Safety and Efficacy of Cardiac Ultrasound Contrast in Children and Adolescents for Resting and Stress Echocardiography

Safety and Efficacy of Cardiac Ultrasound Contrast in Children and Adolescents for Resting and Stress Echocardiography Shelby Kutty, MD, FASE, Yunbin Xiao, MD, PhD, Joan Olson, RDCS, Feng Xie, MD, David A. Danford, MD, Christopher C. Erickson, MD, and Thomas R. Porter, MD, FASE, Omaha, Nebraska

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 6 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. (J Am Soc Echocardiogr 2016;-:---.) Keywords: Ultrasound contrast, Echocardiography, Stress echocardiography, Adult congenital heart disease, Pediatric

Multiple studies in adults have demonstrated significantly enhanced image quality for transthoracic echocardiography with the use of ultrasound contrast (UC).1-3 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.4 UC also improves the assessment of the right ventricle and intracardiac masses and enhances Doppler signals used for evaluating valvular function.5 From the Division of Pediatric Cardiology, University of Nebraska College of Medicine, Children’s Hospital & Medical Center, Omaha, Nebraska (S.K., Y.X., D.A.D., C.C.E.); and the Department of Internal Medicine, Section of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska (J.O., F.X., T.R.P.). Dr. Kutty receives support from the American Heart Association. Reprint requests: Shelby Kutty, MD, FASE, University of Nebraska Medical Center, 982265 Nebraska Medical Center, Omaha, NE 68198-2265 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2016 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2016.02.019

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.6 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.7-11 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,5,12,13 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 1

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Abbreviations

CHD = Congenital heart disease

FDA = US Food and Drug Administration

MI = Mechanical index MP = Myocardial perfusion RTMCE = Real-time myocardial contrast echocardiography UC = Ultrasound contrast WM = Wall motion

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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.14 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.15 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.5 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 mg/kg/min and increased every 3 min to 10, 20, and 30 mg/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

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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 c2 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 6 3 years (range, 5–21 years), and 55% were male. Thirtynine 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. 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 6 1 per patient without UC at rest to 16 6 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

Figure 1 Results summary breaking down the indications for UC in the pediatric patient population studied. 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. Seventeen patients had electrocardiographic abnormalities during stress echocardiography (12 patients with CHD, three with acquired heart disease, two with other diagnoses), which included ST-segment depression (n = 13), premature atrial contractions (n = 2), premature ventricular contractions (n = 1), and nonsustained ventricular tachycardia (n = 1). The peak heart rate and metabolic equivalents achieved in the CHD group were lower than in the other two groups (peak heart rate, 149 6 28 beats/min vs 173 6 16 and 185 6 18 beats/min [P < .001]; metabolic equivalents, 9.4 6 4.1 vs 12.0 6 3.5 and 13.9 6 3.3 [P = .002]).

Adverse Events in All Patients Thirteen patients (11%) experienced reported symptoms during administration of contrast. These included four patients with CHD, two with acquired heart disease, and seven with other diagnoses. The symptoms reported were chest pain (n = 7), fatigue (n = 3), back pain (n = 1), dizziness (n = 1), neck pain (n = 1), headache (n = 1), and shortness of breath (n = 1). The symptoms lasted <1 min in all cases and resolved without any treatment. There were no instances of hypotension, anaphylactoid, or allergic reaction in any patient. The UC echocardiographic and/or stress perfusion protocols were complete in all patients. All were outpatients and were discharged the same day. Patients were not actively contacted after UC echocardiography to determine if they might have experienced potential UC-related complications, but documentation of any symptomrelated calls from patients within 1 day of discharge was reviewed. Of 140 age-matched patients who underwent routine exercise testing without contrast echocardiography, 23 (16%) reported symptoms during the test (six chest pain, five dizziness, five shortness of breath, four palpitations, and three fatigue). There were 18 instances (13%) of electrocardiographic abnormalities (14 ST-segment changes, two premature atrial contractions, and two premature ventricular contractions) reported. Comparison with the UC stress echocardiographic

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Table 1 Patient characteristics UC use (all indications)

Parameter

n Gender (male/female)

