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Ann Thorac Surg 2009;88:117-122. doi:10.1016/j.athoracsur.2009.04.009
© 2009 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Cardiac Vagal Stimulation Eliminates Detrimental Tachycardia Effects of Dobutamine Used for Inotropic Support

Youhua Zhang, MD, PhD*, Todor N. Mazgalev, PhD, FACC

Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio

Accepted for publication April 3, 2009.

* Address correspondence to Dr Zhang, Cleveland Clinic, NE6-206, 9500 Euclid Ave, Cleveland, OH 44195 (Email: zhangy2{at}ccf.org).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Many patients require temporary inotropic support after cardiac surgery, and dobutamine is one of the commonly used drugs for this purpose. However, dobutamine infusion is frequently associated with unwanted sinus tachycardia. Selective sinus node electrical vagal stimulation through a discrete epicardial ganglionic plexus (fat pad) approach can achieve sinus rate slowing. Because sinus node fat pad vagal stimulation (SNFP-VS) can easily be applied during or after cardiac surgery, we hypothesized that combining selective SNFP-VS with dobutamine could produce desired hemodynamic improvement while avoiding sinus tachycardia in patients when inotropic drug support is needed.

Methods: This exploratory experimental study was performed in 7 open-chest dogs. Dobutamine (2.5 to 10 µg · kg–1 · min–1) was infused at a rate producing at least 30% increase in sinus rate and cardiac output. Then electrical SNFP-VS was applied in the epicardial ganglionic plexus located at the right pulmonary vein-atrial junction, to slow the sinus rate back to control level. Hemodynamic data during control, with steady-state dobutamine infusion, and with dobutamine plus SNFP-VS were collected and compared.

Results: Dobutamine significantly increased heart rate, systolic and diastolic blood pressures, peak left ventricular systolic pressure, positive and negative maximal derivatives of left ventricular pressure, and cardiac output. Combining SNFP-VS with dobutamine eliminated sinus rate increase while preserving all major hemodynamic benefits. Selective SNFP-VS itself had no direct effect on cardiac contractility during atrial pacing.

Conclusions: Combining SNFP-VS with dobutamine could achieve hemodynamic improvement while avoiding sinus tachycardia in this dog model, suggesting that similar strategy may also be applied in patients.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Despite recent advances in cardiac surgical techniques and myocardial protection, myocardial dysfunction after cardiac surgery, resulting in so-called low cardiac output syndrome, is still common, especially in the aged population with coexisting pathologic disease [1–4]. Low cardiac output syndrome can persist for several hours to days and is associated with significantly increased morbidity and mortality. Low cardiac output syndrome also increases the length of intensive care unit and hospital stays and costs [2].

Many patients experiencing low cardiac output syndrome require temporary inotropic support during and after cardiac surgery. Early inotropic drug support is believed to have a favorable outcome in these patients. Among a wide range of available inotropic agents, dobutamine is one of the most frequently used drugs for this purpose [1, 4, 5]. However, dobutamine infusion is frequently associated with unwanted sinus tachycardia [1, 4, 5]. Exaggerated heart rate increase could lead to increased myocardial oxygen demand with consequent risk of myocardial ischemia, especially in patients with coronary artery disease and heart failure [6]. Thus, the side effect of sinus tachycardia could limit application of dobutamine in some patients. Therefore, it would be desirable to avoid this side effect while preserving the inotropic effect.

It has been demonstrated that vagal efferent postganglionic neurons innervating the sinus node are primarily located in a discrete epicardial ganglionic structure (fat pad) at the right pulmonary vein-atrial junction [7–9]. Application of electrical stimulation to this fat pad (called sinus node fat pad, SNFP) can selectively slow the rate by releasing acetylcholine in the sinus node [7–10]. On the other hand, the vagal efferent postganglionic neurons innervating the ventricles are identified mainly in the cranial medial ventricular fat pad [11, 12] located at the base of the aorta between the atrial appendages. The SNFP is not involved in mediating the negative inotropic effect of cervical vagal stimulation [12].

In this study, we hypothesized that selective SNFP vagal stimulation (SNFP-VS) can be used to eliminate sinus tachycardia induced by dobutamine while not interfering with the drug's positive inotropic effect. In other words, by combining the two strategies, dobutamine infusion plus selective cardiac SNFP-VS, we aimed to achieve hemodynamic improvement while avoiding sinus tachycardia, as required in patients when inotropic support is needed after cardiac surgery. Successful evaluation of the above hypothesis was performed in experiments on dogs, and provides a novel therapeutic approach for patients requiring inotropic drug support after cardiac surgery when sinus tachycardia is a concern.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
This study was approved by the Institutional Animal Care and Use Committee and is in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health.

