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CMDIOVASCULAR EFFECTS OF
GALLAMINE AND SUCCINYLCHOUME
IN THE DOG

Thesis for the Degree of M. S.
MICHIGAN STATE UNIVERSITY
A. THOMAS EVANS
1974

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ABSTRACT

CARDIOVASCULAR EFFECTS OF GALLAMINE AND
SUCCINYLCHOLINE IN THE DOG

BY

A. Thomas Evans

The use of muscle relaxants in veterinary medicine has been
limited to purposes of restraint, specifically restraint of the horse.
Small animal practitioners rarely use muscle relaxants in conjunction
with anesthesia due in part to a lack of knowledge of the cardio-
vascular effects of muscle relaxants in the dog.

The purpose of this study was to provide evidence that the use
of gallamine or succinylcholine does not adversely affect the cardio-
vascular system of the dog anesthetized with halothane.

In the current study cardiac output, cardiac index, stroke
volume, heart rate, peripheral vascular resistance, arterial pressure
and central venous pressure were measured in dogs given either 0.4
mg/kg gallamine or .4 mg/kg succinylcholine intravenously. Eight dogs
were used in the study, with each dog receiving each relaxant once.
0n the day of the study, a cannula was implanted in both the common
carotid artery and jugular vein of each animal. The arterial catheter
contained a thermistor probe for thermal dilution cardiac output

determinations. Muscle relaxation was monitored by recording the

A. Thomas Evans
twitch response to electrical stimulation of the peroneal nerve.
Anesthesia was induced with a mixture of halothane and oxygen by mask,
dogs were intubated with endotracheal catheters, and end-expired halo-
thane concentration was maintained at 1.1%. Cardiovascular variables
were recorded prior to injection, one minute after injection, five
minutes after injection, and ten minutes after injection of the muscle

relaxant. Blood PCO P0 and blood pH were maintained within normal

2’ 2

limits by controlling respiration and base excess. The administration
of either muscle relaxant resulted in total paralysis as determined by
absence of muscle twitch. Mean time from total paralysis to return of
one-tenth of total twitch was 26 minutes for gallamine and 22 minutes
for succinylcholine. An increase in heart rate and mean arterial
pressure at the one minute time period was the only statistically sig-

nificant finding during the succinylcholine study, while injection of

gallamine did not cause significant changes.

The study demonstrated that 0.4 mg/kg of gallamine or succinylcholine

does not adversely affect the cardiovascular system of Beagle dogs

anesthetized with halothane.

CARDIOVASCULAR EFFECTS OF GALLAMINE AND

SUCCINYLCHOLINE IN THE DOG

BY

A. Thomas Evans

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

MASTER OF SCIENCE

Department of Small Animal Surgery and Medicine

1974

ACKNOWLEDGEMENTS

Appreciation is expressed to the various individuals making
this research and thesis possible. Particular thanks goes to Dr.
George E. Eyster for his advice and direction in planning and conduct-
ing this research as well as for his assistance in preparation of
this manuscript. Gratitude is also extended to Dr. Mark Heerdt, Dr.
D. J. Krahwinkel, and Dr. James Gibson for their advice and time
spent as members of my guidance committee. Thanks also goes to Dr.
Donald C. Sawyer for his advice and guidance while serving as a member
of my graduate committee. Credit goes to Ms. Ardith Chaffee and Ms.
Gail Bender for their help with research and data analysis. Apprecia-
tion goes to Ms. Janice Fuller for typing of the manuscript and to
Dr. Lorel Anderson for help with research and proofreading. Thanks
is extended to Ms. Dixie Middleton for preparation of illustrations.
Gratitude is expressed to Ayerst Laboratories, Incorporated, New York,
N.Y. for the Fluothane which was used in this investigation. Research
support for this study was through a General Research Support Grant
(RR 05623-05) of the College of Veterinary Medicine effective July 1,

1971.

ii

TABLE OF CONTENTS

Page
INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . 1
REVIEW OF LITERATURE. . . . . . . . . . . . . . . . . . . . . . 5
Cardiovascular Effects of Gallamine. . . . . . . . . . . 5

