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Ann Thorac Surg 1998;66:1185-1190
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Controlled intermittent asystole: pharmacologic potentiation of vagal-induced asystole

^a Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Crawford Long Hospital, Atlanta, Georgia, USA

Address reprint requests to Dr Puskas, Carlyle Fraser Heart Center, Crawford Long Hospital of Emory University, 550 Peachtree St NE, Suite 7700, Atlanta, GA 30365-2225

Presented at the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26–28, 1998.

	Abstract

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Minimally invasive direct coronary artery bypass graft operations have, to date, displayed a higher rate of early graft failure than conventional coronary artery bypass procedures using extracorporeal technology. Construction of the coronary artery anastomosis on a beating heart versus a quiescent heart is likely an important factor in this difference between the two approaches. Controlled intermittent asystole induced by vagal stimulation to give transient nonchemically induced asystole for brief intervals sufficient for placement of coronary artery sutures might improve the precision of minimally invasive direct coronary artery bypass graft anastomoses and reduce graft failure while increasing the technical ease of operation.

Methods. The feasibility of producing transient, reversible asystole with combined vagus nerve stimulation and treatment with a pharmacologic regimen of (1) an acetylcholinesterase inhibitor (pyridostigmine, 0.5 mg/kg), (2) a ß-adrenergic receptor blocker (propranolol, 80 µg/kg), and (3) a calcium-channel blocker (verapamil, 50 µg/kg) was studied in a sheep model. Seven animals underwent right vagus nerve stimulation in two modes: (1) a single continuous 60-second impulse and (2) multiple sequential 15-second impulses.

Results. Vagal stimulation alone achieved bradycardia without consistent and reproducible cardiac arrest. After drug administration 6 animals displayed significant potentiation of vagal-induced asystole in the 60-second stimulation protocol (1.6 ± 0.9 seconds non–drug-treated versus 52.0 ± 5.6 seconds drug-treated; p < 0.05). In the sequential 15-second impulse protocol after drug treatment, 6 animals achieved consistent, escape-free asystole during five to six sequential 15-second stimulations versus a brief pause and bradycardia produced without drug treatment.

Conclusions. Increased acetylcholine activity by acetylcholinesterase inhibition and prevention of electromechanical escape activity by ß-adrenergic receptor and calcium-channel blockade during vagal stimulation produced a marked potentiation of vagal-induced asystole and a means of achieving controlled intermittent asystole. Controlled intermittent asystole achieved by pharmacologic potentiation of vagal-induced asystole may be a useful technique for enhancing technical ease in minimally invasive direct coronary artery bypass graft operations.

	Introduction

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 

" ... the probability of performing a technically perfect operation and of having no deaths caused by the operation itself is enhanced by working in a perfectly quiet and bloodless field."

John W. Kirklin, MD [1]

The reintroduction of coronary artery bypass graft (CABG) operation without cardioplegic arrest and cardiopulmonary bypass (CPB) challenges the surgical precision and success of heretofore routine CABG procedures. The quality of the distal anastomosis is a primary concern among cardiac surgeons who observe and perform CABG procedures unaided by cardioplegic arrest and CPB [2]. Coronary artery bypass graft failure rates reported with minimally invasive direct coronary artery bypass grafting (MIDCABG) range from 3.8% to 8.9% [3–6], whereas CABG on CPB has a reported anastomotic failure rate of 0.12% [7]. In the report by Subramanian and associates [6] of a series of patients revascularized with MIDCABG techniques, there was an 8% early (less than 36 hours) patency failure rate by Doppler analysis; the use of stabilization devices was associated with a significantly increased patency rate compared with those in which stabilization was not used (97% versus 89% patency). The difference in patency and failure rates between conventional revascularization using chemical cardioplegia with cardiopulmonary bypass and no cardioplegia in "off-pump" techniques may reflect a difference in anastomotic precision achieved in a beating heart versus an arrested heart on CPB. Although the benefits of avoiding CPB in MIDCABG procedures may be important, they do not outweigh the need for a technically acceptable coronary anastomosis.

