Pharmacologic Stress Testing

Exercise testing is a cardiovascular stress test using treadmill bicycle exercise with ECG and blood pressure monitoring. Pharmacologic stress testing, established after exercise testing, is a diagnostic procedure in which cardiovascular stress induced by pharmacologic agents is demonstrated in patients with decreased functional capacity or in patients who cannot exercise.[1] Pharmacologic stress testing is used in combination with imaging modalities such as radionuclide imaging and echocardiography.

Radionuclide uptake and ECG images are depicted below:

Adenosine, dipyridamole (Persantine), and dobutamine are the most widely available pharmacologic agents for stress testing. Regadenoson, an adenosine analog, has a longer half-life than adenosine, and therefore a bolus versus continuous administration.

Adenosine, dipyridamole, and regadenosine are cardiac vasodilators. They dilate coronary vessels, which causes increased blood velocity and flow rate in normal vessels and less of a response in stenotic vessels. This difference in response leads to a steal of flow, and perfusion defects appear in cardiac nuclear scans or as ST-segment changes.

Dobutamine is a cardiac inotrope and chronotrope. The heart responds to dobutamine similarly to the way it responds to exercise.

Adenosine

Adenosine is a naturally occurring substance found throughout the body in various tissues. It functions to regulate blood flow in many vascular beds, including the myocardium. The mechanisms by which adenosine is produced intracellularly are the S -adenosyl homocysteine and the adenosine triphosphate pathways; the latter plays a role during ischemia.

Once transported across cell membranes, adenosine interacts and activates the A1 and A2 cell surface receptors. In the vascular smooth muscles, adenosine primarily acts by activation of the A2 receptor, which stimulates adenylate cyclase, leading to an increase in cyclic adenosine monophosphate (cAMP) production. Increased cAMP levels inhibit calcium uptake by the sarcolemma, causing smooth muscle relaxation and vasodilation. Activation of the vascular A1 receptor also occurs, which stimulates guanylate cyclase, inducing cyclic guanosine monophosphate production, leading to vasodilation.

This direct coronary artery vasodilation induced by adenosine is attenuated in diseased coronary arteries, which have a reduced coronary flow reserve and cannot further dilate in response to adenosine. This is not the case in healthy or less-diseased coronary arteries in the same patient, which produces relative flow heterogeneity throughout the coronary arteries, resulting in relatively more coronary blood flow in the healthy or less-diseased coronary arteries compared with the more-diseased coronary artery. In most cases, coronary blood flow in the diseased coronary arteries does not decrease.

In cases of severe vessel stenosis or total occlusions with compensatory collateral circulation, a decrease in coronary blood flow may occur in the diseased coronary artery, thus inducing ischemia via a coronary steal phenomenon. This regional flow abnormality also induces a perfusion defect during radionuclide imaging.

Dipyridamole (Persantine)

Dipyridamole is an indirect coronary vasodilator that works by increasing intravascular adenosine levels. This occurs by the inhibition of intracellular reuptake and deamination of adenosine. However, the increase in coronary blood flow induced by dipyridamole is less predictable than that of adenosine.

In one comparative study of dipyridamole and adenosine, 66% of patients (10 of 15) receiving dipyridamole versus 80% of patients (12 of 15) receiving adenosine had a maximal hyperemic response. However, this difference may not be apparent clinically. The mechanism of inducing a perfusion abnormality is similar to that of adenosine (see adenosine discussion above) except true coronary steal occurs more frequently.

Dobutamine

Dobutamine is a synthetic catecholamine, which directly stimulates both beta-1 and beta-2 receptors. A dose-related increase in heart rate, blood pressure, and myocardial contractility occurs.

As with physical exertion, dobutamine increases regional myocardial blood flow based on physiological principles of coronary flow reserve. A similar dose-related increase in subepicardial and subendocardial blood flow occurs within vascular beds supplied by significantly stenosed arteries, with most of the increase occurring within the subepicardium rather than the subendocardium. Thus, perfusion abnormalities are induced by the development of regional myocardial ischemia.

