JACC Vol. 27, No. 5 1251 April 1996:1251-6
Dobutamine Stress Echocardiography for Detection of Coronary
Artery Stenosis in Children With Kawasaki Disease
N O B U T A K A N O T O , M D , M A M O R U A Y U S A W A , M D , K E N S U K E K A R A S A W A , M D , H I D E O Y A M A G U C H I , M D , N A O K A T A S U M I T O M O , M D , T O M O O O K A D A , M D , K E N S U K E H A R A D A , M D
Tokyo, Japan
Objectives. This study was designed to assess the feasibility and diagnostic accuracy of dobutamine stress echocardiography for detection of coronary artery stenosis in children with Kawasaki disease.
Background. Dobutamine stress echocardiography is valuable as an alternative test for detection of coronary artery disease in adult patients; however, its usefulness for children has been demonstrated only in limited cases.
Methods. Dobutamine stress echocardiography (up to 30/tg/kg body weight per rain) was performed in 50 patients at the convalescent stage of Kawasaki disease, including 26 patients with coronary sequelae documented by previous coronary angiography (sequelae group, 3 to 15 years old) and 24 patients with normal coronary arteries documented by eehocardiography (normal group, 7 to 16 years old), who underwent quantitative coronary angiography on a separate day. Left ventricular regional wall motion divided into 16 segments was assessed in relation to the extent of coronary artery disease. A positive test response was defined as a new or worsened wall motion abnormalities.
Results. Significant coronary artery disease (>50% diameter stenosis of major vessels) was present in 21 patients in the
sequelae group. There was no significant difference in the maxi- mal dose of dobutamine between the sequelae and normal groups ([mean -+ SD] 22.4 _+ 5.1 vs. 24.2 + 2.5/~g/kg per rain). Heart rate and systolic blood pressure were significantly increased (p < 0.01) at maximal dose of dobutamine compared with values at rest in both groups; consequently, the rate-pressure product exceeded 20,000 in 20 (40%) of the 50 patients during dobutamine infusion. Ten patients had self-limiting side effects; however, there were no serious complications from stress-induced ischemia. New wall motion abnormalities corresponding to the extent of coronary artery disease were detected in 19 of 21 patients in the sequelae group, whereas no wall motion abnormalities were detected in the normal group. Thus, the sensitivity and specificity of dobutamine stress echocardiography for the detection of coronary artery disease were 90% and 100%, respectively.
Conclusions. We conclude that dobutamine stress echocardiog. raphy is a safe and accurate diagnostic method for detection of coronary artery stenosis in Kawasaki disease. Moreover, this is a possible alternative method for patients unable to exercise ade- quately, even if they are small children.
(JAm CoU Cardiol 1996;27:1251-6)
Stress echocardiography, a relatively new technique for the diagnosis of coronary artery disease, is based on the principle that stress-induced ischemia results in regional wall motion abnormality that can be detected by two-dimensional echocar- diography (1-3). More recently, pharmacologic stress echocar- diography has been documented as a sensitive and alternative stress imaging test, especially in patients unable to perform standard treadmill or bicycle exercise (4-7). In adults, stress echocardiography now has been reported to be a safe and accurate diagnostic method for detection of coronary artery disease; however, its usefulness in children has been evaluated in only limited cases (8). The purpose of this study was to
From the Department of Pediatrics and Cardiology, Nihon University School of Medicine, Tokyo, Japan. This work was supported by a grant for Kawasaki disease from the Ministry of Health and Welfare of Japan.
Manuscript received September 1, 1994; revised manuscript received Sep- tember 14, 1995, accepted November 14, 1995.
Address for correspondence: Dr. Nobutaka Noto, Department of Pediatrics, Nihon University School of Medicine, 30-10yagnchi, Itabashi-ku, To~o 173, Japan,
assess the feasibility and diagnostic accuracy of dobutamine stress echocardiography in the evaluation of functional se- quelae of coronary artery stenosis in children with Kawasaki disease.