The key difference in the anastomotic results between conventional CABG and MIDCABG is likely related to achieving elective asystole during construction of the distal anastomosis. There is significant motion in the target vessel area because of not only cardiac motion but also respiratory motion [8]. Cardiac motion can be minimized during MIDCABG procedures via pharmacologically induced bradycardia (adenosine, ß-blockade) and mechanical stabilization using various devices [2, 6, 8]. Although these techniques do improve operative conditions, they only approximate the advantages of elective asystole achieved with CPB and cardioplegia. A recent report suggested that bradycardia induced by vagus nerve stimulation may be used as a method for cardiac stabilization [9]. However, optimal repetitive arrest intervals and hemodynamic alterations were not determined in this case report. In the present study, we propose that a state of controlled intermittent asystole (CIA) may be consistently produced with a predictable, rhythm-free duration off CPB which might approach the conditions achieved with cardioplegic arrest. The present study tested the hypothesis that CIA may be achieved with unilateral vagus nerve stimulation coupled with pharmacologic suppression of electromechanical escape activity without hemodynamic compromise or complications.

	Material and methods

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The sheep in this study received humane care in compliance with "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guides for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985). The experimental protocol was approved by the Institutional Animal Care and Use Committee of Emory University.

Experimental preparation
Seven sheep weighing 45 to 55 kg underwent premedication with xylazine (0.1 mg/kg) and atropine (0.2 mg/kg) for 30 minutes before induction of anesthesia with intravenous thiopental (2.2 mg/kg) and lidocaine (2.2 mg/kg). The animals were endotracheally intubated and placed on a volume ventilator with isoflurane for maintenance of anesthesia. Limb leads and a precordial lead were placed for electrocardiographic monitoring. The right femoral artery was cannulated for arterial pressure and arterial blood gas monitoring. Tidal volume was adjusted to 10 mL/kg and a rate of 12 breaths per minute, with adjustments made to maintain pH between 7.35 and 7.45, oxygen tension greater than 100 mm Hg, and carbon dioxide tension between 35 and 45 mm Hg.

A right cervical incision was performed, the vagus nerve was carefully isolated, and a nerve stimulation probe (Harvard Apparatus, South Natick, MA) was placed on the right vagus nerve. A median sternotomy was made to expose the heart. A high-fidelity solid-state micromanometer (Millar Inc, Houston, TX) was secured in the ascending aorta for aortic blood pressure monitoring. An additional micromanometer was introduced into the left ventricle through the apex for left ventricular pressure monitoring.

Experimental protocol
Each animal underwent vagal stimulation before and after drug administration. The pharmacologic regimen consisted of pyridostigmine (0.5 mg/kg) for acetylcholinesterase inhibition, propranolol (80 µg/kg) for ß-adrenergic receptor blockade, and verapamil (50 µg/kg) for calcium-channel blockade. Vagal stimulation was performed with a nerve stimulator (Grass Instrument Co, Quincy, MA) in the monopolar mode at a frequency of 40 Hz, an impulse duration of 0.4 ms, and an amplitude of 2 to 6 volts. Vagal stimulations were delivered in two regimens: (1) continuous 60-second impulse and (2) sequential 15-second impulses. The continuous 60-second stimulation was designed to determine the longevity of vagal-induced asystole and the physiologic effects of prolonged vagal-induced hypotension. Sequential 15-second vagal stimulations were performed to simulate the suturing intervals required for graft anastomoses and to determine neural fatigue, electromechanical escape, and physiologic effects under practical conditions.

Data acquisition and analysis
Electrocardiographic and hemodynamic data were gathered via an analog-to-digital conversion board (Data Translation, Inc, Marlboro, MA) and processed, stored, and analyzed via a microprocessor (model 468; Intel, Houston, TX) with interactive proprietary software (Spectrum; Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC). The system was formatted to collect four channels of physiologic data at a frequency of 50 Hz (sufficient for slow-wave waveforms) over a 200-second period that encompassed the 60-second stimulation or the sequential 15-second train of stimulations. The software allowed subsequent analysis and graphic reproduction of the hemodynamic data.

	Results

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Before drug administration, vagal stimulation for 60 seconds produced a brief pause in electromechanical activity (1.6 ± 0.9 seconds) followed by a reduction in heart rate (19.4% ± 11.9%). Similarly, sequential 15-second vagal stimulation performed to simulate the suturing intervals required for CABG anastomoses produced a short pause (1.1 ± 0.4 seconds) followed by a reduction in heart rate (37% ± 6%).