Slmmary I O C O O O I I I O O C O O O O O O 0
Cardiovascular Effects of Succinylcholine. . . . . . . . 11
smary I O I O I O O O O O O C O O O O O O O O O O I O O 20
MATERIAL S AND MTHOD S O O O O O O O O O O O O Q 0 O O O O O O O 2 2
Animls O O O O O O O I O O C O O O O O O O O O O O O O O 22
Materials. . . . . . . . . . . . . . . . . . . . . . . . 23
Equipment and Calibration. . . . . . . . . . . . . . . . 24
calculations 0 O O O O O O O O O O O O O O O O O O O O O 26
Procedure. . . . . . . . . . . . . . . . . . . . . . . . 29
Data Analysis. . . . . . . . . . . . . . . . . . . . . . 31
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
General Considerations . . . . . . . . . . . . . . . . . 33
Cardiovascular Effects of Gallamine. . . . . . . . . . . 36
Cardiovascular Effects of Succinylcholine. . . . . . . . 37
DISCUSSION 0 O O O O O O O O O O 0 O O O O 0 O O O O O O O O O 0 40
CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . 51

REFERENCES. . . . . . . . . . . . . . . . . . . . . . . . . . . 52

iii

LIST OF TABLES
Table Page
1 Blood evaluations for 8 dogs prior to study. . . . . . . 33

2 Mean temperatures of 8 dogs given either gallamine
or succinylcholine . . . . . . . . . . . . . . . . . . . 34

3 Duration of paralysis of 8 dogs given either
gallamine or succinylcholine . . . . . . . . . . . . . . 35

4 Mean end tidal halothane concentration of 8 dogs
given either gallamine or succinylcholine. . . . . . . . 3S

5 Mean serum potassium concentrations from 8 dogs
given either gallamine or succinylcholine. . . . . . . . 36
6 Mean cardiovascular variables from 8 dogs given

0.4 mg/kg gallamine. . . . . . . . . . . . . . . . . . . 38

7 Mean cardiovascular variables of 8 dogs given 0.4
mg/kg succinylcholine. . . . . . . . . . . . . . . . . . 39

iv

LIST OF FIGURES
Figure - Page

1 Diagrammatic sketch of equipment arrangement . . . . . . 27

INTRODUCTION

The use of muscle relaxants in veterinary medicine has been
largely limited to equine restraint. Contrary to the rare use of
muscle relaxants in small animal practice, relaxants have been used
extensively as an adjunct to anesthesia in man. Benefits realized
include profound muscle relaxation, ease of controlling ventilation,
and reduced concentrations of anesthetics, allowing utilization of
balanced anesthesia techniques.

An understanding of the physiology of the neuromuscular junction
is necessary before a discussion of the action of muscle relaxants
is begun. A nerve action potential passes from the motor nerve
located in the spinal cord to the nerve terminal at the myoneural
junction. The nerve action potential causes the release of quanta
of acetylcholine from the synaptic vesicles in the nerve terminal
adjacent to the synaptic cleft. The released acetylcholine crosses
the synaptic cleft where it reacts with endplate receptors to increase
permeability of both sodium and potassium. The change in permeability
to sodium and potassium ions causes a depolarization of the endplate
potential which in turn causes a depolarization of the muscle membrane
adjacent to the endplate. This ultimately results in muscle contrac-
tion. The acetylcholine then rapidly diffuses away from the endplate
or is quickly hydrolyzed by cholinesterase. Muscle relaxants have

1

2
been categorized as being either depolarizing or nondepolarizing
depending on their action at the myoneural junction. Gallamine, a
nondepolarizing muscle relaxant, exerts its action by competing with
acetylcholine for endplate receptors (competitive inhibition).
Succinylcholine initially mimics the action of acetylcholine at the
endplate receptors and may cause depolarization sufficient to cause
muscle fasciculations (depolarization block). The muscle is then
desensitized to the action of acetylcholine.

Why haven't veterinarians utilized muscle relaxants to a greater
extent? One reason might be the required presence of a ventilator,
whether human or mechanical, to insure adequate respiratory excursion.
This problem is being alleviated by the development of mechanical
ventilators by veterinary suppliers and improved educational oppor-
tunities for undergraduate and graduate veterinarians in respiratory
and anesthesia physiology.

