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\begin{document}

\title{Site-Specific Effects of Dobutamine on Cardiac Conduction and
Refractoriness}



\author[1]{Bruce Goldner}%
\author[1]{Haisam Ismail}%
\author[1]{James Gabriels}%
\author[1]{David Chang}%
\author[1]{Joseph Donnelly}%
\author[1]{Beom Soo Kim}%
\author[1]{Laurence Epstein}%
\author[1]{Roland Hentz}%
\author[1]{Joanna Fishbein}%
\author[1]{Marcin Kowalski}%
\affil[1]{Northwell Health Feinstein Institutes for Medical Research}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Isoproterenol, a non-specific beta agonist, is
commonly used during electrophysiology studies (EPS). However, with the
significant increase in the price of isoproterenol in 2015 and the
increasing number of catheter ablations performed, the cost implications
cannot be ignored. Dobutamine is a less expensive synthetic compound
developed from isoproterenol with a similar mechanism to enhance cardiac
conduction and shorten refractoriness, thus making it a feasible
substitute with a lower cost. However, the use of dobutamine for EPS has
not been well-reported in the literature. \textbf{Objective:} To
determine the site-specific effects of various doses of dobutamine on
cardiac conduction and refractoriness and assess its safety during EPS.
\textbf{Methods:} From February 2020 to October 2020, 40 non-consecutive
patients scheduled for elective EPS, supraventricular tachycardia,
atrial fibrillation, and premature ventricular contraction ablations at
a single center were consented and prospectively enrolled to assess the
effect of dobutamine on the cardiac conduction system. At the end of
each ablation procedure, measures of cardiac conduction and
refractoriness were recorded at baseline and with incremental doses of
dobutamine at 5, 10, 15, and 20 mcg/kg/min. For the primary analysis,
the change per dose of dobutamine from baseline to each dosing level of
dobutamine received by the patients, comparing atrioventricular node
block cycle length (AVNBCL), ventricular atrial block cycle length
(VABCL) and sinus cycle length (SCL), was tested using mixed-effect
regression. For the secondary analysis, dobutamine dose level was tested
for association with relative changes from baseline of each
electrophysiologic parameter (SCL, AVNBCL, VABCL, atrioventricular node
effective refractory period (AVNERP), AH, QRS, QT, atrial effective
refractory period (AERP), ventricular effective refractory period
(VERP), using mixed-effect regression. Changes in systolic and diastolic
blood pressures were also assessed. The Holm-Bonferroni method was used
to adjust for multiple testing. \textbf{Results:} For the primary
analysis there was no statistically significant change of AVNBCL and
VABCL relative to SCL from baseline to each dose level of dobutamine.
The SCL, AVNBCL, VABCL, AVNERP, AERP, VERP and the AH, and QT intervals
all demonstrated a statistically significant decrease from baseline to
at least one dose level with incremental dobutamine dosing. Two patients
(5\%) developed hypotension during the study and one patient (2.5\%)
received a vasopressor. Two patients (5\%) had induced arrhythmias but
otherwise no major adverse events were noted. \textbf{Conclusion:} In
this study, there was no statistically significant change of AVNBCL and
VABCL relative to SCL from baseline to any dose level of dobutamine. As
expected, the AH and QT intervals, and the VABCL, VERP, AERP and AVNERP
all significantly decreased from baseline to at least one dose level
with an escalation in dobutamine dose. Dobutamine was well-tolerated and
safe to use during EPS.%
\end{abstract}%



\sloppy


Site-Specific Effects of Dobutamine on Cardiac Conduction and
Refractoriness

Short Title: The Effects of Dobutamine on the Cardiac Conduction System

Haisam Ismail, M.D.\textsuperscript{1}, James K. Gabriels,
M.D.\textsuperscript{1}, David Chang, M.D.\textsuperscript{1}, Joseph
Donnelly, M.D.\textsuperscript{1}, Beom Soo Kim,
M.D.\textsuperscript{1}, Laurence M. Epstein, M.D.\textsuperscript{1},
Roland Hentz, M.S.\textsuperscript{2}, Joanna Fishbein,
M.P.H.\textsuperscript{2}, Marcin Kowalski M.D.\textsuperscript{1},
Bruce Goldner, M.D.\textsuperscript{1} , and other members of the
Dobutamine Study Group

