Discussion
Isoproterenol, a non-selective beta agonist, is commonly used during EPS for its effects on enhancing conduction and shortening refractoriness of the AV node, particularly in sedated patients.5However, the cost of isoproterenol increased exponentially following ownership changes in 2015 such that the wholesale acquisition cost (WAC) per milligram increased from $26.20 in 2012 to $1,790.11 in 2015.6,7 The cost implications were significant given the increasing number of catheter ablations. An estimated 10,000 atrial fibrillation ablation procedures were performed in the United States in 1992. The number increased to approximately 50,000 in 2013 and is continuing to rise.1,2 Healthcare systems and electrophysiologists have coped with the financial burden by rationing the use of isoproterenol. A study reported 40% reduction in the number of hospitalized patients treated with isoproterenol from 2012 to 2015.7
Another response to the cost increase was substituting isoproterenol with dobutamine. The cost of dobutamine has remained steady with the WAC per milligram of $17.78 in 2012 and $16.50 in 2015, and the number of patients treated with dobutamine increased during this time.7 Isoproterenol is a potent β1-adrenergic agent associated with chronotropic and proarrhythmic responses. Dobutamine was synthesized in hopes of mitigating the side effects of isoproterenol. Removing the hydroxyl group from isoproterenol led to the discovery of dobutamine, which has two isomers.8 The S(-)-enantiomer dobutamine is a potent α1-adrenoceptor agonist with minor β1 and β2-adrenoceptor agonist activities. In contrast, the R(+)-enantiomer dobutamine possesses minimal α1-agonist effects with predominantly β1 and β2-adrenoceptor agonist activities. The net effect of dobutamine is mostly β1-activity with mild β2 and α1-agonist effects. In addition, α1-activity helps offset β2-activity thus mitigating vasodilation-mediated hypotension, which is reported with high-doses of isoproterenol.9
Dobutamine is commonly used for cardiac stress imaging studies to assess the severity of coronary artery disease and its utilization has been well-studied.10 Dobutamine stress echocardiography (DSE) was introduced as an alternative method for patients who cannot tolerate exercise, to provoke myocardial ischemia, leading to ST-segment changes on the ECG and regional wall motion abnormalities on two-dimensional echocardiography.11 While dobutamine has a half-life of 2 minutes and may take up to 10 minutes to achieve a steady state, DSE is routinely performed with 3 minute intervals of dose increase, derived from the standard exercise Bruce protocol. There is no evidence to support this protocol, but the dose increase before reaching steady state has been largely adopted for safety concerns.11 We used a hybrid approach in our study and started with 5 mcg/kg/min at increments of 5 mcg/kg/min up to 20 mcg/kg/min for five minutes each.
Buxton et al. studied the site-specific effects of isoproterenol at varying doses, and we conducted our study in a similar manner with dobutamine. Isoproterenol decreased the sinus cycle length at each incremental dose with the largest drop from 0.007 to 0.014 mcg/kg/min.5 Dobutamine also decreased the sinus cycle length significantly by 10 mcg/kg/min with the largest decrease from 5 to 10 mcg/kg/min. Interestingly, the largest decrease in the AVNBCL and the VABCL also occurred between 5 and 10 mcg/kg/min. Similar to isoproterenol, dobutamine decreased the AH interval significantly by 15 mcg/kg/min, but there was no significant change in the HV interval. The lack of significant effect on the His-Purkinje system was consistent with previously reported studies in both animals and humans.5 In contrast to the effects of isoproterenol more notable in the AV node compared to the sinus node, our study showed no significant difference in changes in the SCL relative to the changes in the AVNBCL or the VABCL over time with dose escalation. The AVNERP was often less than or equal to the AERP and therefore unable to be measured. Three patients (7.5%) had no retrograde conduction at baseline but two demonstrated retrograde conduction with 5 and 20 mcg/kg/min, which suggests bidirectional conduction enhancement.
At 5 mcg/kg/min of dobutamine, the VABCL decreased by a significant degree, indicating that even at low doses, there can be a significant effect on retrograde conduction, thus theoretically facilitating induction of specific arrhythmias like AVNRT at relatively low doses. Isoproterenol had been shown to improve retrograde conduction through the AV conducting system, thus facilitating induction of AVNRT.5
The safety of the use of dobutamine was an important observation of our study. Mazeika et al. utilized the same increments of dobutamine at 5, 10, 15, and 20 mcg/kg/min for eight minutes each during DSE and reported that all adverse reactions were minimal and resolved within two minutes of discontinuing the dobutamine infusion. Notably, seven patients (14%) had dobutamine-induced symptomatic hypotension of which three had transient junctional rhythms.12 In our study, four patients (10%) were hypotensive at baseline (SBP 87, 83, 86, and 84) and a total of six patients (15%) developed hypotension during the study. One patient (2.5%), who did not meet our definition of hypotension (SBP <90 mmHg), was preemptively given a vasopressor by the anesthesiologist during the dobutamine infusion of 15 mcg/kg/min and did not experience any adverse events. Another patient (2.5%) developed junctional rhythm during 20 mcg/kg/min of dobutamine infusion but remained normotensive and spontaneously recovered normal sinus rhythm.
Multiple studies have shown that even higher doses of dobutamine for prolonged duration causes low incidence of serious side effects.11 Gianni et al. reported that two patients (4.2%) with significant history of myocardial ischemia experienced paradoxical hypotension during the high-dose dobutamine infusion and two other patients (4.2%) had hypertensive responses while on norepinephrine for anesthesia-induced hypotension. The incidence of atrial arrhythmias and outflow tract premature ventricular contractions with high-dose dobutamine was comparable to high-dose isoproterenol.9 In our study, AF was induced in one patient (2.5%) at 10 mcg/kg/min and AVNRT was induced in one patient (2.5%) at 15 mcg/kg/min of dobutamine at which point the study protocol was terminated.