A second issue may be an inadequate understanding of the pharma-
cology of muscle relaxants and specifically their effects on the cardio-
vascular system. A comprehensive review of the literature reveals
that many studies have been completed but that results are conflicting
and confusing.

For example, early studies did not monitor blood gas values or
depth of anesthesia. A rise in blood pressure often seen after
administration of succinylcholine was usually attributed to the drug.
subsequent studies revealed that the increase in blood pressure could

often be explained by a concurrent rise in PC02.

3

Anesthesia also has profound effects on the cardiovascular
system. Early studies in dOgS used no anesthesia, while recent
studies in man did not monitor depth of anesthesia. Since depth
of anesthesia affects cardiovascular function, it would be diffi-
cult to separate cardiovascular effects caused by the anesthetic
from cardiovascular effects related to the muscle relaxant. Results
obtained from these studies should be suspect.

Studies on cardiovascular effects of muscle relaxants have
involved the use of many species of animals. Dogs, cats, horses,
cattle, guinea pigs, nonhuman primates, and man have each played a
role in gathering information on the cardiovascular effects of
muscle relaxants. The only reliable information to arise from all
of these studies is that each species reacts somewhat differently
to the administration of relaxants. One would surmise that, if infor-
mation was needed on the cardiovascular effects of muscle relaxants
in the dog, the dog should be the experimental animal studied. Data
from the human extrapolated to the dog would not be acceptable.

This is in fact the case, as the human reacts to succinylcholine with
a shorter duration of action than the dog. Consequently, the dog
was chosen as the experimental subject for the current experiment.

The manner in which muscle relaxation is monitored has been a
subject of debate among researchers studying relaxants. A recent
review (53) mitigated some of the uncertainty by accepting both
mechanical and electrical methods of monitoring muscle relaxation.
The current study employs a mechanical method of monitoring duration

of paralysis.

 

4
The purpose of the study was to determine whether or not muscle
relaxants could be safely used in the dog without any serious cardio-
vascular deviations. The major areas controlled were depth of
anesthesia and prevention of severe blood gas abnormalities. This was
accomplished by controlling end-tidal concentration of halothane and

the serial analysis of arterial samples, respectively.

 

REVIEW OF LITERATURE

Cardiovascular Effects of Gallamine

In 1951, Marbury at al. (69) studied the effects of gallamine in
patients anesthetized with ether or cyclopropane and found an increase
in pulse rate 35% greater than control values. This was attributed
to a vagolytic effect of gallamine.

Doughty and Wylie (31) studied the effects of gallamine the same
year and found an increase in pulse rate in 100% of 245 human cases.
Patients were anesthetized with thiopentone, nitrous oxide and oxygen.
If cyclopropane was used as the anesthetic, the increase in heart
rate did not occur. They concluded that the tachycardia was due to a
vagal block unaccompanied by a sympathetic block. In further studies
involving cats and rabbits, performed by the same investigators, it
proved impossible to produce tachycardia either by reflex or by direc-
action on the heart. By way of explanation, they proposed the possi-
bility of reduced vagal tone in the two species.

Independent clinical studies by Artusio at al. (3) and Condon
(23) in 1951 confirmed the occurrence of tachycardia in anesthetized
man, probably due to a vagolytic action of gallamine. Both investi-
gators found negligible effect on blood pressure as measured by cuff.

Riker and Wescoe (82), in 1951, found that gallamine increased
heart rate by an atropine—like effect, that is, reducing the activity

5

6
of the vagus at postganglionic nerve endings, but was devoid of other
atropine-like effects. Studies were performed by injection of gallamine
into intact cats lightly anesthetized with pentobarbital.

Bovet (14), working with dogs in 1951, found no modification of
blood pressure by gallamine in an experiment in which the type of
anesthetic was not mentioned.

Further evidence of a vagolytic action of gallamine was shown in
1955 by Roberts et al. (83) in cats anesthetized with Dial Urethane.

In their experiment, gallamine diminished the occurrence of cardiac
arrhythmias induced by epinephrine.