\textsuperscript{1}Department of Cardiac Electrophysiology, Northwell
Health, New York, New York, USA, and the \textsuperscript{2}Department
of Biostatistics, The Feinstein Institutes for Medical Research

Northwell Health, New York, New York, USA

Financial Disclosure: None

Corresponding Author:

Bruce Goldner, MD

270-05 76\textsuperscript{th} Avenue

New Hyde Park, New York 11040

Phone: +1-516-729-3778

Fax: +1-718-470-1821

Email: bgoldner@northwell.edu

\emph{}

\emph{Background:} Isoproterenol, a non-specific beta agonist, is
commonly used during electrophysiology studies (EPS). However, with the
significant increase in the price of isoproterenol in 2015 and the
increasing number of catheter ablations performed, the cost implications
cannot be ignored. Dobutamine is a less expensive synthetic compound
developed from isoproterenol with a similar mechanism to enhance cardiac
conduction and shorten refractoriness, thus making it a feasible
substitute with a lower cost. However, the use of dobutamine for EPS has
not been well-reported in the literature.

\emph{Objective:} To determine the site-specific effects of various
doses of dobutamine on cardiac conduction and refractoriness and assess
its safety during EPS.

\emph{Methods:} From February 2020 to October 2020, 40 non-consecutive
patients scheduled for elective EPS, supraventricular tachycardia,
atrial fibrillation, and premature ventricular contraction ablations at
a single center were consented and prospectively enrolled to assess the
effect of dobutamine on the cardiac conduction system. At the end of
each ablation procedure, measures of cardiac conduction and
refractoriness were recorded at baseline and with incremental doses of
dobutamine at 5, 10, 15, and 20 mcg/kg/min. For the primary analysis,
the change per dose of dobutamine from baseline to each dosing level of
dobutamine received by the patients, comparing atrioventricular node
block cycle length (AVNBCL), ventricular atrial block cycle length
(VABCL) and sinus cycle length (SCL), was tested using mixed-effect
regression. For the secondary analysis, dobutamine dose level was tested
for association with relative changes from baseline of each
electrophysiologic parameter (SCL, AVNBCL, VABCL, atrioventricular node
effective refractory period (AVNERP), AH, QRS, QT, atrial effective
refractory period (AERP), ventricular effective refractory period
(VERP), using mixed-effect regression. Changes in systolic and diastolic
blood pressures were also assessed. The Holm-Bonferroni method was used
to adjust for multiple testing.

\emph{Results:} For the primary analysis there was no statistically
significant change of AVNBCL and VABCL relative to SCL from baseline to
each dose level of dobutamine. The SCL, AVNBCL, VABCL, AVNERP, AERP,
VERP and the AH, and QT intervals all demonstrated a statistically
significant decrease from baseline to at least one dose level with
incremental dobutamine dosing. Two patients (5\%) developed hypotension
during the study and one patient (2.5\%) received a vasopressor. Two
patients (5\%) had induced arrhythmias but otherwise no major adverse
events were noted.

\emph{Conclusion:} In this study, there was no statistically significant
change of AVNBCL and VABCL relative to SCL from baseline to any dose
level of dobutamine. As expected, the AH and QT intervals, and the
VABCL, VERP, AERP and AVNERP all significantly decreased from baseline
to at least one dose level with an escalation in dobutamine dose.
Dobutamine was well-tolerated and safe to use during EPS.

Key words: Dobutamine, electrophysiology study, supraventricular
tachycardia, cardiac conduction, cost analysis

\emph{Introduction}

Isoproterenol is a non-specific beta agonist commonly used during
electrophysiology studies (EPS). Its \selectlanguage{greek}β\selectlanguage{english}1-stimulation promotes
tachyarrhythmia induction by improving cardiac conduction and shortening
AV nodal refractoriness. However, the financial burdens of using
isoproterenol are significant given the high cost of the medication and
the increasing number of catheter ablations.\textsuperscript{1,2}

Dobutamine is a less expensive synthetic compound developed from
isoproterenol that is predominantly a \selectlanguage{greek}β\selectlanguage{english}1-agonist with mild \selectlanguage{greek}β\selectlanguage{english}2 and
\selectlanguage{greek}α\selectlanguage{english}1-activities.\textsuperscript{3} It has been well-studied and used in
cardiac stress imaging as well as treatment for cardiogenic
shock.\textsuperscript{4} Therefore, dobutamine is a feasible, less
expensive alternative to isoproterenol. However, its use for EPS has not
been extensively studied.

