Stress Echocardiography. Part II. Dobutamine Stress Echocardiography: Techniques, Implementation, Clinical Applications, and Correlations

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Stress Echocardiography. Part II. Dobutamine Stress Echocardiography: Techniques, Implementation, Clinical Applications, and Correlations A. PELLIKKA, M.D., VERONIQUE L. ROGER, M.D., JAE K. OH, M.D., FLETCHER A. MILLER, M.D., B. SEWARD, M.D., AND A. JAMIL TAJIK, M.D.

PATRICIA JAMES

• Objective: To describe the rationale, methods, and clinical applications for dobutamine stress echocardiography. • Design: We review our experience with the first 1,000 Mayo Clinic patients who underwent this procedure and discuss studies from the literature that have assessed the accuracy of dobutamine stress echocardiography in determining the presence and extent of coronary artery disease. • Material and Methods: The Mayo protocol for dobutamine stress echocardiography is presented, and the indications for use of this test and comparisons of sensitivity and specificity with other tests are summarized. • Results: Although exercise stress testing is the usual noninvasive method for the detection and assessment of coronary artery disease, a substantial number of patients are unable to perform adequate exercise because of physical limitations. In these patients, dobutamine stress echocardiography has emerged as a feasible, safe, and accurate method for

the evaluation of coronary artery disease. The test has been proved to be valuable in the noninvasive diagnosis of coronary artery disease and to have an accuracy comparable to that of tomographic perfusion imaging. Other indications for dobutamine stress echocardiography include risk stratification before noncardiac surgical procedures, risk stratification after myocardial infarction, and identification of viable myocardium in patients with left ventricular dysfunction. • Conclusion: Dobutamine stress echocardiography is an accurate, safe, cost-effective, and portable procedure for the noninvasive diagnosis of coronary artery disease and for the preoperative assessment of patients with such disease, especially those who are unable to perform adequate exercise tests. (Mayo Clin Proc 1995; 70:16-27) ECG =electrocardiography; MIDI =methoxyisobutyl isouitrile; RVU = relative value units; SPECT = single photon emission computed tomography

Exercise stress testing, with or without nuclear or echocardiographic imaging, is the time-honored noninvasive method used for the detection and functional assessment of coronary artery disease (see companion article, page 5). A substantial number of patients, however, are unable to perform adequate leg exercise because of debility or because of neurologic, respiratory, peripheral vascular, or orthopedic limitations. Alternative types of stress, such as handgrip, cold pressor testing, and arm ergometry, have demonstrated low sensitivity in the detection of severe coronary artery disease.'? Dipyridamole" and adenosine' perfusion imaging have been demonstrated to be useful in the evaluation of

coronary artery disease; however, these agents are relatively contraindicated in patients with symptomatic cerebrovascular disease or in patients with a history of bronchospasm. These vasodilators cannot be used in patients who are receiving theophylline (an inhibitor of adenosine). Additionally,

For accompanying editorial, see page 95 imaging cannot be performed in patients with upper extremity orthopedic limitations that prevent elevation of the arms as required for tomographic perfusion imaging. Lastly, the equipment and facilities needed for the stress nuclear perfusion test are comparatively expensive. In the past few years, dobutamine stress echocardiography has emerged as a feasible, safe, and accurate method for the evaluation of known or suspected coronary artery disease."? The purpose of this article is to provide a comprehensive review of the rationale, methods, and implementa-

From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. P. A. Pellikka, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905. Mayo Clin Proc 1995; 70: 16-27

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© 1995 Mayo Foundation for Medical Education and Research

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tion of dobutamine stress echocardiography. In addition, we summarize our clinical experience with the initial 1,000 patients III whom this procedure was done at the Mayo Clinic.

findings suggest that dobutamine may be a superior pharmacologic agent for use with an imaging modality that assesses wall motion, and dipyridamole may be better for perfusion imaging.

PHARMACOLOGY

METHODS AND IMPLEMENTATION Equipment.-As with exercise echocardiography, dobu-

Dobutamine is a synthetic cathecholamine that has been developed as a positive inotropic agent for short-term intravenous administration. The predominant mechanism of action, augmentation of myocardial contractility, is mediated through ~l-adrenergic receptor stimulation. Although often referred to as a selective ~1-adrenergic receptor agonist, dobutamine also has mild ~2 - and aI-adrenergic receptor agonist effects. Because the ~2 - and ai-adrenergic agonist effects are relatively balanced, the net effect on the systemic vasculature is minimal in most patients." Direct linear correlations exist among the dose of dobutamine, the plasma concentration, and the hemodynamic effects." Cardiac output increases as a result of an increase in both heart rate and stroke volume." Dobutamine is ineffective orally, and because its half-life in plasma is approximately 2 minutes, it must be administered by continuous intravenous infusion. It is rapidly metabolized in the liver to inactive metabolites. The literature reflects a broad clinical experience with administration of dobutamine in the treatment of congestive heart failure,":" including patients with acute myocardial infarction." Dobutamine stress echocardiography, however, necessitates the short-term administration of substantially higher doses of dobutamine than are used therapeutically.