Surgical Preparation
The experiments were performed on 7 adult mongrel dogs (body weight, 21 to 30 kg) instrumented as previously described [13]. Briefly, dogs were premedicated with thiopental sodium 20 mg/kg intravenously, intubated, and ventilated with room air supplemented with oxygen as needed to maintain normal arterial blood gases by a respirator (Integra II SP Anesthesia Machine, DRE, Inc, Louisville, KY). Anesthesia was then maintained with 1% to 2% isoflurane throughout the experiment. Normal saline solution was infused through a peripheral vein at 100 to 200 mL/h to replace spontaneous fluid losses. Standard surface electrocardiographic leads I, II, and III were monitored continuously throughout the entire study. Intermittent arterial blood gas measurements were taken, and if needed, adjustments of ventilator settings were made to correct metabolic abnormalities. Body temperature was monitored with a rectal probe, and an electrical heating pad placed under the animal and operating room lamps were used to maintain a body temperature of 36° to 37°C.

The right femoral artery was cannulated, and a micromanometer-tipped catheter pressure transducer (Millar, Inc, Houston, TX) was inserted and advanced into the thoracic aorta to monitor systemic blood pressure. Another Millar catheter was inserted through the left carotid artery and advanced so that the tip was in the left ventricle (LV) to record LV pressure. Before being inserted, both catheters were soaked in warm saline solution for 30 minutes and precalibrated. After the chest was opened through a median sternotomy, a pericardium cradle was created to support the heart. Custom-made plate electrodes were sutured to the right atrium and right ventricular apex for signal recording. Temporary epicardial pacing wires (Model 6491, Unipolar Pediatric Temporary Pacing Lead, Medtronic, Minneapolis, MN) were inserted into the SNFP, which projects parasympathetic nerve fibers to the sinus node, for delivering SNFP-VS. The SNFP is located at the right pulmonary vein-atrial junction [7–9], as shown in Figure 1. The ascending aorta was isolated, and a Transonic flow probe (16A or 20A) was placed around the aorta and connected to a flowmeter (HT 207, Transonic System, Inc, Ithaca, NY) to measure aortic flow and subsequently calculate cardiac output (CO). All signals (surface electrocardiogram, right atrial and right ventricular electrocardiograms, aortic blood pressure, LV pressure, and aortic flow) were properly amplified, filtered, and displayed on Prucka Cardiolab EP System (GE Medical Systems, Fairfield, CT). In addition, the signals were simultaneously recorded on magnetic tape (Vetter digital model 4000A, Vetron Technology, Howard, PA) for later computer analysis with AxoScope (Axon Instruments, Union City, CA) and a custom-written software program.


Figure 1
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  		Fig 1. Photograph showing the anatomic location of the sinus node fat pad. The heart has been slightly rotated to the left to show the anatomic position of the epicardial sinus node fat pad (dashed triangle). (IVC = inferior vena cava; PC = pericardium; RA = right atrium; RAA = right atrial appendage; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein; RV = right ventricle; SVC = superior vena cava.)

 
Study Protocol
Drug delivery
Our major goal was to evaluate the capability of selective SNFP-VS to reverse dobutamine-induced sinus tachycardia; a secondary goal was to evaluate concomitant effects on cardiac contractility. Thus, the dosage of dobutamine was determined in each dog by titration to achieve at least 30% increase in heart rate (tachycardia) while monitoring CO (positive inotropic effect). Dobutamine (Ben Venue Labs, Inc, Bedford, OH) was infused using a pump (Horizon Nxt modular infusion system, McGaw, Inc, Irvine, CA) starting at low dose (eg, 1 µg · kg–1 · min–1) and gradually increasing it (range, 2.5 to 10 µg · kg–1 · min–1). The steady-state dobutamine infusion was then kept during delivery of SNFP-VS.

