ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
John D. Puskas
Robert A. Guyton
Jakob Vinten-Johansen
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Morris, C. D.
Right arrow Articles by Vinten-Johansen, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Morris, C. D.
Right arrow Articles by Vinten-Johansen, J.
Related Collections
Right arrow Electrophysiology - arrhythmias

Ann Thorac Surg 2001;72:679-687
© 2001 The Society of Thoracic Surgeons

Hawley H. Seiler Resident Award paper

Electroplegia: an alternative to blood cardioplegia for arresting the heart during conventional (on-pump) cardiac operation1

Cullen D. Morris, MD*,a, Jason M. Budde, MDa, Daniel A. Velez, MDa, Satoshi Muraki, MDa, Zhi-Qing Zhao, MDa, John D. Puskas, MDa, Robert A. Guyton, MDa, Jakob Vinten-Johansen, PhDa

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

Address reprint requests to Dr Vinten-Johansen, Cardiothoracic Research Laboratory, Crawford Long Hospital of Emory University, 550 W Peachtree St, Atlanta, GA 30308
e-mail: jvinten{at}emory.edu

Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 9–11, 2000.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 Discussion
 References
 
Background. Aortic cross-clamping is contraindicated in patients with severe atherosclerosis of the ascending aorta, and administration of chemical cardioplegia may be cumbersome in these patients. In this study, we demonstrate an alternative method of achieving cardioplegia by electrical stimulation of the vagus nerve.

Methods. In anesthetized canines, the left anterior descending coronary artery was reversibly ligated for 90 minutes, followed by cardiopulmonary bypass (CPB) and randomization to three groups (n = 8 each): (1) BCP group: 1 hour of intermittent hypothermic (4°C) blood cardioplegia infusion; (2) CPB group: 1 hour of CPB alone; (3) EP group (group receiving electroplegia): 1 hour of intermittent vagal stimulation (total of 60 20-second electrical stimuli at 40 Hz, 6 to 10 V) with adjunctive pyridostigmine (0.5 mg/kg), verapamil (50 µg/kg), and propranolol (80 µg/kg) to potentiate hyperpolarization and suppress ectopic escape beats.

Results. The EP group achieved consistent intervals of arrest with 3.8 ± 1.2 escape beats per 20-second stimulation period. After 2 hours of reperfusion off CPB, the left anterior descending coronary artery segmental shortening was reduced from baseline in all groups, but the segmental shortening recovered to a greater extent in the EP group than in either the CPB or BCP group (2.4% ± 1.4% versus -1.3% ± 1.3% versus -4.0% ± 0.8%, p < 0.05). Infarct size (TTC stain, percentage of area at risk) was comparable among groups (EP: 20.9% ± 4.7%; CPB: 29.6% ± 3.2%; BCP: 25.1% ± 5.7%). Postischemic left anterior descending coronary artery endothelial function (percent maximum relaxation to acetylcholine) was depressed in the EP group (68.6% ± 7.6% versus 102.3% ± 6.4%, p < 0.05), but was comparable versus nonischemic circumflex function in the BCP group (77.1% ± 11.9% versus 100.4% ± 10.0%, p = 0.15) and the CPB group (93.8% ± 6.6% versus 93.3% ± 6.6%).

Conclusions. Electroplegia achieves elective intermittent cardiac arrest, avoids hypothermia, chemical cardioplegia, and aortic cross-clamping, with physiological outcomes comparable to blood cardioplegia.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 Discussion
 References
 
Chemical cardioplegia maintains a quiet, bloodless field to avoid ischemic injury and ensure surgical precision. However, hyperkalemic solutions may have disadvantages related to depolarized arrest [1] and hypothermia [2, 3]. In addition, aortic cross-clamping is contraindicated in patients with severe atherosclerotic disease of the proximal aorta. An alternative technique for cardioplegia in patients with fragile aortae is cold, fibrillatory "arrest" without cross-clamping, but this method may be associated with subendocardial ischemia and necrosis [4–6] resulting from high oxygen demands and extravascular compressive forces in the subendocardial vascular bed. In such high-risk patients, a new method for elective arrest in cardiac operations is needed.

Vagus nerve stimulation (VNS) and its cholinergically mediated influence on the heart have been realized since the late nineteenth century [7], and the effects of acetylcholine on the myocardium have been well described [8, 9]. Furthermore, acetylcholine as an arresting agent was investigated in the 1950s for its ability to limit ventricular deterioration imposed by ischemia [10]. Recently, VNS has been applied to clinical cardiac procedures as a method of transiently arresting the heart [11], and experimental models have explored the use of VNS in the setting of off-pump cardiac operation [12, 13]. Bufkin and associates [12] reported that stimulation of the vagus nerve without pharmacologic enhancement resulted in short periods of arrest interrupted by frequent "escape beats," but that combined administration of the cholinesterase inhibitor pyridostigmine, the ß-blocker propranolol, and the calcium-channel blocker verapamil allowed vagal-induced pauses for up to 60 seconds. Evaluation of VNS as a means of achieving elective cardiac arrest in conventional on-pump applications has not been documented, and the ability of VNS to reduce reperfusion-induced arrythmias in models of coronary artery revascularization remains unknown. Vagal-induced arrest, in contrast to fibrillatory "arrest," would transiently reduce myocardial oxygen demand.

