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United States Patent |
6,184,239
|
Puskas
|
February 6, 2001
|
Pharmacologic drug combination in vagal-induced asystole
Abstract
Controlled cessation of heart beat during coronary bypass surgery and other
cardiac surgeries on a beating heart improves surgical technique, and is
achieved typically by electrical stimulation of the vagus nerve and
administration of a combination of drugs.
Inventors:
|
Puskas; John D. (Atlanta, GA)
|
Assignee:
|
Emory University (Atlanta, GA)
|
Appl. No.:
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139442 |
Filed:
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August 25, 1998 |
Intern'l Class: |
A61K 031/41 |
Field of Search: |
514/346,652,654,650
|
References Cited
U.S. Patent Documents
5651378 | Jul., 1997 | Matheny et al. | 128/898.
|
5668117 | Sep., 1997 | Shapiro | 514/55.
|
5889033 | Mar., 1999 | Kaminski | 514/370.
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Other References
Matheny, R.G., "Vagus Nerve Stimulation as a Method to Temporarily Slow or
Arrest the Heart,", Ann. Thorac Surg., vol. 63, pp. S28-S29, (1997).
Thompson, G.W., et al, "Bradycardia Induced by Intravascular Versus Direct
Stimulation of the Vagus Nerve,", Ann. Thorac Surg., vol. 65, pp.,
637-642, (1998).
Bradley L. Bufkin et al.; Controlled Intermittent Asystole: Pharmacologic
Potentiation of Vagal-Induced Asystoel; The Society of Thoracic Surgeons;
1998; pp. 1185-1190.
Dipiro, J.T., et al. Pharmacotherapy: A Pathophysiologic Approach. New
York: Elsevier. pp. 153-157. 1989.
Goodman and Gilman's, The Pharmacological Basis of Therapeutics (6.sup.th
Ed.). New York: Macmillan. pp. 93-94 and 104-108. 1980.
|
Primary Examiner: Moezie; F. T.
Attorney, Agent or Firm: Kilpatrick Stockton LLP
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. application Ser. No. 60/056,994
filed Aug. 26, 1997 and 60/072,284 filed Jan. 23, 1998, both are now
abandoned.
Claims
What is claimed is:
1. A pharmaceutical composition, comprising an acetylcholinesterase
inhibitor, a .beta.-adrenergic receptor blocker, and a calcium channel
blocker.
2. The composition of claim 1, wherein the acetylcholinesterase inhibitor
is pyridostygmine bromide.
3. The composition of claim 2, wherein the amount of acetylcholinesterase
inhibitor is in the range of about 0.01 mg/kg to about 100.0 mg/kg.
4. The composition of claim 3, wherein the amount of acetylcholinesterase
inhibitor is in the range of about 0.1 mg/kg to about 2.0 mg/kg.
5. The composition of claim 1, wherein the .beta.-adrenergic receptor
blocker is propranolol hydrochloride.
6. The composition of claim 5, wherein the amount of .beta.-adrenergic
receptor blocker is in the range of about 0.01 mg/kg to about 100.0 mg/kg.
7. The composition of claim 6, wherein the amount of .beta.-adrenergic
receptor blocker is in the range of about 0.01 mg/kg to about 2.0 mg/kg.
8. The composition of claim 1, wherein the calcium channel blocker is
verapamil bromide.
9. The composition of claim 8, wherein the amount of calcium channel
blocker is in the range of about 0.001 mg/kg to about 1.0 mg/kg.
10. The composition of claim 9, wherein the amount of calcium channel
blocker is in the range of about 0.01 mg/kg to about 0.2 mg/kg.
11. A pharmaceutical composition, comprising an acetylcholinesterase
inhibitor, wherein the acetylcholinesterase inhibitor is pyridostigmine
bromide, a .beta.-adrenergic receptor blocker, wherein the
.beta.adrenergic receptor blocker is propranolol hydrochloride, and a
calcium channel blocker, wherein the calcium channel blocker is verapamil
bromide.
