Dobutamine Stress Echo

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Dobutamine Stress Echocardiography Dr Rajdeep S. Khattar DM FRCP FACC FESC Department of Cardiology and Echocardiography Laboratory, Royal Brompton and Harefield NHS Trust, London, UK. Biomedical Research Unit, National Heart and Lung Institute, Imperial College, London, UK.

Contents

Introduction

The treadmill exercise ECG has traditionally been the first line investigation for the diagnostic evaluation of patients with suspected cardiac chest pain. However, in view of its limited diagnostic accuracy and the emergence of more accurate imaging-based techniques, its use in clinical practice is gradually reducing. Moreover, approximately 20-30% of patients are unable to exercise adequately because of limiting co-morbidities such as osteoarthritis, chronic pulmonary disease or peripheral vascular disease. Over the last two decades, a large evidence base has established the use of stress echocardiography in clinical practice. Stress echocardiography may be performed either in conjunction with physiological exercise or with the use of pharmacological stressor agents such as dobutamine or dipyridamole. Dobutamine is an inotropic drug and the most widely used stressor agent for echocardiography based stress testing. Dobutamine stress echocardiography has similar diagnostic accuracies to exercise echocardiography, but provides the additional benefit of being able to investigate those unable to exercise and to assess myocardial viability. Although, the use of this technique may also be indicated for certain valve conditions, this review will be limited to the investigation of coronary artery disease. Rationale for dobutamine stress echocardiography The rationale for stress echocardiography is based on an understanding of the pathophysiology of myocardial ischaemia. An unobstructed coronary artery has the capacity to increase myocardial blood flow at least four-fold to meet myocardial oxygen demand during stress. Although a coronary artery stenosis >50% in diameter may exhibit normal blood flow at rest, during stress the obstruction may not allow an adequate increase in myocardial blood flow to match oxygen demand. This regional flow heterogeneity is the first manifestation of myocardial ischaemia leading on sequentially to diastolic dysfunction, metabolic changes, reduced wall motion or thickening and later to electrocardiographic changes and the development of chest pain (Figure 1) (ref 1). The purpose of combining echocardiography with physical or pharmacological stress is to detect changes in regional wall thickening during stress compared to rest. In the presence of unobstructed coronary arteries and normal myocardial function, increasing levels of stress lead to a progressive increase in wall thickening and contraction. However, in the presence of a flow-limiting coronary stenosis, stress-induced myocardial ischaemia leads to a reduction in wall thickening compared to rest. The sub-endocardial layer of the myocardium contributes most to the endocardial thickening seen on echocardiography and it is this area that is most susceptible to myocardial ishaemia (ref 2). The sub-epicardial layer is only involved at the later stages if ischaemia is prolonged. The early reductions in regional perfusion and wall thickening and late onset of ECG changes in the ischaemic cascade, in part explain the superior accuracy of imaging techniques such as myocardial perfusion imaging and stress echocardiography over the exercise ECG. Dobutamine is the most widely used stressor agent and acts by stimulating alpha-1, beta-1 and beta-2 adrenoceptors (ref 3). This leads to an increase in heart rate, blood pressure and inotropic activity, thereby increasing myocardial oxygen demand.

Technique

The use of a pharmacological approach to stress testing has the advantage of being able to offer a diagnostic test in those unable to exercise. In conjunction with echocardiography, pharmacological stress testing avoids the challenges posed by exercise such as hyperventilation and excessive chest wall movement immediately post-exercise. Moreover, compared to treadmill exercise echocardiography, the stress images can be obtained more leisurely at a controlled peak heart rate. A screening echocardiogram should be performed at the start of the test, primarily to exclude any significant cardiac structural abnormalities that might provide an alternative explanation for the presenting symptoms or preclude stress testing. Dobutamine stress echocardiography is performed using a weight-adjusted incremental intravenous dobutamine infusion. An intravenous cannula is inserted into an arm vein and the patient is attached to a sphygmomanometer and cardiac monitor for monitoring of heart rate, blood pressure and cardiac rhythm. Echocardiography is performed with harmonic imaging and if necessary, intravenous contrast ultrasound agents are administered to enhance endocardial definition. The images acquired consist of the parasternal long and short axis views and apical 4-, 2- and 3-chamber views. Resting images are acquired and if wall motion is normal, the dobutamine infusion is started at a dose of 10mcg/kg/min increasing to 20mcg/kg/min, 30mcg/kg/min and finally 40mcg/kg/min every 3 minutes. Endpoints of the test include achievement of 85% of the age-predicted heart rate, development of cardiac symptoms and associated regional wall motion abnormality, arrhythmias and intolerable side-effects to dobutamine. Intravenous atropine up to a dose of 0.6 mg may be given to achieve target heart rate if the maximal dose of dobutamine proves to be inadequate. Further echocardiographic images are taken at mid-dose of dobutamine and at peak stress. On rare occasions, short-acting intravenous beta-blockade may be administered to reverse the effects of doutamine. If the resting echocardiogram shows regional wall motion abnormality, a low-dose dobutamine protocol should be used to assess myocardial viability in this region. Under these circumstances, dobutamine is started at a dose of 5 mcg/kg/min increasing at 5 minute intervals to 10mcg/kg/min and if necessary to 15 mcg/kg/min, before resuming the standard protocol to a maximal dose of 40mcg/kg/min. An additional echocardiogram is acquired at 10-15 mcg/kg/min of dobutamine, ensuring that the heart rate has not gone up more than 10-20 beats/min from baseline. All images are acquired digitally on a quad screen display for side-by-side comparison of equivalent views at each stage of the test.

