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Pediatric stress echocardiography
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Pediatric Cardiology ELSEVIER
Progressin PediatricCardiology7 (1997)107-115
Pediatric stress echocardiography Thomas R. Kimball* Division of Cardiology, Department of Pediatrics, Children’s Hospital Medical Center, 3333 Bumet Avenue, Cincinnati, OH 45229, USA
_______~ Abstract
In investigating cardiovascular dynamics, echocardiography performed during stress is superior to resting echocardiography because it provides information which more accurately mimics a child’s typical active state and it is often capable of detecting disease states earlier. Specifically, it is useful in the evaluation for ischemia in children with coronary artery disease (e.g. Kawasaki disease, cardiac transplant vasculopathy, and congenital anomalies) and how hemodynamics in congenital heart disease (e.g. aortic stenosis, hypertrophic cardiomyopathy) change during an active cardiovascular state. Dobutamine is the ideal stressing agent because it does not share some of the limitations of exercise and the other pharmacologic agents. For an evaluation of ischemia, dobutamine is administered in increasing doses at 5-min intervals until a heart rate of 85% of age-related maximal heart rate is attained. Echocardiography is performed throughout the test but particular emphasis is placed on four conditions (rest, low dose dobutamine, peak heart rate, and recovery). Ischemia is identified by a new or worsening regional wall motion abnormality. The site of a regional wall motion abnormality localizes the diseased coronary artery. Analysis of regional wall motion is particularly difficult and requires additional training beyond that of a traditional pediatric cardiologist. For a stress evaluation investigating hemodynamics other than ischemia (e.g. aortic stenosis), dobutamine is administered in increasing doses until symptoms develop or hemodynamics become severe (e.g. severe aortic stenosis gradient). Usually less dobutamine is required before these conditions are met. Stress echocardiography is a valuable adjunct to the pediatric echocardiographic examination. Since children are rarely sedentary, stress echocardiography provides an opportunity to view the pediatric heart through a more physiologic window. 0 1997 Elsevier Science Ireland Ltd. Keywords: lschemia; Coronary artery disease; Kawasaki disease; Aortic stenosis; Hypentrophic cardiomyopathy; Dobutamine
1. Introduction As a means of assessing cardiac anatomy, echocardiography is obviously best performed while the patient is in a quiet, resting state. However, in truly understanding cardiovascular dynamics, resting echocardiography, although valuable, provides only a limited window into a pediatric patient’s cardiac physiology. Firstly, an echocardiogram performed in a
*Corresponding author. Tel.: +l 513 6368270;fax: +l 513 6367468.
quiet, resting state provides minimal insight on cardiovascular dynamics during a child’s typical active state. Secondly, it is increasingly obvious that a disease may not necessarily be detected on a resting echocardiogram and may only be unmasked if the heart is examined during stress. Echocardiography performed during stress opens additional windows into understanding cardiac physiology by allowing us to: (1) examine the heart during
the more common, active physiologic state; and (2) detect disease earlier. In adults, stress echocardiography has been most valuable in assessing for coronary ischemia [l]. Al-
105%9813/97/$17.00 0 1997 Elsevier Science Ireland Ltd. All rights reserved PII SlOS8-9813(97)00016-7
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though coronary artery disease is much less common in children, improvement in surgical techniques (e.g. the artificial switch operation for transposition of the great vessels) and enhanced medical care (e.g. cyclosporine in cardiac transplant patients and gamma globulin in Kawasaki patients) have resulted in more children surviving acute disease which, in turn, has created an increased need for monitoring of more chronic coronary artery disease associated with these illnesses. This is a task best accomplished with stress echocardiography. In addition, there is an increasing awareness by pediatric cardiologists that the hemodynamic perturbations of other forms of congenital heart disease may be more problematic to the child during exercise or stress. Therefore, in children, stress echocardiography can be used not only to evaluate for coronary artery disease but also to assesshow hemodynamics in congenital heart disease change during an active cardiovascular state. 2. Stress echocardiography in the assessmentof pediatric coronary artery disease
Table 1
Pediatricdiseases involving the coronary arteries Congenital anatomic causes Anomalous origin of the left coronary artery Single coronary artery Coronary sinusoids Aortic stenosis Inflammatory causes Kawasaki disease Myocarditis Drug-induced causes Cocaine abuse Oral contraceptives Steroids Hematologic causes Thromboembolism Disseminated intravascular coagulation Metabolic causes Familial hyperlipidemia Insulin-dependent diabetes mellitus Sickle cell disease Mucopolysaccharidoses
2.1. Pediatric coronary artery disease
Although coronary artery disease in children is far less prevalent than in adults, there are numerous pediatric diseasesthat can involve the coronary arteries [2] (Table 1). The leading cause of coronary artery disease in children is Kawasaki disease, an inflammatory response which can damage the coronary artery wall in a myriad of ways. Firstly, aneurysms, which can become a nidus for thromboses, and frank stenoses can compromise coronary arterial flow. Although intravenous gamma globulin has improved early morbidity and mortality, some investigators continue to report a 15% incidence of aneurysms even after its administration [3]. Perhaps just as alarming is recent evidence that even coronary arteries without stenoses nor aneurysms behave abnormally during provocative stimulation with coronary vasodilators [4]. The addition of cyclosporine to the cardiac transplant immunosuppressive regimen has made rejection far less problematic, and, currently, the leading cause of death following heart transplant is graft vasculopathy [5]. This is an accelerated, diffuse arteriopathy that up to now has been nastily indolent since it is usually not detectable by coronary arteriography. In the surgical repair of transposition of the great vessels,atria1 baffle procedures have been replaced by the arterial switch operation. Although this technique places the left ventricle in the position of the systemic ventricle, a favorable result improving long-term survival, it also necessitates transfer of the coronary arteries, a condition which may later compromise coronary flow [61.