Hyperemic impedance echocardiography (HIE) may have the potential to detect inducible myocardial ischemia for patients in whom exercise or pharmacologic stress testing is contraindicated or not tolerated. In a pilot study involving 20 consecutive outpatients with suspected stable coronary artery disease who underwent clinically indicated dobutamine stress echocardiography (DSE) and then HIE, HIE was 86% sensitive and 67% specific in identifying inducible myocardial ischemia as evaluated by regional wall motion abnormalities, as well as 83% sensitive for detecting significant CAD (≥50% diameter stenosis) on coronary angiography.[2]

Regadenoson (Lexiscan)

Regadenoson is a pharmacologic stress agent approved by the FDA in 2008 as an additional agent for use in stress testing for patients unable to perform the standard exercise stress test.[3, 4]

Regadenoson produces maximal hyperemia quickly and maintains it for an optimal duration that is practical for radionuclide myocardial perfusion imaging. Regadenoson's simple rapid bolus administration and short duration of hyperemic effect point to an advantage of enhanced control for the clinician.

Regadenoson is an agonist with low affinity (Ki ≈ 1.3 μM) for the A2A adenosine receptor, and at least a 10-fold lower affinity for the A1 adenosine receptor (Ki > 16.5 μM). In addition, it has relatively weak affinity for the A2B and A3 adenosine receptors.

Coronary vasodilation and an increase in coronary blood flow (CBF) results from activation of the A2A adenosine receptor by regadenoson.

Enoximone stress echocardiography

Dobutamine stress echocardiography is frequently used to assess myocardial viability; however, the inotropic response to adrenergic stimulation may be reduced in patients receiving a beta-blocker. In addition, dobutamine may sometimes induce ischemia in patients with a critical coronary stenosis, which might mask hibernation by preventing the improvement in wall motion.

Another approach is the use of an imidazole phosphodiesterase inhibitor such as enoximone or milrinone, drugs that are relatively unaffected by concurrent use of a beta-blocker and are used for inotropic support in congestive heart failure.

Enoximone stress echocardiography as an additional stress testing modality was evaluated in one study of 45 patients with chronic coronary artery disease and left ventricular dysfunction who underwent echocardiography with both dobutamine and enoximone.

Both increased heart rate, but enoximone did not cause a significant change in systolic blood pressure. The positive predictive value and specificity were similar between enoximone and dobutamine. Concordant results were seen in 85% of affected segments, but enoximone had a higher sensitivity (88% vs 79% for dobutamine) and negative predictive value (90% vs 84%) in predicting functional recovery after revascularization.

At this time, enoximone is not approved for use in the United States; however, the pharmacology of milrinone is very similar, and this agent could be considered for use as a pharmacologic stress agent in selected patients on beta-blockers. Further investigations will be required to validate this approach.

Arm exercise as a potential alternative to pharmacologic stress testing

Arm exercise may have the potential to be an effective and low-cost alternative to pharmacologic stress testing.[5] In a 6-year study (1997-2002) with 12 years of follow-up in 446 veterans aged 64 years with lower-extremity disabilities, Martin et al used ergometer stress tests to evaluate exercise variables in predicting long-term all-cause mortality, myocardial infarction, or coronary revascularization. None of the exercise variables predicted myocardial infarction, but factors predictive of 12-year all-cause death included arm exercise capacity, heart rate recovery, and delta heart rate, whereas factors predictive of coronary revascularization included stress-induced ST-segment deviations, limiting angina, and an abnormal perfusion imaging finding.[5]

The American College of Cardiology Foundation (ACCF) appropriateness utilization criteria (AUC) provide guidelines for appropriate testing. Pharmacologic stress testing is generally instituted when contraindications to routine exercise stress exist or when the patient is unable to exercise because of debilitating conditions in various forms. These include the following general indications:

• Elderly patients with decreased functional capacity and possible CAD

• Patients with chronic debilitation and possible CAD

• Younger patients with functional impairment due to injury, arthritis, orthopedic problems, peripheral neuropathy, myopathies, or peripheral vascular disease, in which a maximal heart rate is not easily achieved with routine exercise stress testing, usually because of an early onset of fatigue due to musculoskeletal, neurologic, or vascular problems rather than cardiac ischemia

• Other cases, including patients taking beta-blockers or other negative chronotropic agents that would inhibit the ability to achieve an adequate heart response to exercise

Indications for specific pharmacologic agents are as follows:

Adenosine

Any physical limitation that prevents a patient from exercising maximally is an indication for vasodilator stress testing.

