484 |
The vital signs of 18 cases in sedation with chloral hydrate showed as follows: no statistically significant difference (
The vital signs of the participants in sedation with chloral hydrate.
Subjects (n = 18) | Heart rate (/min) | Respiration rate (/min) | Oxygen saturation (%) | Systolic blood pressure (mmHg) | Diastolic blood pressure (mmHg) |
---|---|---|---|---|---|
Before administration | 117.44 ± 18.64 | 23.33 ± 4.14 | 99.39 ± 0.61 | 90.78 ± 20.14 | 56.22 ± 17.20 |
After administration | 117.89 ± 18.55 | 24.61 ± 6.04 | 99.56 ± 0.62 | 91.22 ± 20.57 | 58.94 ± 16.00 |
|
−0.266 | −1.668 | −1.374 | −0.389 | −1.690 |
|
0.793 | 0.114 | 0.187 | 0.702 | 0.109 |
In comatose participants, the vital signs after administration were not statistically significant different (
There were three cases of rash (
Rash in chest
The allergies and the managements.
Gender | Age | Clinical diagnosis | Drug batch number | Time of allergy | Allergic performance | Management | Outcome | |
---|---|---|---|---|---|---|---|---|
Case1 | Male | 5Y8M | Solitary hematuria | 17A011A | The first CEUS | Chest rash ( |
Intravenous injection of methylprednisolone 20 mg | Complete relief |
Case 2 | Male | 7Y7M | Henoch-Schonlein purpura nephritis | 17A011A | The second CEUS | Rash in posterior neck, facial, and back | Intravenous injection of methylprednisolone 40 mg | Complete relief |
Case 3 | Female | 7Y11M | Nephrotic syndrome | 17A023A | The second CEUS | Flushed face, and rash in posterior neck, facial, and back | Intravenous injection of methylprednisolone 40 mg | Complete relief |
Case 4 | Male | 13Y3M | Inflammatory myofibroblastic tumor | 17A023A | The first CEUS | Rash in face, chest, and abdominal, a high heart rate (148 bpm), hypotension (66/34 mmHg) | Intravenous injection of dexamethasone 5 mg, methylprednisolone 40 mg, calcium gluconate 10 ml, adrenaline ((0.02 + 0.03+0.05) mg, 0.05 mg/kg*min) | Complete relief |
Case 5 | Male | 6Y3M | Henoch-Schonlein purpura nephritis | 17A038A | The first CEUS | Continuous cough, hypotension (53/17 mmHg) | Intravenous injection of methylprednisolone 40 mg | Complete relief |
Case 6 | Female | 6Y3M | Nephrotic syndrome | 17A052A | The first CEUS | Hypotension (78/47 mmHg) | Intravenous injection of methylprednisolone 40 mg | Complete relief |
In our study, CEUS was performed for many organs, including liver, kidney, spleen, pancreas, thyroid, testicles, and so on. The arrival time (AT), time to peak (TTP), and the wash-out time were documented in
The arrival time, time to peak, and the wash-out time of liver and kidney.
Arrival time (s) | Time to peak (s) | Wash-out time (s) | |
---|---|---|---|
Liver (35 cases) | 8.75 ± 2.06 | 26.25 ± 1.25 | 462.50 ± 2.33.24 |
Kidney (187 cases) | 10.17 ± 3.83 | 24.41 ± 6.53 | 450.98 ± 164.18 |
With different doses, renal CEUS was performed and the wash-out time was recorded. It was showed below (
The wash-out time of renal CEUS with different doses of contrast agents.
Wash-out time (s) | |
---|---|
Dose 1 | 517.91 ± 138.78 |
Dose 2 | 386.38 ± 102.96 |
|
7.001 |
|
0.025 |
Dose 1: 2.4 ml/time; Dose 2: 0.03 ml/kg/time. And one case can’t acquire the wash-out time because of the severe adverse effect.
Among 312 subjects, 287 cases were made the terminal diagnosis by biopsy, surgery, or clinical diagnostic standards, while 25 cases were available for follow-up. (
The clinical or pathologic diagnosis of the subjects.