RATIONALE Because of its property of increasing myocardial oxygen demand by way of enhancing heart rate and contractility, dobutamine infusion has been recognized as an alternative to exercise testing. Atropine sulfate may also be administered if the desired heart rate response is not achieved with dobutamine. In the myocardial region supplied by a coronary artery with a critical stenosis, the increase in oxygen demand cannot be met by an adequate increase in blood flow. Hence, regional ischemia develops and eventuates in regional wall motion abnormalities. Such abnormalities can be reliably detected by two-dimensional echocardiography.v'v-" In an experimental model, blood flow to the myocardium supplied by a partially occluded major coronary artery increases when dobutamine is infused at low doses.1 9•20 At doses sufficiently high to produce positive chronotropic effects, however, the flow to ischemic areas seems to decrease." In a comparison of dobutamine and dipyridamole in a dog model, dobutamine was the better agent for inducing wall motion abnormalities during ischemia, whereas dipyridamole resulted in greater flow heterogeneity." These

tamine stress echocardiography requires a two-dimensional echocardiographic Doppler instrument, preferably in conjunction with a digital acquisition system. Electrocardiography (ECG) is performed by using I2-channel monitoring equipment. An echocardiographic bed with cutout windows can assist in imaging from the cardiac apex. An automated blood pressure cuff is used, and an infusion pump delivers the dobutamine. The area where stress echocardiography is performed is equipped with resuscitation equipment. Personnel.-The study is supervised by an echocardiologist or highly trained nurse-sonographer versed in stress testing, the pharmacologic effects of dobutamine, and, in particular, the recognition of resultant wall motion abnormalities. The ECG is monitored by a technician, who records heart rate and blood pressure responses during the study. A sonographer performs a sequence of echocardiographic examinations in accordance with an established protocol. Preparation for Examination.-The patient should abstain from all oral intake for at least 3 hours before the procedure. Typically, ~-blockers and other medications are not withheld before testing. The procedure as well as side effects and potential complications are explained to the patient. If baseline echocardiographic images are adequate for assessment of regional wall motion, a 20-gauge needle with a stopcock is placed in an arm vein for administration of medications. An infusion solution that consists of 100 mg of dobutamine in 100 mL of 5% dextrose in water is prepared, and the appropriate infusion rates in milliliters per minute, based on the patient's weight, to provide dosages from 5 /lg/ kg per min are determined. Atropine (1 mg/lO mL) should be available if needed to increase the heart rate. The shortacting ~-blocker, esmolol hydrochloride, in premixed vials of 100 mgllO mL, should be available to administer at 0.5 mg/kg during a l-rninute period, if necessary, to reverse the ~-adrenergic effects of dobutamine. Nitroglycerin is available for sublingual administration as needed. Lidocaine hydrochloride is also available for treatment of ventricular arrhythmias. In the event of extravasation of the dobutamine, phentolamine mesylate is available to prevent or minimize tissue injury." As an a-adrenergic blocking agent, it competitively inhibits the a-adrenergic effects of dobutamine and thereby decreases local vasoconstriction and ischemia. If extravasation occurs, the intravenous cannula is removed, the extremity is elevated, and phentol-

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amine (5 to 10 mg, diluted in 10 mL of isotonic saline) is injected into the area of extravasation with a fine needle. Examination Procedure.-Dobutamine is administered intravenously by an infusion pump at a starting dosage of 5 ug/kg per min. Our protocol and endpoints for termination of the dobutamine infusion are summarized in Table 1. At 3minute intervals, the dosage is increased to 10, 20, 30, and 40 ug/kg per min until a predetermined endpoint is reached. In our practice, if neither target heart rate nor any of the other endpoints is reached, the infusion rate may be increased to 50 Ilg/kg per min, or atropine is administered intravenously. These changes were added to our protocol after performance of the first 600 studies, in an attempt to achieve the target heart rate in a larger percentage of patients. Of these alternatives, an increase in the infusion rate to 50 ug/kg per min is selected if the heart rate is within 10 to 20 beats of the target heart rate; for slower heart rates, atropine is administered. A dose of 0.25 to 0.5 mg of atropine is repeated at I-minute intervals to a maximal dose of 2 mg or until an endpoint is reached; dobutamine infusion is continued during atropine administration. Although atropine is used by several investigators to augment the heart rate response to dobutamine.t':" others have continued to follow a protocol that does not include administration of atropine.v-" Atropine has been used in numerous studies and can be administered safely in conjunction with the dobutamine test." Three-channel ECG monitoring of the cardiac rhythm is performed continuously. The heart rate and I2-lead ECG are recorded every minute, and the blood pressure is recorded every third minute. Ischemia is assumed to be present when more than 1 mm of horizontal or downsloping ST-segment depression is noted on the ECG 80 ms after the J point in a patient with normal ST segments at rest. Two-dimensional echocardiography is performed with the patient in the left lateral decubitus position. Baseline images are obtained, and imaging is repeated before each increase in dose of dobutamine and stored on videotape. Digitized images (parasternal long-axis and short-axis and apical two-chamber and four-chamber views) are obtained before stress, during administration of dobutamine at low dosage (5 to 10 ug/kg per min), at peak dose, and during recovery, When atropine is administered to increase the heart rate, images during peak heart rate after atropine administration are digitized and stored in the fourth quadrant instead of recovery images. Echocardiographic images from each level of stress are also stored on videotape.