Another clinical study (94) was reported in 1963 involving 116
human patients anesthetized with thiopentone, nitrous oxide and oxygen.
Ventilation was assisted and blood pressure obtained by auscultating
the arm. Gallamine caused a rise in blood pressure in 74% of 116
patients with a mean rise of 12 mm Hg. A fall in blood pressure was
also noted in 24% of the patients studied. They explained that factors
which could affect changes in blood pressure included increased
carbon dioxide tension of the blood, which would increase blood
pressure, and controlled ventilation, which would decrease blood
pressure.

Conflicting results were reported by Watts and Prescott (98) in
1965, when the effect of gallamine on cardiac rhythm during halothane,
nitrous oxide, and oxygen anesthesia in human patients was studied.
There was no change in blood pressure in 19 out of 20 patients; how-
ever, all patients exhibited at least a 20% increase in heart rate.

In 1967, a more complete study of cardiovascular effects of gallamine

7

was reported by Smith and Whitcher (87). In this study, the hemodynamic
effects of gallamine administered during halothane anesthesia were an
increase in cardiac output, arterial pressure, left ventricular work
with a variable response in stroke volume. The action of gallamine
was attributed to cardiovagal block, myocardial stimulation and a
slight sympathetic ganglionic block. They proposed that the sympa-
thetic blocking action of gallamine is weaker than the cardiovagal
action so the sympathetic system dominates and a tachycardia results.

Kennedy (57) reported similar results the following year during
a study of the cardiovascular effects of gallamine in man anesthetized
with thiopentone, tubocurarine, nitrous oxide and trichlorethylene.
Patients were artificially ventilated. Heart rate and cardiac output
increased 40% and 35%, respectively. There was no change in stroke
volume, but a slight increase in mean arterial pressure and a slight
decrease in total peripheral resistance.

Brown and Crout reported on the ionotrOpic effect of gallamine
on guinea pig heart muscle in 1966 (17). They concluded that gallamine
stimulates heart rate and force through a release of norepinephrine.
The effect was not seen if propranolol or reserpinized atria were used.
Preparations made tachyphylactic to gallamine responded normally to
norepinephrine, and if the tissue exposed to norepinephrine was washed,
the response to gallamine was restored.

Further studies by Brown and Crout (18) were reported in 1970.
The results of studies in open chest cat anesthetized with pentobar-
bital complemented their earlier work. Cardiac rate and right

ventricular contractile force were increased. Reserpine pretreatment

8

inhibited the response to gallamine almost completely and any residual
effect was abolished by propranolol. It was concluded that the
positive ionotropic effect of gallamine is due mainly to the release
of norepinephrine from adrenergic neurons.

In 1970, decorticate rats and cats were given propranolol followed
by gallamine in a study by Rathbun and Hamilton (79). Gallamine had
an anticholinergic effect on the heart in both species, so a true
atropine-like action may complement any sympathomimetic action of
gallamine in producing the tachycardia seen in clinical practice.
They concluded that the action of gallamine is a competitive antagonism
of acetylcholine, but the vagolytic action of gallamine is confined
to the heart and possibly vascular system.

Working with open chest dogs maintained with chlorolose, Hughes
(47) found that gallamine slightly increased stroke volume and cardiac
output which he related to cardiovagal block. Blood pressure and
total peripheral resistance were slightly reduced.

Finally, in 1973, evidence was found by Reitan at al. (81) to
show that, at least in humans, there is a lack of cardiac ionotrOpic
effect of gallamine. Experiments were carried out in 12 women anesthe-
tized lightly with halothane, nitrous oxide and oxygen. The cardiac
pre-ejection period and its quotient with left ventricular ejection
time were used to measure the ionotropic state. Six patients were
given atropine to stabilize their heart rate, followed by two doses of
gallamine. There was a significant decrease in both indices (positive
ionotropy) in this group. When atropine alone without gallamine was

given to a second group of 6 patients, a similar significant decrease

9
in the indices occurred. When this group was immediately reatropinized
and given gallamine similar to the protocol sequence of the first
group, there was no change in pre-ejection period and its quotient
with left ventricular ejection time. It was concluded that there was
no positive cardiac ionotropic action demonstrated by gallamine in

human subjects anesthetized with halothane.