Electrical neural stimulation
Electrical SNFP-VS (20 Hz, pulse width 100 µs) was delivered to the SNFP to slow the sinus rate back to the baseline level from the level reached at steady-state dobutamine infusion. A programmable eight-channel stimulator (Master-8; AMPI, Jerusalem, Israel) was used to generate the desired sequence of rectangular impulses for SNFP-VS. The intensity (in milliamperes) was determined by a current isolator (model A385; WPI, Sarasota, FL) that also permitted alternation of the polarity of the impulses to reduce the effects of polarization at the electrode-tissue interface. The SNFP-VS intensity was progressively adjusted (titrated) to eliminate dobutamine-induced sinus tachycardia. The precise SNFP-VS currents differed among animals. The vagal stimulation intensities at the point of tachycardia elimination were from 0.5 mA to 4 mA.

Hemodynamic data at baseline, during dobutamine infusion, and during dobutamine plus SNFP-VS were acquired and compared. We acquired first the baseline control data after a 30-minute stabilization period. Then dobutamine was infused and adjusted to achieve a steady-state increase in heart rate and CO during 15 minutes of data collection. Finally, the vagal stimulation was applied and adjusted to slow the sinus rate back to the control level, and this condition was maintained for another 15 minutes. There were no pauses between the three steps, except for the brief times of adjustments.

After stopping the vagal stimulation at the end of the study, while still maintaining the dobutamine infusion, the heart rate as well as other hemodynamic variables promptly returned to the pre–vagal stimulation levels achieved with dobutamine alone.

We further investigated whether SNFP-VS alone has a direct effect on cardiac contractility and hemodynamics. Because SNFP-VS slows the sinus rate, to avoid the effects of heart rate changes on cardiac contractility and hemodynamics, we paced the right atrium at fixed coupling intervals of 450 milliseconds (a constant rate of 133 beats/min). We then applied SNFP-VS at the same intensity used to slow sinus rate back to control levels as previously observed during dobutamine infusion. These tests were performed in 4 of the dogs. Hemodynamic data were collected and compared with and without SNFP-VS during the constant pacing protocol.

Data Collection
Hemodynamic data including heart rate, systolic and diastolic blood pressures, LV systolic and end-diastolic pressures, and stroke volume were calculated beat by beat and averaged by custom-written software. Positive and negative maximal derivatives of LV pressures (±dP/dt) were derived from the LV pressure signal, and CO was calculated by multiplying the heart rate by the stroke volume.

Statistical Analysis
Data are expressed as mean ± standard deviation. The heart rate and hemodynamic variables at baseline, during dobutamine infusion, and during dobutamine infusion plus SNFP-VS were compared using analysis of variance, followed by post hoc Tukey's honestly significant difference test. The hemodynamic data during constant atrial pacing with and without SNFP-VS were compared using paired Student's t test. A probability value of less than 0.05 was required for statistical significance.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Effects of Dobutamine Infusion and Sinus Node Fat Pad Vagal Stimulation on Cardiac Hemodynamics
Figure 2 shows an example of original hemodynamic traces at baseline, during dobutamine infusion, and during combined application of dobutamine plus SNFP-VS. Compared with control, dobutamine increased the spontaneous sinus rate (RR interval shortened from 571 ms to 393 ms), the systemic blood pressure, and the peak LV systolic pressure, together with the aortic flow. When SNFP-VS was added during dobutamine infusion, the sinus rate was slowed back to the control level (579 ms), whereas pressures and aortic flow remained increased as during the dobutamine infusion alone.


Figure 2
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  		Fig 2. An example of typical electrical and hemodynamic signals. The records were made in the same dog at baseline control (top), during steady-state dobutamine infusion (middle), and during dobutamine plus sinus node fat pad vagal stimulation (bottom). Note that dobutamine increased pressures and aortic flow signal (CO), but also produced marked tachycardia (short RR interval). Sinus node fat pad vagal stimulation slowed heart rate back to control while preserving inotropic effects. (BP = blood pressure in mm Hg; CO = aortic flow signal used to calculate cardiac output in L/min; ECG = surface electrogram; LVP = left ventricular pressure in mm Hg.)

 
The combined hemodynamic data from all 7 dogs are shown in Table 1. In general, heart rate increased 34% after dobutamine administration from 107 ± 5 beats/min to 143 ± 12 beats/min. Along with the heart rate, all other hemodynamic variables (systolic and diastolic blood pressures, peak LV systolic pressure, +dp/dt and –dp/dt, and CO) increased. Notably, SNFP-VS fully reversed the sinus rate back to control level (107 ± 3 beats/min), whereas all other positive inotropic effects remained (increased pressures, LV ±dP/dt, and CO) at levels significantly higher than control. Not surprisingly, the slowing of the heart rate produced a small attenuation of maximal inotropy.