Analysis of Dobutamine Echocardiograms.-Echocardiograms should be reviewed by an echocardiographer experienced in interpretation of regional ventricular wall motion. The wall motion is assessed in each of 16 segments'? The segments are classified into three coronary artery distributions (anterior, inferior, and lateral), and this model is used

Mayo Clin Proc, January 1995, Vol 70

Table 1,-Summary of Mayo Protocol for Dobutamine Stress Echocardiography

Procedures 1, Dobutamine is delivered intravenously by infusion pump (starting rate, 5 ug/kg/min) 2. Three-channel electrocardiographic monitoring of rhythm is performed continuously 3, At 3-min intervals, the infusion rate is increased to 10,20, 30, and 40 ug/kg/min. If another endpoint is reached, test may be terminated before reaching maximal dose 4, If no endpoint is reached, atropine sulfate (0.5 mg) may be administered intravenously at peak infusion rate to increase heart rate, Additional doses of 0.25-0.5 mg may be repeated at l-min intervals to a maximum of 2 mg. Alternatively, infusion rate may be increased to 50 ug/kg/min 5, Heart rate and 12-channel electrocardiogram are recorded each minute 6, Blood pressure is recorded at each stage of infusion 7, Digitized images are obtained at baseline, low dosage (usually 10 ug/kg/min), peak dose, and recovery (or with atropine, if used), with use of a quad-screen format. Four standard views (parasternal long-axis and short-axis and apical 2- and 4-chamber views) are obtained 8. Echocardiographic images from each level of stress are stored on videotape

Endpoints 1. Target heart rate (85% of age-predicted maximal heart rate or, if soon after myocardial infarction, 70% of agepredicted maximal heart rate) 2, Development of new regional wall motion abnormalities of at least moderate severity 3. Peak dose 4. Ventricular tachycardia or sustained supraventricular tachycardia 5. Severe hypertension (systolic blood pressure >220 mm Hg or diastolic blood pressure>110 mm Hg) 6. Substantial decrease in systolic blood pressure (a decrease of 20 mm Hg from previous level of infusion may be used as a guideline for terminating the test, but amount depends on baseline blood pressure and judgment of person monitoring the test) 7, Intolerable symptoms

to predict the presence and the extent of coronary artery disease. The development of hyperdynamic wall motion during dobutamine infusion is considered normal. Failure to develop hyperdynamic function or development of hypokinesia, akinesia, or dyskinesia represents various degrees of ischemic response (Fig. 1). The dose of dobutamine and the heart rate at which wall motion abnormalities develop ("ischemic threshold") are noted. Segments that are hypokinetic or akinetic at rest and do not change during

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Fig. 1. Example of dobutamine stress echocardiogram in 37-year-old man 5 days after uncomplicated anterior wall myocardial infarction (the patient had received thrombolytic therapy). With patient at rest (upper left), apical two-chamber view at end-systole showed mild hypokinesia of anteroapex. With infusion of low-dose dobutamine (10 ug/kg per min) (upper right), contractility increased. At peak dose (30 ug/kg per min) (lower left), apex and basal inferior wall became severely hypokinetic, consistent with ischemia. Subsequent coronary arteriography showed 90% diameter stenosis of midportion of left anterior descending coronary artery and 70% diameter stenosis of right coronary artery.

infusion of dobutamine are considered to represent variably infarcted tissue, depending on the resting diastolic wall thickness. Segments that have normal thickness are thought to represent nontransmural infarction; those that are thinned and hyperrefractile represent transmurally infarcted myocardium or scar. Worsening of a preexisting wall motion abnormality is considered to represent ischemia in a region of prior infarction. Improvement in a severely hypokinetic or akinetic segment during administration of low-dose dobutamine suggests the presence of viable myocardium.P" A decrease in global left ventricular function during dobutamine-induced stress seems to be a less sensitive marker of ischemia than development of regional wall motion abnormalities. With dobutamine radionuclide ventriculography." an abnormal ejection fraction response was noted in only 28% of patients with severe coronary artery disease. This result likely reflects exaggerated hyperkinesia of normal segments in patients with regional wall motion abnormalities. With dobutamine administration, the typical decrease in end-systolic volume, if substantial, may contribute to the difficulty in interpreting the images.

EXPERIENCE WITH THE PROCEDURE As a means of relating the clinical utility and feasibility of dobutamine stress echocardiography and summarizing our experience with the procedure, we reviewed our initial 1,000 consecutive examinations. Patient Population and Indications.-All dobutamine stress echocardiographic studies were requested by the physician responsible for clinical management. The 536 male and 464 female patients ranged in age from 30 to 94 years (mean, 69 ± 10). The indications for the study are summarized in Figure 2. The largest proportion of studies involved risk assessment before noncardiac surgical procedures (50%). Of the 1,000 patients, 94% had a physical limitation that precluded conventional exercise testing (Fig. 3). A contraindication to dipyridamole thallium testing was present in 295 patients (30%), including symptomatic cerebrovascular disease in 220 (22%), aminophylline therapy or history of bronchospasm in 71 (7%), and previous adverse reaction to intravenously administered dipyridamole in 4 (less than 1%). No patient had unstable angina pectoris, uncontrolled hypertension (systolic blood pressure of more

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Mayo ClinProc, January 1995, Vol 70

Evaluation of CAD (189)