Patients taking beta-blockers or other negative chronotropic agents that would inhibit the ability to achieve an adequate heart rate response to exercise are also appropriate candidates for vasodilator stress.

Patients with left bundle branch block or ventricular pacemaker (particularly those with severely diseased AV nodes or status post-AV node ablation who are unable to override their ventricular pacing rate) should undergo pharmacologic vasodilator stress because exercise stress often produces a false-positive perfusion defect in the interventricular septum.

These defects are probably related to decreased septal contractility, which is accompanied by an autoregulated fall in coronary blood flow to the interventricular septum. Exercise stress or any other cause of tachycardia tends to enhance this heterogeneous perfusion by increasing the flow proportionately more in the normally contracting myocardium, resulting in a falsely underperfused interventricular septum on perfusion imaging. Vasodilator stress has been shown to overcome this coronary blood flow autoregulation, resulting in a more homogeneous perfusion pattern.

Dipyridamole (Persantine)

Any physical limitation that prevents a patient from exercising maximally is an indication for vasodilator stress.

Patients taking beta-blockers or other negative chronotropic agents that would inhibit the ability to achieve an adequate heart rate response to exercise are also appropriate candidates for vasodilator stress.

Patients with left bundle branch block or a ventricular pacemaker (particularly those with severely diseased AV nodes or status post-AV node ablation who are unable to override their ventricular pacing rate) should undergo vasodilator stress, because exercise stress often produces a false-positive perfusion defect in the interventricular septum. These defects are probably related to decreased septal contractility, which is accompanied by an autoregulated decrease in coronary blood flow to the interventricular septum. Exercise stress or any other cause of tachycardia tends to enhance this heterogeneous perfusion by increasing the flow proportionately more in the normally contracting myocardium, resulting in a falsely underperfused interventricular septum with perfusion imaging. Vasodilator stress has been shown to overcome this coronary blood flow autoregulation, resulting in a more homogeneous perfusion pattern.

Note that a case of ST-elevation myocardial infarction has been reported in a patient with Wellens syndrome following dypyridamole stress testing.[6]

Dobutamine

Consider dobutamine as a second-line pharmacologic stressor to be used in patients who cannot perform exercise stress and have a contraindication to vasodilator stress.

Regadenoson (Lexiscan)

Regadenoson injection is indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress testing due to body habitus or other comorbidities as outlined in contraindications for exercise stress testing in Medscape Drugs & Diseases article Treadmill Stress Testing.

Current AUC guidelines do not recommend routine testing within 2 years for patients who have undergone coronary revascularization procedures. However, one study has shown that 12% of these patients who visit their physician at least 3 months after the procedure undergo stress echocardiography testing within 30 days of the visit. The study shows discretionary stress testing is performed more frequently by physicians who bill for technical and professional fees compared to physicians who do not bill for these services, possibly as a way to recoup upfront costs for imaging equipment.[3]

Specific pharmacologic agents have specific contraindications, as follows:

Adenosine

Absolute contraindications include the following:

• Patients with active bronchospasm or patients being treated for reactive airway disease should not be administered adenosine because this can lead to prolonged bronchospasm, which can be difficult to treat or can remain refractory.

• Patients with more than first-degree heart block (without a ventricular-demand pacemaker) should not undergo adenosine infusion because this may lead to worsening of the heart block. While this is usually transient, due to the extremely short half-life of adenosine (approximately 6 s), cases of prolonged heart block (and asystole) have been reported.

• Patients with an SBP less than 90 mm Hg should not undergo adenosine stress testing because of the potential for further lowering of the blood pressure.

• Patients using dipyridamole or methylxanthines (eg, caffeine and aminophylline) should not undergo an adenosine stress test because these substances act as competitive inhibitors of adenosine at the receptor level, potentially decreasing or completely attenuating the vasodilatory effect of adenosine. In general, patients should refrain from ingesting caffeine for at least 24 hours prior to adenosine administration. Patients should avoid decaffeinated products, which typically contain some caffeine, as opposed to caffeine-free products, which do not.