The purpose of this study was to determine the site-specific effects of
various doses of dobutamine on cardiac conduction and refractoriness and
assess its safety during EPS.

\emph{Methods}

This study was approved by the Institutional Review Board of Northwell
Health and exempted from the investigational new drug (IND) based upon a
Food and Drug Administration (FDA) review.

From February 2020 to October 2020, 40 non-consecutive patients
scheduled for elective EPS, supraventricular tachycardia (SVT), atrial
fibrillation (AF), and premature ventricular contraction (PVC) ablations
at a single center were consented and prospectively enrolled for the use
of dobutamine. The inclusion criteria were patients between the ages of
18 and 80 and those undergoing EPS. Patients were excluded from the
study for the following conditions: (1) hypertrophic obstructive
cardiomyopathy or other forms of left ventricular outflow tract
obstruction, (2) severe aortic stenosis, (3) prior sustained ventricular
tachycardia or ventricular fibrillation, (4) prior allergic reaction to
dobutamine or sulfates, and (5) pregnancy.

All procedures were performed in the EP laboratory under general
anesthesia or conscious sedation monitored by an anesthesiologist.
Standard multi-electrode catheters were inserted via the femoral vein
and positioned fluoroscopically at the His-bundle position, coronary
sinus, and right ventricular apex. Stimulation was performed with a
programmable stimulator EP-4\textsuperscript{TM} (St. Jude Medical,
Little Canada, MN, USA). The procedures were performed by three
experienced electrophysiologists and the standard EPS protocol was
performed as previously reported.\textsuperscript{5}

At the conclusion of each ablation, the baseline blood pressure and the
following parameters were recorded: (1) sinus cycle length (SCL), (2) AH
interval, (3) HV interval, (4) QRS duration, (5) QT interval, (6) AV
node block cycle length (AVNBCL), (7) AV node effective refractory
period (AVNERP), and (8) VA block cycle length (VABCL), (9) atrial
effective refractory period (AERP) and (10) ventricular effective
refractory periods (VERP). Dobutamine was then infused at 5, 10, 15, and
20 mcg/kg/min with a waiting period of five minutes before the blood
pressure and the same parameters noted from baseline were recorded.
Blood pressures were recorded from an arterial line or manual cuff at
five-minute interval. Electrogram intervals were measured using
CardioLab\textsuperscript{TM} (GE Healthcare, Chicago, IL, USA). The
study endpoint was at protocol completion with measurements at baseline
and at each incremental dose of dobutamine. If any sustained arrhythmia
was induced, the arrhythmia was ablated and the study was stopped.

Stimulation was performed by pacing at the coronary sinus and the right
ventricular apex at cycle lengths just shorter than the prevailing sinus
cycle length, and then at progressively shorter cycle lengths to the
point of AV or VA block. Programmed stimulation was then performed at
each site beginning with an 8-beat drive train at 600 msec in the atrium
and the ventricle with single extrastimuli beginning in late diastole,
and then progressively earlier in 10-msec decrements (with increasing
doses of dobutamine, the drive train cycle was decreased to avoid
competition during sinus tachycardia), which understandably affected
atrial, AV nodal and ventricular refractoriness. The SCL, and AH and HV
intervals were measured from an average of at least ten consecutive
intervals recorded from the His-bundle catheter. The AVNBCL and VABCL
were determined as the longest pacing cycle length from the coronary
sinus and right ventricular apex, respectively, which resulted in AV
nodal block during gradually increasing pacing rates. The anterograde
AVNERP was measured as the longest A1-A2 interval (measured in the His
bundle recording), at a drive cycle length of 600 msec, in which the A2
failed to propagate through the AV node. Similarly, the retrograde
AVNERP was the longest V1-V2 coupling interval, at a drive cycle length
of 600 msec, at which the premature stimulus failed to propagate to the
atrium. Pacing cycle lengths of 600, 500, 450 and 400 msec were used to
measure the refractory periods, in view of the shortening of the sinus
cycle length in response to dobutamine. Although we understand the
limitation of pooling the refractory periods with varying drive cycle
lengths, we preferred reporting a single mean refractory period for each
dose of dobutamine.

