Background
Small pilot studies of ultrasound contrast (UC) echocardiography in children have suggested that it is safe; therefore, larger scale evaluation of safety and efficacy in this population is of particular interest.
Methods
This was a retrospective study (January 2005 to June 2014). Known intracardiac shunt was the only exclusion criterion. UC echocardiography was performed on commercially available ultrasound systems using Definity (3% infusion). When indicated, real-time myocardial contrast echocardiography was performed at rest and stress, with examination of myocardial contrast replenishment, plateau intensity, and wall motion. The primary outcome was short-term safety and efficacy (<24 hours).
Results
In all, 113 patients (55% male; mean age, 17.8 ± 3 years; age range, 5–21 years) underwent UC echocardiography for left ventricular opacification or stress wall motion and perfusion analysis. Diagnosis categories were congenital heart disease (30%), acquired heart disease (21%), and other (suspected cardiac complications of disease of other organ systems; 49%). Twelve patients (11%) with right ventricular systolic pressures > 40 mm Hg received UC without complications; four of these (33%) had the highest right ventricular–right atrial gradient recorded with ultrasound contrast–enhanced Doppler. Myocardial perfusion and/or UC echocardiography–detected wall motion abnormalities were seen in 13 patients (12%); four had confirmed correlations by angiography or magnetic resonance imaging. There were 13 instances of adverse events or reported symptoms during UC echocardiography. All symptoms and events were transient, all patients completed protocols, and there were no immediate sequelae.
Conclusions
These data demonstrate the usefulness and safety of UC echocardiography in children and adolescents for a wide variety of indications. UC echocardiography provided myocardial perfusion and wall motion information important in clinical decision making.
Multiple studies in adults have demonstrated significantly enhanced image quality for transthoracic echocardiography with the use of ultrasound contrast (UC). The US Food and Drug Administration (FDA) has approved UC for left ventricular opacification and endocardial border definition in patients with technically suboptimal echocardiograms under rest conditions. UC also improves the assessment of the right ventricle and intracardiac masses and enhances Doppler signals used for evaluating valvular function. Although the use of UC may add time and cost to transthoracic echocardiography, it has been shown to reduce the need for additional diagnostic studies in >30% of patients. Stress echocardiography using UC and real-time myocardial contrast echocardiography (RTMCE) has also been shown to be helpful in examining both myocardial perfusion (MP) and wall motion (WM) in adult patients. Improved wall segment visualization and reader confidence have been observed with UC enhancement at peak stress.
Despite extensive use and proven benefits in adults, there is limited experience with UC in children and adolescents, and UC agents are not yet approved by the FDA for pediatric use. However, pilot studies of UC in this population have reported potential clinical benefits, and the black-box warning in the United States has recently been completely removed for the UC agent Definity (Lantheus Medical Imaging, North Billerica, MA). The current contraindications to UC are (1) right-to-left, bidirectional, or transient right-to-left cardiac shunts; (2) hypersensitivity to perflutren; and (3) hypersensitivity to blood, blood products, or albumin (in the case of Optison) ( FDA.gov ). At our institution, we have used UC off label for various clinical indications since 1996. Our practice has been to consider using UC off label in older children, adolescents, and adults with repaired or unrepaired congenital heart disease (CHD), if clinically indicated, as long as a right-to-left shunt did not exist.
The purpose of this study is to present our institutional data on the safety and efficacy of UC in patients <21 years of age. Furthermore, we sought to evaluate the incidence and types of adverse events associated with the use of UC for rest and stress echocardiography in this population.
Methods
The institutional review board at the University of Nebraska Medical Center approved this retrospective study. Inclusion criteria were (1) age < 21 years at the time of UC echocardiography; (2) UC echocardiography performed between January 2005 and June 2014; and (3) diagnosis of known CHD, known acquired heart disease in a pediatric patient, or “other,” defined as suspected heart disease in the setting of a primary condition of another organ system. Patients with any known intracardiac shunt (left to right, right to left, or bidirectional), or known hypersensitivity to perflutren were excluded by review of medical records and previous echocardiogram reports.