Relative contraindications include the following:

• Patients with a remote history of reactive airway disease (COPD/asthma) that has been quiescent for a long time (approximately 1 y) may be candidates for adenosine. However, if a question exists concerning the status of the patients' airway disease, a dobutamine stress test may be the safer choice.

• Patients with a history of sick sinus syndrome (without a ventricular-demand pacemaker) should undergo adenosine stress testing with caution. These patients are prone to significant bradycardia with adenosine; therefore, use caution if they are to undergo adenosine stress. Similarly, those patients with severe bradycardia (heart rate of 40 bpm) should undergo adenosine stress with caution.

Dipyridamole (Persantine)

Absolute contraindications include the following:

• Patients with active bronchospasm or patients being treated for reactive airway disease should not be administered dipyridamole because this can lead to prolonged bronchospasm, which can be difficult to treat or can remain refractory.

• Patients with more than first-degree heart block (without a ventricular demand pacemaker) should not undergo dipyridamole infusion because this may lead to worsening of the heart block.

• Patients with an SBP of less than 90 mm Hg should not undergo dipyridamole stress testing because of the potential for further lowering of the blood pressure.

• Patients using methylxanthines (eg, caffeine, aminophylline) should not undergo dipyridamole stress testing because these substances act as competitive inhibitors of dipyridamole at the receptor level, potentially decreasing or completely attenuating the vasodilatory effect of dipyridamole. In general, patients should refrain from ingesting caffeine for at least 24 hours prior to dipyridamole administration. Patients should avoid decaffeinated products, which typically contain some caffeine, as opposed to caffeine-free products, which do not.

Relative contraindications include the following:

• Patients with a remote history of reactive airway disease (COPD/asthma) that has been quiescent for a long time (approximately 1 y) may be candidates for dipyridamole. However, if a question exists concerning the status of the patients' airway disease, dobutamine stress testing may be the safer choice.

• Patients with a history of sick sinus syndrome (without a ventricular demand pacemaker) should undergo dipyridamole stress testing with caution. These patients are prone to significant bradycardia with dipyridamole; therefore, use caution if they are to undergo dipyridamole stress. Similarly, those patients with severe bradycardia (heart rate 40 bpm) should undergo dipyridamole stress with caution.

Dobutamine

Patients with recent (1 wk) myocardial infarction; unstable angina; significant aortic stenosis or obstructive cardiomyopathy; atrial tachyarrhythmias with uncontrolled ventricular response; history of ventricular tachycardia, uncontrolled hypertension, or thoracic aortic aneurysm; or left bundle branch block should not undergo dobutamine stress testing.

Regadenoson (Lexiscan)

Regadenoson should not be administered to patients with second-degree atrioventricular block or sinus node dysfunction, unless these patients have a functioning artificial pacemaker.

Due to the increased risk for a fatal myocardial infarction, the FDA issued a warning in November 2013 that the imaging agents regadenoson (Lexiscan) and adenosine (Adenoscan) should not be used for cardiac nuclear stress tests in patients with signs or symptoms of unstable angina or cardiovascular instability.[7, 8]

The FDA has received reports of 26 myocardial infarctions and 29 deaths after the administration of regadenoson since its approval in 2008. Six myocardial infarctions and 27 deaths have been reported with adenosine.[7, 8]

Best Practices

Review the patient's medication and caffeine intake.

Theophylline can reduce ischemic changes on the ECG with vasodilator stress testing.

Caffeine has been reported to reduce ischemic changes on ECG with vasodilator stress testing. However, one study demonstrated that one cup of coffee, one hour prior to stress testing did not attenuate the results of adenosine nuclear imaging.[9]

Calcium channel blockers, beta-blockers, and nitrates can also alter perfusion defects on pharmacologic stress tests and therefore ideally should be withheld for 24 hours prior to pharmacologic stress testing.

Dipyridamole and adenosine can lead to bronchospasm; they are generally avoided in patients with severe reactive airway disease or active wheezing. Dobutamine is safe to use in these patients.

Instruct patients with diabetes regarding insulin requirements.