Diffuse Renal Lesions (cases) | Mass (cases) | Others (cases) | Loss of Follow-ups (cases) |
---|---|---|---|
Minimal change disease (MCD) (60) | Hepatoblastoma (11) | Gastrointestinal hemorrhage (2) | Hepatic mass (8) |
Purpura nephritis (44) | Hepatocellular carcinoma (3) | Postoperative hemorrhage (3) | Renal mass (3) |
IgA nephropathy (32) | Neuroblastoma (15) | Subcutaneous hemorrhage (1) | Cervical mass (2) |
lupus nephritis (LN) (19) | Lymphoma (12) | Trauma (2) | Testicular mass (1) |
Mesangial proliferative glomerulonephritis (MsPGN) (8) | Teratoma (6) | Renal segmental infarction (1) | Thyroid nodules (1) |
Thin basement membrane nephropathy(TBMN)(7) | Yolk sac tumor (3) | Hepatic vascular malformation (2) | Pelvic mass (1) |
Focal segmental glomerular sclerosis (FSGS) (3) | Rhabdomyosarcoma (3) | Budd-Chiari syndrome (2) | Retroperitoneal mass (1) |
Alport syndrome (2) | Nephroblastoma (2) | Venous thrombosis (2) | Diffuse renal lesions (8) |
Membranous nephropathy (MN) (2) | Hemangioma (4) | Infection (4) | |
Thrombotic microangiopathy (TMA) (1) | Langerhans cell histiocytosis (LCH) (2) | Fatty liver (1) | |
Hepatitis B virus-associated membranous nephritis (HBV-MN) (1) | Inflammatory myofibroblastic tumor (IMT) (2) | ||
Endocapillary proliferative glomerulonephritis (EPGN) (1) | Malignant triton tumor (1) | ||
Crescentic glomerulonephritis (1) | Clear cell sarcoma (1) | ||
Interstitial nephritis (1) | Malignant rhabdoid tumor (MRT) (1) | ||
Sclerosing glomerulonephritis (1) | Pheochromocytoma (1) | ||
Cystic nephroma (1) | |||
Failing to acquire the glomeruli (2) | Fibrosarcoma (1) | ||
Malignant mixed germ cell tumor (1) | |||
Neurofibroma (1) | |||
Solid-pseudopapillary tumor (SPT) (1) | |||
Benign lymph nodes (1) | |||
Papillary thyroid carcinoma (PTC) (1) | |||
Renal cyst (2) | |||
Splenic cyst (1) | |||
Small cell lung cancer (1) | |||
Focal nodular hyperplasia (FNH) (1) | |||
Glycogen storage disease (GSD) (1) |
In a 5-year-old boy with IgA nephropathy, CEUS showed the microbubble exuded from kidney to abdominal cavity (arrow) after puncture.
CEUS of hepatocellular carcinoma. The mass had a rapid enhancement and became heterogeneous.
CEUS of inflammatory myofibroblastic tumor (IMT) showed a heterogeneous enhancement and rapid wash-out in the thickened gastric and intestinal wall.
A solid-pseudopapillary tumor of pancreas (SPT) in the head of pancreas. It enhanced simultaneously with the normal pancreas parenchyma and had non-enhanced loculi inside it.
The blood clot in stomach. It showed as an isoechoic mass in baseline US and no enhancement in CEUS.
Thrombosis in superficial femoral artery. No enhancement in the proximal part (arrow) of right superficial femoral artery in CEUS.
CEUS of Splenic necrosis. It showed as splenomegaly, non-enhancement in the spleen parenchyma.
Most of the studies were performed for evaluating renal microcirculation and assisting renal biopsy (192/312 [61.5%]), which had a 98.9% effectiveness in the identification of pathology in the specimens (
The effective rate of the pathological specimens with renal CEUS.
Cases for renal biopsy with renal CEUS | Cases with effective pathological specimen | Cases with ineffective pathological specimen | Effective rate |
---|---|---|---|
192 | 190 | 2 cases failing to acquire the glomeruli | 98.9% |
Some were used to identify the mass in almost the whole body, including 99 (31.4%) cases for the liver (31 cases), retroperitoneum (14 cases), abdominal cavity (14 cases), mediastinum (6 cases), kidney (10 cases), testicles (4 cases), thyroid (3 cases), pancreas (2 cases), spleen (3 cases), and so on. Except for loss to follow-up for 17 cases, it had a 97.6% accuracy as shown by the comparison of CEUS findings with pathology. The others were for identifying 21 (6.73%) cases for trauma, vascular malformation, infection, thrombosis, hemorrhage, infarction, and fatty liver, which had the same accuracy compared with enhanced CT (
The effective rate of the pathological specimens with renal CEUS.