Fig. 2. Indications for dobutamine stressechocardiography among 1,000consecutive Mayo Clinic patients. CAD = coronary artery disease; MI = myocardial infarction; post = after; preop preoperative.

than 190 mm Hg or diastolic blood pressure that exceeded 100 mm Hg), or uncontrolled supraventricular or ventricular arrhythmia. Patients with atrial fibrillation and a controlled ventricular rate were not excluded from analysis. Dosage and Endpoints.- The peak dosage of dobutamine administered ranged from 10 to 50 ug/kg per min (mean, 34 ± 9). The mean increase in heart rate was 51 beats/min. The target heart rate was achieved in 555 patients (56%). Since atropine and a peak dosage of 50 ug/kg per min were added to the protocol, the target heart rate has been reached in 245 of 400 patients (61%). Atropine (mean dose,

0.6 ± 0.3 mg) was administered in 20% of the total patient group and in 49% of patients who were receiving ~-blocker therapy. Esmolol was administered to 70 patients (7%) to reverse the effects of dobutamine. The endpoints for termination of the study are shown in Figure 4. In most patients, the blood pressure changed minimally (mean change in systolic value, -4 mm Hg; mean change in diastolic measurement, -9 mm Hg). In 151 patients (15%), however, the systolic blood pressure increased more than 20 mm Hg (maximal increase, 114 mm Hg). In 236 patients (24%), the systolic blood pressure decreased more than 20 mm Hg (maximal decrease, 78 mm Hg). Dynamic Intracavitary Obstruction.-Using Doppler echocardiography, we observed the development of dynamic intracavitary obstruction as a result of hyperdynamic left ventricular function in approximately 20% of patients during dobutamine stress echocardiography. This finding was associated with a decrease in blood pressure during the test in the absence of evidence of ischemia.F During such tests, other investigators have also noted a decrease in blood pressure that may occur in the absence of regional wall motion abnormalities and, in this situation, does not indicate severe coronary artery disease or portend a poor prognosis.v-" In our experience, the frequency of dynamic intracavitary obstruction or hypotension was not decreased by administration of a 500-mL bolus of isotonic saline at the onset of the study. Sajety.-The dobutamine infusion was well tolerated by most patients, although mild side effects (Table 2), including chest pain and palpitations, were common. Asymptomatic arrhythmias were frequently noted. Supraventricular tachycardia occurred in 70 patients (7%) (sustained and necessitating treatment with esmolol in 1 patient), and nonsustained

Angina 2% (19) Arrhythmias 6% (59) Hypertension 1% (13) Hypotension 3% (29) Side effects 3% (30)

Lung disease 8% (85)

Debility 8% (85)

Fig.3. Limitations to physical exercisethatprecluded conventional exercise testing among 1,000 consecutive Mayo Clinic patients whounderwent dobutamine stressechocardiography.

Fig. 4. Indications for terminating dobutamine stress echocardiographyamong 1,000consecutive Mayo Clinic patients. HR = heart rate; RWMA = regionalwall motionabnormality.

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Table 2.-Side Effects of Dobutamine Infusion for Stress Echocardiography in 1,000 Consecutive Mayo Clinic Patients Patients* Side effect

No.

%

Chest pain Palpitations Tremor or shivering Headache Nausea Dyspnea Light-headedness Arrhythmias Frequent or complex ventricular ectopic beats Ventricular tachycardia Nonsustained Sustained Supraventricular tachycardia Atrial fibrillation or flutter Junctional rhythm

139 122 104 91 69 63 48

14 12 10 9 7 6

189

19

56 4 70 22 22

6 <1 7 2 2

5

*Some patients had more than one side effect.

ventricular tachycardia, for which no therapy was needed, occurred in 56 patients (6%). Atropine was well tolerated, but it prolonged the duration of sinus tachycardia. Dobutamine extravasation occurred in two patients and was treated by injection of phentolamine without complications. In both instances, the test was terminated and successfully performed the next day with use of a different intravenous site. Complications of dobutamine stress echocardiography occurred in six patients (less than 1%). One patient who underwent dobutamine stress echocardiography 5 days after a nontransmural myocardial infarction suffered extension of the myocardial infarction. The images with the patient at rest showed severe hypokinesia of the anterior wall, anteroseptum, and apex. With dobutamine infusion to 10 ug/kg per min, the severe hypokinesia showed improvement consistent with myocardial viability. At higher doses, function of these walls again worsened, an indication of ischemia. The patient was asymptomatic throughout the study. Approximately 15 minutes after termination of the infusion, chest pain and ECG changes developed. Immediate coronary angiography showed an occluded proximal left anterior descending coronary artery; angioplasty was successfully performed. Complications of dobutamine stress echocardiography in five other patients included sustained ventricular tachycardia in four-treated with a lidocaine bolus in three and chest thump in one-and transient ischemic attack in one. This last patient had a history of frequent transient ischemic attacks and a high-grade carotid stenosis. Typical symptoms occurred in this patient after a decline of 20 mm Hg in blood pressure during the test. No deaths occurred.