Summary
The cardiovascular effects of gallamine have been studied in many
species under a variety of conditions. Investigators have established
that gallamine causes a tachycardia, but they do not agree on its
origin. Much of the confusion may be due to species variation.
Indeed, Wylie and Churchill-Davidson, in discussing the effects of
muscle relaxants in man, state "there is no single species that responds

' For example, Reitan

to these drugs in exactly the same manner as man.‘
(81), in his study involving humans, found no positive cardiac iono-
tropic action of gallamine. Conversely, Brown and Crout, working with
guinea pigs in 1966 (17) and with cats in 1970 (18), reported a
positive ionotropic action of gallamine which they explained by a
release of norepinephrine from adrenergic neurons.

A second explanation for varying results is related to different
investigative techniques. Brown and Crout measured ionotropy by means
of a strain gauge sutured to the left ventricle of cats. Reitans'
experimental method consisted of clinical evaluation of cardiac func-
tion by measuring cardiac pre-injection period and its quotient with

left ventricular ejection time. The two completely different methods

of measuring ionotropy may have resulted in conflicting results.

10

The only study which did not report a tachycardia was one per-
formed on cats and rabbits. It was theorized that these particular
animals have a reduced vagal tone and consequently do not respond to
the vagolytic action of gallamine. However, Riker (82) and Roberts
(83), in separate studies, found that cats do indeed respond to
gallamine administration with a tachycardia. Part of the discrepancy
may be due to choice of anesthetics as Doughty and Wylie (31) anesthe-
tized their cats with nitrous oxide and oxygen.

Other factors which affect the presence of tachycardia and hyper-
tension include: presence of premedication, spontaneous or controlled

ventilation, blood PCO and dose of gallamine. Premedication with

2.
atropine may reduce effect of gallamine on cardiac ganglia. Vigorous
positive pressure ventilation may reduce cardiac output by reducing
venous return. Another possible mechanism in dogs, cats and rabbits
involves the effect of various doses of gallamine on sympathetic
ganglia. Paralyzing doses of gallamine facilitate transmission
through the sympathetic ganglia and potentiate hypertensive reflexes
mediated by them and the adrenal medulla. With somewhat larger doses
ganglionic transmission returns to normal while very large doses block
ganglia (82). Hypertension with small doses could be due to the
initial ganglionic stimulation and the decreasing effect of larger
doses to the subsequent return of transmission to normal.

Another possible explanation for the confusion surrounding the
alleged effects of gallamine on the cardiovascular system involves

the amount of vagal tone present. ”In two separate studies involving

dogs, Bovet (14) and Hughes (47) found no increase in blood pressure

11

after gallamine administration. However, Hughes did find that heart
rate was slightly increased, along with small increases in cardiac
output and stroke volume. He theorized that atrial contraction
increased because of vagal block causing more effective filling of
the ventricle which results in increases in stroke volume and cardiac
output.

Because gallamine seldom caused tachycardia in dogs, Hughes
speculated that vagal influence on heart rate in anesthetized dogs
is less than in humans. In general, the cardiovascular effect of
gallamine can be summarized as one related to the amount of vagal tone
with the possibility of an additional effect from release of norepi-
nephrine from adrenergic neurons. In addition, differences in
response can be related to different species, anesthetics, and experi-

mental protocol.

Cardiovascular Effects of Succinylcholine

One of the first studies concerned with the cardiovascular effects
of succinylcholine was reported in 1952 by Bourne et a1. (13), who
monitored human patients anesthetized with thiopentone, nitrous oxide,
and oxygen anesthesia. There was no effect on blood pressure after a
single dose; however, large doses caused blood pressure to rise.
Further studies on anesthetized dogs and cats revealed that succinyl-
choline in large doses has a nicotinic effect on blood pressure. In
the dog, a dose greater than 5 mg/kg and in the cat a dose greater
than 10 mg/kg is needed to raise blood pressure. This action is

abolished by administration of the ganglionic blocking agents

12
hexamethonium and tetraethylammonium. A hypotensive effect of
succinylcholine was not seen in either the cat or the dog.