All patients

Known CHD

UC use for stress perfusion

Known acquired heart disease

Others

All patients

Known CHD

Known acquired heart disease

Others

113

34

24

55

74

30

13

31

62/51

19/15

13/11

30/25

40/34

16/14

6/7

18/13

17.8 6 3.0

15.8 6 3.4

17.7 6 3.3

19.1 6 1.8

17.2 6 3.4

15.3 6 3.2

17.2 6 4.0

19.1 6 2.1

Height (cm)

168.6 6 12.8

167.2 6 13.2

167.5 6 16.8

169.9 6 10.8

168.3 6 13.4

167.4 6 13.8

162.4 6 17.4

171.9 6 10.6

Weight (kg)

76.5 6 20.9

70.9 6 21.5

77.8 6 23.1

79.3 6 19.5

73.2 6 20.5

69.4 6 21.2

64.5 6 17.7

80.7 6 19.5

1.9 6 0.3

1.8 6 0.3

1.9 6 0.3

1.9 6 0.2

1.8 6 0.3

1.8 6 0.3

1.7 6 0.3

1.9 6 0.2

Age (y)

BSA (m2)

BSA, Body surface area. Data are presented as number or as mean 6 SD.

Figure 2 Representative example of continuous-wave Doppler envelope of tricuspid regurgitation jet enhanced with intravenous UC in a 16-year-old patient with repaired tetralogy of Fallot. cohort revealed no statistically significant differences in adverse events (P = .656) or electrocardiographic changes (P = .405).

DISCUSSION There is sufficient evidence from studies in adult patients to believe that UC agents have a high benefit-to-risk ratio and certainly less risk than other commonly used contrast agents in other imaging modalities.16 Our data demonstrate that UC was safe in pediatric patients undergoing echocardiography for a wide range of indications, and provided useful information that assisted with clinical decision making and management. Although the only approved indication for UC at the present time remains the enhancement of ventricular borders in adults,17 we found it to be useful for many off-label purposes as well, including contrast-enhanced Doppler and the detection of MP abnormalities. Data reported here also attest to the safety of UC in patients <21 years of age, with a 0% incidence of allergic reactions for Definity contrast in this cohort. We realize that several thousands of patients are necessary for adequately conclusive safety studies, which is extremely difficult to achieve in the context of pediatrics. Because the complement system is more active in younger children, one might anticipate that younger children might be at higher risk for anaphylactoid toxicity from UC manifesting as hypersensitivity reactions that do not involve immunoglobulin E but arise as a consequence of activa-

tion of the complement system. These reactions, collectively referred to as complement activation–related pseudoallergy, include angioedema, bronchospasm, hypotension, hypoxemia, low back pain, and urticaria.18 No such reaction was observed in the >100 patients in this study, indicating that anaphylactoid reactions may still be rare even in this potentially higher risk setting. In patients with CHD, transthoracic echocardiography can be challenging because of acoustic window limitations secondary to previous cardiac operations, chest wall problems, and alterations in cardiac geometry. In our study, we demonstrated that UC provides important information to guide management in these patients in three specific areas. First, UC allows improved visualization of segmental WM in both the left and right ventricles, leading to better quantification of ventricular function at rest and during physiologic or pharmacologic stress. Second, UC-enhanced Doppler signals improved the quantification of right ventricular systolic pressure in 33% of patients in our study who needed this measured as part of their hemodynamic evaluation. This is similar to adult studies, in which Doppler enhancement with UC resulted in more accurate measurements of transvalvular pressure gradients, right ventricular systolic pressure, and transvalvular pressure.5,17 Third, UC with RTMCE provided right and left ventricular MP information simultaneous with WM analysis. In this context, the advantages of UC were that one could immediately assess perfusion without requiring radiation exposure or magnetic resonance imaging. The added temporal resolution permitted WM and MP to be analyzed simultaneously. Therefore, the present

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Table 2 Hemodynamic and echocardiographic data at rest and stress Variable

Resting HR (beats/min) Peak HR (beats/min)

All patients

CHD

Acquired heart disease

Other

P

75 6 15

76 6 17

84 6 18

72 6 11

.07

169 6 28

149 6 28

173 6 16

185 6 18

<.001

89 6 11

84 6 20

87 6 7

91 6 9

.193

Resting SBP (mm Hg)