12. The composition of claim 11, wherein the amount of acetylcholinesterase
inhibitor is in the range of about 0.01 mg/kg to about 100.0 mg/kg,
wherein the amount of .beta.-adrenergic receptor blocker is in the range
of about 0.01 mg/kg to about 100.0 mg/kg, and wherein the amount of
calcium channel blocker is in the range of about 0.001 mg/kg to about 1.0
mg/kg.
13. The composition of claim 12, wherein the amount of acetylcholinesterase
inhibitor is in the range of about 0.1 mg/kg to about 2.0 mg/kg, wherein
the amount of .beta.-adrenergic receptor blocker is in the rage of about
0.1 mg/kg to about 2.0 mg/kg, and wherein the amount of calcium channel
blocker is in the range of about 0.01 mg/kg to about 0.2 mg/kg.
14. A pharmaceutical composition, comprising acetylcholinesterase inhibitor
pyridostigmine bromide at a concentration in the range of about 0.1 mg/kg
to about 2.0 mg/kg, .beta.-adrenergic receptor blocker propanolol
hydrochloride at a concentration in the range of about 0.01 mg/kg to about
2.0 mg/kg, and calcium channel blocker verapamil bromide at a
concentration in the range of about 0.01 mg/kg to about 0.2 mg/kg.
Description
BACKGROUND OF THE INVENTION
Minimally invasive direct coronary artery bypass (MIDCAB) surgery, both via
sternotomy and alternative incisions, is a substantially revolutionary
development in surgery for allowing bypass surgery to be conducted on a
beating heart. However, beating heart surgery shows an undesirably higher
rate of early graft failure than conventional coronary artery bypass
procedures using cardiopulmonary bypass and cardioplegia. The technical
difficulty of sewing the coronary artery anastomosis on a beating heart is
likely an important factor in this difference in outcome between the two
techniques. Controlled intermittent asystole (CIA) during brief intervals
required for placing anastomotic sutures is suitable for improving the
precision of coronary anastomoses performed on a beating heart and
reducing graft failure while increasing ease of operation.
Cardiopulmonary bypass (CPB) and chemical arrest using cardioplegia
solutions have traditionally provided surgeons with optimal operative
conditions: hemodynamic control and cardiac quiescence. This optimal field
has contributed to technical success in increasingly complex cardiac
surgical operations. However, there has been recent interest in performing
coronary artery bypass surgery without either complete cardiopulmonary
bypass or cardioplegia. The quality of the distal anastomosis is a primary
concern among cardiac surgeons who observe and perform coronary artery
bypass graft (CABG) procedures unaided by cardioplegic arrest and
cardiopulmonary bypass. Coronary artery bypass graft failure rates
reported with minimally invasive direct coronary artery bypass range from
3.8 to 8.9%, while traditional CABG on CPB has a reported anastomotic
failure rate of 0.12%. This may reflect a difference in anastomotic
precision between MIDCAB and CPB-aided CABG. Although the benefits of
avoiding extracorporeal circulation and global cardioplegia in beating
heart procedures are important, they do not outweigh the performance of an
optimal coronary anastomosis.
The key difference in the anastomotic results between conventional CABG and
beating heart CABG is related to achieving elective asystole during
construction of the distal anastomosis. Cardiac motion can be minimized
during MIDCAB procedures via pharmacologic bradycardia (adenosine, .beta.
blockade) and mechanical stabilization using various devices. Although
these techniques do improve operative conditions, they only approximate
the advantages of elective asystole achieved with CPB and cardioplegia.
Applicants show that a state of controlled intermittent asystole (CIA) is
produced off CPB, which provides a major advantage otherwise gained by
cardioplegic arrest on CPB. In particular, CIA is achieved using
unilateral (or bilateral) vagus nerve stimulation coupled with
pharmacologic suppression of electromechanical escape activity.
Applicants demonstrate that elective, controlled intermittent asystole is
produced by vagus nerve stimulation after treatment with an
acetylcholinesterase inhibitor, a .beta.-adrenergic receptor blocker, or a
calcium channel blocker, or combinations thereof.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1. Duration of asystole achieved during 60 second vagal stimulation.
