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Ann Thorac Surg 1998;65:637-642
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Bradycardia Induced by Intravascular Versus Direct Stimulation of the Vagus Nerve

Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada,
Ethicon Endo-Surgery, Johnson & Johnson, Cincinnati, Ohio, USA

Accepted for publication August 24, 1997.

Dr Armour, Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4H7, Canada.

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Electrical stimulation of the parasympathetic nervous system results in slowing of the heart. We sought to determine whether cardiac vagal efferent axons can be stimulated adequately to induce bradycardia without disturbing the integrity of the thorax.

Methods. Cardiodepressor effects elicited by direct stimulation of a vagus nerve in anesthetized dogs and pigs were compared with those generated when the same nerve was stimulated indirectly through bipolar electrodes placed in the adjacent superior vena cava.

Results. The heart rate of dogs decreased by about 80% when electrical stimuli were delivered to the right thoracic vagus at the level of the thoracic outlet through bipolar electrodes placed either in the adjacent superior vena cava (intravascular method) or directly on the nerve (direct method). Maximal responses were achieved with 10-V, 5-ms, and 20-Hz stimuli. In anesthetized pigs, similar bradycardia occurred when the right cervical vagus or the right cranial thoracic vagus was stimulated either directly or indirectly through the intravascular method. Atrial dysrhythmias occurred when the stimulating electrodes were placed by either method within 1 cm of the right atrium in both animal models.

Conclusions. Controlled bradycardia can be induced during operation without the risk of generating cardiac dysrhythmias using electrical stimuli (10 V, 5 ms, and 10 to 20 Hz) delivered to the right cervical vagus nerve or the right cranial thoracic vagus nerve through adjacent intravascular electrodes.

	Introduction

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Electrical stimulation of vagal efferent axons induces profound depressor effects on the sinoatrial and atrioventricular nodes as well as depressor effects on atrial and, to a lesser degree, ventricular contractility [1][2][3][4][5][6][7][8]. Few studies have attempted to investigate the cardiac effects elicited by stimulating parasympathetic efferent nerves in humans [9][10]. It has been shown recently that electrical stimulation of cardiac nerves adjacent to the heart or neural elements in the intrinsic cardiac nervous system of patients undergoing coronary artery bypass grafting can cause bradycardia [11][12][13].

Vagal stimulation prolongs the cardiac cycle length, achieving steady-state bradycardia about 150 ms after the stimulation begins [14]. The capacity to slow the heart rate during minimally invasive cardiac procedures may be of value while performing coronary arterial anastomoses. However, direct electrical stimulation of the human vagus nerve is difficult to achieve given the relative inaccessibility of this nerve in the operating theater [15]. Thus, it may be attractive to stimulate the vagus nerve during cardiac operations using the intravascular route of electrode placement, a technique that would induce reliable bradycardia without interfering with the surgical field.

This study was undertaken to determine whether it is practical to reduce the heart rate by stimulating a vagus nerve indirectly through the intravascular route. To test this hypothesis, portions of the cervical and thoracic vagi in anesthetized animal models were stimulated directly or indirectly through bipolar electrodes placed in an adjacent vein and the effects of these stimuli on cardiac indices were compared. This included the determination of stimulus-response curves (ie, frequency, duration, voltage) to identify the appropriate stimulation parameters required to induce bradycardia during vagus nerve stimulation.

	Material and Methods

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All experiments were performed in accordance with the guidelines for animal experimentation described in "Guide for the Care and Use of Laboratory Animals" (NIH publication 85-23, revised 1996).

Canine Experimental Model
Eight mongrel dogs (18 to 26 kg) of either sex were tranquilized with sodium pentothal (20 mg/kg, given intravenously [IV]) and then anesthetized with sodium pentothal (10 to 15 mg/kg, given IV every 5 minutes). After the operation was completed (see later), -chloralose was administered as a bolus (75 mg/kg, given IV); repeated doses of -chloralose (12.5 mg/kg, given IV) were given throughout the experiment, as required. The heart rate was monitored continuously using a lead II electrocardiogram (see later). Noxious stimuli were applied to a paw during the experiment to ascertain the adequacy of anesthesia. After intubation, positive-pressure ventilation was maintained using a Bird (Palm Springs, CA) Mark 7A ventilator. Body temperature was maintained at a constant level throughout the experiment with a heating pad.