M e t h o d s
Study patients. Between September 1991 and November 1993, 50 consecutive patients underwent dobutamine stress echocardiography for the assessment of progression of coro- nary artery aneurysm to stenotic lesion. Twenty-six of the 50 patients had coronary artery sequelae with Kawasaki disease documented by previous coronary angiography (sequelae group: 3 to 15 years old, mean age 8.9; number of years since initial onset of illness ranged from 2 to 14 years, mean 5.8). Among them were 4 patients with left coronary aneurysm, 7 with right coronary aneurysm and 15 with bilateral coronary aneurysms. Twenty-four patients had normal coronary arteries documented by echocardiography (normal group: 7 to 16 years old, mean age 11.2; number of years since initial onset ranged
©1996 by the American College of Cardiology 0735-1097/96/$15.00
from 3 to 15 years, mean 8.2). These patients had a history of regression of coronary ectasia or small coronary aneurysm. Twenty-one of the 26 patients in the sequelae group were receiving medical therapy: 15 were receiving aspirin only, and 5 were receiving both aspirin and warfarin for prevention of coronary thrombosis. One patient was receiving both beta- blocker and calcium channel blocker in addition to aspirin for control of sustained ventricular tachycardia. One patient in the sequelae group had chest pain accompanied by myocardial infarction. The other patients had no symptoms of myocardial ischemia. Informed consent to perform dobutamine stress echocardiography was obtained from the families of all the patients.
Dobutamine infusion protocol.
After 3 h of fasting, an intra- venous dobutamine infusion was begun at a dose of 5/xg/kg per rain, and the dose was increased every 5 min in 5-/zg/kg steps up to 30 Izg/kg per min. Throughout the study, continuous electro- cardiographic (ECG) monitoring was performed. Heart rate and blood pressure were recorded every minute, and a 12-lead standard ECG was recorded at the end of each stage of dobut- amine infusion. The dobutamine infusion was terminated for any of the following: development of ischemia manifested by new or worsening regional wall motion abnormalities demonstrated by echocardiography; severe chest pain; appearance of complex arrhythmia; intolerable side effects, such as headache, palpitation, tremor, nausea or vomiting; severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 rnm Hg); target heart rate (85% of the age-predicted maximal heart rate); ST segment depression >2 mm in any lead of the standard ECG, or attainment of the maximal dose of dobutamine of 30 p~g/kg per rain.Echocardiographic protocol.
With the patients in the left lateral decubitus position, two-dimensional echocardiograms were obtained with a 2.5- or 3.75-MHz sector scanner (SSH 65A or SSH 140A, Toshiba). Echocardiograms were continu- ously monitored during each stage of dobutamine infusion. In addition to videotape recording, off-line analysis systems (Color Cardiology Workstation, TomTec) were used for acqui- sition and digital storage of images. Quad-screen images, by digital acquisition, of parasternal long-axis, short-axis, apical four-chamber and two-chamber views were obtained at rest, at low-dose dobutamine infusion (5/xg/kg per rain), at peak-dose dobutamine infusion and at recovery.Echocardiographic analysis.
The wall motion of the left ventricle was assessed with a 16-segment model (9). The digitized images were independently interpreted by two re- viewers unaware of the history and angiographic findings on the patients. Discrepancies in the interpretations of the two reviewers were resolved by a third reviewer. A normal re- sponse to dobutamine infusion was defined as a progressive increase in myocardial thickening and hyperdynamic wall motion from rest to peak dose of dobutamine infusion. An abnormal response to dobutamine infusion was defined as a reduction in myocardial thickening or wall motion at any stage of the dobutamine infusion compared with the previous stage. Segmental wall motion was graded as normal, hypokinetic,aldnetic, or dyskinetic. Multivessel disease was defined as abnormal wall motion and reduced myocardial thickening identified in more than two vascular distribution areas.