Analysis

Image interpretation remains qualitative rather than quantitative and therefore requires appropriate training and hands-on experience in both performing and reporting stress echo examinations. Visual assessment is based on analysis of myocardial thickening rather than motion which may be influenced by pushing and pulling forces. Each image should be assessed for its quality and potential technical limitations e.g. it should be noted whether equivalent imaging planes have been acquired at each stage of the stress protocol and that ventricular ectopic beats have been excluded from the analysis. Table 1 summarizes the stress-induced changes in wall thickening that define myocardial ischaemia, viability and infarction. Analysis and scoring of the study are usually performed using a 16 or 17 segment model of the left ventricle and a four grade scale of wall motion analysis of each segment (Figure 2). This allows an assessment of not only whether the test is normal or abnormal but also describes the location, extent and severity of the abnormalities detected. The ischaemic threshold may also be assessed by determining the haemodynamic workload at which stress-induced regional wall thickening abnormalities were detected.

Indications

Stress echocardiography per se is indicated in patients with an intermediate pre-test probability of coronary artery disease, an abnormal resting ECG (ST/T wave changes, LBBB), an inconclusive exercise ECG because of equivocal ST changes, suspicion of a false positive exercise ECG and functional assessment of an equivocal coronary artery stenosis. These patients may undergo exercise echocardiography whereas dobutamine stress echocardiography is usually reserved for those unable to exercise, those with a non-diagnostic exercise ECG because of failure to exercise adequately, or for the assessment of myocardial viability. Dobutamine stress echocardiography may also be preferred over exercise in those with technically challenging echocardiographic images at rest to maximize the chances of obtaining diagnostic images at peak stress. Stress echocardiography may also be indicated for prognostic evaluation and pre-operative risk assessment.

Contra-indications

A poor acoustic window, despite the use of ultrasound contrast agents, makes any form of stress echocardiography unfeasible. In addition, dobutamine may be contra-indicated in patients with a history of ventricular arrhythmias or severe hypertension. Safety and feasibility Advances in imaging technology, in particular the introduction of harmonic imaging and use of intravenous ultrasound contrast agents (ref 4), have significantly improved endocardial definition . Accordingly, stress echocardiography is now feasible in over 95% of patients referred for the test (ref 5). The use of dobutamine is associated with side-effects such as headache, tremor, palpitations and anxiety, but with appropriate counselling and reassurance these are adequately well tolerated and do not usually require test termination. A minority of patients develop a reflex vagal response to dobutamine leading to hypotension and relative heart rate reduction. Nevertheless, in about 5% of patients either the test is terminated prematurely because of adverse effects or the heart rate response is inadequate to obtain a diagnostic result. Moreover, every test carries a definite, albeit minor risk and exercise is generally safer than pharmacological stress. For dobutamine stress echocardiography, ventricular arrhythmias, prolonged ischaemia and myocardial infarction have a reported incidence of about 1 in 1,000 with an incidence of death of 1 in 5,000 (ref 6). Supervision by highly experienced personnel who perform stress echocardiography and are very familiar with the use of dobutamine serves to minimize any hazards associated with the test.

Diagnostic accuracy

Both exercise and dobutamine stress echocardiography have similar sensitivities and specificities for the detection of coronary artery disease and are superior to the treadmill exercise ECG (Figure 3) (ref 7). A number of studies of dobutamine stress echocardiography have shown sensitivities, specificities and overall diagnostic accuracies approximating to 80-90%. However, these figures are dependent on the prevalence and severity of disease in the patient population studied. Sensitivities for the detection of coronary artery disease are lower in those with single vessel disease compared to those with multivessel disease. Although patients with multivessel disease are more likely to have a positive test, the presence of multivessel ischaemia is only detected in about 50% of these patients. Other factors that affect diagnostic accuracy include the adequacy of stress and echocardiographic image quality. The normalcy rate of dobutamine stress echocardiography is approximately 90-95%. It should be borne in mind that coronary angiography, an anatomical investigation, is an imperfect gold standard for evaluating the diagnostic performance of a functional test for ischaemia. Stress echocardiography is not only more accurate than the exercise ECG for the detection of coronary artery disease, but is also far superior at identifying the location, extent and severity of ischaemia.