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  		Table 1 Hemodynamic Data in Baseline Control, During Steady-State Dobutamine Infusion, and During Dobutamine Infusion With Sinus Node Fat Pad Vagal Stimulation (n = 7)
 
Effects of Sinus Node Fat Pad Vagal Stimulation During Constant Atrial Pacing
As shown in Figure 3, during constant atrial pacing at 450 ms (133 beats/min), SNFP-VS had no effect on blood pressure, LV systolic pressure, LV ±dp/dt, and CO. Thus, SNFP-VS had no direct effect on ventricular contractility and hemodynamics. This can explain the preservation of dobutamine-induced inotropic effects during the combined therapy.


Figure 3
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  		Fig 3. Average hemodynamic data obtained at constant atrial rate. The four panels show data during atrial pacing at 133 beats/min (baseline, open bars) and during atrial pacing plus sinus node fat pad vagal stimulation (filled bars). Note that sinus node fat pad vagal stimulation did not affect the measured hemodynamic variables. (±dp/dt = positive and negative maximal derivative of left ventricular pressure.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Major Findings
The results of this study clearly demonstrated that dobutamine infusion significantly improved ventricular contractility and CO, which, however, was associated with sinus tachycardia. Selective SNFP-VS could fully eliminate sinus rate increase by dobutamine while other major positive inotropic effects were preserved. Thus, selective SNFP-VS could be a novel approach to oppose the tachycardia side effects while sustaining the positive inotropic effects of dobutamine. Our data confirmed that SNFP-VS itself has no direct effect on ventricular contractility and hemodynamics.

Dobutamine Infusion and Sinus Tachycardia
Inotropic drugs are routinely used to improve cardiac performance after cardiopulmonary bypass, especially when low cardiac output syndrome is present. As one of the best-studied β-agonists and the one with the most favorable side effect profile, dobutamine is frequently used for its positive inotropic effect [1]. As an adrenergic β-receptor agonist, dobutamine increases ventricular myocardial contractility through the β-receptor–mediated cyclic adenosine monophosphate pathway. However, through the same pathway dobutamine also increases the automaticity of the sinus node pacemaking cells. Thus, undesired sinus tachycardia is one of the most frequent side effects associated with dobutamine infusion [1, 4]. It was found that sinus tachycardia induced by dobutamine is dose dependent [5]. There is also dose dependence for dobutamine to increase LV performance. The interrelationship of increased sinus rate and ventricular performance by dobutamine infusion is not straightforward. Thus Romson and colleagues [5], using dobutamine levels as high as 40 µg · kg–1 · min–1, reported that the stroke volume index actually decreased. These authors concluded that the improved ventricular performance in such cases is primarily attributable to an increased heart rate. However, exaggerated sinus tachycardia can result in increased myocardial oxygen consumption, leading to myocardial ischemia, especially when coronary artery disease or heart failure is present [6]. In our study, dobutamine at dosages of 10 µg · kg–1 · min–1 or less produced marked tachycardia, and the side effects of such rhythm acceleration could limit dobutamine use in some patients.

It would therefore be desirable to eliminate sinus tachycardia while preserving the beneficial inotropic effects of dobutamine. Although there are many drugs with negative chronotropic effect, such as calcium-channel blockers and β-receptor antagonists, they also possess strong negative inotropic effect and thus are not suitable as rate-slowing agents in these patients.

Selective Sinus Node Fat Pad Vagal Stimulation as a Novel Approach To Control Sinus Rate and Preserve the Positive Inotropic Effect of Dobutamine
In normal conditions, vagal nerves mediate negative chronotropic, dromotropic, and inotropic effects on the heart. Thus, cervical vagus nerve stimulation can slow the spontaneous sinus rate, but it also inhibits ventricular contractility. Indeed, it has been demonstrated that cervical vagus nerve stimulation attenuates the dobutamine effect on ventricular contractility [14]. We therefore sought to achieve a selective neural control of the sinus rate while avoiding interference with ventricular inotropy. Selective SNFP-VS provided such a possibility.