Coronary angiography.
All patients underwent left ven- triculography and selective coronary angiography a few days after the dobutamine stress echocardiography. The locations of coronary aneurysms and stenosis were determined according to the American Heart Association reporting system (10). Quantitative angiographic measurements were performed with an edge detection program (10). The percent coronary stenosis was calculated with the nearest normal-appearing portion of the coronary artery (either distal or proximal to the stenosis) used as a standard (11). Significant coronary artery disease was defined as 50% or more diameter reduction in major coronary arteries. Intercoronary collateral circulation was classified ac- cording to the Rentrop grading (ranging from grade 0, no visible filling of any collateral channels, to grade 3, complete filling of the vessel being dilated) (12); good collateral circu- lation was defined as collateral arteries at Rentrop grade 2 or higher.Statistical analysis.
The data are summarized using mean values and standard deviations for continuous variables. Mul- tiple group comparisons were performed with analysis of variance and the Tukey test for individual comparisons within groups. A value of p < 0.05 was considered significant.R e s u l t s
Clinical data.
The baseline standard ECG results were normal in 49 patients, and the remaining patient had nonspe- cific ST-T changes caused by chronic myocardial infarction in the right precordial leads. On left ventriculography, no wall motion abnormalities were detected in any patient, whereas on coronary angiography, significant coronary artery disease was present in 21 patients in the sequelae group, including 6 with left, 11 with right and 4 with bilateral coronary artery stenosis (Table 1). Good intercoronary collateral circulation (Rentrop grade ---2) was noted in four patients with right coronary obstruction. The other patients presented poor or no visual- ization of collateral circulation.Dobutamine infusion.
Table 2 summarizes the mean values of heart rate, systolic blood pressure, rate-pressure product at rest and maximal dose of dobutamine infusion. There was no significant difference in peak dose of dobutamine between the sequelae and normal groups ([mean _+ SD] 22.4 _ 5.1 vs. 24.2 +_ 2.5 /~g/kg per rain). All variables showed significant increases at maximal dose compared with those at rest (p < 0.01), but there was no significant difference between the sequelae and normal groups for any value either at rest or at maximal dose.During dobutamine infusion, heart rate showed a slight linear increase in a dose-dependent manner; consequently, heart rate was >140 beats/rain in 23 (46%) of the 50 patients at peak dobutamine infusion. In contrast, systolic blood pres- sure tended to increase logarithmically up to 30 ~g/kg per rain.
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April 1996:1251-6 DOBUTAMINE IN KAWASAKI DISEASE
Table 1. Clinical Data and Results of Dobutamine Stress Echocardiography in Patients With Significant Coronary Artery Disease
Coronary Angiography
Pt Age (yr)/
No. Gender WMA on Dobutamine Echo Aneurysm Stenosis (%)
Collateral Circulation (Rentrop grade)
1 ll/F Mid-sept, Mid-inf Bilateral LAD (50%), RCA (100%) 0
2 ll/F Mid-ant sept Bilateral LAD (thrombus) 1
3 10/M Mid-inf, Basal-sept RCA RCA (90%) 2
4 8/M Mid-inf Bilateral RCA (100%) 3
5 3/M Mid-ant sept, Mid-sept, Mid-inf Bilateral LAD (thrombus), RCA (90%) 1
6 12fM Mid-lat Cx Cx (50%) 0
7 9/M ND RCA RCA (90%) 3
8 10/M Mid-ant sept LAD LAD (50%) 1
9 15/F ND Bilateral LAD (90%) 1
10 4/F Mid-inf Bilateral RCA (90%) 0
11 4/F Mid-inf RCA RCA (50%) 0
12 ll/M Mid-inf, Basal-sept Bilateral RCA (100%) 3
13 13/M Mid-inf Bilateral RCA (90%) 1
14 9/M Mid-ant sept, Apical-sept Bilateral LAD (90%) 0
15 ll/F Mid-inf Bilateral RCA (100%) 1
16 ll/F Mid-ant sept, Mid-ant Bilateral LAD (75%) 0
17 12/M Mid-ant, Mid-inf Bilateral RCA (100%) 1
18 3/M Mid-ant sept, Mid-ant, Mid-inf Bilateral LAD (50%), RCA (100%) 1
19 ll/M Mid-ant sept, Mid-ant, Mid-inf Bilateral LAD (50%), RCA (90%) 0
20 3/M Mid-ant, Mid-sept Bilateral RCA (90%) 0
21 9/M Mid-ant sept, Mid-ant, Mid-inf Bilateral RCA (100%) 1
Apical-sept = apical septum; Basal-sept = basal septum; Cx = circumflex coronary artery; Echo = echocardiography; F = female; LAD = left anterior descending coronary artery; M = male; Mid-ant = midanterior; Mid-ant sept = midanterior septum; Mid-inf = midinferior; Mid-lat = midlateral; Mid-sept = midseptum; Pt = patient; RCA = right coronary artery; WMA = wall motion abnormalities.