121 6 17

120 6 12

111 6 15

127 6 20

.017

Peak SBP (mm Hg)

153 6 25

158 6 25

146 6 24

152 6 26

.399

Resting DBP (mm Hg)

68 6 12

62 6 9

68 6 13

79 6 10

<.001

Peak DBP (mm Hg)

76 6 17

74 6 17

74 6 9

79 6 18

.487

Rest LVEF

57 6 12

55 6 14

59 6 6

58 6 12

.154

Exercise duration (min:sec)

12:5 6 3:5

14:39 6 4:2

11:24 6 3:2

11:51 6 2:5

.005

METs

12.0 6 4.1

9.4 6 4.1

12.0 6 3.5

13.9 6 3.3

.002

461

461

361

461

.113

Maximum HR (%)

Bruce stage

DBP, Diastolic blood pressure; HR, heart rate; LVEF, left ventricular ejection fraction; METs, metabolic equivalents; SBP, systolic blood pressure. Data are expressed as mean 6 SD.

Figure 3 Adolescent following aortic valve repair with a severe inducible WM and MP defect during exercise stress (arrows). Subsequent surgery confirmed that the repaired leaflet obstructed the left main coronary ostium. See also Video 1 (available at www.onlinejase.com).

series demonstrates the feasibility of image acquisition for RTMCE during peak stress for the evaluation of MP and WM across a wide age range of children and adolescents. Although the data reported here represent the largest pediatric series on UC, spanning almost a decade, the number of patients in whom UC was deemed to be appropriate for clinical use was relatively small. There are several potential explanations for why UC has not been used more in this clinical setting. No UC agent is currently approved in the pediatric or adolescent population for use in rest echocardiography to improve left ventricular endocardial border definition in patients with suboptimal unenhanced imaging. Therefore, there is limited exposure and experience among pediatric cardiologists with UC. Because there is little published information on the use of UC on this population, caregivers are often reluctant to use UC in the pediatric population. Safety concerns have been raised by the FDA in previous years, although several subsequent studies have confirmed the clinical safety of UC, and the black-box warning in the United States has been removed for the agent Definity. A phase III

multicenter clinical evaluation of the safety and efficacy of the UC agent Lumason (Bracco Diagnostics, Monroe Township, NJ) in pediatric echocardiography (ClinicalTrials.gov identifier NCT02282163) is currently under way. This agent (under the trade name SonoVue) is approved for rest and stress echocardiography in the European Union for the adult population. We anticipate increased clinical use in pediatrics concomitant with greater experience and data. Stress protocols using UC and real-time perfusion imaging have proved very helpful and safe for the detection of coronary artery disease in adults.19 In a similar way, stress protocols with UC could disclose clinically important changes in the younger patients that are not evident with conventional transthoracic echocardiography. We expect UC use both at rest and during stress echocardiography to increase in children, adolescents, and young adults (even for just left ventricular opacification) because of (1) the increased number of arterial switch procedures and coronary artery manipulations for various types of coronary anomalies in association with CHD being performed in infancy and childhood; (2) the increasing frequency

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Figure 4 Patient with extracardiac Fontan repair and coronary artery fistula. Perfusion defects seen in the apical, distal anterior, and distal anteroseptal segments (arrows) despite normal WM in these segments during stress imaging. The patient subsequently underwent transcatheter device closure of this coronary fistula. See also Video 2 (available at www.onlinejase.com).

Figure 5 Adolescent with apical form of hypertrophic cardiomyopathy who had an easily identifiable apical perfusion defects (arrows) with normal WM during bicycle stress, which was helpful in the decision making for septal myectomy. See also Video 3 (available at www.onlinejase.com). of difficult windows due to prior surgical procedures and obesity; (3) the increased need for evaluation of ischemia in the follow-up of acquired heart disease, including coronary sequelae of Kawasaki disease; (4) the need to address risk and inform clinical decision making in the heterogeneous population of young patients increasingly diagnosed nowadays with anomalous aortic origin of a coronary artery, which may be rarely associated with myocardial ischemia and sudden death in the young; and (5) the desperate need for non-

radiation-exposure techniques in all patient populations. The clinical use of radionuclide techniques has been limited in children not only because of radiation concerns but also because of the general unavailability of those tests. UC with RTMCE has the benefit of superior spatial and temporal resolution compared with radionuclide techniques, allowing simultaneous analysis of WM and MP. CHD at any age may be associated with elevated pulmonary vascular resistance or pulmonary artery pressures. Pulmonary