Prognostic value

Dobutamine stress echocardiography offers important prognostic information in a variety of patient groups including chronic stable angina, following myocardial infarction, left ventricular dysfunction and major non-cardiac surgery. A normal stress echocardiogram yields an annual event rate of <1% and therefore obviates the need for coronary angiography (ref 8). Irrespective of the findings of stress echocardiography, the risk increases in those with advanced age and conditions associated with accelerated atherosclerosis such as diabetes and chronic renal disease. A positive stress echocardiogram carries a >10% risk of events over subsequent years and certain stress echo parameters help to further risk stratify patients by providing incremental prognostic information over and above clinical data. These include resting ejection fraction, the ischaemic threshold and the location, extent and severity of stress-induced wall motion abnormality. In patients undergoing major non-cardiac surgery, stress echocardiography is recommended in patients with an estimated cardiac risk >5% undergoing a high risk elective surgical procedure (ref 9). Coronary angiography and revascularization prior to non-cardiac surgery is generally not advocated, but may be considered on an individual basis in those with results suggestive of widespread multivessel ischaemia. In those with less severe ischaemia, cardioprotection with beta-blockers and statins may be recommended. A negative test is associated with a very low incidence of cardiac events and usually permits a safe operation. Ischaemia testing is not recommended in low or intermediate risk patients.

Assessment of myocardial viability

Myocardial walls which are akinetic at rest may either be completely infarcted and therefore irreversibly damaged or be in a state of stunning or hibernation. Myocardial stunning tends to occur following an episode of acute coronary occlusion followed by rapid resumption of normal coronary and myocardial blood flow as in patients who undergo early successful recanalization of an infarct-related artery following thrombolysis or percutaneous coronary intervention. Myocardial contractile function to this territory tends to return within a few days or weeks. Hibernating myocardium refers to chronically dysfunctional myocardium which has the ability to regain contractile function following revascularization. It tends to result from a state of chronic low blood flow (enough to sustain viability) to the affected myocardium and associated repetitive stunning. Dobutamine stress echocardiography is the most widely used method for assessing myocardial viability. The varying patterns of contractile response to dobutamine of the akinetic myocardial region help to differentiate between infarcted, stunned and hibernating myocardium (ref 10). When dobutamine is given at a low dose of between 5-15 mcg/kg/min an inotropic effect is evoked with only a small increase in heart rate. In areas of myocardial viability (stunned or hibernating myocardium), contractile proteins are recruited and wall thickening is observed on echocardiography. When dobutamine is then gradually increased to higher doses the increase in myocardial oxygen consumption may provoke ischaemia in hibernating myocardium, leading to severe hypokinesia or akinesia. This is known as the biphasic response and is the best predictor of recovery of left ventricular function following revascularisation. In stunned myocardium, higher doses of dobutamine lead to further augmentation of contractile function in the previously akinetic area and therefore do not demonstrate a biphasic response. Truly infarcted myocardium fails to show any improvement in contractile function at low dose dobutamine and remains akinetic throughout the entire test. The prediction of myocardial viability is based on the recovery of regional left ventricular function following coronary revascularization. The sensitivities and specificities of dobutamine stress echocardiography for the detection of myocardial viability are approximately 80-85%, respectively. Retrospective data from a number of studies suggest that in patients with coronary artery disease and resting left ventricular dysfunction, the demonstration of significant myocardial viability (>25% of the myocardium) is associated with better outcomes if treated with coronary revascularisation rather than medical therapy. Conversely, patients who do not have evidence of significant myocardial viability do not seem to derive any prognostic benefit from revascularization, even though many of these patients may have multivessel disease and poor left ventricular function.

Comparison with alternative imaging techniques

Perfusion scintigraphy is a long established technique for ischaemia testing and is the main diagnostic alternative to stress echocardiography. The overall diagnostic accuracies and prognostic value of the two techniques are similar; there is a non-significant trend towards higher sensitivity with perfusion scintigraphy, but higher specificity with stress echocardiography. The two techniques have broadly similar clinical applications and the choice as to which test is used depends mainly on local availability and expertise. Although stress echocardiography is operator dependent and more subjective, it has the benefits of lower cost, widely available equipment, truly bedside nature and no exposure to radio-activity. Moreover, it has the major advantage of excluding other causes of cardiac symptoms such as valvular disease, cardiomyopathies, pericardial disease and congenital heart defects. Cardiac magnetic resonance imaging allows the assessment of myocardial perfusion or wall motion with good accuracy. The advantages of the technique are related to high image quality and the absence of ionising radiation. However, the high costs, lengthy image acquisition and low availability makes CMR a good option only when stress echo is non-diagnostic or not feasible. CT coronary angiography and coronary calcification scoring is the latest technique to enter the field of cardiac imaging. It has the inherent limitations of radiation exposure and more fundamentally provides anatomical rather than functional information. Nevertheless, consistent with the other competing techniques, its use has been advocated in patients with an intermediate pre-test probability of coronary artery disease. New technologies Training

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