Complication Prevention

The American College of Cardiology/American Heart Association Clinical Competence Statement on Stress Testing emphasizes the importance of knowledge of possible complications and rates of complications for particular agents for patients and those supervising stress tests. The following guidelines are of particular importance:

• Avoid contraindications.

• Do not exceed standard dosages.

• Perform tests only after informed consent has been obtained.

• Ensure an attending physician is present.

• Retain outpatients for 60 minutes after testing.

• Ensure indications for testing are met.

Stress testing does not successfully identify all high-risk patients.

The table below depicts findings and results for stress testing.

Table 1. Findings and Likely Associated Results (Open Table in a new window)

Potential findings are illustrated in the images below:

Patient Instructions

Provide patients with the following instructions:

• Do not eat, drink anything other than water, or smoke for 3 hours prior to the test.

• Do not consume anything with caffeine, including products that say “decaffeinated or “caffeine free,” after midnight the night before the test.

• Wear comfortable clothing.

• Bring a list of all current medications, along with times and dosages. (Before the test, consider each patient’s medications and withdraw those that will interfere with results prior to test if possible.)

• Avoid strenuous activities (eg, jogging, running) before the appointment.

Elements of Informed Consent

Patients are exposed to small amounts of radiation, and risks, while minimal, should be discussed.

Patients should be instructed regarding complications and complication rates for the relevant pharmacologic stress testing agents.

IV pharmacologic stress testing requires a controlled delivery infusion pump.

A sphygmomanometer is used to record baseline blood pressure and repeat blood pressures during the test.­­

A 12-lead echocardiogram (ECG) is used for continuous monitoring.

Radioiodinated tracers are used to document stress testing results. Radioiodine (123I)-labeled agents are used to evaluate blood flow to the heart and left ventricular function.

Myocardial perfusion imaging (MPI) offers a method of visualizing blood flow to the heart by injection of a radioactive cardiac-specific tracer. This improves the diagnostic accuracy of a cardiovascular stress test by providing another method of detecting perfusion defects aside from measuring ST depression on the ECG. MPI offers the additional advantage of estimating left ventricular function.

Anesthesia

Anesthesia is not used in pharmacologic stress testing.

Positioning

Some centers prefer to use pharmacologic stress testing in conjunction with echocardiogram, MRI, or CT scanning because it avoids repositioning the patient, which may be necessary during nuclear imaging. Repositioning the patient may cause a false-positive pharmacologic stress test result because of different degrees of attenuation of myocardial tissue imaging with changes in the breast positions, as seen in women.

Continue monitoring (both electrocardiographically and hemodynamically) for at least 4 minutes after the effects of the pharmacologic stress testing agent have resolved.

Patients typically have no activity restrictions after the test.

Instruct breastfeeding women regarding when breastfeeding can be resumed, depending on the specific agent used.

Other follow-up may be required based on the results of the stress test or other related conditions.

Specific pharmacologic agents have specific adverse effects, as follows:

Adenosine

Approximately 80% of patients experience minor adverse effects from adenosine infusion. However, an absence of these effects does not imply a lack of efficacy of the adenosine with respect to coronary vasodilation. The chest pain experienced during adenosine infusion is very nonspecific and does not indicate the presence of CAD. However, approximately a third of patients with ischemia after perfusion imaging have ST-segment depression during the infusion of adenosine.

Three categories of adverse effects exist, including systemic effects (dizziness [7%], headache [21%], symptomatic hypotension [3%], dyspnea [19%], and flushing [35%]), gastrointestinal effects (nausea [5.1%]), and cardiac effects (chest pain [34%] and ST-segment changes [13%]).

Dipyridamole (Persantine)

The adverse effects experienced are similar to those with use of adenosine. While adverse effects are less frequent with dipyridamole (47% of patients), they tend to be more serious than those associated with adenosine.

The most common adverse effects of dipyridamole are chest pain (19%), headache (12%), and hypotension (4.6%). In addition, 12% of patients require aminophylline for reversal of adverse effects.

Dobutamine

Adverse effects occur in approximately 75% of patients undergoing dobutamine stress testing. Effects include ST changes (50%), chest pain (31%), palpitations (29%), and significant supraventricular or ventricular arrhythmias (8-10%).