Administration of the pharmacologic regimen (propranolol, verapamil, pyridostigmine) reduced heart rate and increased the left ventricular end-diastolic pressure but did not affect the mean arterial pressure or maximum developed left ventricular pressure, as shown in Table 1. In addition, the drug regimen without vagal pacing did not arrest the heart. After drug administration, 60-second vagal stimulation produced 52 ± 5.6 seconds of consistent, event-free asystole. The individual responses of the animals before and after drug administration are graphically displayed in Figure 1. Five animals achieved asystole for greater than 50 seconds. One individual displayed minimal prolongation of asystole in the drug-treated state; incremental doses of drugs did not improve responsiveness. This animal was termed a nonresponder and was excluded for further analysis. The differences in consistency in asystole achieved with 60-second stimulation before versus after drug treatment are contrasted by representative left ventricular and aortic pressure tracings displayed in Figure 2.

View larger version (15K): [in this window] [in a new window]   Fig 1. Duration of asystole during 60-second vagal stimulation. Lines connect the periods of asystole observed in the non–drug-treated and drug-treated states. Drug administration lengthened significantly the period of asystole.

View larger version (29K): [in this window] [in a new window]   Fig 2. Representative left ventricular and aortic pressure tracings during 60-second vagal stimulation in the non–drug-treated and drug-treated states. Dark and open arrows mark respectively the initiation and termination of the vagal impulse. Before drug treatment (A), a short pause followed by bradycardia was observed during the 60-second impulse. After drug treatment (B), prolonged asystole occurred during the 60-second impulse, with return of mechanical function after termination. (AoP = aortic pressure; LVP = left ventricular pressure.)

View larger version (28K): [in this window] [in a new window]   Fig 3. Representative left ventricular and aortic pressure tracings during sequential 15-second vagal stimulations in the non–drug-treated and drug-treated states. Dark and open arrows mark respectively the initiation and termination of the vagal impulses. Before drug treatment (A), each 15-second stimulation produced a short pause followed by bradycardia, whereas after drug treatment (B), asystole lasted the duration of each 15-second stimulation. (AoP = aortic pressure; LVP = left ventricular pressure.)

	Comment

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

The chronotropic effects of vagal nerve stimulation have been well described and typically produce an initial pause followed by a sustained bradycardia during continuous optimal stimulation of the vagus nerve [10]. Cardiac responses to a 60-second vagal stimulation without adjunctive therapy achieved an average pause of only 1.6 seconds and a 19% reduction in heart rate reflecting bradycardia. However, vagus nerve stimulation alone did not produce a controlled period of asystole that was free of escape beats. In addition, the drug regimen alone without vagal stimulation did not succeed in arresting the heart.

It is apparent that suppression of the electromechanical escape beat during vagal stimulation is necessary to produce a sufficient duration of complete asystole that allows a single stitch to be reliably placed during construction of a distal CABG anastomosis. The negative chronotropic effects of vagal stimulation are produced by acetylcholine release. Acetylcholine-induced chronotropic effects may be further enhanced by inhibition of acetylcholinesterase activity by agents such as pyridostigmine. Additionally, it is known that calcium-channel blockade by verapamil potentiates the negative chronotropic effect of vagus nerve stimulation [11]. Another component in electromechanical escape may be related to sympathetic nervous system influence via catecholamine activity. This potential contributor to the genesis of escape beats was addressed by ß-adrenergic receptor blockade via propranolol.

The above reasoning led to the proposed pharmacologic combination of pyridostigmine, verapamil, and propranolol as a method for potentiating asystole produced by vagus nerve stimulation. As summarized in Table 1, administration of this regimen produced a significant reduction in heart rate and maximum developed ventricular pressure along with an increase in left ventricular end-diastolic pressure. The pharmacologic combination did not alter mean arterial pressure. The animals appeared to tolerate this pharmacologic regimen with other obvious adverse hemodynamic side effects.

The clinical utility of CIA during CABG depends on the ability to produce multiple sequential intervals of asystole that are both brief and controlled. Six of 7 animals displayed consistent predicted asystolic intervals with sequential 15-second vagal stimulations. This report contains the results of five to six sequential intervals over a 200-second period of time without apparent decline in subsequent asystoles secondary to vagal "fatigue."