This study was designed to test the hypotheses that VNS achieves (1) intervals of arrest during surgical experimental reperfusion of acute myocardial infarction on cardiopulmonary bypass and (2) comparable postreperfusion physiologic outcomes in the reperfused myocardium compared to chemical cardioplegia.


   Material and methods
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 Discussion
 References
 
Twenty-four adult dogs weighing 20 to 35 kg were handled in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, received 1985). The Institutional Animal Care and Use Committee of Emory University approved the study protocol.

The animals were anesthetized with sodium pentobarbital (20 mg/kg) and endotracheally intubated. Deep anesthesia was maintained with intravenous fentanyl citrate (0.3 µg · kg-1 · min-1) and diazepam (0.03 µg · kg-1 · min-1). Each dog was ventilated with a volume-cycled respirator using oxygen-enriched room air, and adjustments were made to keep blood partial pressure of carbon dioxide between 35 to 45 mm Hg and arterial oxygen tension more than 75 mm Hg. A rectal temperature probe measured core body temperature. The right femoral artery and vein were cannulated with polyethylene catheters for blood sampling, fluid administration, and pressure measurement.

The dogs were instrumented as described previously [14]. After median sternotomy, the superior and inferior vena cavae were encircled with umbilical tapes, the azygos vein was ligated, and the heart was suspended in a pericardial cradle. Millar pressure catheters (Millar instruments, Houston, TX) were placed in the proximal aorta through the right internal mammary artery and in the left ventricle through a stab incision. A 1-cm portion of the left anterior descending coronary artery (LAD) distal to the first diagonal branch was encircled loosely with a 2-0 silk suture, which was later used to produce regional myocardial ischemia. A pair of 2.5-mm, 5-MHz piezoelectric ultrasonic crystals was implanted in the subendocardium of the myocardium perfused by the LAD (the area at risk, AAR) to measure segmental systolic contractile function and diastolic characteristics using a model 120 sonomicrometer (Triton Technology, Inc, San Diego, CA). Heparin was given (300 U/kg) before occlusion of the LAD, and was supplemented (150 U/kg) every 90 minutes thereafter. The left subclavian artery was cannulated for aortic perfusion. The superior and inferior vena cavae were cannulated through the right atrium for venous return, and the cannula tips were retracted into the atrial appendage to avoid interference with venous return. The bypass circuit was primed with 1,500 mL of 6% hetastarch in 0.9% sodium chloride.

The LAD was occluded for 75 minutes off-pump. A lidocaine infusion of 1 mg/min was started at the onset of LAD occlusion and continued until the animals were weaned from bypass. After 75 minutes of LAD occlusion, all animals were placed on bypass as described previously [14] and randomized to three groups (n = 8 in each group): cardiopulmonary bypass (CPB) group, total vented bypass for 90 minutes; blood cardioplegia (BCP) group, 1 hour of hypothermic multidose antegrade blood cardioplegia [14]; electroplegia (EP) group, 1 hour of intermittent vagal nerve stimulation at 40 Hz, 6 to 10 V, and duration of 1 to 2 milliseconds with adjunctive propranolol (80 µg/kg), pyridostigmine (0.5 mg/kg), and verapamil (50 µg/kg) [12]. The LAD was reperfused 15 minutes after initiation of bypass thereby replicating successful surgical revascularization of the ischemic segment while on bypass.

Sodium bicarbonate was used in some cases of metabolic acidosis, and neosynephrine was administered for blood pressure support when necessary to keep mean arterial pressure at about 70 mm Hg off CPB. No other vasopressors or inotropic agents were used. Insulin and glucose were used to control hyperkalemia when necessary. Atropine (0.5 mg) was used in one animal for persistent bradycardia in the EP group. Countershocks of 5 to 30 J was used to convert ventricular fibrillation to normal sinus rhythm.

In the CPB group, bypass was discontinued after 90 minutes, and the LAD was further reperfused for 120 minutes in the beating working state.

In the BCP group, the aorta was cross-clamped, and hypothermic multidose hyperkalemic blood cardioplegia (8 parts blood: 1 part crystalloid) [14] was delivered through a double lumen catheter (DLP, Inc, Grand Rapids, MI) at 50 mm Hg using the Myocardial Protection System console (MPS, Quest Medical, Allen, TX). Cardioplegia [14] was delivered for 3 minutes during induction (20 MEq KCl/L, 4°C), and for 2 minutes after 20 and 40 minutes of arrest (10 MEq KCl/L, 4°C) (Table 1). The terminal (60 minutes) cardioplegia was a 3-minute hot shot (20 MEq/L KCl, 27°C) infusion delivered immediately before cross-clamp removal. Systemic blood was rewarmed to 37°C, and the aorta was unclamped. After mechanical activity appeared, the mean arterial pressure was gradually increased from 50 to 80 mm Hg over a period of 5 minutes. The heart was maintained on vented bypass for the first 30 minutes of reperfusion (beating empty), after which CPB was discontinued. Total CPB time was 90 minutes in all three groups.