A midline incision was made in the neck to facilitate exposure of the right and left cervical vagosympathetic trunks so that they could be stimulated directly. A bilateral thoracotomy also was made in the fifth intercostal space to expose the intrathoracic vagi. The ventral pericardium was incised and retracted laterally to expose the heart. Miniature solid-state pressure transducers measuring 5 x 1.2 mm (model P19; Konigsberg Instruments, Pasadena, CA) were inserted into the midwall regions of the right ventricular conus and the left ventricular ventral wall to record regional intramyocardial pressures. These sensing devices were used because intraventricular systolic pressure represents a less sensitive index for detecting ventricular force changes induced by efferent autonomic neurons [16]. Left atrial chamber pressure was measured using a PE-50 catheter inserted directly into the left atrial chamber through its appendage. Left ventricular chamber pressure was measured using a Cordis (Miami, FL) number 6 pigtail catheter that was inserted into that chamber through a femoral artery. Systemic arterial pressure was measured using a Cordis number 7 catheter placed in the descending aorta through a femoral artery. All catheters were attached to Bentley (Irvine, CA) Trantec model 800 transducers. All data, including a lead II electrocardiogram, were recorded on an Astro-Med model MT 9500 eight-channel rectilinear recorder (Astro-Med, West Warwick, RI).

A quadripolar electrode catheter (Medtronic Cardiorhythm Inc, Minneapolis, MN) connected to a Grass SD-9 square wave stimulator was inserted through a femoral vein into the superior vena cava. The electrodes used for stimulation were 4 mm apart. The tip of the intravascular stimulation catheter was positioned using fluoroscopy at different levels in the superior vena cava or internal jugular vein: (1) adjacent to the caudal third of the right cervical vagus, (2) at the level of the thoracic outlet adjacent to the cranial portion of the right thoracic vagus, and (3) at the level of the carina adjacent to the right midthoracic vagus. Thereafter, the right cervical or thoracic vagus was stimulated for 20 seconds using various stimulation parameters (1 to 20 Hz, 1 to 5 ms, and 1 to 20 V) through bipolar electrodes placed adjacent to these nerves in the superior vena cava.

To determine the stimulation parameters that would result in the production of maximal bradycardia, the value of each stimulus (ie, frequency, duration, strength) was changed in a stepwise manner while the remaining stimuli were held constant. Approximate values were based on those determined previously [10]. Once the value that produced maximal bradycardia was determined for a single stimulus (ie, volts), that value was used for determining values for the remaining stimuli (ie, duration, frequency).

After the stimulation protocol was completed using the intravascular electrodes, stimulation was performed using a bipolar electrode (with the electrode tips 5 mm apart) applied directly to the right cervical or right thoracic vagus. The electrode was connected to a Grass (Quincy, MA) SD-9 square wave stimulator, the output of which was monitored on a Telequipment (Beaverton, OR) D-54 oscilloscope. These direct nerve stimulations were performed using various stimulation parameters (1 to 20 Hz, 1 to 5 ms, and 1 to 10 V). At least 5 minutes was allowed to elapse between nerve stimulations.

Porcine Experimental Model
Experiments also were carried out on the porcine model. The first group consisted of 9 pigs (14 to 18 kg) of either sex that were tranquilized with sodium pentothal (20 mg/kg, given IV) and then anesthetized with sodium pentothal (10 to 15 mg/kg, given IV every 5 minutes). After the operation was completed, -chloralose was administered as a bolus (75 mg/kg, given IV); repeated doses of -chloralose (12.5 mg/kg, given IV) were given throughout the experiment, as required. The thoracic contents of these pigs were exposed by a bilateral thoracotomy and the cervical vagi were exposed through a midline neck incision. In this group of pigs, cardiac variables (electrocardiogram, left atrial chamber pressure, right ventricular intramyocardial pressure, left ventricular intramyocardial pressure, left ventricular chamber pressure, and aortic pressure) were monitored in a fashion similar to that described earlier for the canine model. The middle of the right and left cervical vagi and the cranial portions of the right and left thoracic vagi were stimulated electrically through bipolar electrodes placed directly on the vagi using 10-V, 5-ms, and 20-Hz stimulation parameters.