\textbf{Statistical Methods:}

Retrospective data of the use of dobutamine in our EP lab since March
2015 was used for the sample size calculation, which showed that the
mean and standard deviation for the difference between the change as a
percent from baseline in the SCL and the change from baseline in the
AVNBCL is 7.7\% \selectlanguage{ngerman}± 16.0\% at 20 mcg/kg/min of dobutamine.~We enrolled 40
patients based on the finding that a study of 37 patients yields 80\%
power with respect to the primary endpoint with an alpha of 0.05 using a
paired 2-tail t-test.

The change per dose of dobutamine from baseline to each dosing level of
dobutamine received by the patients, comparing AVNBCL, VABCL and SCL,
was tested using mixed-effect regression.

Dobutamine dose level was tested for association with relative changes
from baseline of each electrophysiologic parameter (SCL, AVNBCL, VABCL,
AVNERP, AH and QT intervals) using mixed-effects regression. The
Holm-Bonferroni method was used to adjust for multiple testing.
Estimates of the change from baseline in each electrophysiologic
parameter at each dose of dobutamine were provided along with 99\%
confidence intervals and plots.

\emph{Results}

Between February 2020 to October 2020, 40 non-consecutive patients
median age 63 years (IQR 55-69), 11 (28\%) females, scheduled for
elective EP procedures at a single center consented and received
dobutamine at the end of the procedure for EPS. The patient demographics
and the diagnoses for the procedure indications are listed in Table 1.

There was no significant difference in the change in AVNBCL relative to
the SCL and the change in the VABCL relative to the SCL at each
incremental dose of dobutamine (Tables 2, 3 and 4, Figures 1 and 2).

The SCL shortened with incremental doses of dobutamine (Table 2, 3, 4,
Figure 1). The change only became statistically significant at 10
mcg/kg/min and greater doses. The largest percentage decrease in the SCL
from one consecutive dose escalation to the next was noted between 5 and
10 mcg/kg/min. Similarly, antegrade and retrograde AV nodal conduction
shortened with each dose of dobutamine and the largest decrease in
AVNBCL and VABCL between consecutive dose escalations was also noted
between 5 and 10 mcg/kg/min (Table 2, 3, 4, Figures 2). The AH interval
shortened at 15 mcg/kg/min and greater doses (Tables 2, 3, 4, Figure 3)
but the HV interval did not show evidence of change (Tables 2, 3, 4,
Figure 4). As expected, the QRS duration did not change significantly
from baseline to each incremental dose of dobutamine (Tables 2, 3, 4,
Figure 5). The QT interval decreased with escalation in dobutamine dose
starting at 15 mcg/kg/min, an expected finding given that the sinus
cycle length decreased with higher doses of dobutamine, and the QT was
not corrected for rate (Tables 2, 3, 4, Figure 5).

The effects of dobutamine on the anterograde AVNERP could not be
determined consistently because, in many cases, it was shorter than the
AERP. The SCL shortened with each dobutamine dose escalation and
required shortening of the drive cycle length when measuring effective
refractory periods. Shorter drive train cycle length also led to AV
nodal block precluding measurement of the AVNERP. AVNERP was not
reported when it was shorter than the AERP. The retrograde AVNERP could
not be assessed consistently because retrograde conduction was limited
by His-Purkinje refractoriness or inability to see a stable retrograde
His deflection. The AVNERP data were included in the analysis; however,
the results should be viewed in the context of the limitations described
above (Table 3, 4, Figure 6). The change in the AVNERP only reached
statistical significance at 15 mcg/kg/min and 20 mcg/kg/min.

Although there was no significant decrease in the AERP from baseline up
to 15 mcg/kg/min of dobutamine, there was a significant decrease in the
AERP from baseline to 20 mcg/kg/min (Tables 2, 3, 4, Figure 6). However,
the shortening of the AERP was likely due to shortening of the drive
cycle length necessary to avoid competition with the shortening of the
SCL. Although there was no significant decrease in the VERP from
baseline to 5 mcg/kg/min of dobutamine, there was a significant decrease
in the VERP from baseline to 10 mcg/kg/min, to 15 mcg/kg/min and to 20
mcg/kg/min dobutamine (Tables 2, 3, 4, Figure 6). The decrease in the
VERP was likely secondary to the necessity of having to decrease the
drive train cycle length due to the decrease in SCL with each dose
escalation of dobutamine dose.