Regadenoson (Lexiscan)

During clinical development, of 1,337 patients in whom Lexiscan was administered, adverse effects occurred in 80% as follows: dyspnea (28%), headache (26%), flushing (16%), chest discomfort (13%), angina pectoris or ST-segment depression (12%), dizziness (8%), chest pain (7%), nausea (6%), abdominal discomfort (5%), dysgeusia (5%), feeling hot (5%).

In pharmacologic stress testing, the patient reclines while the pharmacologic agent is injected through an IV line. A nuclear tracer is injected through the IV. Blood pressure, heart rate, and ECG are monitored before, during, and after the test, and imaging is obtained at specified times.

Additional imaging may be considered. Software fusion of coronary computed tomography angiography (CCTA) and single photon emission computed tomography (SPECT) images allows for a comprehensive, noninvasive assessment of coronary artery disease (CAD). According to a study by Pazhenkottil et al, hybrid SPECT/CCTA images have a demonstrated synergistic prognostic value. The annual rate of death/myocardial infarction among patients who underwent hybrid imaging was 6%, 2.8%, and 1.3% for patients with matched, unmatched, and normal defect findings, respectively.[4] Stress imaging by MRI with strain encoding improves predictive accuracy of coronary events and stenoses at catheterization even further. In a 28-month follow up, MRI with strain encoding improved sensitivity from 84% to 96% (p< 0.001) with an insignificant drop in specificity (88% vs. 94%).[10] Various pharmacologic agents are used for cardiovascular stress testing and are usually used in combination with radionuclideisotopesthataretakenupby the myocardium during routine testing. The common ones are discussed below.

Dosing and practical considerations

The use of adenosine requires an infusion pump that delivers the dose (140 mcg/kg/min) over a 6-minute period. The patient should have an intravenous line with a 3-way stopcock or should have 2 intravenous lines. If one intravenous line is used, take care to inject the radiopharmaceutical slowly because a bolus or any forceful injection will cause an abrupt increase in the infusion rate of the adenosine running through the same line. This can lead to significant AV nodal block. ECG monitoring of the vital signs is necessary as with exercise stress testing.

Adenosine is infused at a rate of 140 mcg/kg/min for 6 minutes. At the 3-minute mark, the stress radiopharmaceutical is injected and the infusion is continued for 3 more minutes. Some have suggested that patients determined to be at high risk for complications (eg, questionable history of asthma, hypotension, recent ischemic event, severe bradycardia) should undergo an incremental 7-minute adenosine protocol. This protocol starts at 50 mcg/kg/min and increases to 75, 100, and 140 mcg/kg/min at 1-minute intervals followed by injection of the stress radiopharmaceutical at 1 minute after the highest tolerated dose.

The test continues for 3 minutes following injection of the radiopharmaceutical. Unlike dipyridamole, the effect of adenosine dissipates promptly with discontinuation of the infusion. Thus, the infusion must continue during stress imaging until the imaging is completed, whereas for dipyridamole, imaging may follow but in a limited time window. For a stress/rest protocol, adenosine does not require reversal, whereas dipyridamole requires theophylline administration to assure prompt reversal of its stress effects.

Early termination indications

Early termination indications include the following:

• Severe hypotension (SBP < 90 mm Hg)

• Symptomatic Mobitz-I second-degree heart block

• Mobitz-II or third-degree heart block

• Bronchospasm

• Severe chest pain associated with ECG changes (>2 mm ST depression or any ST elevation in a non–Q-wave lead): In most cases, discontinuation of the adenosine infusion is followed by a prompt (< 1 min) resolution or improvement of the adverse effect. In rare cases, aminophylline may be required.

Adenosine-walk protocol

For patients who are able, combined low-level treadmill exercise during adenosine infusion has been demonstrated in several reports to be associated with a significant decrease in the frequency of adverse effects (eg, flushing, nausea, headache). In addition, less-symptomatic hypotension and bradycardia occur. These studies have also uniformly reported improved image quality, as demonstrated by an increased target-to-background ratio.

An additional advantage is that simultaneous low-level exercise allows for immediate imaging, as would be performed with exercise stress testing. This is due to the peripheral vasodilation and splanchnic vasoconstriction induced by exercise.