Cases for identifying the mass with CEUS | Loss of following up | Cases for CEUS finding fitting to the pathology | Cases unfitting to the pathology | Accurate rate |
---|---|---|---|---|
99 | 17 | 80 | 2 | 97.6% |
SonoVue® has been widely used in adults in the recent years, and has been proven to be safe (
Our study institute was qualified to conduct the clinical trial, due to the qualified staff, standard equipment, and the approval of the Ethics Committee.
Our results showed that CEUS was effective for the diagnosis of most diseases, especially those that were associated with the microcirculation. (
CEUS in pediatric interventional therapy had its own advantage. In our study, 174 cases undergoing renal CEUS provided clinically useful results pertaining to evaluating the renal microcircular perfusion and the hemorrhage after puncture. This enabled the early identification of stanch bleeding in time. Forty-six (n = 46) cases for mass puncture evaded the necrosis and facilitated the acquisition of eligible tissue for pathology. After intravenous injection, microbubble became the maker of the vascular bed, which made the blood vessels and tissue perfusion images very clear due to the enhancement, in both the great vessels as well as the capillaries. The avascular, potential necrotic and liquefied areas could be recognized due to the expansion of the vision in the interventional operation and avoiding the damage of adjacent normal tissue after enhancement. Many structures were hard to recognize in B-mode US, but were exhibited in CEUS.
In our study, CEUS was performed for evaluating the post-traumatic kidney, renal infarction, splenic cyst, splenic necrosis, splenic hemangioma, hemorrhage in stomach and duodenum, arterial thrombosis, and mass in various organs, and had a high diagnostic accuracy rate compared with the result of surgery pathology and clinical follow-up. Besides, CEUS has been already used in organ transplantation. It was demonstrated that CEUS can help to access the vessels of target organs, the perfusion of transplanted organs, and the post-transplanted complications (
According to the recommendation by the FDA, the optimal dose of SonoVue® in adult was 2.4 ml/time, and the dose range was 1.0–4.8 ml depending on the target organs and the equipment (
In our study, there were three cases of mild allergic reactions, which occurred after administering CEUS from different batches. The earliest allergy occurred within 5 min after injection of contrast agent, and relieved gradually after the immediate administration of dexamethasone injection. For the other allergic reactions, we used methylprednisolone dexamethasone, and acquired a better therapeutic effect. By now, it was known that methylprednisolone had a quicker effectiveness than dexamethasone for anti-allergy therapy. And what’s more, some researchers suggested that, using dexamethasone for prevention should be a routine before CEUS examinations (
According to our experience from the trial, we made a conclusion for the measures dealing with abrupt adverse effects. Firstly, to stop administration and to keep a suitable position—that is, lying down and raising legs when hypotension happened. Secondly, to keep the airways open and to provide oxygen should be done. And then the anti-allergy drugs should be intravenously injected, and the vital signs should be monitored in real time. For the anti-allergy therapy, we can use a dose of 1–2 mg/kg of methylprednisolone for the subjects with rash, and use a dose of 0.01 mg/kg of 0.1% adrenaline for the subjects with hypotension. And they can be used repeatedly 5–15 min after the first use if necessary. The hemodynamic change can be monitored by the arterial cannulation as well.
Intravenous CEUS for pediatric applications was generally safe as observed with a low frequency of adverse effects. In addition, it was associated with better diagnostic effectiveness so that it can be performed for many kinds of medical issues.
There were limitations in our study. The study was in a single center, and lack of cooperation with other institutions. Besides, the disease entities were so complex that there was no specific CEUS modality. In the next step, we will collaborate with other institutions and make our study more standard and systematic, which are favorable for promoting the CEUS application in children and make it more feasible.
The datasets generated for this study are available on request to the corresponding author.
The studies involving human participants were reviewed and approved by the Chinese Ethics Committee (No: 2016[003], ChiCTR-ONh-16009236). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in the article.
The corresponding author BX conceived and conducted the study and gave the guidance in the whole study. The first author M-yM collected and chose the cases, performed the literature search and data extraction, and wrote the paper. The author W-IC assisted to the statistical analysis. Other authors participated in the study and provided some professional guidance. All authors read and approved the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.