As a result, rate-pressure product was >20,000 in 20 (40%) of the 50 patients at peak dobutamine infusion.
Ten (20%) of the patients developed side effects during dobutamine stress echocardiography that included headache in four, premature atrial contraction in three, palpitation in two and nausea in one. These side effects were self-limiting and resolved spontaneously with discontinuation of the infusion. No patient developed premature ventricular contraction or ventricular tachycardia during dobutamine infusion.
The reasons for termination of dobutamine stress echocar- diography were reaching the maximal dose of 30/xg/kg per min in 25 patients (50%), stress-induced wall motion abnormalities in 19 (38%), headache in 2 (4%), hypertension (systolic blood pressure ->200 mm Hg) in 2 (4%) and target heart rate and palpitation in one (2%) each. Although the test protocol could not be completed because of limiting side effects in three patients (headache in two, palpitation in one), most patients tolerated the dobutamine infusion well.
Feasibility analysis. All patients were in stable condition during dobutamine infusion, and good quality echocardio- grams were obtained. Minimal discrepancy in interpretation by the two reviewers of whether wall motion abnormalities were present was noted for the echocardiograms in two patients (4%). Localized rest wall motion abnormalities of the mid- inferior segment was detected in one patient who had chronic myocardial infarction. Stress-induced wall motion abnormali- ties corresponding to the distribution of coronary artery dis- ease were detected in 19 of 21 patients in the sequelae group. No such abnormalities, however, were detected in the normal group. In an analysis according to the number of affected vessels, single-vessel disease was detected in 15 (88%) of 17 patients, and multivessel disease was detected in 4 (100%) of 4 patients on dobutamine stress echocardiography. False- negative findings were observed in two patients, one of whom had significant coronary artery disease in the left main coro- nary artery and was receiving beta-adrenergic blocking therapy
Table 2. Hemodynamic Findings During Dobutamine Infusion Sequelae Group (mean -- SD) Rest Maximal Dose
Normal Group (mean _+ SD) Rest Maximal Dose Heart rate (beats/min) 81.0 _+ 11.8 128.1 _+ 21.3' 81.5 + 18.1 135.1 _+ 21.1' Systolic BP (ram Hg) 96.8 _+ 15.2 147.5 _+ 21.8' 105.5 -* 15.7 153.5 _+ 25.4* Rate-pressure product (/1,000) 7.9 + 1.4 18.5 _+ 3.5* 8.7 _* 2.3 21.1 _+ 3.7*
SAX
4C
E - S
E - D
Figure 1. Basal (BASE) and peak dose (PEAK D) dobutamine stress echocardiographic images of short-axis (SAX) and four-chamber (4C) views obtained in a patient with bilateral coronary aneurysms. At rest, asynergy is not visible. At peak dose, midseptal dyskinesia and midinferior akinesia are present (arrows). E-D = end-diastole; E-S = end-systole.
for control of sustained ventricular tachycardia, and the other had right coronary artery obstruction with sufficient collateral circulation from the circumflex coronary artery to the distal portion of the obstructive lesion. There were no false-positive findings in either group. Thus, the overall sensitivity and specificity of dobutamine stress echoeardiography correspond- ing to the extent of coronary artery disease was 90% and 100%, respectively (Fig. 1 and 2).