Lines connect the periods of asystole observed in the non-drug treated and
drug treated states in each experimental animal. Drug administration
lengthened significantly the period of asystole.
FIG. 2. Representative left ventricular and aortic pressure tracings during
60 second vagal stimulation in the non-drug treated (A) and drug treated
states (B). Dark and open arrows mark the initiation and termination of
the vagal impulse, respectively. Before drug treatment, a short pause
followed by escape and bradycardia was observed during the 60 second
impulse. After drug treatment, prolonged asystole occurred during the 60
second impulse with return of mechanical function after termination.
lvp--left ventricular pressure; aop--aortic pressure.
FIG. 3. Representative left ventricular and aortic pressure tracings during
sequential 15 second vagal stimulations in the non-drug treated (A) and
drug treated states (B). Dark and open arrows mark the initiation and
termination of the vagal impulses, respectively. Before drug treatment,
each 15 second stimulation produced a short pause followed by bradycardia,
while after drug treatment, asystole lasted the duration of each 15 second
stimulation. lvp--left ventricular pressure; aop--aortic pressure.
Abbreviations and Definitions
CABG Coronary artery bypass
graft
CIA Controlled intermittent
asystole
CPB Cardiopulmonary bypass
MIDCAB Minimally invasive direct
coronary artery bypass;
intended to include any
CABG without the use of
global cardioplegia;
synonymous with beating
heart surgery, irrespective
of incision
DETAILED DESCRIPTION OF THE INVENTION
Increased acetylcholine activity by acetylcholinesterase inhibition and
prevention of electromechanical escape activity by .beta.-adrenergic
receptor and calcium channel blockade during vagal stimulation produces a
marked potentiation of vagal-induced asystole and a means of achieving
CIA. CIA achieved by pharmacologic potentiation of vagal-induced asystole
is a suitable technique to facilitate MIDCAB operations. In particular,
anastomoses and other complex suturing is facilitated during such
controlled asystolic events, a readily appreciated advantage in surgery
involving minimally invasive direct coronary artery bypass operations on a
beating heart. CIA might have particular advantages in partially or
totally endoscopic CABG, and possibly in percutaneous or surgical
transmyocardial laser revascularization.
The present invention provides a pharmaceutical composition, comprising an
acetylcholinesterase inhibitor, .beta.-adrenergic receptor blocker, and a
calcium channel blocker, said composition useful for performing beating
heart surgery. The invention also provides that the composition is useful
for controlled intermittent asystole in minimally invasive direct coronary
artery bypass surgery. The invention further provides that the
compositions can be administered in combination with vagus nerve
stimulation. Vagus nerve stimulation can be achieved by direct or indirect
electrical stimulation.
In preferred independent embodiments, the acetylcholinesterase inhibitor
can be pyridostygmine bromide, the .beta.-adrenergic receptor blocker can
be propranolol hydrochloride, and the calcium channel blocker can be
verapamil bromide.
The invention also provides a pharmaceutical composition, comprising an
acetylcholinesterase inhibitor and a .beta.-adrenergic receptor blocker,
said composition useful for performing beating heart surgery. In preferred
embodiments, the acetylcholinesterase inhibitor can be pyridostygmine
bromide, the .beta.-adrenergic receptor blocker can be propranolol
hydrochloride, and the calcium channel blocker can be verapamil bromide.
The invention also provides that the composition is useful for controlled
intermittent asystole in minimally invasive direct coronary artery bypass
surgery. The invention further provides that the compositions can be
administered in combination with vagus nerve stimulation. Vagus nerve
stimulation can be achieved by direct or indirect electrical stimulation.
The invention also provides a pharmaceutical composition, comprising an
acetylcholinesterase inhibitor and a calcium channel blocker, said
composition useful for performing beating heart surgery. In preferred
embodiments, the acetylcholinesterase inhibitor can be pyridostygmine
bromide, the .beta.-adrenergic receptor blocker can be propranolol
hydrochloride, and the calcium channel blocker can be verapamil bromide.