Dosing and practical considerations

The standard dose of dipyridamole 0.56 mg/kg infused over 4 minutes.

Dipyridamole should be infused via an infusion pump over 4 minutes. However, some choose to infuse the dipyridamole by hand, which is also acceptable. The radiopharmaceutical is then injected 3-5 minutes following the completion of the dipyridamole infusion.

Perform a standard ECG and monitoring of the vital signs as with exercise stress testing until the hemodynamic effects of dipyridamole have resolved.

Dipyridamole-walk protocol

The protocol is similar to that of adenosine; however, the treadmill portion does not begin until 1 minute prior to the injection of the radiopharmaceutical (after completion of the infusion of dipyridamole) and should be continued for at least 2 minutes after the injection of the radiopharmaceutical.

Dosing and practical considerations

Dobutamine is infused in incremental doses starting at 5 mcg/kg/min for 3 minutes. Then, 10, 20, 30, and 40 mcg/kg/min are administered until the stress end point is reached. The end points are similar to those of exercise stress testing (eg, target heart rate, chest pain with ECG changes, hypotension).

Dobutamine must be infused using an infusion pump. The patient should have an intravenous line with a 3-way stopcock or should have 2 intravenous lines. If 1 intravenous line is used, take care to infuse the radiopharmaceutical slowly because a bolus or forceful injection will cause an abrupt increase in the infusion rate of the dobutamine running through the same line, which can lead to significant tachycardia, hypotension, and myocardial ischemia. Perform standard ECG and blood pressure monitoring as with exercise stress testing.

Dobutamine is infused at a rate of 5 mcg/kg/min for 3 minutes, followed by infusion of 10, 20, 30, and 40 mcg/kg/min each at 3 minutes until a target heart rate is achieved. If the target heart rate is not achieved, atropine can be administered (as much as 2 mg). Once the target heart rate is achieved, the radiopharmaceutical is injected and the dobutamine infusion is discontinued.

The indications for early termination of dobutamine stress testing are similar to those of exercise stress testing. ST elevation and ventricular tachycardia are more likely with dobutamine stress testing than any other type of stress testing.

Typically, adverse effects requiring early termination subside within 5-10 minutes of discontinuation of the infusion (the half-life of dobutamine is 2 min). The effect of dobutamine can be reversed with beta-blockers; typically, an intravenous agent with an ultrashort half-life, such as esmolol, is used. Because most patients who undergo dobutamine stress testing have bronchospastic lung disease, beta-blockers should be used with caution.

Hemodynamic effects

A dose-related increase in both heart rate and SBP occurs with dobutamine. However, diastolic pressure falls as the dose of dobutamine increases. These hemodynamic changes are similar to those of exercise stress.

Dosing and practical considerations

The recommended intravenous dose of regadenoson is 5 mL (0.4 mg regadenoson)

Administer regadenoson as a rapid (approximately 10 seconds) injection into a peripheral vein using a 22 gauge or larger catheter or needle. This should be followed by a 5 mL saline flush immediately after the injection of regadenoson. Administer the radionuclide myocardial perfusion imaging agent 10–20 seconds after the saline flush. The radionuclide may be injected directly into the same catheter as regadenoson.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not administer regadenoson if it contains particulate matter or is discolored.

Hemodynamic effects

A rapid increase in coronary blow flow of a short duration occurs when regadenoson is the agent of choice. Clinical studies showed that most patients manifested a decrease in blood pressure and an increase in heart rate within 45 minutes after administration of regadenoson.

Laboratory tests are used to determine myocardial ischemia or risk of infarction; electrolytes, drug levels; toxicities; levels of thyroid-stimulating hormone; and BNP level.

Clinical chemistry

Clinical chemistry studies include measurements of the following:

• Troponin-1

• Creatine kinase

• Myoglobin

• Brain-type natriuretic peptide

• Calcium

• Magnesium

• Potassium

• Bicarbonate

Elevations in cardiac enzyme (troponin, creatine kinase, myoglobin) levels may indicate ischemia and MI. The extent of myocardial damage usually can be correlated to the extent of elevation in the enzyme levels. Patients are at increased risk for arrhythmia in the peri-infarct period.