Miscellaneous causes Arterial switch operation Cardiac transplant graft vasculopathy
In hypoplastic left and right heart syndromes, coronary-camera1 fistulae can develop in order to decompress the exceedingly high pressure of the small ventricle. Not only does retrograde flow develop through these coronary arteries from the hypoplastic ventricle to the aorta but myocardial perfusion may also be exclusively dependent on this retrograde flow since coronary artery interruptions can develop. In these instances, management of the coronary circulation must be meticulously planned and monitored. An anomalous left coronary artery originating from the pulmonary artery is another congenital lesion which may compromise coronary blood flow both before and after surgical repair. Metabolic conditions can impair coronary artery blood flow in later adolescence. Children with homozygous familial hyperlipidemia have accelerated coronary atherosclerosis, and children with insulin-dependent diabetes mellitus can develop coronary artery disease as young adults [7]. 2.2. The physiology and detection of &hernia
Ischemia is the condition of oxygen deprivation and inadequate removal of waste products as a result of a reduction in coronary artery blood flow relative to myocardial demands. Ischemia occurs when the oxy-
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gen demand of the myocardium exceeds the ability of the coronary arteries to supply oxygen to it, and, as such, develops when either: (1) coronary flow is diminished; (2) myocardial oxygen demand is increased; or (3) both. The underlying principle of all tests employing stress to detect or assessthe severity of coronary artery disease is that stress leads to a temporary disparity in this balance between coronary blood flow and myocardial oxygen demand. There is a great variety of methods for assessingischemis, but all are similar in that each employs a stressing agent (to increase myocardial oxygen demand) and a sensing monitor (to detect changes induced by the stressor) (Table 2). 2.3. Sensing monitors
Although each sensing monitor can be used with any of the stressing agents, echocardiography has attractive advantages over the other sensing monitors. During stress electrocardiography, the hallmark of ischemia is negative displacement of the ST segment which is a later, less sensitive marker for ischemia than wall motion changes, resulting in relatively low diagnostic accuracy [8]. Single photon emission computed tomography (SPECT) necessitates intravenous injection of a radiopharmaceutical (thallium or sestamibi are most commonly used) at peak stress and imaging with a gamma camera 30 min later. Ischemia manifests itself by a decreased tracer concentration in the affected segment. The test is limited by the radiation exposure and lower accuracy. Magnetic resonance imaging and positron emission tomography are relatively accurate modalities, but both are very expensive and not readily available. The latter also involves significant radiation exposure. Using echocardiography, ischemia is evident as a new or worsening regional wall motion abnormality (defined as decreased endocardial excursion and decreased systolic wall thickening) [9]. Echocardiography is perhaps the most powerful sensing monitor in Table 2 Methods used in the assessment of myocardial
perfusion
Stressing agents Exercise Dobutamine Arbutamine Adenosine Dipyridamole Sensing monitors Echocardiography Electrocardiography Single photon emission computed tomography (SPECT) Magnetic resonance imaging (MRI) Positron emission tomography (PET)
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children because it is readily available, less expensive, radiation-free, and accurate. The usually excellent image quality of children makes echocardiography the ideal sensing monitor. 2.4. Stressing agents used with echocardiography
There are two basic types of stressing agents: (1) exercise; and (2) pharmacologic. However, in the evaluation of coronary artery disease, exercise echocardiography is clearly limited. Patients less than 10 years of age cannot exercise effectively (thereby resulting in delivery of an inadequate, sub-maximal dose of stress) or cannot exercise at all. Patient respirations and movement are prohibitive in obtaining image quality satisfactory enough to detect regional wall motion abnormalities. Therefore, imaging at peak stress is actually performed after exercise, with the sonographer obtaining these ‘peak’ images within 90-120 s following exercise since ischemic areas may recover quickly. Further, since imaging is performed only after exercise, a complete dose of exercise (or stress) must be given. There is no ability to detect a lesser dose of stress at which regional wall motion abnormalities may develop allowing for earlier test termination and enhancing patient safety. Pharmacologic agents extend the applicability of stress echocardiography to children of any age. High quality images can be obtained throughout the study since the patients are supine and the hyperpnea associated with exercise is eliminated. In addition, the test can be terminated before peak stress if a regional wall motion abnormality is identified at a lower dose thereby improving patient safety. The main disadvantage of pharmacologic agents is that they do not exactly duplicate the hemodynamic changes of exercise stress [lo]. In addition, the complementary information of total work capacity performed during exercise is lost. The pharmacologic agents induce ischemia via two different mechanisms. Adenosine and dipyridamole act by inducing coronary artery dilatation of normal coronary artery segments. This dilatation secondarily produces steal of blood flow from diseased segments (which are incapable of dilating) and ischemia. Adneosine is a direct coronary vasodilator and is given in increasing doses from 50 pg/kg/min to 180 pg/kg/min. Dipyridamole inhibits cellular re-uptake of endogenous adenosine thereby promoting coronary vasodilation. It is given in up to two intravenous boluses. Both dobutamine and arbutamine, synthetic catecholamines, operate by increasing heart rate and contractility by stimulating pi and (pi receptors in the heart. Ischemia is induced when the resulting increase in oxygen demand of the heart fails to be matched by
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a concomitant increase in blood flow. Arbutamine has a unique computer-controlled closed loop delivery and monitoring system. The closed loop system measures the heart rate every 5 s, compares it to a preand user-defined response curve from resting to target heart rate, and adjusts the rate of arbutamine infusion accordingly to match this pre-set curve [ll]. Dobutamine has been widely tested and, as such, has been the agent of choice for pharmacologic stress echocardiography in the assessmentof coronary artery disease. 2.5. Dobutamine stress echocardiography in children [12] 2.5.1. Equipment and personnel
The ultrasound system should be equipped with digital storage and retrieval capabilities so that cardiac cycles can be stored during the test, and retrieved and compared side-by-side at the different stress stages after the test. Traditionally, all stages are recorded on videotape, and four stages(rest, low dose dobutamine, peak heart rate, and recovery) are stored digitally (Fig. 1). A 1Zlead electrocardiographic system is necessary to provide continuous monitoring of heart rhythm and ST-segments. In addition, this affords the opportunity to perform simultaneous stress electrocardiography. Blood pressure and oxygen saturation monitors and supplies for intravenous line are also necessary. The laboratory must be equipped with sedatives for younger patients and resuscitative equipment (airway management supplies, defibrillator, and emergency cardiac medications). The personnel necessary to conduct a dobutamine stress echocardiogram are the sonographer, a nurse, and a cardiologist who is specialized in echocardiography. The sonographer and the cardiologist should have additional training in regional wall motion interpretation. The nurse is primarily responsible for the intravenous line, providing comfort for the patient, and recording vital signs. The physician conducts and terminates the test, oversees the general care of the patient, and interprets the test in conjunction with the sonographer. 2.5.2. Technical aspects
The suitability of a particular patient to undergo a dobutamine stress echocardiogram must first be assessed.In some instances, dobutamine echocardiography is contraindicated and should not be performed (Table 3). The goal of the test is to deliver an adequate dose of stress defined by achievement of the target heart rate (85% of the age-related maximal heart rate, where the maximal heart rate = 220 - [age in years]). This is accomplished by administering dobutamine in increasing doses (5, 10, 20, 30, 40, 50 pg/kg/min) in
5-min intervals as needed. Atropine (0.01 mg/kg, max = 1.0 mg in 0.25-mg aliquots) is usually required to increase heart rate further as necessary. Esmolol (0.25 mg/kg up to two doses) is given after test termination if ischemia develops or if the patient is having adverse reactions. Echocardiography is performed in four views (the parasternal long and short axes and the apical fourand two-chamber views) at each stage. By the convention of the American Society of Echocardiography, the left ventricular myocardium can be divided in to 16 segments from these four views (Fig. 2) [13]. Each segment is perfused by one of the three coronary arteries and, therefore, the wall motion of a particular segment is reflective of the flow through the coronary artery to that segment. 2.5.3. Assessing regional wall motion
Wall motion of each segment is judged at each stage of the stress test to be either normal, hypokinetic, akinetic, or dyskinetic. Hypokinesis is defined as decreased endocardial excursion and myocardial thickening, akinesis as no endocardial motion or myocardial thickening, and dyskinesis as paradoxical endocardial excursion with no myocardial thickening. A new or worsening (e.g. hypokinetic motion becoming akinetic) wall motion abnormality at peak stress is diagnostic for ischemia. Grading wall motion is the most difficult aspect of the test and should not be performed by pediatric cardiologists until they have had some training in wall motion analysis and/or have competent adult cardiologists for assistance.The wall motion is assessedby examining the extent of endocardial excursion and myocardial thickening through systole. Of these two parameters, myocardial thickening is most important since endocardial excursion can occur not only from systolic contraction of the heart but also from translational motion of the heart through the chest. The judgement of regional wall motion can be facilitated after the test by placing a grid or cursor on the edge of the endocardium being interrogated at end-diastole and determining on a frame-by-frame basis if the endocardium crosses the grid or cursor and if the myocardium thickens over it. This process can be repeated for other difficult segments as needed. Doppler tissue imaging and color kinesis are two new modalities that can aid in detecting regional wall motion abnormalities. Doppler tissue imaging uses low pass Doppler filters to filter the high velocity blood profiles and to measure the relatively low velocities associated with wall motion. Just as with traditional color Doppler of blood velocities, these wall velocities can be color coded and overlaid on the two-dimensional image to give a visual display which can be analyzed on a regional basis. A disadvantage is
T.R. Kimball /Progress in Pediatn’c Cardiology 7 (1997) 107-115
Fig. 1. Quad screen display of end-systolic digital images acquired in the parasternal short axis view at rest (upper left), low dose dobutamine (upper right), peak heart rate (lower left), and recovery (lower right) in a child with no regional wall motion abnormalities. Note that the end-syr stolic area progressively becomes smaller from rest to low dose dobutamine to peak stress when there is cavity obliteration. This side-by ,-side display of cardiac cycles at different stages, when reviewed in motion as loops, facilitates comparison of regional wall motion betwee :n stages. Fig. 3. Quad screen display of apical four-chamber color kinesis images at end-systole during a dobutamine stress echocardiogram on a 4-year- old girl with a heart transplant and accelerated coronary artery disease. The upper left image is at rest, the upper right at a dobutamine dose o f 10 pg/kg/min, the lower left at peak heart rate, and the lower right at recovery. At rest, there is hypokinesis of the three septal segmerIts (lateral wall depicts normal motion for comparison). At peak heart rate, the motion of the mid-septal segment worsens becoming dyskinc :tic (red color).