View this table:
[in this window]
[in a new window]
  		Table 1. Blood Cardioplegia Composition (8 Parts Blood to 1 Part Crystalloid)

 
In the EP group, the right vagus nerve was isolated through a cervical incision, as previously described [12]. Intravenous pyridostigmine (0.5 mg/kg), propranolol (80 µg/kg), and verapamil (50 µg/kg) were administered intravenously (and every 20 minutes thereafter during bypass), and the animals were placed on vented bypass. To simulate the VNS protocol applicable to a three-vessel coronary artery bypass grafting procedure, each EP animal received three "sets" of 20 sequential VNS stimulations (Grass Instruments Corp, Quincy, MA) at 40 Hz, 6 to 10 V, and for a duration of 1 to 2 milliseconds. Each stimulation was applied for 20 seconds (heart arrested) followed by 20 seconds of no stimulation (heart beating). (In practice, surgeons would control the time of arrest to place a suture in the target vessel. They would allow mechanical beating to resume by "turning off" the stimulation when they needed to prepare the needle for the next stitch.) Each set of 20 sequential stimulations was separated by 10 minutes of no electrical stimulation. The total time for intermittent vagus nerve stimulation was approximately 60 minutes. After 60 minutes of intermittent VNS, the heart was maintained on vented bypass for an additional 30 minutes of empty beating.

All hearts were weaned from CPB after 90 minutes of bypass time, and reperfusion was continued in the working beating state for an additional 120 minutes. The experiment was terminated with a bolus of intravenous sodium pentobarbital (100 mg/kg).

To quantify coronary artery endothelial function, all hearts were immediately excised and placed into cold oxygenated Krebs-Henseleit buffer of the following millimolar composition: 118 NaCl, 4.7 KCl, 1.2 KH2PO4, 1.2 MgSO4 · 7H2O, 2.5 CaCl2 · 2H2O, 12.5 NaHCO3, and 11 glucose at pH 7.4.

Data acquisition
Analog hemodynamic and cardiodynamic data were sampled by a personal computer using an analog-to-digital converter (model DT2801A; Data Translation, Marlboro, MA) sampling at 250 Hz, as previously described [14]. Measurements were taken before LAD occlusion (baseline), after 75 minutes of LAD occlusion (ischemia), and after 30, 60, and 120 minutes off bypass (R30, R60, R120, respectively) during 12-second periods of respiratory apnea.

Determination of AAR and infarct size
After experimental excision of the heart, the myocardial AAR was determined by religating the LAD and infusing unisperse blue dye into the aortic root to outline the AAR. The left ventricle was isolated and sliced transversely into approximately 1-cm thick sections and weighed. Nonischemic tissue (blue) was separated from the undyed AAR. The AAR was incubated in phosphate buffered 1% 2,3,5-triphenyltetrazolium chloride (TTC; Sigma Chemical, St. Louis, MO) at 38°C for 10 minutes. Viable tissue was stained red and necrotic tissue remained pale. The percent AAR was calculated as the sum of the weights of the ischemic tissue, and the percent infarct size was calculated as the weight of the necrotic tissue divided by the AAR and multiplied by 100.

Plasma creatine kinase activity
Arterial blood samples to measure creatine kinase activity were analyzed spectrophotometrically (CK-10 kit; Sigma Diagnostics, St. Louis, MO) and expressed as international units per gram of protein.

Myocardial edema
Postexperimental myocardial tissue samples weighing about 0.3 g were taken from the subepicardial and subendocardial regions of the AAR and nonischemic left ventricle and dessicated for 48 hours. Percent myocardial water was defined as: .

Cardiac myeloperoxidase activity
Tissue samples weighing about 0.4 g were taken from the subepicardial and subendocardial regions of the AAR and nonischemic myocardium for spectrophotometric analysis of myeloperoxidase activity as an assessment of neutrophil accumulation in the myocardium [15].

Postexperimental endothelial function
Postexperimental LAD and left circumflex (LCx) coronary arteries were excised, divided into 4- to 5-mm rings, placed into Krebs-Henseleit perfused organ baths at 37.5°C aerated with 95% O2 and 5% CO2, and connected to isometric force transducers (model TR001; Radnoti, Monrovia, CA). The rings were stabilized at 3 g resting tension for 30 minutes and incubated throughout the assay with 10 µmol/L indomethacin to prevent vascular response to endogenous prostacyclin. The rings were preconstricted with 5 nmol/L U46619 (Sigma Chemical), a thromboxane A2 mimetic. The endothelium-dependent receptor-mediated nitric oxide synthase stimulator acetylcholine was given in incremental concentrations (1 x 10-9 to 6.86 x 10-7 mol/L). Concentration-dependent vascular responses were also determined for the calcium ionophore A23187, a nonreceptor-mediated, endothelium-dependent stimulator of nitric oxide synthase, and for the endothelium-independent smooth muscle relaxant and nitric oxide donor, sodium nitroprusside [16]. Changes in isometric force were digitized at 2 Hz using an analog-to-digital converter (DT2827; Data Translation) and personal computer. Relaxation was expressed as a percentage of U46619-induced constriction. The EC50 (in -log[mol/L]) for each drug was calculated as the dose of the drug required to cause 50% relaxation from preconstricted levels. All drug concentrations are expressed as the final concentration in the organ baths.