The following information was abstracted from chart review: date of birth, gender, weight, body surface area, diagnoses, type of CHD or acquired heart disease, and date and indication for UC echocardiography. UC was administered with resting echocardiography or in conjunction with stress echocardiography. Doppler-estimated right ventricular systolic pressure, any electrocardiographic changes, and WM or MP abnormalities during UC echocardiography were noted. The prevalence of electrocardiographic abnormalities and reported symptoms in patients of the same age group (5–21 years; 76 male and 64 female patients), who underwent routine exercise stress testing during the year from June 2013 to June 2014 were also recorded for comparison purposes. Medical records, including all nursing notes of the UC echocardiographic study, were reviewed for any patient-reported symptoms or documented signs, and thus the primary outcome of short-term safety (<24 hours) was ascertained.
UC Protocol
Before UC imaging, all patients underwent complete diagnostic transthoracic echocardiography, including spectral and color Doppler evaluation of ventricular inflow and outflow and the atrioventricular and semilunar valves according to standard institutional practice. UC echocardiography was performed on commercially available ultrasound systems (Philips iE33 [Philips Medical Systems, Andover, MA] or Siemens Sequoia [Siemens Medical Solutions USA, Mountain View, CA]) using the lipid-encapsulated microbubble contrast agent Definity infused as a 3% dilution (4–6 mL/min). RTMCE was performed using very low mechanical index (MI) (<0.2) real-time pulse sequence schemes at frame rates of 20 to 25 Hz. Intermittent high-MI impulses (4–40 frames at an MI >1.0) were administered in the apical views to clear microbubbles from the microcirculation and allow visual assessment of myocardial contrast replenishment. The high-MI impulse duration was adjusted to optimize clearance of UC from the myocardium without visually affecting ventricular cavity contrast.
Stress Echocardiographic Protocols
Standard stress echocardiographic protocols were used as reported previously from our center. These were either treadmill stress testing (GE T2100; GE Healthcare, Waukesha, WI) with the Bruce protocol or supine bicycle stress (Medical Positioning, Kansas City, MO) using a symptom-limited protocol. Patients exercised until exhaustion. Blood pressures were monitored every minute and 12-lead electrocardiograms continuously. In patients who had dobutamine stress, an infusion of dobutamine was started at 5 μg/kg/min and increased every 3 min to 10, 20, and 30 μg/kg/min until the target heart rate was achieved. The stress tests were considered diagnostically adequate if the target heart rate (>85% predicted maximum) or an ischemic end point was achieved, defined as an abnormal electrocardiographic response of ≥2 mm horizontal or down-sloping ST-segment depression in any lead or a new or worsening WM abnormality. A 30-min period of monitoring with electrocardiography and oxygen saturation after contrast agent administration was observed in all subjects.
UC-Enhanced Image Analysis
MP and WM with RTMCE were interpreted using the American Society of Echocardiography’s recommended 17-segment model for the left ventricle. The time period of myocardial UC replenishment to reach a plateau intensity after the high-MI impulse was considered abnormal if the subendocardial or transmural portion of any two contiguous segments required >2 sec to replenish at peak stress or required >4 sec to replenish under resting conditions. During the replenishment phase after the brief high-MI impulse, regional WM was also analyzed because this time period provided optional endocardial border delineation. Each WM segment of the left ventricle was scored at rest and at peak stress using the following scoring system: 1 = normal, 2 = mild to moderate hypokinesis, 3 = severe hypokinesis, 4 = akinesis, and 5 = dyskinesis. Quantitative right ventricular assessment was performed in the apical four-chamber view for patients with CHD by dividing the chamber into three parts (basal, midcavity, and apical), each part as one third of the axial length of the cavity from the plane of the tricuspid valve annulus to the apex. The resulting right ventricular segments were the basal free wall, midcavity free wall, apical free wall, apical septum, midcavity septum, and basal septum. All studies were supervised, reviewed and interpreted by a cardiologist with expertise in myocardial contrast echocardiography (T.R.P.). A blinded observer (S.K.) assessed the adequacy of endocardial border detection for the left ventricle by scoring the total number of segments visualized in the UC-enhanced versus noncontrast images at rest in each patient.