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Table 3 Contraindications to dobutamine stress echocardiography in children Acute myocarditis Hypovolemia Impending, acute, or healing myocardial infarction Known hypersensitivity to dobutamine Severe aortic stenosis or idiopathic hypertrophic sub-aortic stenosis Severe hypertension Uncontrolled cardiac dysrhythmias
that, in order for the wall velocities to be accurately recorded, the wall motion must be parallel to the Doppler beam. Therefore, the wall motion of the lateral left ventricular wall, portions of the septum, and other segments cannot be analyzed because the motion of these segments occurs perpendicular to the Doppler beam. Color kinesis is a new modality that avoids this problem. This technology processes the ultrasonic backscatter information to differentiate pixels of my-
ocardial density from those of blood density. In this manner, the border between these two types of pixels, the endocardium, is tracked. In each echocardiographic frame, the color kinesis system superimposes a color overlay on each pixel of the two-dimensional image which changes from blood to myocardial density. The type of color that is laid over the image by the system is dependent on when the motion occurred relative to the QRS of the electrocardiogram. If motion occurs early in systole soon after the QRS, oranges and yellows are portrayed. If motion occurs later in systole, greens and blues are depicted. The end-systolic frame has special meaning because it represents a ‘snapshot’ of the temporal and spatial history of motion for the immediate preceding systole. If the motion of all segments is normal, a rainbow of concentric rings of color will be depicted over the image. Wherever there is no motion (i.e. akinesis), no color is shown. Wherever there is little motion (i.e. hypokinesis), less colors are laid over the image. If a pixel changes from tissue density to blood density (i.e.
WALL
PARASTERNAL LONG AXIS
APICAL FOUR CHAMBE’R
PARASTERNAL SHORT AXIS
APICAL TWO CHAMBER
Fig. 2. The ventricular myocardium is divided into 16 segments from the four echocardiographic views: (A) parastemal long axis; (Bl parastemal short axis; (C) apical four-chamber; and (D) apical two-chamber (note that some segments, e.g. the mid-septum, can be visualized from more than one view). The wall motion of each of the 16 segments is scored as being normal, hypokinetic, akinetic, or dyskinetic. Abnormal wall motion of a regional segment reflects inadequate blood flow through the coronary artery (either left anterior descending (LAD), left circumflex (CFX), or right coronary (RCA) artery) perfusing that particular segment.
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motion opposite to what is expected during systole) or dyskinesis, the system depicts a red color by convention. Abnormal regional wall motion can readily be detected (Fig. 3) and even quantitated [14]. Since color kinesis tracks endocardial motion, it can be misleading when there is significant cardiac translation. 2.5.4. Test termination The test can be terminated for a variety of specific endpoints (Table 4). A test is considered diagnostic if one of two endpoints is achieved: either ischemia is induced or the target heart is attained without ischemia (in our experience, the test is diagnostic in about 85% of cases>. 2.5.5. Adverse reactions Dobutamine stress echocardiography has proven very safe in children. In our experience of nearly 75 patients, only two have experienced side effects requiring test termination (hypertension with headache and ventricular ectopy). Less serious side effects include nausea and vomiting (19% of studies) and dysrhythmias (premature ventricular and atria1 contractions in 9% of studies). 2.4. Proven clinical applications Despite its limitations, investigators have used exercise echocardiography to successfully evaluate regional wall motion in children. For instance, Pahl et al. [ 151 have demonstrated that exercise echocardiography is more sensitive in detecting ischemia in Kawasaki patients than exercise electrocardiography. Pilot data from our group suggest that many Kawasaki patients do not have ischemia despite the presence of aneurysms [16]. Notably, images were interpretable in only 77% of the patients. In our series [12], dobutamine echocardiograms were concordant with coronary arteriography in 94% of children with Kawasaki disease, heart transplants or arterial switch operations. More importantly, in the majority of the patients with both a positive dobutamine echocardiogram and angiogram, the dobutamine echocardiogram was positive before the arteri-
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ogram. These results suggest that dobutamine stress echocardiography may detect disease earlier than coronary arteriography. Likewise Noto et al. [171,have shown a 96% concordance rate between dobutamine stress echocardiography and arteriography in Kawasaki patients. These promising results suggest an alternative approach to the evaluation of coronary artery disease in children. Specifically, a dual approach examining both coronary artery physiology and anatomy is most appropriate. Coronary artery anatomy is best examined by modalities such as resting echocardiogram or coronary arteriography. Coronary artery physiology is best investigated by dobutamine stress echocardiography. This approach can be illustrated in the evaluation of a child with Kawasaki disease. The coronary artery anatomy and the presence of aneurysms can be defined with resting echocardiography. Once the acute illness has subsided, dobutamine stress echocardiography can be used to determine the physiologic significance of aneurysms or other coronary artery lesions if present. In addition, dobutamine stress echocardiography can be used to serially assesscoronary physiology during mid- and long-term follow-up. If a serial evaluation becomes abnormal, then coronary anatomy should be compulsively delineated with coronary arteriography. 3. Stress echocardiograpy in the assessment of noncoronary disease During most of their waking hours children rarely lie supine in a dark room, but usually are very active individuals. Further, symptoms are not always indicative of severity of non-coronary disease. Finally, resting conditions do not define cardiac reserve. Therefore, the underlying principle for employing stress echocardiography in the evaluation of non-coronary disease (Table 5) is that hemodynamic perturbations may be absent or minimal at rest and may become exacerbated and only problematic during exercise or stress, conditions more representative of a child’s typical daily routine. This application of stress echocardiography to noncoronary disease requires obtaining a completely difTable 5
Table 4 Endpoints for dobutamine stress echocardiography in children
Non-coronary diseases in which stress echocardiography is applied
New or worsening wall motion abnormality ST-segment depression 2 2 mm Adverse reaction Angina Attainment of target heart rate Administration of maximal dose (dobutamine: 50 pg/kg/min, atropine:0.01 mg/kg up to 1 mg in 0.25mg aliquouts)
Patients receiving doxorubicin Transplant rejection Coarctation and coarctation repair Mild aortic stenosis Mild pulmonic stenosis Mild hypertrophic cardiomyopathy Dilated cardiomyopathy Pulmonary disease