Statistical analysis
The data were analyzed by one-way analysis of variance for discrete variables, and by two-way analysis of variance for repeated measures for group, time, and group–time interactions for longitudinal data. If significant differences were found, Student-Neuman-Keul’s post hoc multiple comparisons tests were applied to locate the source of differences. p less than 0.05 was considered significant; means ± standard error of the mean are reported.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 Discussion
 References
 
Vagal escape beats in the EP group
In the EP group, the number of escape beats per 20-second stimulation period averaged 0.5 ± 0.1 beats in the first EP set (EP1) while the LAD remained occluded. Escape beats increased to 6.6 ± 2.6 beats in the second EP set (EP2) and 4.2 ± 2.0 beats in the third EP set (EP3) after the LAD was reperfused. The overall number of escape beats per 20-second period averaged 3.8 ± 1.2 beats. The time to return of mechanical activity after each 20-second stimulation was discontinued averaged 2.6 ± 0.6 seconds after EP1, 3.4 ± 1.1 seconds after EP2, and 3.9 ± 0.9 seconds after EP3.

Hemodynamics
Heart rate increased from baseline in all groups after LAD occlusion with no group differences and increased further during reperfusion in the CPB and BCP groups (Table 2). Heart rate was persistently lower in the EP group throughout reperfusion (Table 2). Mean aortic pressure was comparable among groups at all times (Table 2). Left ventricular end-diastolic pressure increased significantly from baseline by R120 in EP and CPB, but not in BCP. However, there were no differences in left ventricular and end-diastolic pressure among groups at any time.


View this table:
[in this window]
[in a new window]
  		Table 2. Hemodynamic and Cardiodynamic Data

 
There were no group differences in phenylephrine usage, and only one animal (EP group) required 0.5 mg of atropine during weaning from bypass to reverse extreme bradycardia.

Cardiodynamics
All groups demonstrated comparable segmental systolic contractile function in the AAR during baseline. During ischemia, all groups achieved a comparable level of dyskinesis (Table 2). There was no significant recovery of segmental systolic contractile function during reperfusion in the CPB or BCP groups (Table 2). However, segmental systolic contractile function was significantly greater in the EP group (9% of baseline shortening). Segmental work, the integral of the pressure–length loop, showed a similar pattern of recovery and significance. Diastolic stiffness of the AAR was comparable at baseline and did not increase significantly after LAD occlusion or during reperfusion in any group (Table 2).

AAR and infarct size
The area placed at risk by occluding the LAD, expressed as a percentage of left ventricular mass was comparable (AAR/left ventricle) among EP (21.2% ± 2.0%), CPB (22.2% ± 2.3%), and BCP (26.3% ± 0.7%) groups. The infarct size, calculated as a percentage of the AAR (necrotic tissue/AAR), was similar among the three groups (Fig 1).



View larger version (23K):
[in this window]
[in a new window]
  		Fig 1. Infarct size evaluated by 1% 2,3,5-triphenyltetrazolium chloride solution. There are no differences between groups. (BCP = group receiving intermittent hypothermic blood cardioplegia; CPB = group receiving cardiopulmonary bypass only; EP = group receiving electroplegia.)

 
Plasma creatine kinase activity
There were no differences in plasma creatine kinase activity at baseline among the three groups (Fig 2). There was no significant increase in plasma creatine kinase activity after 75 minutes of LAD occlusion. However, significant increases in plasma creatine kinase activity were observed after 15 minutes of reperfusion, which generally reached a plateau. There were no significant differences in plasma creatine kinase activity among groups at any time.



View larger version (27K):
[in this window]
[in a new window]
  		Fig 2. Plasma creatine kinase activity in international units per gram of tissue (IU/g) confirms the infarct size data. There were no significant differences among groups at any time. (Base = baseline data point; BCP = group receiving intermittent hypothermic blood cardioplegia; CPB = group receiving cardiopulmonary bypass only; EP = group receiving electroplegia; Ischemia = data point at 75 minutes of left anterior descending coronary artery occlusion; R = reperfusion; 15, 30, 60, and 120 = minutes of reperfusion.)

 
Cardiac myeloperoxidase activity
Neutrophil accumulation, assessed by myeloperoxidase activity in transmural myocardium, was greater in the ischemic-reperfused AAR compared to the nonischemic myocardium. In addition, myeloperoxidase activity was greater in the subepicardial region than the subendocardial region in both AAR and nonischemic segments. However, there were no group differences in the AAR and nonischemic zone (Fig 3).