Statistical Analysis
Mean, SD, and range were determined for continuous variables. Analysis of variance was used for comparison of hemodynamic and echocardiographic data between the CHD, acquired heart disease, and “other” groups. Differences in the mean number of left ventricular segments visualized before and after UC per patient were tested using Student’s t test. Comparisons of proportions of reported adverse events and electrocardiographic changes between UC stress echocardiography and routine exercise stress testing was performed using χ 2 tests. P values < .05 were considered to indicate statistical significance. Statistical analyses were performed using Minitab version 16.1 (Minitab, State College, PA).
Results
From January 2005 to June 2014, a total of 113 patients <21 years of age underwent UC echocardiography ( Figure 1 ). Demographic data in all subjects are shown in Table 1 . The mean age was 17.8 ± 3 years (range, 5–21 years), and 55% were male. Thirty-nine patients (35%) had UC for resting studies only, while UC was administered to 74 patients (65%) for stress WM and MP analysis with RTMCE (37 treadmill, 23 supine bike, and 14 dobutamine). Thirty-four patients (30%) had CHD. CHD diagnoses (all postoperative patients) were atrioventricular septal defect, tetralogy of Fallot, pulmonary atresia, tricuspid atresia, Ebstein’s anomaly, transposition of the great arteries, and single ventricle status post Fontan palliation. Twenty-four patients (21%) had acquired heart disease that included hypertrophic cardiomyopathy, dilated cardiomyopathy, status post orthotopic heart transplantation, Kawasaki disease with coronary sequelae, hypertension, and coronary artery disease. The remaining 55 studies (49%) were for other indications: suspected ischemia and evaluations for cardiac complications in the setting of kidney, liver, or small bowel transplantation. Of these 55, stress echocardiograms comprised 31 studies.
| Parameter | UC use (all indications) | UC use for stress perfusion | ||||||
|---|---|---|---|---|---|---|---|---|
| All patients | Known CHD | Known acquired heart disease | Others | All patients | Known CHD | Known acquired heart disease | Others | |
| n | 113 | 34 | 24 | 55 | 74 | 30 | 13 | 31 |
| Gender (male/female) | 62/51 | 19/15 | 13/11 | 30/25 | 40/34 | 16/14 | 6/7 | 18/13 |
| Age (y) | 17.8 ± 3.0 | 15.8 ± 3.4 | 17.7 ± 3.3 | 19.1 ± 1.8 | 17.2 ± 3.4 | 15.3 ± 3.2 | 17.2 ± 4.0 | 19.1 ± 2.1 |
| Height (cm) | 168.6 ± 12.8 | 167.2 ± 13.2 | 167.5 ± 16.8 | 169.9 ± 10.8 | 168.3 ± 13.4 | 167.4 ± 13.8 | 162.4 ± 17.4 | 171.9 ± 10.6 |
| Weight (kg) | 76.5 ± 20.9 | 70.9 ± 21.5 | 77.8 ± 23.1 | 79.3 ± 19.5 | 73.2 ± 20.5 | 69.4 ± 21.2 | 64.5 ± 17.7 | 80.7 ± 19.5 |
| BSA (m 2 ) | 1.9 ± 0.3 | 1.8 ± 0.3 | 1.9 ± 0.3 | 1.9 ± 0.2 | 1.8 ± 0.3 | 1.8 ± 0.3 | 1.7 ± 0.3 | 1.9 ± 0.2 |
Twelve patients (11%) had mild or greater elevation of right ventricular pressure at baseline, defined as right ventricular systolic pressure, estimated by the tricuspid regurgitation Doppler peak velocity, >40 mm Hg. Among these 12 patients, eight had CHD and four had acquired heart disease. In four patients in this group (33%), the use of contrast provided an improvement in the completeness of the peak tricuspid regurgitation Doppler waveform velocity, compared with baseline noncontrast imaging ( Figure 2 ).