Another group of 6 pigs (16 to 24 kg), tranquilized with telazol (4 mg/kg, given intramuscularly) and xylazine (4 mg/kg, given intramuscularly) and then anesthetized with sodium pentothal (20 mg/kg, given IV), was intubated and positive-pressure respiration was begun. Thereafter, anesthesia was maintained using isoflurane (1.5% to 2.0% in oxygen). A lead II electrocardiogram and aortic pressure were monitored in this group of animals, as described earlier. The vagi were stimulated in this closed-chest anesthetized preparation through a quadripolar Cardiorhythm stimulator (Medtronic Cardiorhythm Inc) that was inserted under fluoroscopy into the superior vena cava through a femoral vein. The stimulation electrodes were withdrawn gradually in a stepwise fashion so that various levels of the cervical and thoracic vagi could be stimulated electrically using 20-Hz, 5-ms, and 10-V stimulation parameters, as described earlier.

Using fluoroscopy in this closed-chest preparation, the tip of the intravascular electrode was positioned at the following levels: (1) the level of the right and left caudal cervical vagi, (2) the cranial level of the right thoracic vagus, and (3) the midthoracic level of the right vagus. In 4 pigs, the quadripolar stimulating electrode was removed from the venous system and placed adjacent to the midthoracic vagus through an esophageal route. Thereafter, the cervical and thoracic vagi were exposed surgically, as described earlier. Then the cervical and thoracic vagi were stimulated directly at the same levels that were used when these nerves were stimulated by electrodes placed in the adjacent major vein.

Data Analysis
Cardiac and vascular data obtained before and after each stimulation are presented as the mean plus or minus the standard error of the mean. These data were compared using the two-tailed Student’s t-test for paired data. Statistical significance was assigned at the 0.01 level.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Bradycardia was induced by electrical stimulation of the caudal cervical or cranial thoracic vagus of dogs or pigs when the bipolar stimulating electrodes were placed either in an adjacent vein (the indirect, transvenous route) (Fig 1) or directly on the nerve (the direct route). This occurred in anesthetized open-chest dogs (n = 8) (Table 1), anesthetized open-chest pigs (n = 9) (Table 2), and anesthetized closed-chest pigs (n = 6) (Table 3). Further, the degree of bradycardia induced in the closed- and open-chest porcine models by such stimulations was similar (Table 2Table 3). Cardiodepressor responses occurred when the vagus nerve was stimulated by intravascular electrodes placed in the superior vena cava in the thoracic outlet. The greatest degree of bradycardia occurred when the tip of the stimulation electrodes was positioned in a dorsomedial direction (ie, toward the adjacent vagus nerve) in the superior vena cava at the level of the thoracic outlet. This ensured that the electrodes were located closest to the adjacent right vagus, as determined by palpation.

View larger version (56K): [in this window] [in a new window]   Cardiac effects elicited by the stimulation (20 Hz, 5 ms, and 10 V) of a canine right thoracic vagus nerve at the level of the thoracic outlet using electrodes placed in the adjacent superior vena cava. (AP = aortic pressure; ECG = electrocardiogram; LVP = left ventricular chamber pressure.)

View larger version (18K): [in this window] [in a new window]   Graphic representation of average heart rate responses elicited when the right cranial thoracic vagus of 8 dogs was stimulated electrically with different voltage (A), duration (B), or frequency (C) stimuli delivered through a bipolar electrode placed in the adjacent vein. When one stimulation variable was changed, the others were maximal (voltage = 10 V, duration = 5 ms, and frequency = 20 Hz). The asterisk indicates p < 0.01.