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Similarly, other studies have reported the test to be safe and well tolerated. In a recent report of 1,118 patients who underwent dobutamine stress echocardiography," noncardiac side effects were usually minor and only rarely (in 3%) necessitated termination of the test. Treatment for arrhythmias was seldom necessary. Neither death nor myocardial infarction was noted as a complication of dobutamine stress echocardiography in nine previous series that included more than 2,000 patients. 8 ,17,26,33-38 One patient reportedly had a ventricular fibrillation arrest during the peak dose of dobutamine and was successfully resuscitated." The constant echocardiographic monitoring of wall motion during the study facilitates prompt recognition of induced ischemia, at which time the dobutamine infusion is terminated. The continuous echocardiographic monitoring and short half-life of dobutamine contribute to the safety of this test. Feasibility, Accuracy, and Incidental Findings.-Images were satisfactory for interpretation in all but 18 patients referred for dobutamine stress echocardiography (feasibility, 98%). In these 18 patients, baseline images were inadequate; therefore, dobutamine stress testing was not performed. Of note, two factors that might be expected to make image interpretation difficult were present in some patients: 85 (8%) had a diagnosis of severe chronic obstructive pulmonary disease and 193 (19%) weighed in excess of 90 kg. Patient motion and respiratory artifact, common with exercise echocardiography, are absent with dobutamine stress testing-hence, the higher feasibility. Another factor that accounts for the higher feasibility of this technique is the longer time available for imaging at each level of dobutamine infusion. Echocardiographic findings included regional wall motion abnormalities present at rest in 401 patients (40%). New or worsening regional wall motion abnormalities occurred with dobutamine-induced stress in 345 patients (34%). Incidental or unsuspected echocardiographic findings are listed in Table 3. In 67 consecutive patients (44 men and 23 women; mean age, 67 ± 13 years) who underwent dobutamine stress echocardiography and coronary angiography within 6 months, studies were reviewed independently by experienced observers who were unaware of clinical information and other test results. Quantitative coronary angiography was performed by using electronic calipers. No patient had intervening or prior revascularization,' and 18 patients were receiving /3-blocker therapy at the time of the dobutamine study. The mean regional wall motion score index with the patients at rest was 1.5 ± 0.5, and the mean ejection fraction was 49 ± 14%. Stenosis of 50% or more of the diameter of one of the coronary arteries or major branches was present in 44 patients (66%). Dobutamine stress echocardiography indicated the presence of ischemia in 46 patients (69%). In

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Table 3.-Incidental or Unsuspected Findings on Dobutamine Stress Echocardiography in 1,000 Consecutive Mayo Clinic Patients Patients Finding Left ventricularhypertrophy Aortic stenosis(mild to moderate) Dilatedcardiomyopathy Mitral valve prolapse Left ventricularaneurysm Mitral stenosis Left ventricularthrombus Hypertrophic cardiomyopathy

No.

%

251 48 26

25 5 3

15 8 6 5

2 1 1 <1

20

2

this study group , the sen srn vity and spec ific ity of dobutamine stress echo cardiography for detection of coronary artery disease were 97 and 65%, respectively. The sensitivity and specificity for detection of major lesions in the indi vidual coronary vascular territories were as follow s: left anterior descending coronary artery , 88 and 73%; right coronary artery, 96 and 51 %; and left circumflex coronary artery , 69 and 87 %.

VALIDATION AND COMPARISON Correlation With Angiographic Coronary Artery Disease.-The ability of dobutamine stress echocardiography to detect angiographically significant coronary artery disease (50% or more diameter stenosis) has been assessed in several studies (Table 4). Sawada and associates? reported their experience in 103 patients who underwent dobutamine stress echocardiography and quantitative coronary angiography. Significant coronary artery disease, defined as 50% or more diameter stenosis, was present in 81 patients. In 55 patients, echocardiographic findings were norm al at rest. Among these patients, the sensitivity and specificity of dobutamineinduced wall motion abnormalities for coronary artery disease were 89% (3 1 of 35) and 85% (17 of 20), respectively, and the sensitivity was 81% (17 of 21) in tho se with singlevessel disease and 100% ( 14 of 14) in those with multi vessel disease. Among patient s with wall motion abnormalities at rest, the development of a separa te wall motion abnormality during dobutamine-induced stress had an accuracy of 83% for the identification of multi vesse l disease ." In another study from the same gr oup " in whic h quantitative angiography was used in 85 patients, the overall sensitivity of the technique for the detection of significant coronary artery disease was 95% and the specificity was 82%. The sensitivity for the detection of individual coronary artery lesions with a rninimalluminal diameter of less than 1 rom, based on the presence of wall motion abnormalities in the region supplied by that vessel, was 88% for lesions in the left anterior descending coronary artery, 82% for lesions in the

left circumflex coronary artery, and 86% for lesions in the right coronary artery. In a study by Mazeika and colleagues? of 50 pat ients who underwent dobutamine echocardiography, the use of baseline (N = 14) or reversible (N = 24) region al wall motion abnormalities to determine an abnormal finding resulted in a sensitivity for detecting coronary artery disease of 78% and a specificity of 93%. In several studies.v'' !? the accuracy of dobutamine stress echocardiography for detection of coronary artery disease was much greater than that of dobutamine stress ECG. Reproducibility.-The reproducibility of dobutamine stress echocardiography has been evaluated in two small studies. In one study , 23 patients underwent two dobutamine stress studies at a mean interval of 3 days." Ischemic wall motion abnormalities and ECG changes were observed at the same stage of the two tests, the mean values for heart rate and blood pressure were comparable for each stage in dupli cate test s, and the same symptoms developed during the same stage of both tests . The reproducibility of wall motion abnormalities was 100%. In another study of 98 patients who underwent dobutamine stress ec hocardiography, studies were analyzed by two independent observers who used a standard 16-segment model " and who graded each segment with use of 6 gradations from normal to dyskinetic." Complete agreement between the two observers was present in 90 of 98 cases (92%). In each of the other eight case s, disagreement existed about only one myo cardial segment.

