Pharmacologic Stress

Several drugs are available to perform cardiac stress. Which one should I use?  

Three drugs are most commonly used in CMR stress-perfusion studies: adenosine, regadenoson, and dobutamine. The first two (adenosine and regadenoson) are vasodilators, while the latter (dobutamine) is a positive inotrope used to directly assess myocardial contractility. 

Adenosine

Adenosine is a potent vasodilator of the coronary and most other vascular beds (except hepatic and renal), acting through nonselective stimulation of A1, A2A, A2B, and A3 receptors. A2A receptors dilate high-resistance myocardial arterioles, allowing stress-induced ischemic regions caused by epicardial coronary artery stenosis to be identified.   

Adenosine

The standard adult dose of adenosine is 140 μg/kg/min administered by continuous IV infusion over about 4 minutes. Gadolinium is usually injected during the final minute of adenosine infusion through a separate IV line (the two drugs are chemically incompatible).  

Common side effects of adenosine include mild-to-moderate (<10 mmHg) reduction in blood pressure with a reflex increase in heart rate. Mild dyspnea occurs in about 15%. Due to direct depressant effects on the SA and AV nodes, heart block or bradycardia may occur. Significant drop in blood pressure, severe respiratory difficulty, or persistent/symptomatic AV block are grounds for termination of the infusion. Due to its short half-life (4-10 seconds), most complications of adenosine will spontaneously resolve. Occasionally aminophylline (250 mg by slow IV infusion with EKG monitoring) is required for treatment. Significant complications such as myocardial infarction, stroke, and death are rare but have reported.

Contraindications for adenosine include recent (< 3 days old) myocardial infarction, unstable angina, second or third degree AV block, and asthma/emphysema/chronic obstructive pulmonary disease. It should be given with caution to patients with valvular stenosis, autonomic dysfunction, or cerebrovascular insufficiency.

Regadenoson

Regadenoson is a systemic vasodilator with similar structure and function to adenosine. However, regadenoson is a selective A2A receptor agonist, thus avoiding the undesirable negative inotropic (A1) and bronchoconstrictive (A2B and A3) effects of adenosine. It is thus the stress CMR drug of choice for patients with asthma or obstructive airways disease.

Regadenoson

Regadenoson is marketed under the tradename Lexiscan® and is significantly more expensive than generic adenosine. It is supplied in pre-filled 5 mL syringes containing a "standard" 0.4 mg dose given to all adults independent of body weight. Bolus IV injection is performed over 10 seconds followed by a saline flush. To allow time for circulation and onset of action, a waiting period of about 2 minutes should be allowed between regadenoson injection and stress imaging/administration of gadolinium.

Although it has a lower incidence of respiratory side-effects, regadenoson poses the same risks and has the same contraindications as adenosine. Regadenoson has a significantly longer half-life than adenosine. Although peak coronary vasodilatation occurs in the first 5 minutes, systemic pharmacologic effects may last for 30 minutes or longer. Thus, nonspecific vasodilatory side effects such as headache may last longer and be more severe with regadenoson than adenosine.  

Dobutamine

Dobutamine is a synthetic catecholamine whose primary effect is to stimulate β1 receptors of the sympathetic nervous system. In the heart it produces coronary vasodilatation, increased myocardial contractility (positive inotropic effect), and increased heart rate (positive chronotropic effect). 

Dobutamine

Dobutamine causes myocardial cells to contract harder and faster, resulting in increased myocardial oxygen demand and blood flow. It has been used for stress echocardiography since the early 1980's and for stress CMR since the early 1990's. As with the vasodilatory agents (adenosine and regadenoson), dobutamine may reveal wall motion and perfusion abnormalities not apparent in the non-stressed state.

Contraindications to dobutamine include marked arterial hypertension (≥ 220/120 mmHg), severe aortic stenosis, acute aortic dissection, unstable angina, obstructive hypertrophic cardiomyopathy, complex cardiac arrhythmias, and severe congestive heart failure. As atropine is often given in conjunction with dobutamine to increase heart rate, patients with closed-angle glaucoma, myasthenia gravis, and obstructive uropathy should also be excluded from dobutamine stress protocols.  

Dobutamine is a potentially dangerous drug, and life-threatening complications occur in approximately 1:500 cardiac patients subjected to high-dose (20-40 μg/kg/min) regimens. Reported adverse events include sustained ventricular tachycardia and other arrhythmias, coronary spasm, myocardial infarction, cardiac rupture, and systemic hypotension. Because of these significant risks high-dose dobutamine CMR has gradually fallen out of favor during the last decade, being replaced by stress testing using vasodilators. Nevertheless there are still arguments for the use of high-dose dobutamine CMR (see Advanced Discussion section below).

At my institution, we now perform only low-dose (5-10 μg/kg/min) dobutamine stress imaging for assessment of myocardial viability prior to proposed coronary artery revascularization surgery. The degree of end-systolic wall thickness during dobutamine stress is an indicator of "contractile reserve", and segments that do not thicken significantly during stress tesing will not likely improve from surgery. Low-dose dobutamine stress CMR may also be used to forecast future myocardial infarction and cardiac death in these patients independently of other risk factors.

Advanced Discussion (show/hide)»

Dobutamine and vasodilator drugs have different mechanisms of action, and we should not expect the results of CMR stress testing using these different agents to be identical. Adenosine and regadenoson induce blood flow disparities by vasodilation of intracardiac arterioles and shunting. Because the effect of dobutamine is primarily on heart muscle (to increase contractility), it is more likely than vasodilators to elicit wall motion abnormalities as an indicator of inducible ischemia. In certain clinical subgroups dobutatamine-stress CMR has proved more sensitive (but less specific) than vasodilator-stress CMR.

A typical high-dose dobutamine protocol requires 30-40 minutes (versus <10 minutes for an adenosine protocol). It is performed under EKG monitoring as well as continuous viewing of cine MRI loops of wall motion. The goal is to achieve a target heart rate given by the formula

Target HR = 0.85 x (220 − age)

Dobutamine infusion is typically begun by intravenous infusion at a rate of 10 μg/kg/min. Every three minutes the dose is incremented by 10 units (to 20, 30, or 40 μg/kg/min) until the target HR is reached. If still not reached at the 40 level, up to two 0.5 mg doses of intravenous atropine may be administered to reduce vagal tone and increase heart rate. The study is stopped once the target HR is reached, a wall motion abnormality is detected, or serious side effect noted. At this point gadolinium contrast may be administered and a perfusion/enhancement module may be played out to complete the evaluation.

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References
     Al Jaroudi W, Iskandrian AE. Regadenoson: a new myocardial stress agent. J Am Coll Cardiol 2009; 54:1123-1130. 
     Berger A, Fleck E, Gebker R. Update on dobutamine stress magnetic resonance. Curr Cardiovasc Imaging Rep 2012; 5:116-125.
     Botvinick EH. Current method of pharmacologic stress testing and the potential advantages of new agents. J Nucl Med Technol 2009; 37;14-25
     Charoenpanichkit C, Hundley WG. The 20 year evolution of dobutamine stress cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2010; 12:59.
     Geleijnse ML, Krenning BJ, Nemes A, et al. Incidence, pathophysiology, and treatment of complications during dobutamine-atropine stress echocardiography. Circulation 2010; 121:1756-1767.
     Hage FG. Regadenoson for myocardial perfusion imaging: Is it safe? J Nucl Cardiol 2014; 21:871-876.
     Karamitsos TD, Ntusi NAB, Francis JM, et al. Feasibility and safety of high-dose adenosine perfusion cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2010; 12:66. (Showed that infusion rates of up to 210  can be safely tolerated in patients with inadequate hemodynamic response to standard 140 μg/kg/min dose of adenosine).
     Lexiscan® prescribing information (pdf, revised July 2014). See Astrellas Pharma US web site for the most up-to date version.
     Paetsch I, Jahnke C, Wahl A, et al. Comparison of dobutamine stress magnetic resonance, adenosine stress magnetic resonance, and adenonsine stress magnetic resonance perfusion. Circulation 2004; 110:835-842. (Shows that wall motion abnormalities seen with dobutamine stress are more sensitive but less specific than adenosine for detection of coronary artery disease.)
     Vasu S, Bandettini WP, Hsu L-Y, et al. Regadenoson and adenosine are equivalent vasodilators and are superior than dipyridamole- a study of first pass quantitative perfusion cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2013; 15:85

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Related Questions
    What risks and complications should patients be informed about when undergoing stress perfusion testing?  

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