Changes in diastolic and systolic blood pressure with escalating doses
of dobutamine are shown in Tables 2, 3, 4 and Figure 7. The systolic
blood pressure increased significantly by 11 mm of Hg to a maximum at 15
mcg/kg/min and then decreased slightly at 20 mcg/kg/min. The diastolic
blood pressure decreased significantly by 8 mm Hg to a minimum at 20
mcg/kg/min.

Three patients had no retrograde conduction at baseline. One patient
developed retrograde conduction at 5 mcg/kg/min of dobutamine, one
patient at 20 mcg/kg/min, and one patient had no retrograde conduction
during the study.

Four patients (10\%) were hypotensive, defined as systolic blood
pressure \textless{}90 mmHg, at baseline (87, 83, 86, and 84), secondary
to the effects of sedation. All four patients were able to tolerate
dobutamine with no limitations. Hypotensive episodes were recorded in
two additional patients (5\%), a total of six patients (15\%), during
the study but none required a vasopressor nor subsequently developed end
organ damage as a result. Another patient (2.5\%) received a vasopressor
for systolic blood pressure in the 90s based on the discretion of the
anesthesiologist during 15 mcg/kg/min of dobutamine infusion and the
dobutamine dose was not increased to 20 mcg/kg/min. One patient (2.5\%)
developed junctional rhythm at 20 mcg/kg/min of dobutamine but remained
normotensive.

One patient (2.5\%) developed atrial fibrillation at 10 mcg/kg/min and
another patient (2.5\%) developed AVNRT at 15 mcg/kg/min. For both
patients, dobutamine was held and subsequently tolerated ablation with
no further adverse events.

We did not perform ventricular pacing for VABCL or VERP in 13 patients
who underwent AF ablations given the length of the procedure and the
effect of ventricular pacing on the blood pressure.

\emph{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.\textsuperscript{5}However, 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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{7} Isoproterenol is a potent \selectlanguage{greek}β\selectlanguage{english}1-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.\textsuperscript{8} The
S(-)-enantiomer dobutamine is a potent \selectlanguage{greek}α\selectlanguage{english}1-adrenoceptor agonist with
minor \selectlanguage{greek}β\selectlanguage{english}1 and \selectlanguage{greek}β\selectlanguage{english}2-adrenoceptor agonist activities. In contrast, the
R(+)-enantiomer dobutamine possesses minimal \selectlanguage{greek}α\selectlanguage{english}1-agonist effects with
predominantly \selectlanguage{greek}β\selectlanguage{english}1 and \selectlanguage{greek}β\selectlanguage{english}2-adrenoceptor agonist activities. The net effect
of dobutamine is mostly \selectlanguage{greek}β\selectlanguage{english}1-activity with mild \selectlanguage{greek}β\selectlanguage{english}2 and \selectlanguage{greek}α\selectlanguage{english}1-agonist effects.
In addition, \selectlanguage{greek}α\selectlanguage{english}1-activity helps offset \selectlanguage{greek}β\selectlanguage{english}2-activity thus mitigating
vasodilation-mediated hypotension, which is reported with high-doses of
isoproterenol.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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 \textless{}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.\textsuperscript{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.\textsuperscript{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.

\emph{Limitations}

This was a single center study with limited number of patients. Our
protocol did not go beyond 20 mcg/kg/min of dobutamine and does not
qualify as a high dose dobutamine study. Anesthesia was not uniformly
given with either general anesthesia or conscious sedation, which may
have had variable effects on the cardiac conduction. In addition,
anti-arrhythmic and/or rate control agents were not uniformly held
before the procedure as the decision was up to the electrophysiologist
based on the individual patient. Selection of patients was not
consecutive because it was not always feasible to perform the study
protocol due to time constraints. Moreover, we did not perform a VABCL
or VERP in 13 patients who underwent AF ablations given the length of
the procedure and the effect of ventricular pacing on the blood
pressure. There were other limited missing variables which the authors
deemed insignificant. Exclusion of patients due to time constraints
could possibly introduce bias and affect the study results, especially
if we excluded patients when procedures were long. Safety is always the
priority, and if patients were under anesthesia for a prolonged period,
we did not want to extend the procedure and place the patient at greater
risk. Therefore, the more complicated, sicker patients with more cardiac
substrate and longer procedure times (those patients undergoing atrial
fibrillation ablation) were either excluded or ventricular pacing was
not performed. Patients included in this study underwent
electrophysiologic testing for a variety of indications. The
heterogeneity of indications must be considered when interpreting
results.