The invention also provides that the composition is useful for controlled
intermittent asystole in minimally invasive direct coronary artery bypass
surgery. The invention further provides that the compositions can be
administered in combination with vagus nerve stimulation. Vagus nerve
stimulation can be achieved by direct or indirect electrical stimulation.
The principal challenge of beating heart CABG surgery has been to recreate
the advantageous operative conditions of a quiescent operative field
provided during conventional CABG with CPB and cardioplegic arrest. A
variety of pharmacologic manipulations and mechanical stabilizing
techniques assist in performing CABG off pump. These interventions to date
minimize, but do not eliminate, cardiac motion. The concept that a state
of controlled intermittent asystole improves the conditions for
construction of distal coronary artery bypass anastomosis in non-CPB
assisted cases was demonstrated by applicant. CIA is defined as
operator-initiated and controlled intervals of mechanical cardiac
standstill. These intervals may be timed to coincide with placement of
sutures in the anastomosis, after which normal cardiac rhythm and
hemodynamics are restored while preparations are made for the next
successive stitch. Experiments reported by the applicant indicate that the
minor bradycardia known to be produced by vagus nerve stimulation is
dramatically augmented to function as an electromechanical "on-off switch"
by pharmalogical inhibition of acetylcholinesterase and blockade of
.beta.-adrenergic receptors and calcium channels. Controlled intermittent
asystole may prove equally useful for CP.beta.-assisted cardiac surgery
without global cardioplegia.
The chronotropic effects of vagal nerve stimulation have been well
described and typically produce an initial pause followed by a "vagal
escape" beat and sustained bradycardia during continuous optimal
stimulation of the vagus nerve. Cardiac responses to a 60 second vagal
stimulation without adjunctive therapy achieved an average pause of 1.6
seconds terminated by vagal escape beats with a 19% reduction in heart
rate. Vagus nerve stimulation alone did not produce a controlled period of
asystole desired for CIA. In contrast, a triple pharmacologic regimen of
e.g., pyridostigmine, propranolol and verapamil inhibited vagal escape,
and allowed sustained periods of asystole lasting up to 60 seconds and
sequential asystoles of 15 seconds each. Segmental asystoles had no
significant hemodynamic consequences.
It is apparent that suppression of the electromechanical escape during
vagal stimulation is necessary to produce a sufficient interval of
asystole to allow during which a single stitch may be reliably placed
during construction of a distal CABG anastomosis. The negative
chronotropic effects of vagal stimulation are produced by acetylcholine
release. Acetylcholine activity may be enhanced by inhibition of
acetylcholinesterase activity by agents such as pyridostigmine.
Additionally, it is known that calcium channel blockade by e.g. verapamil
potentiates the negative chronotropic effect of vagus nerve stimulation.
Another component in electromechanical escape may be related to increased
catecholamine activity in the sympathetic nervous system, triggered by
hypotension. Catecholamines increase the rate of diastolic depolarization
and decrease the threshold potential. .beta.-adrenergic receptor blockade
via e.g. propanolol reduces the effects of catecholamine activity and
facilitates suppression of electromechanical escape.
Administration of this combination therapy produced a significant reduction
in heart rate and maximum developed ventricular pressure along with an
increase in left ventricular end-diastolic pressure, but did not alter
mean arterial pressure. There was no apparent fatigue of this
pharmacologic effect after sequential stimulations. The animals used for
pilot experiments appeared to tolerate this pharmacologic regimen without
other adverse hemodynamic side effects, such as acidosis.
The short-term hemodynamic effects of a single prolonged stimulation were
found to be substantially insignificant. Likewise the metabolic
consequences as detected by pH and changes in base deficit were
insignificant.
The pharmacologic regimen used in this investigation sustained the period
of vagal-induced asystole for about sixty seconds. This interval would
allow more than sufficient time for construction of a distal CABG
anastomosis. Animals followed for two hours after administration of drugs
displayed responses to vagal stimulation similar to those in the non-drug
treated state, confirming reversibility of the drug effects.