D i s c u s s i o n
Fate of coronary aneurysms. Coronary artery abnormali- ties develop in -20% of children with untreated Kawasaki disease. Recently, it was revealed that intravenous gamma- globulin therapy instituted at the early stage of illness reduced both the morbidity of Kawasald disease and the apparent incidence of coronary artery abnormalities. Coronary artery aneurysm, however, occurs in - 5 % of patients receiving intravenous gamma-globulin and aspirin therapy (11,13,14), and it often leads to obstructive or stenotic lesions, especially in patients with giant coronary aneurysms (maximal diameter
Figure 2. Coronary angiograms from the same patient as in Figure 1 reveal 75% stenosis of the left anterior descending coronary artery (LAD) (arrow) and obvious right coronary artery obstruction (RCA). CX = circumflex coronary artery.
>-8 mm) at the convalescent stage (15). Myocardial ischemia may occur in such patients, in whom higher risk of sudden death may also occur. Therefore, it is desirable to screen for the progression of coronary aneurysm to stenotic lesions. In this application, coronary angiography is an accurate method of evaluating coronary artery involvement (13). This method, however, cannot be applied repeatedly. Moreover, the coro- nary angiography findings reflect only the status of the free cavity of the coronary aneurysm but not that of the original aneurysm. In contrast, two-dimensional echocardiography dis- closes an echo-free space representing the original aneurysm, in which some materials suggesting thrombi or organization are seen. However, it does not clearly reveal whether the aneurysm is occlusive (16).
Myocardial scintigraphy with pharmacologic stress has been reported to be useful in adult patients (17,18), but there are some clinical limitations of scintigraphy in children, among them the relatively poor spatial resolution, modest specificity, exposure to radiation, necessity for sedation of younger chil- dren, and long time required to obtain the data (19). Recently, pharmacologic stress echocardiography has come to be seen as an alternative to scintigraphy in the detection of coronary
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stenotic lesions in adult patients (6,7,20,21), but the data for children are limited (8).
Rationale of dobutamine stress echocardiography. Dobut-
amine is a synthetic catecholamine that acts predominantly as a beta-l-receptor agonist. ~:fter the increment of dobutamine infusion, cardiac output is increased by augmentation of myocardial contractility and by an increase in heart rate, resulting in an increase in myocardial oxygen demand. Myo- cardial ischemia will be induced if the coronary flow reserve is inadequate to meet the increase in demand (22). Heart rate is thought to be one of the major determinant factors relating to oxygen consumption in induced myocardial ischemia. Recently there have been some trials in dobutamine stress echocardiog- raphy to obtain the target heart rate by using high dose dobutamine infusion (>30 /~g/kg per min) in addition to atropine infusion (23,24) in attempts to provoke greater myo- cardial stress and subsequent ischemia by increasing the value of the rate-pressure product. According to the present results, the heart rate tended to increase linearly, and subsequently it was possible to obtain a rate-pressure product >20,000 in 40% of patients at peak dobutamine infusion. Compared with previous studies using high doses of dobutamine infusion in adult patients (6,20,25,26), in which the heart rate reached at most 120 to 130 beats/rain at peak dose, our study revealed that a response pattern of the heart rate in a manner similar to that in exercise might account for the higher sensitivity and greater suitability of dobutamine stress echocardiography for children than for adult patients.