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ferent set of echocardiographic parameters than in a coronary artery evaluation. Rather than examining regional wall motion, a non-coronary artery evaluation will include indices of global left ventricular function, preload, afterload and contractility; valve gradients; outflow gradients; ventricular pressure estimates; and valve regurgitation severity (Table 6). A powerful example of this application is demonstrated by Klewer et al. [18] who administered dobutamine to oncology patients who had received doxorubicin to unmask left ventricular dysfunction not present at rest. The test can therefore be used to detect sub-clinical dysfunction. A potential application in this regard is to evaluate heart transplant patients for transplant rejection. Currently, cardiac biopsy is the only reliable method of detecting rejection and a non-invasive method to diagnose rejection is lacking. The administration of dobutamine to unmask abnormalities during rejection that are not present at rest is an exciting and promising application. We have used dobutamine stress echocardiography to determine if the severity of various non-coronary artery diseases increases with increasing chronotropy and inotropy. The aim of our protocol changes for these type of evaluations. Instead of aiming for a target heart rate, we administer dobutamine more slowly and deliberately while continuously evaluating disease severity by symptoms and echocardiography. The test is terminated with the development of symptoms or achievement of predefined cutpoints in the echocardiographic indices. Usually it requires only moderate doses of dobutamine to reach one or both of these endpoints. In our experience, dobutamine stress echocardiography is very helpful in evaluating the changes in a mild resting left ventricular outflow tract gradient in children with hypertrophic cardiomyopathy. In this evaluation, in addition to monitoring symptoms, we assessthe left ventricular outflow tract and mitral insufficiency gradients. The latter gradient allows estimation of the peak systolic left ventricular pressure. We have found that, in some instances, the resting gradient in the left ventricular outflow tract Table 6 Stress echocardiographic indices assessedin noncoronary disease Left ventricular function: Shortening fraction Fractional area change Left ventricular preload: Left ventricular end-diastolic dimension Left-ventricular end-diastolic area Left ventricular afterload: end-systolic wall stress f,eft ventricular contractility: stress-velocity relationship Valve gradients Outflow gradients Valve regurgitation severity change
and of the mitral insufficiency can increase markedly and have treated such patients with beta-blockers. Often the clinician needs to know how the severity of a non-coronary disease(e.g. aortic stenosis) changes with exercise specifically. Dobutamine echocardiography can be limited in this type of evaluation because although dobutamine mimics exercise by increasing chronotrophy and inotropy, it does not exactly duplicate the stress of exercise. Further study is needed to determine if hemodynamic changes during dobutamine would also occur during exercise. Therefore, exercise echocardiography may have more use in non-coronary than coronary evaluations. Cyran et al. [19] used exercise Doppler echocardiography to show that following successful coarctation repair in children, exercise hypertension is due to exercise-induced narrowing across the former coarctation site. Looking at a similar group of patients, we have used M-mode exercise echocardiography to demonstrate that exercise hypertension may also be due to an exercise-induced hypercontractile state [20]. The same techniques can be used to ascertain how the gradient across the aortic valve in patients with mild or moderate aortic stenosis and across the left ventricular outflow tract in patients with mild hypertrophic cardiomyopathy behave during exercise. These type of evaluations provide more realistic information on the degree of narrowing during the patient’s waking hours than does the resting echocardiogram. Another application of exercise echocardiography is to evaluate the behavior of the pulmonary artery pressure during exercise. Kaplan et al. [21] used exercise Doppler echocardiography of the tricuspid insufficiency jet in patients with a variety of congenital heart diseasesto measure pulmonary artery pressures. This application of exercise echocardiography will be powerful in patients with lung diseases or patients with heart disease at risk for pulmonary hypertension. 4. Summary Stress echocardiography can be a valuable adjunct to the pediatric echocardiographic examination. Many disease states have minimal or no echocardiographic manifestations at rest, and it is only through the administration of stress that pathology can be identified. Stress echocardiography will be helpful in the field of pediatric cardiology by enabling detection of ischemia associated with coronary artery disease. Since children are rarely sedentary and instead are usually very active, stress echocardiography affords the echocardiographer the opportunity to view the pediatric heart through a more physiologic window.
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References 111 Mertes H, Sawada SG, Ryan T et al. Symptoms, adverse effects, and complications associated with dobutamine stress echocardiography: experience in 1118 patients. Circulation 1993;88:15519. 121 Towbin JA. Myocardial infarction in childhood. In: Garson A, Bricker JT, McNamara DG, editors. The science and practice of pediatric cardiology. Philadelphia: Lea and Febiger, 1990. 131 Akagi T, Rose V, Benson LN, Newman A, Freedom RM. Outcome of coronary artery aneurysms after Kawasaki disease. J Pediatr 1992;121:689-694. [41 Muzik 0, Paridon SM, Singh TP, Morrow WR, Dayanikli F, DiCarli MF. Quantification of myocardial blood flow and flow reserve in children with a history of Kawasaki disease and normal coronary arteries using positron emission tomography. J Am Coil Cardiol 1996;28:757-762. [51 Uretsky BF, Murah S, Reddy S et al. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporin and prednisone. Circulation 1987;76:827-834. Lf-4Weindling SN, Wernovsky G, Colan SD et al. Myocardial perfusion, function, and exercise tolerance after the arterial switch operation. J Am Co11 Cardiol 1994;23:424--433. [71 Krolewski AS, Kosinski EJ, Warram JH et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 1987;59:750-755. k31 Previtali M, Lanzarini L, Fetiveau R et al. Comparison of dobutamine stress echocardiography, dipyridamole stress echocardiography and exercise stress testing for diagnosis of coronary artery disease. Am J Cardiol 1993;72:865-870. [91 Distante A, Rovai D, Picano E et al. Transient changes in left ventricular mechanics during attacks of Prinzmetal’s angina: an M-mode echocardiographic study. Am Heart J 1984;107:465-471. [lOI Attenhofer CH, Pellikka PA, Oh JK, Roger VL, Sohn D-W, Seward JB. Comparison of ischemic response during exercise and dobutamine echocardiography in patients with left main coronary artery disease. J Am Co11 Cardiol 1996; 27:1171-1177. 1111Dennis CA, Pool PE, Perrins EJ et al. Stress testing with closed-loop arbutamine as an alternative to exercise. J Am Coil Cardiol 1995:26:1 151-1158.