Stimuli delivered by the quadripolar electrodes placed in the esophagus at the level of the carina in 4 pigs before the thoracic cavity was opened induced bradycardia (heart rate: 103 ± 5 to 68 ± 7 beats/min; p < 0.01). However, it was difficult to maintain such bradycardia for very long periods (ie, >5 seconds). Aortic pressure was not affected by this intervention (see Table 3).

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The results of this study indicate that heart rate can be reduced in a controlled fashion by stimulating the caudal cervical or cranial thoracic right vagus nerve using bipolar electrodes placed in the adjacent superior vena cava. The degree of bradycardia so induced is similar to that elicited when the right cervical or cranial thoracic vagus nerve is stimulated directly.

Bradycardia, slowing of atrioventricular nodal conduction, and reduction of atrial contractility occurs when vagal efferent preganglionic axons in a vagus nerve are stimulated electrically [2][5][14][17]. The canine vagosympathetic trunk is comprised of four types of axons: afferent axons, preganglionic and postganglionic sympathetic efferent axons, and preganglionic parasympathetic efferent axons [17][18]. When the thoracic vagus nerve is stimulated adjacent to the middle cervical ganglion, a population of cardiac sympathetic efferent axons located at that level of the vagus is activated [17]. Therefore, it is not surprising that cardiac responses elicited by direct electrical stimulation of the right vagus nerve at this level of the thorax induced rebound phenomena (see Table 2Table 3). On the other hand, little or no poststimulation rebound tachycardia occurred when the right cervical vagus was stimulated (see Table 2). Stimulation of the vagus nerve rostral to the middle cervical ganglion (the caudal cervical region) induces cardiac responses that are predominantly depressor in nature. Therefore, to minimize the induction of poststimulation tachycardia after stimulation of a thoracic vagus, the anatomic location of the stimulating electrodes with respect to the level of the nerve stimulated becomes an important consideration.

The results obtained in the present study demonstrate that stimulation of the right cervical or cranial thoracic vagus through electrodes placed in the adjacent vein induces similar degrees of bradycardia as are achieved by direct electrical stimulation of the same nerve. Maximum negative chronotropic effects induced by direct electrical stimulation of vagal efferent axons occurs when the stimulus strength, pulse duration, and stimulation frequency are 20 V, 1 ms, and 5 to 10 Hz, respectively [2][6][7][8]. The stimulation parameters that induced consistent and significant bradycardia when the vagus was stimulated using intravascular electrodes were 10 V, 2 to 5 ms, and 10 to 20 Hz (see Fig 2). These data are in accord with the stimulation parameters that have been reported to induce maximum cardiodepressor effects. Atrial arrhythmias can be induced when vagal efferent axons adjacent to the heart are stimulated electrically [1] presumably due, in part, to direct current spread to adjacent atrial myocytes. As mentioned earlier, poststimulation rebound can be induced when this portion of the vagus is stimulated. Therefore, stimulation of the midthoracic level of the vagus by either method is not recommended for slowing the heart rate in humans during cardiac operations because of the possibility of inducing atrial arrhythmias.

Our data demonstrate that the magnitude of bradycardia achieved by both indirect and direct stimulation of the vagus in the dog was greater than that achieved in the pig. Therefore, species differences do exist that should be taken into consideration if such an intervention is tested in humans. In accordance with these differences, relatively minor bradycardia occurs when feline vagi are stimulated [19]. Much greater degrees of bradycardia occur when the vagi of nonhuman primates [20] or humans [10][12][13] are stimulated. These differences presumably exist because of anatomic and functional differences in the parasympathetic efferent nervous system innervating the heart of different species. Because species differences exist concerning vagal innervation of the heart, cardiac effects induced by intravascular versus direct nerve stimulation were compared within species to determine the most efficacious way in which bradycardia could be induced.