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hypertension was previously considered a contraindication for UC on the basis of early studies demonstrating that intravenously administered unshelled microbubbles could cause arterial desaturation and increases in pulmonary vascular resistance and pulmonary artery pressure.17 The current FDA-approved UC agents (including Definity, used in this series) are composed of very small microbubbles containing high–molecular weight gases enclosed in shells that remain relatively stable in circulation,17 which may promote safety in patients with pulmonary hypertension. Several adult studies have subsequently examined the effects of UC on pulmonary hemodynamics and confirmed safety.20-22 It is noteworthy that in the present series, similar to adult studies, there was no serious adverse event with administration of UC in the 11% of pediatric patients who had elevated right ventricular systolic pressure at baseline. Use of second-generation perflutren-based UC is currently contraindicated in patients with known right-to-left or bidirectional intracardiac shunts. In patients with CHD, intracardiac communications are usually closed at the time of surgical repair, so the presence of residual right-to-left shunt is rare. However, in the presence of a communication, right-to-left shunting may occur with pulmonary hypertension/ Eisenmenger syndrome, right ventricular dysfunction, or diminished right ventricular compliance. It may be seen with biventricular (e.g., native or repaired Ebstein’s anomaly, repaired pulmonary atresia with intact ventricular septum, repaired tetralogy of Fallot) or singleventricle CHD (e.g., some patients with Fontan). After an exhaustive review of current peer-reviewed research, the International Contrast Ultrasound Society Board reported UC to be safe in patients with known right-to-left shunting and certainly safer than radiolabeled albumin.23 They found no scientific basis for UC contraindication with known or suspected cardiac shunts and recommended removal of the contraindication.23 The initial safety concerns were based on limited rodent data and speculation related to macroaggregated albumin microspheres, which have different physical and chemical properties. Radioactive macroaggregated albumin is not contraindicated in adult or pediatric patients with cardiac shunts and is routinely used in these populations. It is noteworthy that there are no known cases of any complications with using intravenous UC in patients with right-toleft shunting.17 A recent large series (review of 39,020 echocardiograms) found a single minor adverse event (back pain) with perflutren-based UC use in 418 patients with intracardiac shunts.24 Recently published adult guidelines state that with regard to rightto-left shunting, the intent of the FDA warning is significant right-toleft shunting.17 We recommend careful review of medical records and results of previous diagnostic studies, as well as confirmation of absence of systemic hypoxemia by pulse oximetry (SpO2 < 96%) before UC administration in children. We believe that it is reasonable to consider using saline contrast injection via intravenous access in a forearm or antecubital vein to rule out significant right-to-left shunt before UC in this particular population. This would include patients with prior rightto-left shunt repairs.

intravenous canula placement and UC administration, but other than that, we clearly could not expect a pediatric population to have a higher risk or complication rate than for routine echocardiography without contrast. Patients with all types of known intracardiac shunts were excluded from the study. The adverse events reported here were collected from a chart review, and therefore some events may have been missed. It is unlikely that any severe events would have been missed because all subjects received UC as outpatients and were discharged home the same day, after a period of observation. Although our subject group ranged in age from 5 to 21 years, it did not include a large number of young children, so the age distribution was skewed toward older children and adolescents. Favorable transthoracic ultrasound windows, and the preference to avoid intravenous access are responsible for the relatively small number of young children. No reference standard was used to evaluate the accuracy of any induced perfusion defects. In the pediatric population, however, no reference standard exists, other than patient outcome. Finally, the varied CHD and acquired heart disease types included in the study preclude meaningful subgroup analyses of any specific congenital or acquired defect.