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TR, Witt SA, Daniels SR. Dobutamine stress echocardiography in the assessment of suspected myocardial ischemia in children and young adults. Am J Cardiol 1997;95:1837-1843. 1131 American Society of Echocardiography Committee on Standards, Sub-Committee on Quantification of 2-Dimensional Echocardiograms. Recommendations for quantification of the left ventricle by 2-dimensional echocardiography. J Am Sot Echocardiogr 1989;2:358-367. 1141 Lang RM, Vignon P, Weinert L et al. Echocardiographic quantification of regional left ventricular wall motion with color kinesis. Circulation 1996;93:187771885. [151 Pahl E, Sehgal R, Chtystof D et al. Feasibility of exercise stress echocardiography for the follow-up of children with coronary involvement secondary to Kawasaki disease. Circulation 1995;91:122-128. I161 Bensky AS, Daniels SR, Meyer RA. Effects of stress on regional wall motion in children with Kawasaki disease. J Am Sot Echocardiogr 1992;5:315. [171 Noto N, Ayusawa M, Karasawa K et al. Dobutamine stress echocardiography for detection of coronary artery stenosis in children with Kawasaki disease. J Am Coil Cardiol 1996;27:1251-1256.
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SE, Goldberg SJ, Donnerstein RL, Berg RA, Hutter JJ. Dobutamine stress echocardiography: a sensitive indicator of diminished myocardial function in asymptomatic doxorubicin-treated long-term survivors of childhood cancer. J Am Co11 Cardiol 1992;19:394-401. [I91 Cyran SE, Grzeszczak M, Kaufman K et al. Aortic ‘recoarctation’ at rest versus at exercise in children as evaluated by stress Doppler echocardiography after a ‘good’ operative result. Am J Cardiol 1993;71:963-970. BOI Kimball TR, Reynolds JM, Mays WA, Khoury P, Claytor RP, Daniels SR. Persistent hyperdynamic cardiovascular state at rest and during exercise in children after successful repair of coarctation of the aorta. J Am Co11 Cardi 1994;24:194-200. 1211Kaplan JD, Foster E, Redberg RF, Schiller NB. Exercise Doppler echocardiography identifies abnormal hemodynamics in adults with congenital heart disease. Am Heart J 1994;127:1572-1580.
Pediatric Cardiology ELSEVIER
Progressin PediatricCardiology7 (1997)107-115
Pediatric stress echocardiography Thomas R. Kimball* Division of Cardiology, Department of Pediatrics, Children’s Hospital Medical Center, 3333 Bumet Avenue, Cincinnati, OH 45229, USA
_______~ Abstract
In investigating cardiovascular dynamics, echocardiography performed during stress is superior to resting echocardiography because it provides information which more accurately mimics a child’s typical active state and it is often capable of detecting disease states earlier. Specifically, it is useful in the evaluation for ischemia in children with coronary artery disease (e.g. Kawasaki disease, cardiac transplant vasculopathy, and congenital anomalies) and how hemodynamics in congenital heart disease (e.g. aortic stenosis, hypertrophic cardiomyopathy) change during an active cardiovascular state. Dobutamine is the ideal stressing agent because it does not share some of the limitations of exercise and the other pharmacologic agents. For an evaluation of ischemia, dobutamine is administered in increasing doses at 5-min intervals until a heart rate of 85% of age-related maximal heart rate is attained. Echocardiography is performed throughout the test but particular emphasis is placed on four conditions (rest, low dose dobutamine, peak heart rate, and recovery). Ischemia is identified by a new or worsening regional wall motion abnormality. The site of a regional wall motion abnormality localizes the diseased coronary artery. Analysis of regional wall motion is particularly difficult and requires additional training beyond that of a traditional pediatric cardiologist. For a stress evaluation investigating hemodynamics other than ischemia (e.g. aortic stenosis), dobutamine is administered in increasing doses until symptoms develop or hemodynamics become severe (e.g. severe aortic stenosis gradient). Usually less dobutamine is required before these conditions are met. Stress echocardiography is a valuable adjunct to the pediatric echocardiographic examination. Since children are rarely sedentary, stress echocardiography provides an opportunity to view the pediatric heart through a more physiologic window. 0 1997 Elsevier Science Ireland Ltd. Keywords: lschemia; Coronary artery disease; Kawasaki disease; Aortic stenosis; Hypentrophic cardiomyopathy; Dobutamine
1. Introduction As a means of assessing cardiac anatomy, echocardiography is obviously best performed while the patient is in a quiet, resting state. However, in truly understanding cardiovascular dynamics, resting echocardiography, although valuable, provides only a limited window into a pediatric patient’s cardiac physiology. Firstly, an echocardiogram performed in a
*Corresponding author. Tel.: +l 513 6368270;fax: +l 513 6367468.
quiet, resting state provides minimal insight on cardiovascular dynamics during a child’s typical active state. Secondly, it is increasingly obvious that a disease may not necessarily be detected on a resting echocardiogram and may only be unmasked if the heart is examined during stress. Echocardiography performed during stress opens additional windows into understanding cardiac physiology by allowing us to: (1) examine the heart during
the more common, active physiologic state; and (2) detect disease earlier. In adults, stress echocardiography has been most valuable in assessing for coronary ischemia [l]. Al-
105%9813/97/$17.00 0 1997 Elsevier Science Ireland Ltd. All rights reserved PII SlOS8-9813(97)00016-7
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though coronary artery disease is much less common in children, improvement in surgical techniques (e.g. the artificial switch operation for transposition of the great vessels) and enhanced medical care (e.g. cyclosporine in cardiac transplant patients and gamma globulin in Kawasaki patients) have resulted in more children surviving acute disease which, in turn, has created an increased need for monitoring of more chronic coronary artery disease associated with these illnesses. This is a task best accomplished with stress echocardiography. In addition, there is an increasing awareness by pediatric cardiologists that the hemodynamic perturbations of other forms of congenital heart disease may be more problematic to the child during exercise or stress. Therefore, in children, stress echocardiography can be used not only to evaluate for coronary artery disease but also to assesshow hemodynamics in congenital heart disease change during an active cardiovascular state. 2. Stress echocardiography in the assessmentof pediatric coronary artery disease
Table 1
Pediatricdiseases involving the coronary arteries Congenital anatomic causes Anomalous origin of the left coronary artery Single coronary artery Coronary sinusoids Aortic stenosis Inflammatory causes Kawasaki disease Myocarditis Drug-induced causes Cocaine abuse Oral contraceptives Steroids Hematologic causes Thromboembolism Disseminated intravascular coagulation Metabolic causes Familial hyperlipidemia Insulin-dependent diabetes mellitus Sickle cell disease Mucopolysaccharidoses
2.1. Pediatric coronary artery disease
Although coronary artery disease in children is far less prevalent than in adults, there are numerous pediatric diseasesthat can involve the coronary arteries [2] (Table 1). The leading cause of coronary artery disease in children is Kawasaki disease, an inflammatory response which can damage the coronary artery wall in a myriad of ways. Firstly, aneurysms, which can become a nidus for thromboses, and frank stenoses can compromise coronary arterial flow. Although intravenous gamma globulin has improved early morbidity and mortality, some investigators continue to report a 15% incidence of aneurysms even after its administration [3]. Perhaps just as alarming is recent evidence that even coronary arteries without stenoses nor aneurysms behave abnormally during provocative stimulation with coronary vasodilators [4]. The addition of cyclosporine to the cardiac transplant immunosuppressive regimen has made rejection far less problematic, and, currently, the leading cause of death following heart transplant is graft vasculopathy [5]. This is an accelerated, diffuse arteriopathy that up to now has been nastily indolent since it is usually not detectable by coronary arteriography. In the surgical repair of transposition of the great vessels,atria1 baffle procedures have been replaced by the arterial switch operation. Although this technique places the left ventricle in the position of the systemic ventricle, a favorable result improving long-term survival, it also necessitates transfer of the coronary arteries, a condition which may later compromise coronary flow [61.