Significant bradycardia can be induced by stimulating the right caudal cervical or right cranial thoracic vagus nerve through bipolar stimulating electrodes placed in an adjacent vein. The location of the bipolar electrodes is crucial to elicit maximum bradycardia while minimizing current spread to adjacent tissues and to prevent the induction of poststimulation tachycardia. These data indicate that controlled reduction of the heart rate can be accomplished in the operating theater using stimulating electrodes placed in the thoracic outlet adjacent to the right vagus nerve through the intravascular route.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We gratefully acknowledge the technical assistance of Richard Livingston. Supported by the Medical Research Council of Canada (MT-10122) and the Nova Scotia Heart and Stroke Foundation.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Armour JA, Randall WC, Sinha S Localized myocardial response to stimulation of small cardiac branches of the vagus. Am J Physiol 1975;228:141-148.[Abstract/Free Full Text]
2. Hamlin RL, Smith CR Effects of vagal stimulation on S-A and A-V nodes. Am J Physiol 1968;215:560-568.[Free Full Text]
3. Levy MN, Martin PJ Neural control of the heart. In: Berne RM, Sperelakis N, eds. Handbook of physiology: section 2: cardiovascular system. Bethesda, MD: American Physiological Society, 1979:581-620.
4. Levy MN, Zieske H Comparison of the cardiac effects of vagus nerve stimulation and of acetylcholine infusions. Am J Physiol 1969;216:890-897.[Free Full Text]
5. Loffelholz K, Pappano AJ The parasympathetic neuroeffector junction of the heart. Pharmacol Rev 1985;37:1-24.[Abstract]
6. Rosenbleuth A, Simeone FE The interrelations of vagal and accelerator effects of the cardiac rate. Am J Physiol 1934;110:42-55.[Free Full Text]
7. Russell R, Warner HR Effect of combined sympathetic and vagal stimulation on heart rate. Physiologist 1967;10:295-300.
8. Warner HR, Cox A A mathematical model of heart rate control by sympathetic and vagus efferent information. J Appl Physiol 1962;17:349-355.[Free Full Text]
9. Kountz WB, Pearson EF, Koenig KF Observations on the effect of vagus and sympathetic stimulation on the coronary flow of the revived human heart. J Clin Invest 1934;13:1065-1078.
10. Matheny RG, Shaar CJ Vagus nerve stimulation as a method to temporarily slow or arrest the heart. Ann Thorac Surg 1997;63:S28-S29.
11. Murphy DA, Johnstone DE, Armour JA Preliminary observations on the effects of stimulation of cardiac nerves in man. Can J Physiol Pharmacol 1985;63:649-655.[Medline]
12. Carlson MD, Geha AS, Hsu J, et al. Selective stimulation of parasympathetic nerve fibers to the human sinoatrial node. Circulation 1992;85:1311-1317.[Abstract/Free Full Text]
13. Murphy DA, Armour JA Human cardiac nerve stimulation. Ann Thorac Surg 1992;54:502-506.[Abstract]
14. Levy MN, Warner MR Parasympathetic effects on cardiac function. In: Armour JA, Ardell JL, eds. Neurocardiology. New York: Oxford University Press, 1994:53-76.
15. Janes RD, Brandys JC, Hopkins DA, Johnstone DE, Murphy DA, Armour JA Anatomy of human extrinsic cardiac nerves and ganglia. Am J Cardiol 1986;57:299-309.[Medline]
16. Armour JA, Randall WC Canine left ventricular intramyocardial pressures. Am J Physiol 1971;220:1833-1839.[Free Full Text]
17. Armour JA, Randall WC Rebound cardiovascular responses following stimulation of canine vagosympathetic complexes or cardiopulmonary nerves. Can J Physiol Pharmacol 1985;63:1122-1132.[Medline]
18. Armour JA, Hopkins DA Anatomy of the extrinsic efferent autonomic nerves and ganglia innervating the mammalian heart. In: Randall WC, ed. Nervous control of cardiovascular function. New York: Oxford University Press, 1984:20-45.
19. Phillips J, Randall WC, Armour JA Functional anatomy of the major cardiac nerves in cats. Anat Rec 1986;214:365-371.[Medline]
20. Randall WC, Armour JA, Randall DC, Smith OA Functional anatomy of the cardiac nerves in the baboon. Anat Rec 1971;170:183-198.[Medline]

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