\emph{Conclusions}

There was no difference in the magnitude of decrease of the AVNBCL and
VABCL relative to the magnitude in decrease of the SCL at each
incremental dose of dobutamine. However, the AVNBCL, the VABCL and the
SCL decreased significantly from baseline with each incremental dose of
dobutamine (except the 3\% decrease in SCL from baseline to 5 mcg/kg/min
dobutamine was not statistically significant). Dobutamine was also seen
to enhance retrograde AV nodal conduction in two out of three patients
who displayed no retrograde conduction at baseline. While hypotension
and arrhythmia-inductions were noted, no significant hypertensive nor
further adverse events were noted, which deems dobutamine a safe
alternative to isoproterenol for EPS.

Other Members of the Dobutamine Study Group:

Aushim Kokroo, M.D.\textsuperscript{1}, Parmanand Dasrat,
M.D.\textsuperscript{1}, Ali Seyar Rahyab\textsuperscript{1},
M.D.\textsuperscript{1}

\emph{References}

\begin{enumerate}
\tightlist
\item
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\item
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  A, Burkhardt JD, Gallinghouse GJ, Hranitzky PM, Horton RP, Di Biase L,
  Natale A. High-Dose Dobutamine for Inducibility of Atrial Arrhythmias
  During Atrial Fibrillation Ablation. JACC Clin Electrophysiol. 2020
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  Sep 30. PMID: 33334450.
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  Piérard LA, Berthe C, Albert A, Carlier J, Kulbertus HE. Haemodynamic
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\item
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  Burger AJ, Notarianni MP, Aronson D. Safety and efficacy of an
  accelerated dobutamine stress echocardiography protocol in the
  evaluation of coronary artery disease. Am J Cardiol. 2000 Oct
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  electrophysiological properties of the specialized conduction system
  in man. J Electrocardiol. 1979 Oct;12(4):361-70. doi:
  10.1016/s0022-0736(79)80004-7. PMID: 512532.
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  Catecholamine-dependent Atrioventricular Nodal Reentrant Tachycardia.
  Circulation 1983;67(3):1983.
\end{enumerate}

Figure Legends.

Figure 1. Demonstrates the relative decrease in sinus cycle length from
baseline to 5 mcg/kg/min, 10 mcg/kg/min, 15 mcg/kg/min and 20 mcg/kg/min
of dobutamine.

Figure 2. Demonstrates the relative decrease in AVNBCL and VABCL from
baseline to 5 mcg/kg/min, 10 mcg/kg/min, 15 mcg/kg/min and 20 mcg/kg/min
of dobutamine.

Figure 3. Demonstrates the relative decrease in AH interval from
baseline to 5 mcg/kg/min, 10 mcg/kg/min, 15 mcg/kg/min and 20 mcg/kg/min
of dobutamine.

Figure 4. Demonstrates the relative change in HV interval from baseline
to 5 mcg/kg/min, 10 mcg/kg/min, 15 mcg/kg/min and 20 mcg/kg/min of
dobutamine.

Figure 5. Demonstrates the relative change in QRS duration and QT
interval from baseline to 5 mcg/kg/min, 10 mcg/kg/min, 15 mcg/kg/min and
20 mcg/kg/min of dobutamine.

Figure 6. Demonstrates the relative change in AERP, AVNERP and VERP from
baseline to 5 mcg/kg/min, 10 mcg/kg/min, 15 mcg/kg/min and 20 mcg/kg/min
of dobutamine.

Figure 7. Demonstrates the relative change in diastolic blood pressure
and systolic blood pressure from baseline to 5 mcg/kg/min, 10
mcg/kg/min, 15 mcg/kg/min and 20 mcg/kg/min of dobutamine.