Miscellaneous causes Arterial switch operation Cardiac transplant graft vasculopathy
In hypoplastic left and right heart syndromes, coronary-camera1 fistulae can develop in order to decompress the exceedingly high pressure of the small ventricle. Not only does retrograde flow develop through these coronary arteries from the hypoplastic ventricle to the aorta but myocardial perfusion may also be exclusively dependent on this retrograde flow since coronary artery interruptions can develop. In these instances, management of the coronary circulation must be meticulously planned and monitored. An anomalous left coronary artery originating from the pulmonary artery is another congenital lesion which may compromise coronary blood flow both before and after surgical repair. Metabolic conditions can impair coronary artery blood flow in later adolescence. Children with homozygous familial hyperlipidemia have accelerated coronary atherosclerosis, and children with insulin-dependent diabetes mellitus can develop coronary artery disease as young adults [7]. 2.2. The physiology and detection of &hernia
Ischemia is the condition of oxygen deprivation and inadequate removal of waste products as a result of a reduction in coronary artery blood flow relative to myocardial demands. Ischemia occurs when the oxy-
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gen demand of the myocardium exceeds the ability of the coronary arteries to supply oxygen to it, and, as such, develops when either: (1) coronary flow is diminished; (2) myocardial oxygen demand is increased; or (3) both. The underlying principle of all tests employing stress to detect or assessthe severity of coronary artery disease is that stress leads to a temporary disparity in this balance between coronary blood flow and myocardial oxygen demand. There is a great variety of methods for assessingischemis, but all are similar in that each employs a stressing agent (to increase myocardial oxygen demand) and a sensing monitor (to detect changes induced by the stressor) (Table 2). 2.3. Sensing monitors
Although each sensing monitor can be used with any of the stressing agents, echocardiography has attractive advantages over the other sensing monitors. During stress electrocardiography, the hallmark of ischemia is negative displacement of the ST segment which is a later, less sensitive marker for ischemia than wall motion changes, resulting in relatively low diagnostic accuracy [8]. Single photon emission computed tomography (SPECT) necessitates intravenous injection of a radiopharmaceutical (thallium or sestamibi are most commonly used) at peak stress and imaging with a gamma camera 30 min later. Ischemia manifests itself by a decreased tracer concentration in the affected segment. The test is limited by the radiation exposure and lower accuracy. Magnetic resonance imaging and positron emission tomography are relatively accurate modalities, but both are very expensive and not readily available. The latter also involves significant radiation exposure. Using echocardiography, ischemia is evident as a new or worsening regional wall motion abnormality (defined as decreased endocardial excursion and decreased systolic wall thickening) [9]. Echocardiography is perhaps the most powerful sensing monitor in Table 2 Methods used in the assessment of myocardial
perfusion
Stressing agents Exercise Dobutamine Arbutamine Adenosine Dipyridamole Sensing monitors Echocardiography Electrocardiography Single photon emission computed tomography (SPECT) Magnetic resonance imaging (MRI) Positron emission tomography (PET)
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children because it is readily available, less expensive, radiation-free, and accurate. The usually excellent image quality of children makes echocardiography the ideal sensing monitor. 2.4. Stressing agents used with echocardiography
There are two basic types of stressing agents: (1) exercise; and (2) pharmacologic. However, in the evaluation of coronary artery disease, exercise echocardiography is clearly limited. Patients less than 10 years of age cannot exercise effectively (thereby resulting in delivery of an inadequate, sub-maximal dose of stress) or cannot exercise at all. Patient respirations and movement are prohibitive in obtaining image quality satisfactory enough to detect regional wall motion abnormalities. Therefore, imaging at peak stress is actually performed after exercise, with the sonographer obtaining these ‘peak’ images within 90-120 s following exercise since ischemic areas may recover quickly. Further, since imaging is performed only after exercise, a complete dose of exercise (or stress) must be given. There is no ability to detect a lesser dose of stress at which regional wall motion abnormalities may develop allowing for earlier test termination and enhancing patient safety. Pharmacologic agents extend the applicability of stress echocardiography to children of any age. High quality images can be obtained throughout the study since the patients are supine and the hyperpnea associated with exercise is eliminated. In addition, the test can be terminated before peak stress if a regional wall motion abnormality is identified at a lower dose thereby improving patient safety. The main disadvantage of pharmacologic agents is that they do not exactly duplicate the hemodynamic changes of exercise stress [lo]. In addition, the complementary information of total work capacity performed during exercise is lost. The pharmacologic agents induce ischemia via two different mechanisms. Adenosine and dipyridamole act by inducing coronary artery dilatation of normal coronary artery segments. This dilatation secondarily produces steal of blood flow from diseased segments (which are incapable of dilating) and ischemia. Adneosine is a direct coronary vasodilator and is given in increasing doses from 50 pg/kg/min to 180 pg/kg/min. Dipyridamole inhibits cellular re-uptake of endogenous adenosine thereby promoting coronary vasodilation. It is given in up to two intravenous boluses. Both dobutamine and arbutamine, synthetic catecholamines, operate by increasing heart rate and contractility by stimulating pi and (pi receptors in the heart. Ischemia is induced when the resulting increase in oxygen demand of the heart fails to be matched by
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a concomitant increase in blood flow. Arbutamine has a unique computer-controlled closed loop delivery and monitoring system. The closed loop system measures the heart rate every 5 s, compares it to a preand user-defined response curve from resting to target heart rate, and adjusts the rate of arbutamine infusion accordingly to match this pre-set curve [ll]. Dobutamine has been widely tested and, as such, has been the agent of choice for pharmacologic stress echocardiography in the assessmentof coronary artery disease. 2.5. Dobutamine stress echocardiography in children [12] 2.5.1. Equipment and personnel
The ultrasound system should be equipped with digital storage and retrieval capabilities so that cardiac cycles can be stored during the test, and retrieved and compared side-by-side at the different stress stages after the test. Traditionally, all stages are recorded on videotape, and four stages(rest, low dose dobutamine, peak heart rate, and recovery) are stored digitally (Fig. 1). A 1Zlead electrocardiographic system is necessary to provide continuous monitoring of heart rhythm and ST-segments. In addition, this affords the opportunity to perform simultaneous stress electrocardiography. Blood pressure and oxygen saturation monitors and supplies for intravenous line are also necessary. The laboratory must be equipped with sedatives for younger patients and resuscitative equipment (airway management supplies, defibrillator, and emergency cardiac medications). The personnel necessary to conduct a dobutamine stress echocardiogram are the sonographer, a nurse, and a cardiologist who is specialized in echocardiography. The sonographer and the cardiologist should have additional training in regional wall motion interpretation. The nurse is primarily responsible for the intravenous line, providing comfort for the patient, and recording vital signs. The physician conducts and terminates the test, oversees the general care of the patient, and interprets the test in conjunction with the sonographer. 2.5.2. Technical aspects