View larger version (26K):
[in this window]
[in a new window]
  		Fig 3. Myeloperoxidase activity (in absorbance [Abs] units per minute per gram of tissue) as a marker for neutrophil accumulation demonstrates no group differences in the area at risk (AAR) and in the nonischemic zone. (BCP = group receiving intermittent hypothermic blood cardioplegia; CPB = group receiving cardiopulmonary bypass only; Endo = subendocardium; EP = group receiving electroplegia; Epi = subepicardium.)

 
Myocardial edema
Tissue water content in normal control myocardium averaged 78.24 ± 0.21% (n = 6). There were no group differences in myocardial edema in the subepicardium or subendocardium of the AAR and nonischmemic zones (Fig 4).



View larger version (28K):
[in this window]
[in a new window]
  		Fig 4. Myocardial edema. There were no group differences in percent tissue water content in the subepicardium or subendocardium of the area at risk (AAR) and nonischemic zones. (BCP = group receiving intermittent hypothermic blood cardioplegia; CPB = group receiving cardiopulmonary bypass only; Endo = subendocardium; EP = group receiving electroplegia; Epi = subepicardium.)

 
Endothelial function
There were no group differences in maximum responses to acetylcholine in the nonischemic LCx. Relaxation responses in the LAD to acetylcholine was similar among the CPB and BCP groups, and was not significantly different from responses in the respective LCx (Fig 5). However, in the EP group, maximal relaxation to acetylcholine in the LAD (68.6% ± 7.6%, p < 0.05) was significantly less compared to the nonischemic LCx (102.3% ± 6.4%). In addition, there were no significant group differences in the EC50 for acetylcholine in the LAD (CPB group, -7.57 ± 0.08; BCP group, -7.11 ± 0.19; EP group, -7.3 ± 0.16) or in the LCx (CPB group, -7.54 ± 0.10; BCP group, -7.49 ± 0.12; EP group, -7.67 ± 0.12). Responses of the LAD to A23187 and nitroprusside were comparable between LAD and LCx with no group differences (data not shown).



View larger version (16K):
[in this window]
[in a new window]
  		Fig 5. Percent maximal relaxation to acetylcholine (Ach) after preconstriction with a thromboxane A2 mimetic in the ischemic-reperfused left anterior descending coronary artery (LAD) and nonischemic left circumflex coronary artery (CX) in all three groups. The maximal relaxation to acetylcholine in the left anterior descending coronary artery was significantly less compared to the nonischemic left circumflex coronary artery in the group receiving electroplegia (EP) group. (BCP = group receiving intermittent hypothermic blood cardioplegia; CPB = group receiving cardiopulmonary bypass only.)

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 Discussion
 References
 
Previously, our laboratory demonstrated the feasibility of inducing complete and uninterrupted cardiac arrest by transient stimulation of the vagus nerve in an experimental model of off-pump cardiac surgery [12] with no associated myocardial or neural injury when used with an acetylcholinesterase inhibitor, a ß-adrenergic blocker, and a calcium-channel blocker [13] in normal (nonischemic) myocardium [13]. In the present study, we used a similar protocol of pharmacologically potentiated VNS (EP) as a method of inducing temporary electromechanical arrest in an experimental model of conventional (on-pump) coronary artery revascularization. We chose this model (1) to test the utility of EP in a clinically relevant model of coronary artery revascularization with the potential for severe arrhythmias and reperfusion injury, and (2) to compare the physiologic outcomes of EP without traditional strategies of myocardial protection to outcomes when a blood cardiopegia strategy was used. In this setting, surgeon-controlled transient electrical stimulation of the right vagus nerve, augmented with acetylcholinesterase inhibition, nonselective ß-blockade, and Ca2+-channel blockade during cardiopulmonary bypass, can achieve predictable intermittent arrest without aortic cross-clamping or use of potassium cardioplegia solutions. Such controlled asystole would presumably generate less myocardial work than a continuously fibrillating heart [17]. Asystole was induced for intervals of 20 seconds, which is sufficient time to place single sutures in the target vessel to construct a distal anastomosis. Our data suggest that EP achieved an infarct size, degree of tissue edema, and degree of neutrophil accumulation comparable to that of the group administered intermittent hypothermic blood cardioplegia. Therefore, EP may be an alternative method of stabilizing the target myocardium in cases where hypothermia, chemical cardioplegia, or aortic cross-clamping are contraindicated.

Vagus nerve stimulation results in acetylcholine release, which causes the physiologic effects of bradycardia and attenuated conduction velocity through the M2 subtype of muscarinic receptors [8]. However, acetylcholine is rapidly cleaved into an acetate ion and choline by acetylcholinesterase [8]. Acetylcholine activates the opening of acetylcholine-controlled K+ channels through a G-protein-mediated signal that hyperpolarizes the cardiac cell membrane by increasing the efflux of K+ [9]. Hyperpolarization of the cell membrane shortens the plateau of the cardiac action potential, slows the sinus pacemaker, and decreases inotropy [7–9]. A second effect, also G-protein mediated, is the inhibition of cyclic AMP production, which limits the inward calcium current [9]. The inward calcium current is the major current during diastolic depolarization leading to the action potential, and calcium is also responsible for the action potential’s plateau [9]. The M2 stimulation by acetylcholine causes negative inotropy independent of its negative chronotropic effects [7].