False-negative studies. The instances of false-negative do-
butamine stress echocardiography occurred mainly in our study patients who were either receiving a beta-blocker or presented sufficient collateral circulation distal to the obstruc- tive lesions. A recent report indicated that the sensitivity of the stress echocardiography was not affected by beta-blocker ad- ministration (6). Although our patients had reduced peak heart rate and rate-pressure product compared with those not receiving beta-blocker, one would expect that myocardial ischemia was not induced by an attenuated heart rate response. Moreover, it is conceivable that sufficient collateral circulation in coronary angiograms may protect against myocardial isch- emia induced by dobutamine infusion, but no clear correlation between a false-negative result and quantitative assessment of collateral circulation was discernible.
Relevance of side effects. The progressive infusion of dobut-
amine used in this study was generally well tolerated. A previous report suggested that dobutamine may be dangerous in patients with coronary artery disease because it frequently induces malig- nant ventricular arrhythmia (26). During the dobutamine infu- sion, no significant arrhythmias occurred that would have require termination of infusion. This finding indicates that although dobutamine undoubtly has an arrhythmogenic potential, it is safer in children than among adult patients (27).
Study limitations. 1) One potential limitation of this study
is the subjective, nonquantitative analysis of the echocardio- graphic images. Qualitative analysis, however, was found to be accurate and reproducible by the use of digital acquisition of
images, which provided high sensitivity and specificity for detection of coronary artery disease. 2) The optimal dose of dobutamine infusion in children is not clear. Whether a more aggressive infusion protocol would enhance the diagnostic value without imposing additional side effects is an issue for ongoing investigation. Further studies in a larger, unselected patient population are necessary to assess the advantages and limitations of this test in the diagnosis of coronary artery disease in Kawasaki disease.
Conclusions. To date, although no actual cause of Ka-
wasaki disease has been documented, it is certain that early detection of myocardial ischemia and its management would be one of the major problems in long-term follow-up of patients with cardiac involvement. Our study disclosed that dobutamine stress echocardiography is a promising new method for assessing the functional significance of coronary lesions, even if they are not depicted as significant by two- dimensional echocardiography.
R e f e r e n c e s
1. Armstrong WF, O'Donnel J, Rayan T, Feigenbaum H. Effect of prior myocardial infarction and extent and location of coronary disease on accuracy of exercise echocardiography. J Am Coll Cardiol 1987; 10:531-8. 2. Limacber MC, Quinones MA, Poliner LR, Nelson JG, Winters WL,
Waggoner AD. Detection of coronary artery disease with exercise two- dimensional echocardiography. Circulation 1983;67:1211-8.
3. Sawada SG, McHenry PL, Armstrong WF, Rayan T, Feigenbaum H. Exercise echocardiographic detection of coronary artery disease in women. J Am Coil Cardiol 1989;14:1440-7.
4. Armstrong WF. Stress echocardiography for detection of coronary artery disease [abstract]. Circulation 1991;84 Suppl I:1-43-9.
5. Picano E, Lattanzi F, Masini M, Distante A, L'Abbate A. Usefulness of the dipyridamole-exercise echocardiography test for diagnosis of coronary artery disease. Am J Cardiol 1988;62:67-70.
6. Sawada SG, Segar DS, Rayan T, et al. Echocardiographic detection of coronary artery disease during dobutamine infusion. Circulation 1991;83: 1605-14.
7. Zoghbi WA, Cbeirif J, Kleiman NS, Verani MS, Trakhtenbroit A. Diagnosis of ischemic heart disease with adenosine echocardiography. J Am Coll Cardiol 1991;18:1271-98.
8. Klewer SE, Goldberg S J, Donnerstein RL, Berg RA, Hutter JJ Jr. Dobut- amine stress echocardiography: a sensitive indicator of diminished myocar- dial function in asymptomatic doxorubicin-treated long-term survivors of childhood cancer. J Am Coll Cardiol 1992;19:394-401.