An untoward effect of the pharmacologic regimen which requires
consideration before clinical application is vagal-induced secretions. All
animals displayed significant salivation after initiation of vagal
stimulation. However, there were no problems with oxygenation and
ventilation due to tracheobronchial secretions in these experiments.
Vagal-induced oripharyngeal and tracheobronchial secretions are pertinent
in the clinical setting. Additionally, the effects on recurrent laryngeal
nerve function require consideration.
Evidence suggests that the long-term effects of this regimen on the vagus
nerve are not harmful. Chronic vagus nerve stimulation has been utilized
as therapy for intractable seizure disorders without apparent nerve injury
or impaired function. Applicants have shown that vagal-mediated
chronotropic control at two hours after completion of the experimental
protocol was similar to the non-drug treated state.
In summary, controlled intermittent asystole can be achieved by
potentiation of vagal-induced asystole via a pharmacologic combination of
e.g., propranolol and verapamil for suppression of electromechanical
escape and e.g., pyridostigmine for acetylcholinesterase inhibition.
Asystole can be reproducibly achieved for prolonged intervals and for
shorter multiple sequential intervals using this technique.
Nerve Stimulation
To achieve consistent asystole, applicants have found that nerve
stimulation of the right vagus nerve before or after treatment with the
pharmacological combinations of the present invention is preferred.
Electrical stimulation is carried out on the right vagus nerve, preferably
at a site on the neck. Other suitable locations for vagus nerve
stimulation include, but are not limited to, unipolar or bipolar
electrical stimulation of the right or left vagus, or both, stimulation of
the vagus in the chest after sternotomy, stimulation with a percutaneous
catheter or electrode probe in the internal jugular vein, esophagus, or
trachea, or combination of these. The nerve stimulator is typically a
Grass wire with a single point of contact, but other suitable stimulators
include a pair of pacing wires or electrodes placed about 1 cm apart to
allow bipolar prodromic stimulation. A single continuous impulse is
applied of between about 5 seconds to about 90 seconds, preferably between
about 5 seconds and about 15 seconds to allow single stitch during
surgery. Impulse parameters can readily be varied, e.g., a frequency range
of between about 1 Hz and about 500 Hz, preferably between about 20 Hz to
about 80 Hz, more preferably about 40 Hz, with an amplitude between about
1 to about 40 volts.
Pharmacologic Potentiation
The acetylcholinesterase inhibitor is also known as a cholinesterase
inhibitor. Suitable acetylcholinesterase inhibitors include, but are not
limited to tacrine hydrochloride, pyridostigmine bromide, neostigmine
methylsulfate, and edrophonium chloride. One preferred
acetylcholinesterase inhibitor is pyridostigmine bromide.
Acetylcholinesterase inhibitors are administered in a dosage range between
about 0.01 mg/kg and about 100 mg/kg, preferably between about 0.1 mg/kg
and about 2.0 mg/kg, more preferably about 0.5 mg/kg.
The beta-adrenergic receptor blocker is also known as a beta-adrenergic
blocking agent. Suitable beta-adrenergic receptor blockers include, but
are not limited to, sotalol HCl, timolol maleate, esmolol hydrochloride,
carteolol hydrochloride, propranolol hydrochloride, betaxolol
hydrochloride, penbutolol sulfate, metoprolol tartrate, acetbutolol
hydrochloride, the combination of atenolol and chlorthalidone, metoprolol
succinate, pindolol, and bisoprolol fumarate. One preferred
beta-adrenergic receptor blocker is propranolol hydrochloride.
Beta-adrenergic receptor blockers are administered in a dosage range
between about 0.01 mg/kg and about 100 mg/kg, preferably between about 0.1
mg/kg and about 2.0 mg/kg, more preferably about 80 .mu.g/kg.
Suitable calcium channel blockers include, but are not limited to,
nifedipine, nicardipine hydrochloride, diltiazem HCl, isradipine,
verapamil hydrochloride, nimodinpine, amlodipine besylate, felodipine,
bepridil hydrochloride, and nisoldipine. One prefererred calcium channel
blocker is verapamil hydrochloride. Calcium channel blockers are
administered in a dosage range of between about 0.001 mg/kg to about 1
mg/kg, preferably between about 0.01 mg/kg and about 0.2 mg/kg, more
preferably about 50 .mu.g/kg.
