Doctors

Introduction

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. Pharmacologic stress testing is used in combination with imaging modalities such as radionuclide imaging and echocardiography.

Indications

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.

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 eMedicine article Treadmill Stress Testing.

Contraindications

Specific pharmacologic agents have specific contraindications, as follows:

Adenosine

• Absolute
  • 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
  • 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.

• Absolute
  • 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
  • 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.

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

• 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 give 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.

  Technique

  Various pharmacologic agents are used for cardiovascular stress testing and are usually used in combination with radionuclide isotopes that are taken up by the myocardium during routine testing. The common ones are discussed below.
  
  Adenosine

  • Mechanism of action
    • 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 A₂receptor, 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 A₁receptor 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.
  • 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
    • Severe hypotension (SBP <90>
    • 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>
  • 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

  Dipyridamole (Persantine)
  

  • Mechanism of action
    • 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.
  • Dipyridamole dosing
    • The standard dose of dipyridamole 0.56 mg/kg infused over 4 minutes.
  • Practical considerations
    • 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.

  Dobutamine
  
  

  • Mechanism of action
    • 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.
  • Dobutamine dosing
    • 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).
  • 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.
  • Practical considerations
    • 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.

  Regadenoson (Lexiscan)
  
  

  Regadenoson is a new 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.^1,2
  
  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.
  • Mechanism of action
    • Regadenoson is an agonist with low affinity (Ki ≈ 1.3 μM) for the A_2A 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 A_2B and A₃ adenosine receptors.
    • Coronary vasodilation and an increase in coronary blood flow (CBF) results from activation of the A_2Aadenosine receptor by regadenoson.
  • Dosing and administration
    • The recommended intravenous dose of regadenoson is 5 mL (0.4 mg regadenoson)
    • Administer 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.
  • 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.
  • Practical considerations
    • 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.

  Complications

  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%).