CONCLUSIONS This analysis in patients <21 years of age demonstrates the potential clinical utility and good safety profile of UC echocardiography for a wide variety of indications. The overall incidence of adverse events is very low, and severe events did not occur in this pediatric cohort. UC was well tolerated by the subset of patients in this series with elevated baseline right ventricular systolic pressure. UC improved the number of visualized left ventricular segments and permitted the detection of the tricuspid regurgitant jet in cases in which it was not seen adequately for measurement on noncontrast images. UC in conjunction with rest and stress imaging provided MP and WM information that proved very useful in clinical decision making and may avoid the need for downstream testing that would require invasive procedures and/or ionizing radiation exposure. Larger prospective studies are under way to further evaluate the safety and utility of UC in pediatric patients.

ACKNOWLEDGMENT We appreciate the assistance of Roberta J. Hess, RN.

SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx. doi.org/10.1016/j.echo.2016.02.019.

Study Limitations This study had inherent limitations associated with a retrospective cohort study. Findings of this study ought to be confirmed by larger prospective multicenter studies. The absence of a control group is a limitation, but the very low undetectable complication rate in this study could not be higher than what would be expected for any pediatric age population undergoing clinical transthoracic echocardiography. We acknowledge that there will be some discomfort with

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a retrospective analysis of 78,383 administered contrast doses. J Am Soc Echocardiogr 2008;21:1202-6. Kusnetzky LL, Khalid A, Khumri TM, Moe TG, Jones PG, Main ML. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies. J Am Coll Cardiol 2008;51:1704-6. Mulvagh SL, Rakowski H, Vannan MA, Abdelmoneim SS, Becher H, Bierig SM, et al., American Society of Echocardiography. American Society of Echocardiography consensus statement on the clinical applications of ultrasonic contrast agents in echocardiography. J Am Soc Echocardiogr 2008;21:1179-201. quiz 1281. Kutty S, Olson J, Danford CJ, Sandene EK, Xie F, Fletcher SE, et al. Ultrasound contrast and real-time perfusion in conjunction with supine bicycle stress echocardiography for comprehensive evaluation of surgically corrected congenital heart disease. Eur Heart J Cardiovasc Imaging 2012;13:500-9. Kurt M, Shaikh KA, Peterson L, Kurrelmeyer KM, Shah G, Nagueh SF, et al. Impact of contrast echocardiography on evaluation of ventricular function and clinical management in a large prospective cohort. J Am Coll Cardiol 2009;53:802-10. Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients). Am J Cardiol 2008;102:1742-6. Erb JM, Shanewise JS. Intraoperative contrast echocardiography with intravenous optison does not cause hemodynamic changes during cardiac surgery. J Am Soc Echocardiogr 2001;14:595-600. Shaikh K, Chang SM, Peterson L, Rosendahl-Garcia K, Quinones MA, Nagueh SF, et al. Safety of contrast administration for endocardial enhancement during stress echocardiography compared with noncontrast stress. Am J Cardiol 2008;102:1444-50. Gabriel RS, Smyth YM, Menon V, Klein AL, Grimm RA, Thomas JD, et al. Safety of ultrasound contrast agents in stress echocardiography. Am J Cardiol 2008;102:1269-72. Tsutsui JM, Xie F, McGrain AC, Mahrous H, Hankins J, O’Leary EL, et al. Comparison of low-mechanical index pulse sequence schemes for detecting myocardial perfusion abnormalities during vasodilator stress echocardiography. Am J Cardiol 2005;95:565-70. McMahon CJ, Ayres NA, Bezold LI, Lewin MB, Alonzo M, Altman CA, et al. Safety and efficacy of intravenous contrast imaging in pediatric echocardiography. Pediatr Cardiol 2005;26:413-7.

Video 1 Adolescent following aortic valve repair with a severe inducible WM and MP defect during exercise stress (arrows). Subsequent surgery confirmed that the repaired leaflet obstructed the left main coronary ostium.

Video 2 Patient with extracardiac Fontan repair and coronary artery fistula. Perfusion defects seen in the apical, distal anterior, and distal anteroseptal segments (arrows) despite normal WM in these segments during stress imaging. The patient subsequently underwent transcatheter device closure of this coronary fistula.

Video 3 Adolescent with apical form of hypertrophic cardiomyopathy who had an easily identifiable apical perfusion defects (arrows) with normal WM during bicycle stress, which was helpful in the decision making for septal myectomy.

Journal of the American Society of Echocardiography - 2016

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