It will be understood that other dosage combinations may be effective. The
appropriate dosage is determined by the age, weight, sex, health status of
the patient, and may vary with a variety of other factors according to
conventional clinical practice.
EXAMPLE 1
Experimental Preparation
The sheep in the examples of the present invention received humane care in
compliance with "Principles of Laboratory Animal Care" formulated by the
National Society for Medical Research and the "Guide for Care and Use of
Laboratory Animals" prepared by the National Academy of Sciences and
published by the National Institutes of Health (NIH Publication No. 80-23,
revised 1985). The experimental protocol was approved by the Institutional
Animal Care and Use Committee of Emory University.
Seven sheep weighing 44 to 45 kg were premedicated with xylazine (0.1
mg/kg) and atropine (0.2 mg/kg) 30 minutes prior to 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
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 cc/kg and a rate of 12 breaths
per minute, with adjustments made to maintain pH at 7.35-7.45, pO2 greater
than 100 mm Hg, and pCO2 between 35-45 mmHg.
A right cervical incision was performed, the vagus nerve was carefully
isolated and a nerve stimulation probe (Harvard Apparatus, South Natick,
Mass.) was placed on the nerve. A median sternotomy was made to expose the
heart. A high-fidelity solid-state micromanometer (Millar Inc., Houston,
Tex.) 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.
EXAMPLE 2
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 .mu.g/kg) for
.beta.-adrenergic receptor blockade, and verapamil (50 .mu.g/kg) for
calcium channel blockade. Vagal stimulation was performed with a nerve
stimulator (Grass Instrument Co., Quincy, Mass.) in the monopolar mode at
a frequency of 40 Hz, an impulse duration of 0.4 msec, and an amplitude of
2-6 volts. Vagal stimulations were delivered in two regiments: 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 whether cardiac fatigue, electromechanical
escape, and physiologic effects occurred under these practical conditions.
EXAMPLE 3
Data Acquisition and Analysis
Electrocardiographic and hemodynamic data were gathered via an
analog-to-digital conversion board (Data Translation, Inc., Marlboro,
Mass.) and processed, stored, and analyzed via a microprocessor personal
486 computer (Compaq Computer Corp., Houston, Tex.) using interactive
proprietary software (Spectrum.TM., Triton Technology, San Diego, Calif.).
The system was configured to collect 4 channels of physiologic data at a
frequency of 50 Hz (sufficient for slow-wave waveforms and mean pressure
data) over a 200 second period that encompassed the 60 second stimulation
or the sequential 15 second train of stimulations. The software allowed
subsequent videographic display and analysis of the hemodynamic data.
EXAMPLE 4
Results
Before drug administration, vagal stimulation for 60 seconds produced a
brief pause in electromechanical activity (1.6.+-.0.9 seconds) followed by
vagal escape and resumption of sinus rhythm with a reduction in heart rate
by 19.4.+-.11.9% compared to pre-stimulation heart rate. Similarly,
sequential 15 second vagal stimulation performed to stimulate the suturing
intervals required for CABG anastomoses produced a short pause (1.1.+-.0.4
seconds) followed by vagal escape and sinus rhythm with a reduction in
heart rate of 37.+-.6%.
Administration of the pharmacologic regimen (propranolol, verapamil,
pyridostigmine) reduced the heart rate and increased the left ventricular
end diastolic pressure, but did not affect the mean arterial pressure or
maximum dP/dt as shown in Table 1.