Stress Echocardiography With Use of Other Pharmacologic Agents.-Echocardiography with use of dobutarnine-induced stres s compares favorably with other types of pharmacologic stress echocardiography. In a study by Martin and coworkers," 40 patients (25 with coronary artery disease) each underwent adenosine, dipyridamole, and dobutamine echocardiography. Dobutamine stress echocardiography was the most sensitive, and infusion of dobutamine was better tolerated than adenosine or dipyridamole infusion. Side effects were more common with use of adenosine and dipyridamole than with use of dobutarnine; most patients preferred dobutamine. In another study, dobutamine stress echocardiography was significantly more sensitive than adenosine echocardiography (85 versus 58 %; P = 0.001) , but the specificities were similar (87 versus 82%; no significant difference).' In comparison with va sodilators such as d ipyridamole and adenosine, dobu tamine is a superior agent for induction of a wall motion abnormality and, therefore, a more suitable agent for stress echocardiography.t-" Dobutamine analogues with a greater effect on increasing systolic blood pressure and more potent inotropic and chronotropic effects are being developed. In preliminary studies, one such drug, arbutarnine, has been highly effective as a stres s agent when used in conjunction with echocardiography.v -? In a porcine model, arbutamine

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Table 4.-Dobutamine Stress Echocardiography: Previously Published Validation Studies* Reference Marcovitz & Armstrong," 1992 Marwick et al,36 1993 Segar et al," 1992 Cohen et al," 1991t Sawada et al," 1991 Mazeika et al," 1992t+ Martin et al," 1992 Berthe et aI,17 1986 Overall

No. of patients

Sensitivity (%)

Specificity (%)

Accuracy (%)

141

96

66

89

97

85

82

84

85

95

82

92

70

86

95

89

55

89

85

87

50

81

93

84

40

76

60

70

30 568

85 89

88 80

87 87

*For detection of ~50% luminal diameter stenosis (except where noted otherwise); patients subsequently underwent coronary angiography. tThese studies used ~70% luminal diameter stenosis. :j:New mitral regurgitation included as a marker of ischemia.

elicited greater differences in wall thickening between ischemic and nonischemic vascular beds than did dobutamine." In a study of 45 patients, arbutamine was as effective as exercise in provoking clinical, ECG, and echocardiographic evidence of ischemia." Comparison With Perfusion lmaging.-Pharmacologic stress tests with use of tomographic perfusion imaging and echocardiography have been compared in prospective studies. In a comparison of dobutamine and adenosine echocardiography and concomitant tomographic perfusion imaging-single photon emission computed tomography (SPECT)-in 97 patients without myocardial infarction, the accuracy of adenosine 99mTc-methoxyisobutyl isonitrile (MIBI)-SPECT and dobutamine stress echocardiography was almost the same: sensitivity, 86 and 85%, respectively; specificity, 71 and 82%, respectively," In a larger study of 217 patients without previous myocardial infarction who were studied by concomitant do butamine stress echocardiography and MIBI-SPECT, severe coronary artery disease was found in 142 patients; 72% were identified by dobutamine echocardiography and 76% by perfusion imaging (no significant difference). In 75 patients without severe coronary artery disease, the specificity of dobutamine echocardiography was 83% in comparison with 67% for scintigraphy (P = 0.05). The difference in specificity was most notable in the 17 patients with left ventricular hypertrophy but without coronary artery disease, in whom the specificity of echocardiography was 94% in comparison with

59% for scintigraphy (P = 0.02).36 Forster and associates"

assessed the relative value of dobutamine stress echocardiography and MIBI-SPECT in the detection of myocardial ischemia among 105 patients studied by both techniques. Three patients were excluded from final analysis, two because of technically inadequate echocardiograms at peak stress and one because of poor-quality MIBI-SPECT images. Three myocardial regions were considered: (1) anterior and septal, (2) posterior and lateral, and (3) apical. Concordance of the two techniques for the presence of ischemia occurred in 84% of 306 regions. Among 59 patients with previous myocardial infarction, concordance was slightly lower (81 %), and the incidence of ischemia detected by SPECT in regions of infarction, especially in akinetic areas, was higher. The importance of areas with fixed echocardiographic defects that show partial redistribution on MIBI-SPECT is uncertain. Unlike pharmacologic stress perfusion testing, dobutarnine stress echocardiography offers the advantage of detecting ischemia at a threshold. The heart rate at which a regional wall motion abnormality occurred during dobutamine stress echocardiography has been correlated with the severity of coronary artery disease. Patients with abnormal findings at a heart rate of 125 beats/min or less had a significantly higher likelihood of multivessel coronary artery disease than did those in whom abnormalities were detected at a heart rate of more than 125 beats/min (11 of 16 versus 4 of 15; P<0.05).18 With perfusion imaging, informa-