9. Gibson RS, Bishop HL, Stature RB, Crampton RS, Belier GA, Martin RP. Value of early two dimensional echocardiography in patients with acute myocardial infarction. Am J Cardiol 1982;49:1110-9.
10. AHA Committee Report. A reporting system on patients evaluated for coronary artery disease. Circulation 1975;51:7-40.
11. Nakanishi T, Takao A, Nakazawa M, Endo M, Niwa K, Yakahashi Y. Mucocutaneous lymph node syndrome: clinical, hemodynamic and angio- graphic features of coronary obstructive disease. Am J Cardiol 1985;55: 662-8.
12. Cohen M, Rentrop KP. Limitation of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study. Circulation 1986;74:469-76.
13. Kato H, Koike S, Yamamoto M, Ito Y, Yano E. Coronary aneurysms in infants and young children with mucocutaneous lymph node syndrome. J Pediatr 1975;51:7-40.
14. Newberger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gammaglobulin. N Engl J Med 1986;315:341-7. 15. Nakano H, Ueda K, Saito A, Nojima K. Reported quantitative angiograms
in coronary artery aneurysm in Kawasaki disease. Am J Cardiol 1985;56: 846-51.
16. Fujiwara T, Fujiwara H, Ueda T, Nishioka K, Hamashima Y. Comparison of macroscopic, postmortem, angiographic and two-dimensional echocardio- graphic findings of coronary aneurysms in children with Kawasaki disease. Am J Cardiol 1986;57:761-4.
17. Mason JR, Palac RT, Freeman ML, et al. Thallium scintigraphy during dobutamine infusion: nonexercise-dependent screening test for coronary disease. Am Heart J 1984;107:481-5.
18. Nishimura S, Mahmarian JJ, Boyce TM, Verani MS. Quantitative thalium 201 single-photon emission computed tomography during maximal pharma- cological coronary vasodilation with adenosine for assessing coronary artery stenosis. J Am Coil Cardiol 1991;18:736-45.
19. Kondo C, Hiroe M, Nakanishi T, Takao A. Detection of coronary artery stenosis in children with Kawasaki disease. Circulation 1989;80:615-24. 20. Cohen JL, Greene TO, Ottenweller J, Binenbaum SZ, Wilchfort SD, Kim
CS. Dobutamine digital echocardiography for detection of coronary artery disease. Am J Cardiol 1991;67:1311-8.
21. Picano E, Lattanzi F, Masini M, Distante A, L'Abbate A. High dose dipyridamole echocardiography test in effort angina pectoris. J Am Coil Cardiol 1986;8:848-54.
22. Fung AY, Gallagher KP, Buda AJ. The physiologic basis of dobutamine as compared with dipyridamole stress interventions in the assessment of critical coronary stenosis. Circulation 1987;76:943-51.
23. McNeill AJ, Fioretti PM, El-Said EM, Salustri A, Forster T, Roelandt JRTC. Enhanced sensitivity for detection of coronary artery disease by addition of atropine to dobutamine stress echocardiography. Am J Cardiol 1992;70: 41-6.
24. Poldermans D, Fioretti PM, Forster T, et al. Dobutamine stress echocardi- ography for assessment of perioperative cardiac risk in patients undergoing major vascular surgery. Circulation 1993;87:1506-12.
25. Mannering D, Cripps T, Leech G, et al. The dobutamine stress test as an alternative to exercise testing after acute myocardial infarction. Br Heart J 1988;59:521-6.
26. Previtali M, Lanzarini L, Ferrario M, Tortorici M, Mussini A, Montemartini C. Dobutamine versus dipyridamole echocardiography in coronary artery disease [abstract]. Circulation 1991;83 Suppl III:III-27-31.
27. Mertes H, Sawada SG, Ryan T, et al. Symptoms, adverse effects, and complications associated with dobutamine stress echocardiography. Circula- tion 1993;88:15-9.