Table 1. Patient Demographics and EP/Ablation Indications

Patient Demographics\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Age (years) & 63 (55-83)\tabularnewline
Female Sex & 11 (28)\tabularnewline
Body Mass Index kg/m\textsuperscript{2} & 29 (26-35)\tabularnewline
Hypertension & 30 (75)\tabularnewline
Hyperlipidemia & 21 (53)\tabularnewline
Coronary Artery Disease & 5 (13)\tabularnewline
Atrial Fibrillation & 23 (58)\tabularnewline
Diabetes Mellitus & 8 (20)\tabularnewline
Anticoagulation & 23 (58)\tabularnewline
Rate-Control Agents & 28 (70)\tabularnewline
Rhythm-Control Agents & 9 (23)\tabularnewline
Ejection Fraction (\%) & 61 (45-65)\tabularnewline
EP/Ablation Procedure Indications & EP/Ablation Procedure
Indications\tabularnewline
Atrial Fibrillation & 18 (45\%)\tabularnewline
Atrial Flutter & 11 (28\%)\tabularnewline
Atrial Tachycardia & 6 (15\%)\tabularnewline
Atrial Ventricular Node Reentry Tachycardia & 6 (15\%)\tabularnewline
Premature Ventricular Contraction & 2 (5\%)\tabularnewline
Electrophysiology Study & 2 (5\%)\tabularnewline
\bottomrule
\end{longtable}

Values are median
(25\textsuperscript{th}-75\textsuperscript{th}percentiles) and frequency
(percentage)

Table 2: Measured Electrophysiologic Parameters with Incremental
Dobutamine Dosing\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
& Baseline & 5 mcg/kg/min & 10 mcg/kg/min & 15 mcg/kg/min & 20
mcg/kg/min\tabularnewline
SCL & 909 (793, 1056) & 850 (761, 1080) & 801 (600, 899) & 618 (545,
744) & 556 (496, 701)\tabularnewline
AVNBCL & 360 (320, 430) & 360 (305, 385) & 305 (270, 370) & 280 (250,
320) & 250 (230, 300)\tabularnewline
VABCL & 455 (360,600) & 420 (330, 530) & 340 (280, 480) & 300 (250, 390)
& 290 (260, 360)\tabularnewline
AH interval & 74 (64, 99) & 71 (61, 87) & 71 (58, 86) & 62 (55, 71) & 58
(51, 70)\tabularnewline
HV interval & 50 (43, 54) & 47 (42, 56) & 48 (41, 52) & 47 (41, 53) & 47
(41, 54)\tabularnewline
QT & 411 (366, 451) & 414 (380, 450) & 394 (365, 427) & 377 (344, 418) &
362 (319, 393)\tabularnewline
AVNERP & 320 (260, 370) & 290 (250, 320) & 260 (220, 310) & 230 (190,
300) & 220 (200, 290)\tabularnewline
QRS duration & 95 (83, 105) & 93 (80, 104) & 90 (82, 104) & 93 (84, 102)
& 88 (78, 100)\tabularnewline
AERP & 230 (200, 260) & 225 (200, 250) & 210 (190, 240) & 200 (180, 240)
& 190 (165, 220)\tabularnewline
VERP & 260 (235, 290) & 240 (220, 280) & 240 (200, 260) & 210 (200, 250)
& 220 (190, 240)\tabularnewline
SBP & 112 (99, 124) & 111 (104, 119) & 118 (108, 126) & 124 (107, 136) &
117 (100, 135)\tabularnewline
DBP & 65 (58, 72) & 64 (58, 70) & 62 (56, 68) & 60 (54, 69) & 59 (53,
65)\tabularnewline
\bottomrule
\end{longtable}

Values are Median
(25\textsuperscript{th}-75\textsuperscript{th}percentile). All values
are in msec.

Table 3: Percent Change from Baseline in Measured Electrophysiologic
Parameter with Incremental Dobutamine Dosing\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& 5 mcg/kg/min & 10 mcg/kg/min & 15 mcg/kg/min & 20
mcg/kg/min\tabularnewline
SCL & -4 (-11, 0) & -20 (-30, -6) & -30 (-39, -17) & -35 (-43,
-23)\tabularnewline
AVNBCL & -5 (-11, 0) & -16 (-29, -9) & -24 (-33, -16) & -29 (-36,
-22)\tabularnewline
VABCL & -7 (-16, 0) & -19 (-27, -8) & -30 (-36, -23) & -32 (-38,
-22)\tabularnewline
AH interval & -5 (-14, 2) & -8 (-19, 4) & -13 (-23, -5) & -18 (-27,
-11)\tabularnewline
HV interval & -2 (-8, 7) & -5 (-12, 12) & -5 (-15, 12) & 0 (-15,
12)\tabularnewline
QT interval & 0 (-4, 8) & -3 (-7, 3) & -9 (-16, 1) & -12 (-18,
-5)\tabularnewline
AVNERP & -7 (-17, 0) & -8 (-29, 0) & -29 (-41, -11) & -33 (-42,
-9)\tabularnewline
QRS Duration & -1 (-9, 4) & -1 (-7, 5) & -3 (-8, 4) & -5 (-12,
3)\tabularnewline
AERP & -4 (-9, 0) & 0 (-13, 0) & -5 (-15, 0) & -13 (-20,
-5)\tabularnewline
VERP & -4 (-8, 0) & -8 (-17, -3) & -14 (-22, -8) & -15 (-23,
-9)\tabularnewline
SBP & 0 (-6, 5) & 6 (-2, 15) & 3 (-4, 25) & 5 (-7, 19)\tabularnewline
DBP & -4 (-8, 6) & -4 (-14, 2) & -8 (-19, 3) & -11 (-18,
2)\tabularnewline
\bottomrule
\end{longtable}