The right vagus nerve innervates primarily the sinoatrial node, whereas the left vagus nerve predominates over the atrioventricular node [8, 12]. Bufkin and colleagues [12] reported that stimulation of the left vagus nerve failed to induce arrest for any length of time, likely due to its innervation of the atrioventricular node. In the study by Bufkin and associates [12], stimulation of the right vagus nerve without drug therapy produced brief (1.6 ± 0.9 seconds) pauses followed by escape beats and sinus bradycardia for the duration of stimulation. Only short and inconsistent pauses could be achieved, similar to the clinical report by Matheny and Shaar [11] in which vagus nerve stimulation was used during critical points in the internal mammary-to-LAD anastomosis. Thus, VNS alone, without pharmacologic adjuncts to reduce the degradation of acetylcholine and attenuate escape rhythms, does not arrest the heart for more than a few seconds. Furthermore, the drug regimen alone, without VNS, did not arrest the heart. Pyridostigmine prevents the degradation of acetylcholine, whereas propranolol and verapamil prevent ventricular escape beats, which occur secondary to sympathetic stimulation. The VNS with pharmacologic potentiation prolonged asystolic pauses for up to 60 seconds and achieved sequential 15-second periods of transient arrest with rare occurrences of escape beats. Normal sinus rhythm returned after cessation of stimulation within 5 seconds of terminating electrical stimulation.

Preliminary work in our laboratory examined the efficacy of the drug combination on suppressing escape beats during vagal-induced arrest. Each drug used in the present study was examined individually and in random combinations, and the combination of pyridostigmine, verapamil, and propranolol demonstrated the greatest efficacy in prolonging asystole and suppressing escape beats [12]. Any drug given individually during VNS had minimal effect in suppressing escape beats during VNS [12].

In the present study, frequent arrhythmias arising from ectopic foci occurred during reperfusion of the previously ischemic LAD. Hence, interruption of vagal-induced arrest was more common after reperfusion was initiated than during ligation, but the time to reanimation after discontinuation of stimulation was similar (overall average, 3.3 ± 0.5 seconds) to that observed by Bufkin and colleagues [12]. Escape beats were also occasionally stimulated by manipulation of the heart. However, the appearance of these beats was unpredictable; they were absent in some animals and present in others. The beats interrupting the vagal-induced pauses were generally of ectopic origin rather than of sinus origin.

The combination drug therapy had some modest hemodynamic effects in the present study. Heart rate was lower in the EP group than in the other two groups during reperfusion (ie, after pharmacologic treatment). This is consistent with the bradycardia and negative inotropic response reported by Bufkin and associates after administration of combined drug therapy [12]. However, the negative chronotropy had no effect on mean aortic pressure in the present study or in the study by Bufkin and co-workers [12]. In addition, the lower heart rate at reperfusion likely had no influence on infarct size, as heart rate is a known determinant of severity of ischemia but not of reperfusion injury [17]. However, the lower heart rate in the EP group may be the cause of the greater postischemic contractile function observed in that group, because fractional shortening is heart rate sensitive (similar to stroke volume) [18]. Lower heart rate in the EP group may have been associated with increased diastolic filling, which has been shown by Vinten-Johansen and associates [18] to convert dyskinesis to active shortening in postischemic myocardial segments by a local Frank-Starling response.

Endothelial function was preserved in the LCx but not the ischemic-reperfused LAD in the EP group. Previous studies have described the effect of ischemia/reperfusion on the endothelium and have documented decreased endothelium-dependent receptor-mediated vasorelaxation [19]. In the EP group, blunted responses to receptor-dependent acetylcholine were observed in the LAD, suggesting endothelial dysfunction. However, the blunted relaxation responses could also represent desensitization of endothelial muscarinic receptor activity secondary to repeated acetylcholine release with vagus nerve stimulation and prolonged exposure to acetylcholine secondary to use of pyridostigmine [20, 21]. This is supported by the observation that there was no reduction in LAD relaxation responses to endothelial-dependent but receptor-independent relaxation with the calcium ionophore A23187. Although the degree of endothelial dysfunction in the LAD of the EP group was not sufficiently large to be significantly different from that seen in the LAD of the other two groups (Fig 5), the responses were significantly lower than those observed in the paired LCx.

Limitations
The lack of myocardial protection in the vagal-induced arrest technique was a concern when comparing it to other arrest methods that incorporate protective strategies. The BCP group represented a popular method of arrest and protection in cases of revascularization for acute coronary occlusion, whereas the CPB group was designed to demonstrate the effect of cardiopulmonary bypass alone on postischemic variables. Therefore, we chose the coronary occlusion/reperfusion model, which allows quantitative comparison of postischemic end points that are sensitive to ischemic/reperfusion injury. Although the acute model does create a heart susceptible to reperfusion arrhythmias and injury, its direct clinical relevance is limited.