The suitability of a particular patient to undergo a dobutamine stress echocardiogram must first be assessed.In some instances, dobutamine echocardiography is contraindicated and should not be performed (Table 3). The goal of the test is to deliver an adequate dose of stress defined by achievement of the target heart rate (85% of the age-related maximal heart rate, where the maximal heart rate = 220 - [age in years]). This is accomplished by administering dobutamine in increasing doses (5, 10, 20, 30, 40, 50 pg/kg/min) in
5-min intervals as needed. Atropine (0.01 mg/kg, max = 1.0 mg in 0.25-mg aliquots) is usually required to increase heart rate further as necessary. Esmolol (0.25 mg/kg up to two doses) is given after test termination if ischemia develops or if the patient is having adverse reactions. Echocardiography is performed in four views (the parasternal long and short axes and the apical fourand two-chamber views) at each stage. By the convention of the American Society of Echocardiography, the left ventricular myocardium can be divided in to 16 segments from these four views (Fig. 2) [13]. Each segment is perfused by one of the three coronary arteries and, therefore, the wall motion of a particular segment is reflective of the flow through the coronary artery to that segment. 2.5.3. Assessing regional wall motion
Wall motion of each segment is judged at each stage of the stress test to be either normal, hypokinetic, akinetic, or dyskinetic. Hypokinesis is defined as decreased endocardial excursion and myocardial thickening, akinesis as no endocardial motion or myocardial thickening, and dyskinesis as paradoxical endocardial excursion with no myocardial thickening. A new or worsening (e.g. hypokinetic motion becoming akinetic) wall motion abnormality at peak stress is diagnostic for ischemia. Grading wall motion is the most difficult aspect of the test and should not be performed by pediatric cardiologists until they have had some training in wall motion analysis and/or have competent adult cardiologists for assistance.The wall motion is assessedby examining the extent of endocardial excursion and myocardial thickening through systole. Of these two parameters, myocardial thickening is most important since endocardial excursion can occur not only from systolic contraction of the heart but also from translational motion of the heart through the chest. The judgement of regional wall motion can be facilitated after the test by placing a grid or cursor on the edge of the endocardium being interrogated at end-diastole and determining on a frame-by-frame basis if the endocardium crosses the grid or cursor and if the myocardium thickens over it. This process can be repeated for other difficult segments as needed. Doppler tissue imaging and color kinesis are two new modalities that can aid in detecting regional wall motion abnormalities. Doppler tissue imaging uses low pass Doppler filters to filter the high velocity blood profiles and to measure the relatively low velocities associated with wall motion. Just as with traditional color Doppler of blood velocities, these wall velocities can be color coded and overlaid on the two-dimensional image to give a visual display which can be analyzed on a regional basis. A disadvantage is
T.R. Kimball /Progress in Pediatn’c Cardiology 7 (1997) 107-115
Fig. 1. Quad screen display of end-systolic digital images acquired in the parasternal short axis view at rest (upper left), low dose dobutamine (upper right), peak heart rate (lower left), and recovery (lower right) in a child with no regional wall motion abnormalities. Note that the end-syr stolic area progressively becomes smaller from rest to low dose dobutamine to peak stress when there is cavity obliteration. This side-by ,-side display of cardiac cycles at different stages, when reviewed in motion as loops, facilitates comparison of regional wall motion betwee :n stages. Fig. 3. Quad screen display of apical four-chamber color kinesis images at end-systole during a dobutamine stress echocardiogram on a 4-year- old girl with a heart transplant and accelerated coronary artery disease. The upper left image is at rest, the upper right at a dobutamine dose o f 10 pg/kg/min, the lower left at peak heart rate, and the lower right at recovery. At rest, there is hypokinesis of the three septal segmerIts (lateral wall depicts normal motion for comparison). At peak heart rate, the motion of the mid-septal segment worsens becoming dyskinc :tic (red color).
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Table 3 Contraindications to dobutamine stress echocardiography in children Acute myocarditis Hypovolemia Impending, acute, or healing myocardial infarction Known hypersensitivity to dobutamine Severe aortic stenosis or idiopathic hypertrophic sub-aortic stenosis Severe hypertension Uncontrolled cardiac dysrhythmias
that, in order for the wall velocities to be accurately recorded, the wall motion must be parallel to the Doppler beam. Therefore, the wall motion of the lateral left ventricular wall, portions of the septum, and other segments cannot be analyzed because the motion of these segments occurs perpendicular to the Doppler beam. Color kinesis is a new modality that avoids this problem. This technology processes the ultrasonic backscatter information to differentiate pixels of my-
ocardial density from those of blood density. In this manner, the border between these two types of pixels, the endocardium, is tracked. In each echocardiographic frame, the color kinesis system superimposes a color overlay on each pixel of the two-dimensional image which changes from blood to myocardial density. The type of color that is laid over the image by the system is dependent on when the motion occurred relative to the QRS of the electrocardiogram. If motion occurs early in systole soon after the QRS, oranges and yellows are portrayed. If motion occurs later in systole, greens and blues are depicted. The end-systolic frame has special meaning because it represents a ‘snapshot’ of the temporal and spatial history of motion for the immediate preceding systole. If the motion of all segments is normal, a rainbow of concentric rings of color will be depicted over the image. Wherever there is no motion (i.e. akinesis), no color is shown. Wherever there is little motion (i.e. hypokinesis), less colors are laid over the image. If a pixel changes from tissue density to blood density (i.e.
WALL
PARASTERNAL LONG AXIS
APICAL FOUR CHAMBE’R
PARASTERNAL SHORT AXIS
APICAL TWO CHAMBER
Fig. 2. The ventricular myocardium is divided into 16 segments from the four echocardiographic views: (A) parastemal long axis; (Bl parastemal short axis; (C) apical four-chamber; and (D) apical two-chamber (note that some segments, e.g. the mid-septum, can be visualized from more than one view). The wall motion of each of the 16 segments is scored as being normal, hypokinetic, akinetic, or dyskinetic. Abnormal wall motion of a regional segment reflects inadequate blood flow through the coronary artery (either left anterior descending (LAD), left circumflex (CFX), or right coronary (RCA) artery) perfusing that particular segment.