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tion about ischemic threshold is unavailable, because isotope injection occurs only after a predetermined stress protocol. OTHER APPLICATIONS Preoperative Risk Stratification.-Dobutamine stress echocardiography is recognized as a valuable technique in the preoperative risk assessment of patients scheduled to undergo noncardiac surgical procedures. 34,35,43-45 New or worsening wall motion abnormalities after dobutamine-induced stress identify patients at increased risk of suffering a perioperative cardiac event. Poldermans and associates" studied a population of 136 consecutive patients who underwent dobutamine stress echocardiography before a major vascular operation; clinicians were blinded to test results to avoid posttest referral bias. The test revealed abnormalities in all 15 patients who suffered cardiac events, including myocardial infarction, unstable angina, and pulmonary edema (negative predictive value, 100%). The positive predictive value was 42%. In a study by Davila-Roman and colleagues" of98 consecutive patients scheduled to undergo peripheral vascular or aortic aneurysm surgical procedures, abnormal and normal dobutamine stress echocardiographic findings were significant predictors of the presence or absence of peri operative events, respectively. No perioperative cardiac events occurred among the patients with normal results of the stress test. Among 10 patients with abnormal results who were not treated with coronary revascularization, perioperative cardiac events occurred in 4 (positive predictive value, 40%). In studies that used 20lTl scintigraphy, positive predictive values from 27 to 50% have been reported." In our experience in 144 patients who were unable to exercise and underwent dobutamine stress echocardiography before noncardiac operations, the risk of a cardiac event in patients with abnormal findings was 16-fold the risk in those with normal results, even though clinicians were not blinded to test results. The sensitivity of abnormal findings in predicting cardiac events was 95%. Furthermore, the dobutamine stress test was thought to be superior to clinical assessment in identifying patients at increased risk." A normal result strongly predicts a low rate of perioperative events. 34,35,43-45 Dobutamine stress echocardiography also provides information about global left ventricular function, which may be useful in perioperative management. Risk Stratification After Myocardiallnfarction.-Several small studies suggest a role for dobutamine stress echocardiography for risk stratification after myocardial infarction. Dobutamine stress echocardiography has been used safely for evaluation of coronary artery disease as early as 5 days after myocardial infarction.":" The development of new wall motion abnormalities during dobutarnine infusion in segments outside the infarction zone accurately disclosed multivessel coronary artery disease.P:" In patients

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with infarction treated with thrombolysis, new or worsening wall motion abnormalities identified those at increased risk of cardiac events during the first year." After thrombolytic therapy, however, the event rate is so low that the yield of any test to identify patients at increased risk would be expected to be low. Thus, the value of any testing is uncertain in this setting.

Detection of Viable Myocardium.-Dobutamine echocardiography has been used to assess myocardial viability-that is, "hibernating" or "stunned" myocardium-in regions of dysfunctional myocardium. Although thallium perfusion imaging has been used to detect viability, it does not allow detection of left ventricular dysfunction, which may be readily assessed by echocardiography. The concept of hibernating myocardium refers to regions of chronic ventricular dysfunction, which result from prolonged severe reductions in blood flow. In these regions, myocardial function may be restored by enhancing the coronary blood supply." Accurate identification of hibernating myocardium is important for the clinical management of these patients because ventricular function may be improved after revascularization, and the extent of improvement correlates with long-term survival.P In regions of hibernating myocardium, function improves after administration of dobutarnine at low dosages (2.5, 5, and 10 ug/kg per min), but with use of higher doses, further ischemia and worsening of wall motion are noted. In a study of 21 patients with acute anterior myocardial infarction and severe residual stenosis in the infarct-related artery, improvement in function with lowdose dobutamine stress echocardiography at 4 ± 2 days identified viable myocardium that improved after revascularization." In another study of 49 consecutive patients who had multivessel coronary disease and decreased left ventricular function, improvement in systolic thickening after infusion of dobutamine predicted the recovery of function in the 25 patients who underwent successful revascularization." Stunned myocardium refers to myocardial regions with prolonged postischemic dysfunction, present despite restoration of normal or near-normal blood flow." The contractility of such regions is also expected to improve with use of lowdose dobutamine and the improvement to be maintained with high-dose dobutamine. In contrast, infarcted tissue remains akinetic despite administration of dobutamine. Currently, positron emission tomography is considered the "gold standard" for identifying viable myocardium. In an important study by Pierard and colleagues," a good correlation was observed between positron emission tomography and lowdose dobutamine echocardiography in identifying myocardial viability. Improvement in myocardial thickening after infusion of dobutamine in dosages of 5 to 10 ug/kg per min predicted the recovery of function after thrombolytic therapy

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Mayo Clin Proc, January 1995, Vol 70

for acute myocardial infarction. Furthermore, concordant interpretation of dobutamine echocardiography and positron emission tomography was present in 79% of affected myocardial segments. In a study of 70 patients with left ventricular dysfunction, dobutamine echocardiography was useful in distinguishing ischemic ventricular dysfunction from dilated cardiomyopathy." Patients with dilated cardiomyopathy responded to infusion of dobutamine with an improvement in ventricular function; those with ischemia exhibited worsening of ventricular wall motion. Further investigation in this area is needed:

PROGNOSTIC VALUE Because dobutamine stress echocardiography is a relatively new technique, meager data about its prognostic value are available. In a recent study of 51 symptomatic patients with suspected coronary artery disease, abnormal findings on dobutamine echocardiography identified patients at high risk of cardiac events, including myocardial infarction or unstable angina, during 24 ± 4 months of follow-up. 37 During a more than 6-month follow-up of patients who underwent dobutamine stress echocardiography for risk stratification before vascular operations, normal results were a strong predictor of decreased long-term cardiac morbidity and mortality." Additional studies pertaining to the prognostic value of dobutamine stress echocardiography are clearly needed; correlation with angiography alone may not reflect the functional significance of coronary artery disease and may not be a true representation of risk and outcome. INDICATIONS AND CONTRAINDICATIONS On the basis of the foregoing published findings, the indications for dobutamine stress echocardiography are summarized in Table 5. In general, in patients who are able to perform an adequate level of exercise, exercise stress testing is preferred. Determination of the patient's functional capacity is valuable for prognosis. 54 In addition, it is useful for evaluating therapy with antihypertensive agents and antiarrhythmic agents as well as for providing an exercise prescription or guidelines for occupational activity. For patients who are unable to perform physical exercise, however, pharmacologic stress testing is a valid alternative. Like exercise testing, pharmacologic stress echocardiography is contraindicated in patients with unstable angina or in patients with severe anemia or electrolyte imbalance. Because of the proarrhythmic effects of dobutamine, it is contraindicated in patients with uncontrolled arrhythmia. Occasionally, dobutamine may increase the blood pressure substantially; thus, it is contraindicated in patients with uncontrolled hypertension (systolic blood pressure of more than 190 mm Hg; diastolic blood pressure of more than 100

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Table5.-Indications for Dobutamine Stress Echocardiography Evaluation of known or suspected coronary artery disease in patients unable to perform adequate exercise test Riskstratification aftermyocardial infarction Riskstratification before noncardiac surgical procedure Identification of viable myocardium in patients withleft ventricular dysfunction mm Hg). Because dobutamine is metabolized by the liver, it must be used with caution in patients with liver failure. Atropine is relatively contraindicated in patients with untreated glaucoma or urinary retention.

LIMITATIONS Dobutamine stress echocardiography is a relatively new technique in comparison with perfusion imaging. Studies in which dobutamine stress echocardiography is correlated with angiography in large representative populations of patients should be conducted. Documentation of the prognostic value will be extremely important. In contrast to exercise echocardiography, dobutamine echocardiography is time intensive, inasmuch as a period of approximately 15 to 20 minutes is needed for infusion of the drug. Imaging throughout this period necessitates careful attention to detail. As with exercise echocardiography, interpretation of studies demands a high degree of expertise. ADVANTAGES Although only a limited number of patients have been studied, the sensitivity and specificity of dobutamine stress echocardiography and perfusion imaging are comparable in well-controlled studies. Distinct advantages of dobutamine stress echocardiography include immediate results, availability at the bedside, convenience for the patient, and ability to assess both global and regional myocardial function as well as to recognize and assess other cardiac abnormalities, such as valvular, myocardial, or pericardial disease (Table 3). Because the changes in ventricular wall motion can be continuously monitored, additional advantages include enhanced safety, assessment of hibernation and stunning of the myocardium, hemodynamic monitoring, and, possibly, determining gradations of ischemia. COST OF STRESS TESTS Ischemic heart disease is the most common cardiac disability. Diagnostic stress tests must be readily available, reliable, accurate, and cost-effective. Both dobutamine echocardiography and exercise echocardiography fulfill these prerequisites. The Medicare fee schedule" has established the following relative value units (RVU) for all costs

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of performing stress tests: treadmill exercise test, 3.36; exercise echocardiography, 7.50; dobutamine stress echocardiography, 10.86; and exercise or pharmacologic myocardial perfusion imaging, 14.50. CONCLUSION Dobutamine stress echocardiography is a well-tolerated, safe, and valuable procedure for the noninvasive diagnosis of coronary artery disease. It is particularly useful in the preoperative assessment of patients with known or suspected coronary artery disease and for risk stratification after myocardial infarction. It is an effective alternative to exercise testing in patients who are unable to perform an adequate exercise test. In the limited number of studies available, dobutamine echocardiography has been comparable in accuracy to nuclear perfusion testing. Potential advantages include continuous and quantifiable monitoring of induced ischemia. In an era of emphasis on cost-containment and universal health-care access, the lower cost, portability, and availability of dobutamine echocardiography make this testing modality extremely appealing. ACKNOWLEDGMENT We appreciate the dedicated help of stress sonographers Barbara N. Nichols-McCallister, RN., RD.C.S., Ronald H. May, R.N., RD.C.S., Laurie J. Anderson, Kim M. Andreen, RD.C.S., Paul M. Bastiansen, RD.C.S., Traci L. Boge, Merri L. Bremer, RN., RD.C.S., Mary Ann Capps, Joyce A. Kukuzke, R.D.C.S., Kristi H. Monahan, R.N., R.D.C.S., Geralyn M. Pumper, RN., RD.C.S., Diane C. Schmidt, RN., R.D.C.S., and Trudy J. Wellik, RD.C.S., and the excellent secretarial assistance of Shawna M. Hanson. We thank Todd D. Miller, M.D., chair, Working Group on Stress Testing, for his constructive comments.

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