TABLE 1
Hemodynamics before and after drug treatment
Before
drugs After drugs p value
(mean .+-. (mean .+-. (paired t
SEM) SEM) test)
Heart rate (bpm) 114 .+-. 4 87 .+-. 4 0.002
MAP (mm Hg) 84 .+-. 5 84 .+-. 5 NS
dP/dt max (mm 3286 .+-. 232 2847 .+-. 140 NS
Hg/sec)
LVEDP (mm HG) 3.9 .+-. 0.5 7.3 .+-. 0.9 0.005
bpm - beats per minute; dP/dt max - maximum developed left ventricular
pressure; LVEDP - left ventricular end diastolic pressure; MAP - mean
aortic pressure; NS - not significant; SEM - standard error of the mean;
sec - seconds.
After drug administration, 60 second vagal stimulation produced asystole
averaging 52.+-.5.6 seconds. The individual responses of the animals
before and after drug administration are shown in FIG. 1. Six animals
achieved controlled asystole. Five of these six achieved controlled
asystole for greater than 50 seconds. The effects of 60 second vagal
stimulation before and after drug treatment in responsive animals are
contrasted by representative left ventricular and aortic pressure tracings
are shown for a representative experiment in FIG. 2. Before drug regimen
treated, vagal stimulation produced no appreciable change in cardiac
rhythm or hemodynamics. In contrast, the triple drug regimen facilitated a
consistent asystole and circulatory arrest until the stimulus was
withdrawn, after which hemodynamics were rapidly restored to
pre-stimulation values. The prolonged asystole and circulatory arrest
produced no significant differences in the hemodynamic parameters measured
before and after drug-aided 60 second vagal stimulation (Table 2).
TABLE 2
Hemodynamics pre- and post-asystole produced by 60
second stimulation after drug treatment
Pre-asystole Post-asystole
(mean .+-. (mean .+-. p value
SEM) SEM) (paired t test)
Heart rate bpm) 91 .+-. 8 87 .+-. 7 NS
MAP (mm Hg) 86 .+-. 6 92 .+-. 6 NS
dP/dt max (mm 3032 .+-. 182 3223 .+-. 212 NS
Hg/sec)
LVEDP (mm Hg) 5.8 .+-. 1.0 6.0 .+-. 0.8 NS
bpm - beats per minute; dP/dt max - maximum developed left ventricular
pressure; LVEDP - left ventricular end diastolic pressure; MAP - mean
aortic pressure; NS - not significant; SEM - standard error of the mean;
sec - seconds.
Likewise there was no difference in the parameters measured by arterial
blood gases at one and five minutes after the 60 second stimulation
compared to pre-stimulation values (Table 3).
TABLE 3
Arterial blood gas data pre-, 1 minute post-, and 5 minutes
post-systole produced by 60 second stimulation after drug treatment
Post-asystole
Pre-asystole 1 minute 5 minutes p p value
(mean .+-. SEM) (mean .+-. SEM) (mean .+-. SEM) (ANOVA)
pH 7.42 .+-. 0.03 7.40 .+-. 0.03 7.42 .+-. 0.03 NS
PCO.sub.2 41 .+-. 4 42 .+-. 4 40 .+-. 4 NS
(mm Hg)
PO.sub.2 377 .+-. 87 380 .+-. 75 390 .+-. 83 NS
(mm Hg)
HCO.sub.3 26 .+-. 1 26 .+-. 1 26 .+-. 1 NS
(mEq/L)
Base 1.2 .+-. 0.7 1.0 .+-. 0.4 1.3 .+-. 0.5 NS
excess
(mEq/L)
ANOVA - one-way analysis of variance with repeated measures; NS - not
significant; SEM - standard error of the mean.
Five to six sequential 15 second vagal stimulations in the drug treated
state produced consistent and stable asystole (FIG. 3). Three of the six
animals had a single escape beat during one of the 15 second stimulations.
The other three displayed complete asystole during each of the 15 second
stimulations. A sustained cardiac rhythm began an average of 5.3.+-.1.8
seconds after termination of each 15 second impulse during which interval
a single beat was often observed immediately after withdrawal of
stimulation.
While the foregoing specification teaches the principles of the present
invention, with examples provided for the purpose of illustration, it will
be understood that the practice of the invention encompasses all of the
usual variations, adaptations, and modifications, as come within the scope
of the following claims and its equivalents.
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