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motion opposite to what is expected during systole) or dyskinesis, the system depicts a red color by convention. Abnormal regional wall motion can readily be detected (Fig. 3) and even quantitated [14]. Since color kinesis tracks endocardial motion, it can be misleading when there is significant cardiac translation. 2.5.4. Test termination The test can be terminated for a variety of specific endpoints (Table 4). A test is considered diagnostic if one of two endpoints is achieved: either ischemia is induced or the target heart is attained without ischemia (in our experience, the test is diagnostic in about 85% of cases>. 2.5.5. Adverse reactions Dobutamine stress echocardiography has proven very safe in children. In our experience of nearly 75 patients, only two have experienced side effects requiring test termination (hypertension with headache and ventricular ectopy). Less serious side effects include nausea and vomiting (19% of studies) and dysrhythmias (premature ventricular and atria1 contractions in 9% of studies). 2.4. Proven clinical applications Despite its limitations, investigators have used exercise echocardiography to successfully evaluate regional wall motion in children. For instance, Pahl et al. [ 151 have demonstrated that exercise echocardiography is more sensitive in detecting ischemia in Kawasaki patients than exercise electrocardiography. Pilot data from our group suggest that many Kawasaki patients do not have ischemia despite the presence of aneurysms [16]. Notably, images were interpretable in only 77% of the patients. In our series [12], dobutamine echocardiograms were concordant with coronary arteriography in 94% of children with Kawasaki disease, heart transplants or arterial switch operations. More importantly, in the majority of the patients with both a positive dobutamine echocardiogram and angiogram, the dobutamine echocardiogram was positive before the arteri-
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ogram. These results suggest that dobutamine stress echocardiography may detect disease earlier than coronary arteriography. Likewise Noto et al. [171,have shown a 96% concordance rate between dobutamine stress echocardiography and arteriography in Kawasaki patients. These promising results suggest an alternative approach to the evaluation of coronary artery disease in children. Specifically, a dual approach examining both coronary artery physiology and anatomy is most appropriate. Coronary artery anatomy is best examined by modalities such as resting echocardiogram or coronary arteriography. Coronary artery physiology is best investigated by dobutamine stress echocardiography. This approach can be illustrated in the evaluation of a child with Kawasaki disease. The coronary artery anatomy and the presence of aneurysms can be defined with resting echocardiography. Once the acute illness has subsided, dobutamine stress echocardiography can be used to determine the physiologic significance of aneurysms or other coronary artery lesions if present. In addition, dobutamine stress echocardiography can be used to serially assesscoronary physiology during mid- and long-term follow-up. If a serial evaluation becomes abnormal, then coronary anatomy should be compulsively delineated with coronary arteriography. 3. Stress echocardiograpy in the assessment of noncoronary disease During most of their waking hours children rarely lie supine in a dark room, but usually are very active individuals. Further, symptoms are not always indicative of severity of non-coronary disease. Finally, resting conditions do not define cardiac reserve. Therefore, the underlying principle for employing stress echocardiography in the evaluation of non-coronary disease (Table 5) is that hemodynamic perturbations may be absent or minimal at rest and may become exacerbated and only problematic during exercise or stress, conditions more representative of a child’s typical daily routine. This application of stress echocardiography to noncoronary disease requires obtaining a completely difTable 5
Table 4 Endpoints for dobutamine stress echocardiography in children
Non-coronary diseases in which stress echocardiography is applied
New or worsening wall motion abnormality ST-segment depression 2 2 mm Adverse reaction Angina Attainment of target heart rate Administration of maximal dose (dobutamine: 50 pg/kg/min, atropine:0.01 mg/kg up to 1 mg in 0.25mg aliquouts)
Patients receiving doxorubicin Transplant rejection Coarctation and coarctation repair Mild aortic stenosis Mild pulmonic stenosis Mild hypertrophic cardiomyopathy Dilated cardiomyopathy Pulmonary disease
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ferent set of echocardiographic parameters than in a coronary artery evaluation. Rather than examining regional wall motion, a non-coronary artery evaluation will include indices of global left ventricular function, preload, afterload and contractility; valve gradients; outflow gradients; ventricular pressure estimates; and valve regurgitation severity (Table 6). A powerful example of this application is demonstrated by Klewer et al. [18] who administered dobutamine to oncology patients who had received doxorubicin to unmask left ventricular dysfunction not present at rest. The test can therefore be used to detect sub-clinical dysfunction. A potential application in this regard is to evaluate heart transplant patients for transplant rejection. Currently, cardiac biopsy is the only reliable method of detecting rejection and a non-invasive method to diagnose rejection is lacking. The administration of dobutamine to unmask abnormalities during rejection that are not present at rest is an exciting and promising application. We have used dobutamine stress echocardiography to determine if the severity of various non-coronary artery diseases increases with increasing chronotropy and inotropy. The aim of our protocol changes for these type of evaluations. Instead of aiming for a target heart rate, we administer dobutamine more slowly and deliberately while continuously evaluating disease severity by symptoms and echocardiography. The test is terminated with the development of symptoms or achievement of predefined cutpoints in the echocardiographic indices. Usually it requires only moderate doses of dobutamine to reach one or both of these endpoints. In our experience, dobutamine stress echocardiography is very helpful in evaluating the changes in a mild resting left ventricular outflow tract gradient in children with hypertrophic cardiomyopathy. In this evaluation, in addition to monitoring symptoms, we assessthe left ventricular outflow tract and mitral insufficiency gradients. The latter gradient allows estimation of the peak systolic left ventricular pressure. We have found that, in some instances, the resting gradient in the left ventricular outflow tract Table 6 Stress echocardiographic indices assessedin noncoronary disease Left ventricular function: Shortening fraction Fractional area change Left ventricular preload: Left ventricular end-diastolic dimension Left-ventricular end-diastolic area Left ventricular afterload: end-systolic wall stress f,eft ventricular contractility: stress-velocity relationship Valve gradients Outflow gradients Valve regurgitation severity change
and of the mitral insufficiency can increase markedly and have treated such patients with beta-blockers. Often the clinician needs to know how the severity of a non-coronary disease(e.g. aortic stenosis) changes with exercise specifically. Dobutamine echocardiography can be limited in this type of evaluation because although dobutamine mimics exercise by increasing chronotrophy and inotropy, it does not exactly duplicate the stress of exercise. Further study is needed to determine if hemodynamic changes during dobutamine would also occur during exercise. Therefore, exercise echocardiography may have more use in non-coronary than coronary evaluations. Cyran et al. [19] used exercise Doppler echocardiography to show that following successful coarctation repair in children, exercise hypertension is due to exercise-induced narrowing across the former coarctation site. Looking at a similar group of patients, we have used M-mode exercise echocardiography to demonstrate that exercise hypertension may also be due to an exercise-induced hypercontractile state [20]. The same techniques can be used to ascertain how the gradient across the aortic valve in patients with mild or moderate aortic stenosis and across the left ventricular outflow tract in patients with mild hypertrophic cardiomyopathy behave during exercise. These type of evaluations provide more realistic information on the degree of narrowing during the patient’s waking hours than does the resting echocardiogram. Another application of exercise echocardiography is to evaluate the behavior of the pulmonary artery pressure during exercise. Kaplan et al. [21] used exercise Doppler echocardiography of the tricuspid insufficiency jet in patients with a variety of congenital heart diseasesto measure pulmonary artery pressures. This application of exercise echocardiography will be powerful in patients with lung diseases or patients with heart disease at risk for pulmonary hypertension. 4. Summary Stress echocardiography can be a valuable adjunct to the pediatric echocardiographic examination. Many disease states have minimal or no echocardiographic manifestations at rest, and it is only through the administration of stress that pathology can be identified. Stress echocardiography will be helpful in the field of pediatric cardiology by enabling detection of ischemia associated with coronary artery disease. Since children are rarely sedentary and instead are usually very active, stress echocardiography affords the echocardiographer the opportunity to view the pediatric heart through a more physiologic window.
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SE, Goldberg SJ, Donnerstein RL, Berg RA, Hutter JJ. Dobutamine stress echocardiography: a sensitive indicator of diminished myocardial function in asymptomatic doxorubicin-treated long-term survivors of childhood cancer. J Am Co11 Cardiol 1992;19:394-401. [I91 Cyran SE, Grzeszczak M, Kaufman K et al. Aortic ‘recoarctation’ at rest versus at exercise in children as evaluated by stress Doppler echocardiography after a ‘good’ operative result. Am J Cardiol 1993;71:963-970. BOI Kimball TR, Reynolds JM, Mays WA, Khoury P, Claytor RP, Daniels SR. Persistent hyperdynamic cardiovascular state at rest and during exercise in children after successful repair of coarctation of the aorta. J Am Co11 Cardi 1994;24:194-200. 1211Kaplan JD, Foster E, Redberg RF, Schiller NB. Exercise Doppler echocardiography identifies abnormal hemodynamics in adults with congenital heart disease. Am Heart J 1994;127:1572-1580.