BNP has predictive value especially in post MI patients and in patients with heart failure. Although preliminary and not conclusive, emerging data support the notion that an elevated BNP level may provide prognostic information on the risk of SCD, independent of clinical information and LVEF.

Severe metabolic acidosis, hypokalemia, hyperkalemia, hypocalcemia, and hypomagnesemia are some of the conditions that can increase the risk for arrhythmia and sudden death.

Metabolic and endocrine tests

Obtain levels of thyroid-stimulating hormone. Hyperthyroidism can lead to tachycardia and tachyarrhythmias. Over a period of time, it also can lead to heart failure. Hypothyroidism can lead to QT prolongation.

Therapeutic-drug monitoring and toxicology

Therapeutic drug monitoring and toxicology includes obtaining the following:

• Drug levels (quinidine, procainamide, tricyclic antedepressants, digoxin)

• Amitriptyline level

• Desipramin level

• Doxepin level

• Imipramine level

• Nortriptyline level

• Serum toxicology screening

Drug (quinidine, procainamide, tricyclic antidepressants, digoxin) levels higher than the levels indicated in the therapeutic index may have a proarrhythmic effect. Subtherapeutic levels of these drugs in patients being treated for specific cardiac conditions also can lead to an increased risk for arrhythmia. Most of the antiarrhythmic medications also have a proarrhythmic effect.

Looking for drugs, such as cocaine, that can lead to vasospasm-induced ischemia is warranted if suspicion exists. Obtaining levels of drugs (antiarrhythmics) also may be warranted.

Urine Analysis

Obtain a urine toxicology screen to test for the types and approximate amounts for legal and illegal drugs that can affect heart function.

Adenosine, dipyridamole (Persantine), and dobutamine are the most widely available pharmacologic agents for stress testing. Regadenoson, an adenosine analog, has a longer half-life than adenosine, and therefore a bolus versus continuous administration.

Adenosine, dipyridamole, and regadenosine are cardiac vasodilators. They dilate coronary vessels, which causes increased blood velocity and flow rate in normal vessels and less of a response in stenotic vessels. This difference in response leads to a steal of flow, and perfusion defects appear in cardiac nuclear scans or as ST-segment changes.

Dobutamine is a cardiac inotrope and chronotrope. The heart responds to dobutamine similarly to the way it responds to exercise.

Class Summary

Pharmacologic stress agents are used in myocardial perfusion for diagnostic purposes.

Adenosine (Adenoscan, Adenocard)

When used in myocardial perfusion scintigraphy reveals areas of insufficient blood flow. Adenosine increases blood flow and causes coronary vasodilation in normal coronary arteries while it causes little or no increase in stenotic coronary arteries. Adenosine is also a short-acting agent that alters potassium conductance into cells and results in hyperpolarization of nodal cells. This increases the threshold to trigger an action potential and results in sinus slowing and blockage of AV conduction. As a result of its short half-life, adenosine is best administered in an antecubital vein as an IV bolus followed by rapid saline infusion.

Regadenoson (Lexiscan)

Pharmacologically induces stress in patients unable to undergo adequate exercise-induced stress. Acts as low-affinity agonist for A2A adenosine receptor. Produces coronary vasodilation and increased coronary blood flow in normal nonstenotic arteries. Indicated for radionuclide myocardial perfusion imaging.

Class Summary

Agents in this class inhibit the activation of factors responsible for platelet aggregation.

Dipyridamole (Persantine)

Platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine, itself an inhibitor of platelet reactivity. In addition, may inhibit phosphodiesterase activity leading to increased adenosine, adenine nucleotides, and cyclic-3', 5'-adenosine monophosphate within platelets. These mediators subsequently inhibit platelet aggregation and may cause vasodilation.

H3 Beta1/Beta2 Adrenergic Agonists

Agents in this class that stimulate beta1-adrenergic receptors and that have little effect on beta2 or alpha receptors are used. The agents cause increased contractility and heart rate.

Dobutamine

Synthetic catecholamine and a direct inotropic agent that stimulates cardiac beta-receptors with minimal increase in systemic vascular resistance.