It has been demonstrated that the vagal efferent postganglionic neurons innervating the heart are located mainly in several epicardial ganglia (fat pads). Discrete cardiac effects have been demonstrated by stimulating these fat pads [7–9]. The sinus node is innervated by vagal nerve terminals projecting from ganglia in so-called SNFP, located at the right pulmonary vein-atrial junction (Fig 1). Stimulation of this fat pad selectively slows the sinus rate [7–9]. The SNFP is not involved in mediating the negative inotropic effect invoked by cervical vagus nerve stimulation [12]. The vagal ganglia innervating the ventricles are located elsewhere in the so-called cranial medial ventricular fat pad [12]. Our results confirmed that SNFP-VS has no direct effect on ventricular contractility (Fig 3). Thus, it is reasonable to expect that selective SNFP-VS could be used to control sinus tachycardia and preserve the positive inotropic effect of dobutamine, and the results of the present study confirmed this hypothesis.

It is worth pointing out that improvement of cardiac performance by dobutamine within the dosages used in the present study was largely independent of heart rate (Table 1). Our results indicated that combining dobutamine infusion with SNFP-VS resulted in slowing of the sinus rate back to the control level, while the positive inotropic effect of dobutamine was clearly manifested. This appears to contradict previously reported conclusions that dobutamine improves ventricular performance primarily by a heart rate increase while the stroke volume index may be actually attenuated in some cases [5]. As our data suggest (Table 1) it is possible that the heart rate increase by dobutamine (especially at higher dosages) may contribute to its hemodynamic benefits. However, this contribution, if any, appeared minor as evident from our observations.

Clinical Implications
As already stated, it is desirable in many conditions to increase cardiac contractility and hemodynamics without concerns of sinus tachycardia. A combined approach of selective SNFP-VS with dobutamine could achieve such a goal. It has already been demonstrated clinically that stimulating the SNFP is feasible in patients undergoing cardiac surgery by attachment of temporary pacing wires, and that such technique produces sinus rate slowing. [15] Further, epicardial temporary pacing wires are routinely used in open chest cardiac surgery patients. Therefore, similar epicardial pacing wires can be used for SNFP-VS in patients when dobutamine infusion is needed but sinus tachycardia may be a concern.

We believe that SNFP-VS could be used to control sinus tachycardia caused not only by dobutamine but also by other inotropic drugs. Furthermore, SNFP-VS may be useful to control sinus tachycardia caused by high sympathetic tone or even by other unknown causes as well.

Study Limitations
Owing to the nature of animal studies, the results from animals need to be confirmed in humans. In addition, our results were obtained in dogs that were not in heart failure, whereas patients who need inotropic drug support are frequently exhibiting different degrees of heart failure. Compared with normal hearts, heart failure may cause reduced responsiveness to dobutamine, as a result of β-receptor desensitization [16]. Also, heart failure may cause some attenuation of the effects of cervical vagal stimulation, although it does not affect the postganglionic transmission initiated by fat-pad stimulation [17]. Our own observations in a congestive heart failure dog model (unpublished data) confirmed that ganglionic fat pad stimulation produces robust slowing of the heart rate.

Because the present study was performed in an acute setup, further observations are needed to evaluate the effects of SNFP-VS during a longer period (eg, several hours or even days). However, we have previously demonstrated in chronic dogs that long-term vagal effects can be sustained for 6 months by stimulating another similar ganglionic structure, the atrioventricular node fat pad [18] to control ventricular rate in atrial fibrillation. It also has been reported that such atrioventricular node fat pad stimulation can be used to control ventricular rate postoperatively in patients [19], suggesting that chronic application of SNFP-VS is clinically feasible. Finally, it should be noted that vagal stimulation, especially at higher intensities, could facilitate atrial fibrillation induction [20, 21]. Therefore, a potential risk of atrial fibrillation during SNFP-VS treatment needs to be further evaluated, despite the fact that no arrhythmias were documented during the current study.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by the Atrial Fibrillation Innovation Center (AFIC), a State of Ohio Wright Center of Innovation, and a Biomedical Research and Technology Transfer Partnership Award (BRTT, Ohio's Third Frontier Project).

The authors would like to thank William Kowalewski and Jackie Kattar, RVT, for their excellent technical assistance during the study.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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Invited Commentary
Richard Lee
Ann. Thorac. Surg. 2009 88: 122-123. [Extract] [Full Text] [PDF]



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Ann. Thorac. Surg., July 1, 2009; 88(1): 122 - 123.
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