Values are \% change
(25\textsuperscript{th}-75\textsuperscript{th}percentile).

Table 4. Percent Change from Baseline of Individual Parameters by
Dobutamine Dose\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Dose & SCL & AVNBCL & VABCL & AH & HV & QRS\tabularnewline
\midrule
\endhead
5 & -3 (-10, 4) & -6 (-11, -1)* & -9 (-15, -3) & -5 (-12, 3) & -2 (-9,
6) & -2 (-7, 4)\tabularnewline
10 & -19 (-27, -12)* & -18 (-23, -13)* & -20 (-26, -14) & -8 (-16, 0) &
-2 (-10, 6) & -2 (-8, 4)\tabularnewline
15 & -28 (-36, -21)* & -25 (-30, -20)* & -30 (-36, -24) & -14 (-21, -6)*
& -1 (-9, 7) & -1 (-7, 4)\tabularnewline
20 & -32 (-40, -25)* & -29 (-34, -24)* & -31 (-37, -25) & -18 (-26,
-11)* & 0 (-8, 8) & -5 (-11, 1)\tabularnewline
\bottomrule
\end{longtable}

Values are \% change. Values in parenthesis are 99\% confidence
intervals. *P \textless{} 0.01\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Dose & QT & AVNERP & AERP & VERP & SBP & DBP\tabularnewline
\midrule
\endhead
5 & 2 (-2, 6) & -10 (-23, -2)* & -5 (-14, 5) & -5 (-10, 1) & 3 (-5, 11)
& -1 (-8, 6)\tabularnewline
10 & -4 (-8, 0)* & -11 (-25, -4)* & -3 (-13, 6) & -12 (-17, -6)* & 7
(-2, 15) & -3 (-10, 4)\tabularnewline
15 & -8 (-12, -4)* & -27 (-42, -12)* & -8 (-17, 2) & -16 (-21, -10)* &
11 (3, 20)* & -5 (-12, 2)\tabularnewline
20 & -12 (-16, -8)* & -28 (-44, -12)* & -14 (-24, -4)* & -16 (-22, -11)*
& 7 (-2, 15) & -8 (-15, 0)*\tabularnewline
\bottomrule
\end{longtable}

Values are \% change. Values in parenthesis are 99\% confidence
intervals. *P \textless{} 0.01

Figure 1. Change in Sinus Cycle Length with Incremental Dobutamine
Dosing\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 2. Change in AVNBCL and VABCL with Incremental Dobutamine Dosing\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\par\null

Figure 3. Changes in AH Interval with Incremental Dobutamine Dosing\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 4. Change in HV with Incremental Dobutamine Dosing\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 5. Change in QRS Duration and QT with Incremental Dobutamine
Dosing

\textbf{Hosted file}

\verb`image5.emf`  available at \url{https://authorea.com/users/376627/articles/583750-site-specific-effects-of-dobutamine-on-cardiac-conduction-and-refractoriness}

Figure 6. Change in AERP, AVNERP and VERP with Incremental Dobutamine
Dosing.

\textbf{Hosted file}

\verb`image6.emf`  available at \url{https://authorea.com/users/376627/articles/583750-site-specific-effects-of-dobutamine-on-cardiac-conduction-and-refractoriness}

Figure 7. Change in Diastolic Blood Pressure and Systolic Blood Pressure
with Incremental Dobutamine Dosing

\textbf{Hosted file}

\verb`image7.emf`  available at \url{https://authorea.com/users/376627/articles/583750-site-specific-effects-of-dobutamine-on-cardiac-conduction-and-refractoriness}

\selectlanguage{english}
\FloatBarrier
\end{document}