The combination drug therapy used in the present study may be associated with undesirable side effects. In the EP group, we observed an elevation of plasma K+ during reperfusion compared to the CPB and BCP groups (Table 2). The acetylcholine-mediated opening of cell membrane potassium channels may be responsible for an increased efflux of K+ and the observed hyperkalemia. This hyperkalemia may predispose a patient to arrhythmias, especially after reperfusion of revascularized myocardium, and could be problematic in patients with such conditions as renal failure. Potassium channel inhibitors may counteract this increased potassium efflux. Other side effects included defecation and occasional excessive salivation of the animal during the procedure. In addition, bradycardia was sufficient in one animal in the EP group to prompt administration of atropine. These problems may be reduced by use of shorter acting drugs, or finding the lowest most effective dose of each drug in combination.

Conclusions
In the present study, we have demonstrated that vagal-induced electroplegia achieves transient periods of asystole in a surgeon-controlled fashion. This alternative method of arresting the heart can induce cardiac quiescence during placement of anastomotic sutures in the target vessel, thereby maintaining surgical precision. Electroplegia avoids the need for aortic cross-clamping and may be applicable in those patients with severely diseased aortae who require the safety net of CPB. By avoiding the aortic cross-clamp, the dislodgement of atherosclerotic debris from the aorta can be limited. The presence of atherosclerosis in the aorta is the most powerful predictor for postoperative stroke after cardiac operations [22]. Using the model of surgical revascularization for acute coronary occlusion, outcomes of physiologic variables sensitive to ischemic–reperfusion injury were largely comparable between EP and BCP despite the absence of specific cardioprotective strategies in the group receiving EP. Future studies should examine methods to better suppress reperfusion ectopic foci that interrupt asystole induced by VNS. In addition, EP should be compared to other nonchemical techniques such as "cold fibrillatory arrest." The appearances of hyperkalemia and potential postischemic endothelial dysfunction with electroplegia need to be addressed before the technique is comfortably applied to clinical practice.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
Discussion
 References
 
We thank L. Susan Schmarkey, BS, Sara Katzmark, BS, Jill Robinson, BA, and Rachel Otto, BA, for technical assistance, and Gail Nechtman and Laurie Berley for help in manuscript preparation. We also thank The Carlyle Fraser Heart Center for their continued support of our research efforts. Cullen D. Morris is a Carlyle Fraser Fellow.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 Discussion
 References
 
1 The Hawley H. Seiler Resident Award is presented annually to the resident with the oral presentation and manuscript deemed the best of those submitted for the competition. This Award was inaugurated in 1997 to honor Dr Seiler for his contributions and dedicated service to the Southern Thoracic Surgical Association. Back

* Recipient of the 2000 Hawley H. Seiler Resident Award. Back


   Discussion
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 Discussion
References
 
DR GEORGE DAICOFF (St. Petersburg, FL): It reminds me of a very old experiment we did on dogs, maybe 40 years ago, using hypothermia and acetylcholine arrest, and I wondered, why not do your technique off-pump? Why not try to arrest the heart or to slow it down to do the suturing and avoid the pump as well? Have you tried that?

DR MORRIS: A very good question. I have to give credit to a member of the audience here. Dr Bufkin did a lot of the early work, essentially the early work in our laboratory, and this was the initial application for vagal-induced arrest when he decided that this would be a great way to stop the heart electively in off-pump applications, and this was before really we got the good stabilizing techniques, and it became quite successful. In that initial slide that I showed you with the data acquisition, the left ventricular pressure and aortic pressure was done in an ovine model of off-pump, and it was quite successful and worked well in our laboratory.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 Discussion
 References
 