The short-term hemodynamic effects of a single prolonged stimulation in this investigation were of limited significance. Likewise the metabolic consequences as detected by pH and changes in base deficit were not remarkable. However, the neurologic consequences of prolonged asystole or multiple sequential brief periods of asystole are an important concern. This technique would produce cerebral hypoperfusion similar to that which occurs during placement and testing of automatic implantable cardioverter-defibrillator devices [12]. Careful electroencephalographic studies have documented reversible electroencephalographic changes of ischemia at 7.5 seconds after fibrillatory arrest; however, neurologic and neuropsychometric evaluation has revealed no new deficits after implantation of implantable defibrillator devices in patients with these changes [12]. Although these findings are encouraging, further investigation of the neurologic effects of cumulative periods of circulatory arrest is needed. In addition, it would be important to determined whether external stimulation to the vagus nerve produced neuronal damage.

The pharmacologic regimen used in this investigation maintained the effect of potentiating intermittent vagal-induced asystole for about 60 minutes. This interval would allow more than sufficient time for construction of a distal CABG anastomosis. Animals followed up for up to 2 hours after administration of drugs displayed similar responses to vagal stimulation as in the non–drug-treated state, displaying reversibility of the drug effects. No animal displayed complete atrioventricular nodal blockade, a potential problem when ß-blockers and calcium-channel blockers are combined.

An untoward effect of the techniques used to achieve CIA that requires consideration before clinical application is vagal-induced secretions, which may be potentiated by pyridostigmine. All animals displayed significant salivation after initiation of vagal stimulation. There were no problems with oxygenation and ventilation caused by tracheobronchial secretions in these experiments. Vagal-induced and pharmacologically induced oropharyngeal and tracheobronchial secretions may produce problems for extubation in the clinical setting, and these effects require further study. Lower doses of pyridostigmine or an alternative agent may need to be chosen with which oropharyngeal and tracheobronchial secretions are not as pronounced. Additionally, the effects of recurrent laryngeal nerve function require consideration.

The long-term effects of this regimen on the vagus nerve are unknown. Chronic vagus nerve stimulation has been used as therapy for intractable seizure disorders without apparent nerve injury or impaired function [13]. In our investigations, vagal-mediated chronotropic control at 2 hours after completion of the experimental protocol was similar to the non–drug-treated state. However, precise nerve conduction investigation may be necessary to appreciate important changes in vagus nerve function after stimulation that may have long-term consequences, and careful histologic assessment may identify significant morphologic changes that occur after sequential stimulus patterns.

The cervical incision used for vagal isolation and stimulation is not an attractive addition to a "minimally invasive" procedure. Therefore, refinements in the method of vagus stimulation are needed. Percutaneous or endoesophageal electrodes are alternative methods of vagal stimulation that warrant further study. Technology specifically directed at this technique will undoubtedly provide less invasive alternatives for vagus stimulation.

In summary, the present study demonstrated in an ovine model that reliable and escape-beat–free controlled intermittent asystole can be achieved by potentiation of vagal-induced asystole with a pharmacologic combination of propranolol and verapamil for suppression of electromechanical escape and pyridostigmine for acetylcholinesterase inhibition. Asystole can be reproducibly achieved for prolonged intervals as well as for more clinically applicable shorter multiple sequential intervals when this technique is used. These experiments demonstrate the feasibility of operator-initiated CIA and suggest the potential clinical utility for reducing cardiac motion during CABG procedures off-CPB. These results are reported to stimulate interest and further investigation of this phenomenon, which may be useful future clinical adjunct in cardiac surgery. Further characterization of the phenomenon of CIA, the cumulative physiologic and neurologic effects of multiple periods of asystole, long-term effects on the vagus nerve, and technologic refinements of the technique are areas for future investigation.

	Acknowledgments

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study was supported in part by the Carlyle Fraser Heart Center of Crawford Long Hospital and Emory University School of Medicine.

	Footnotes

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
After the completion of the study, Emory University, through its Office of Technology Transfer, has filed patent application(s) for some of the basic concepts in this presentation.

	References

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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10. Guyton A.C. Heart muscle: the heart as a pump. In: Guyton A.C., ed. Textbook of medical physiology, eighth ed. Philadelphia: Saunders, 1991:107-108.
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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Bradley L. Bufkin John D. Puskas Jakob Vinten-Johansen Robert A. Guyton Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bufkin, B. L. Articles by Guyton, R. A. Search for Related Content PubMed PubMed Citation Articles by Bufkin, B. L. Articles by Guyton, R. A.