Stress Testing Safety and Efficacy
Hemodynamic and echocardiographic data at rest and stress are displayed for all patients and for the three groups (CHD, acquired heart disease, and other) in Table 2 . MP and/or contrast-detected WM abnormalities were identified in 13 patients (11.5%); all 13 had UC administered with stress echocardiography. Of these, 11 had CHD and two had acquired heart disease. Patients with CHD with MP abnormalities included those with aortic valve disease ( n = 3), tetralogy of Fallot ( n = 3), transposition of the great arteries status post atrial switch ( n = 2), coronary artery fistula ( n = 1), truncus arteriosus ( n = 1), and anomalous origin of the left coronary artery from the pulmonary artery ( n = 1). Acquired heart diseases with MP abnormalities were hypertrophic cardiomyopathy ( n = 1) and Kawasaki disease with coronary dilatation ( n = 1). Representative pediatric examples of CHD and acquired heart disease with MP abnormalities are shown in Figures 3 to 5 and Videos 1 to 3 (available at www.onlinejase.com ). The number of left ventricular segments visualized improved from 13 ± 1 per patient without UC at rest to 16 ± 1 per patient with UC ( P < .001). MP abnormalities found in patients with CHD were in the midseptal and apical segments of the left ventricle (tetralogy of Fallot), the apical septal segment of the right ventricle (transposition of the great arteries status post atrial switch), and the inferoapical and anteroseptal left ventricular segments (aortic stenosis). In patients with acquired heart disease, MP abnormalities were seen in the inferoseptal (Kawasaki disease) and apical/anteroseptal segments (hypertrophic cardiomyopathy). Ten of the 13 patients had WM abnormalities (WM score 2–4) demonstrated in the same segments at peak stress. Of these, four (30%) had corroborative findings in the given vascular territory by alternative diagnostic testing (angiographic demonstration of stenosis or evidence of myocardial scarring by cardiac magnetic resonance angiography) performed within 1 year of stress echocardiography.
| Variable | All patients | CHD | Acquired heart disease | Other | P |
|---|---|---|---|---|---|
| Resting HR (beats/min) | 75 ± 15 | 76 ± 17 | 84 ± 18 | 72 ± 11 | .07 |
| Peak HR (beats/min) | 169 ± 28 | 149 ± 28 | 173 ± 16 | 185 ± 18 | <.001 |
| Maximum HR (%) | 89 ± 11 | 84 ± 20 | 87 ± 7 | 91 ± 9 | .193 |
| Resting SBP (mm Hg) | 121 ± 17 | 120 ± 12 | 111 ± 15 | 127 ± 20 | .017 |
| Peak SBP (mm Hg) | 153 ± 25 | 158 ± 25 | 146 ± 24 | 152 ± 26 | .399 |
| Resting DBP (mm Hg) | 68 ± 12 | 62 ± 9 | 68 ± 13 | 79 ± 10 | <.001 |
| Peak DBP (mm Hg) | 76 ± 17 | 74 ± 17 | 74 ± 9 | 79 ± 18 | .487 |
| Rest LVEF | 57 ± 12 | 55 ± 14 | 59 ± 6 | 58 ± 12 | .154 |
| Exercise duration (min:sec) | 12:5 ± 3:5 | 14:39 ± 4:2 | 11:24 ± 3:2 | 11:51 ± 2:5 | .005 |
| METs | 12.0 ± 4.1 | 9.4 ± 4.1 | 12.0 ± 3.5 | 13.9 ± 3.3 | .002 |
| Bruce stage | 4 ± 1 | 4 ± 1 | 3 ± 1 | 4 ± 1 | .113 |
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