  1. Maskal S.L., Cohen N.M., Hsia P.W., Wechsler A.S., Damiano R.J., Jr Hyperpolarized cardiac arrest with a potassium-channel opener, aprikalim. J Thorac Cardiovasc Surg 1995;110:1083-1095.[Abstract/Free Full Text]
  2. Craver J.M., Bufkin B.L., Weintraub W.S., Guyton R.A. Neurologic events after coronary bypass grafting: further observations with warm cardioplegia. Ann Thorac Surg 1995;59:1429-1434.[Abstract/Free Full Text]
  3. Lichtenstein S.V., Ashe K.A., El Dalati H., Cusimano R.J., Panos A., Slutsky A.S. Warm heart surgery. J Thorac Cardiovasc Surg 1991;101:269-274.[Abstract]
  4. Buckberg G.D., Hottenrott C.E. Ventricular fibrillation. Its effect on myocardial flow, distribution, and performance. Ann Thorac Surg 1975;20:76-85.[Abstract]
  5. Hearse D.J., Stewart D.A., Chain E.B. Recovery from cardiac bypass and elective cardiac arrest. The metabolic consequences of various cardioplegic procedures in the isolated rat heart. Circ Res 1974;35:448-457.[Abstract/Free Full Text]
  6. Buckberg G.D. Collective review: left ventricular subendocardial necrosis. Ann Thorac Surg 1977;24:379-393.[Abstract]
  7. Xenopoulos N.P., Applegate R.J. The effect of vagal stimulation on left ventricular systolic and diastolic performance. Am J Physiol 1994;266(Heart Circ Physiol 35):H2167-H2173.[Abstract/Free Full Text]
  8. Guyton A.C. Heart muscle; the heart as a pump. In: Guyton A.C., ed. Textbook of medical physiology. Philadelphia: WB Saunders, 1991:98-117.
  9. Katz A.M. The cardiac action potential. In: Katz A.M., ed. Physiology of the heart. New York: Raven Press, 1992:438-472.
  10. Weirich W.L., Jones R.W., Burke M.F. The effect of elective cardiac arrest induced by potassium citrate and acetylcholine on ventricular function. Surg Forum 1959;10:528-532.
  11. Matheny R.G., Shaar C.J. Vagus nerve stimulation as a method to temporarily slow or arrest the heart. Ann Thorac Surg 1997;63:S28.
  12. Bufkin B.L., Puskas J.D., Vinten-Johansen J., Shearer S.T., Guyton R.A. Controlled intermittent asystole: pharmacologic potentiation of vagal-induced asystole. Ann Thorac Surg 1998;66:1185-1190.[Abstract/Free Full Text]
  13. Thourani V.H., Ronson R.S., Van Wylen D.G., et al. Adenosine-supplemented blood cardioplegia attenuates postischemic dysfunction after severe regional ischemia. Circulation 1999;100(Suppl 19):II376-II383.
  14. Sato H., Jordan J.E., Zhao Z.-Q., Sarvotham S.S., Vinten-Johansen J. Gradual reperfusion reduces infarct size and endothelial injury but augments neutrophil accumulation. Ann Thorac Surg 1997;64:1099-1107.[Abstract/Free Full Text]
  15. Lefer D.J., Nakanishi K., Johnston W.E., Vinten-Johansen J. Anti-neutrophil and myocardial protecting action of SPM-5185, a novel nitric oxide (NO) donor, following acute myocardial ischemia and reperfusion in dogs. Circulation 1993;88:2337-2350.[Abstract/Free Full Text]
  16. Nakanishi K., Zhao Z.-Q., Vinten-Johansen J., Lewis J.C., McGee D.S., Hammon J.W.J. Coronary artery endothelial dysfunction after ischemia, blood cardioplegia, and reperfusion. Ann Thorac Surg 1994;58:191-199.[Abstract]
  17. Kay H.R., Levine F.H., Fallon J.T., et al. Effect of cross-clamp time, temperature, and cardioplegic agents on myocardial function after induced arrest. J Thorac Cardiovasc Surg 1978;76:590-603.[Abstract]
  18. Vinten-Johansen J., Carroll P.J., Johnston W.E., et al. Reversal of dyskinesis by increased end diastolic segment length in ischaemic-reperfused myocardium. Cardiovasc Res 1989;23:810-820.[Medline]
  19. Evora P.R.B., Pearson P.J., Schaff H.V. Impaired endothelium-dependent relaxation after coronary reperfusion injury: evidence for G-protein dysfunction. Ann Thorac Surg 1994;57:1550-1556.[Abstract]
  20. Bünemann M., Lee K.B., Pals-Rylaarsdam R., Roseberry A.G., Hosey M.M. Desensitization of G-protein-coupled receptors in the cardiovascular system. Annu Rev Physiol 1999;61:169-192.[Medline]
  21. Wellner-Kienitz M.-C., Bender K., Meyer T., Bünemann M., Potts L. Overexpressed A1 adenosine receptors reduce activation of acetylcholine-sensitive K+ current by native muscarinic M2 receptors in rat atrial myocytes. Circ Res 2000;86:643-648.[Abstract/Free Full Text]
  22. John R., Choudhri A.F., Weinberg A.D., et al. Multicenter review of preoperative risk factors for stroke after coronary artery bypass grafting. Ann Thorac Surg 2000;69:30-36.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Ann. Thorac. Surg.Home page
R. S. Ronson, J. D. Puskas, V. H. Thourani, D. A. Velez, B. L. Bufkin, J. Glass, R. A. Guyton, and J. Vinten-Johansen
Controlled intermittent asystole cardiac therapy induced by pharmacologically potentiated vagus nerve stimulation in normal and hibernating myocardium
Ann. Thorac. Surg., June 1, 2003; 75(6): 1929 - 1936.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
John D. Puskas
Robert A. Guyton
Jakob Vinten-Johansen
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Morris, C. D.
Right arrow Articles by Vinten-Johansen, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Morris, C. D.
Right arrow Articles by Vinten-Johansen, J.
Related Collections
Right arrow Electrophysiology - arrhythmias

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS