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.