Thesleff (93) noted in 1952 that the rise in blood pressure after
administration of succinylcholine was due to stimulation of autonomic
ganglia with resulting mobilization of adrenaline and vasoconstriction.
However, ganglionic blocking substances did not entirely prevent the
rise in blood pressure, so Thesleff proposed a direct action on blood
vessels could not be ruled out. In addition, he thought that a large
dose of succinylcholine may cause a ganglionic block.

Adderley and Hamilton (2) found similar results in humans given
succinylcholine after thiopentone, namely a rise in blood pressure
which could be controlled by blocking autonomic ganglia.

Somers (91) also reported a slight rise in pressure in cats given
2 mg succinylcholine. A 10 mg dose caused a larger rise in blood
pressure which was thought to be nicotinic in character. Hexamethonium
or tetraethylammonium blocked the blood pressure increase. Somers
failed to demonstrate any effect of the drug in cats under chlorolase
anesthesia and was unable to produce hypotension in either cats or dogs.

In 1954, Calvert and Morgan (21) produced conflicting results in
man during thiopentone anesthesia. A small but consistent fall in
mean systolic and diastolic blood pressure was noted while pulse rate
was virtually unchanged. They attributed reports by other workers, of
increased blood pressure, to increased carbon dioxide tension and the
stimulus of intubation.

Phillips (77), in the same year, working with human patients,

recorded that succinylcholine produced cardiovascular side effects, but

13

in some patients the relaxant was given prior to barbiturate anesthesia
and doubt exists about the adequacy of oxygenation in such cases.
Under these circumstances he found marked muscle fasciculation
accompanied by a rise in blood pressure which was maintained during
the period of apnea produced by the drug. An initial bradycardia was
followed by tachycardia as relaxation of the skeletal muscles occurred.

The following year Beretervide (9) noted that the bradycardia and
hypotension following administration of succinylcholine resulted from
central nervous system parasympathetic action and that hypertension
and tachycardia resulted from stimulation of sympathetic ganglia.
Beretervide concluded that the drug had no effect on the heart or
circulation, but as many of his experiments were carried out on conscious
animals without artificial ventilation, his results must be suspect.

Also in 1955, Johnston (50), investigating the effects of
succinylcholine on the cardiovascular system of 100 patients who had
been premedicated with atrOpine and anesthetized with small doses of
pentothal, found slight slowing of the pulse in 28 cases and definite
bradycardia in 32 cases. There was also pacemaker shift to the atrio-
ventricular (AV) node in 7 patients. This bradycardia was usually
followed in about two minutes by a brisk tachycardia. The muscarinic
effects could be modified by atr0pine, but not always prevented in the
dosage prescribed. In explaining blood pressure changes, Johnstone
noted that one often sees a slight transient hypertension after a
single dose and prolonged mild hypertension after a continuous drip
infusion of succinylcholine. The initial hypertension has been

attributed to an asphyxial type of response in the absence of adequate

l4
ventilation, possibly aggravated by muscle activity. The prolonged
pressure response is attributed by Paton (76) to the nicotinic
effects of succinylcholine and succinyl monocholine, and these are
not influenced by atr0pine.

During studies in 15 horses by Belling and Booth (8) the same
year, there was a slight increase or decrease of heart rate but
changes were not consistent. Blood pressure was measured in the facial
artery by kymograph with horses restrained and anesthetized on a
surgery table. Blood pressure measured in 5 horses was not impaired
as long as the reapiratory muscles were not impaired. As soon as
paralysis developed, blood pressure increased, presumably due to
hypercapnia.

Bradycardia following intravenous administration of succinyl-
choline to infants and children was reported by Leigh et al. (64)
in 1957. They suggested that infants and young children have a low
true cholinesterase activity and that acetylcholine derived from
succinylcholine accumulates and causes a bradycardia-nodal rhythm.

The same year Elder et a2. (36), in a clinical study of the car-
diovascular effects of muscle relaxants in 6 patients anesthetized
with thiopental, nitrous oxide and oxygen, found very little effect
of succinylcholine on mean blood pressure, central venous pressure
or cardiac output.

In 1958, Heymans and De Vleeschouwer (46) concluded that succinyl—
choline does not decrease systemic arterial pressure or depress the
mechanism of blood pressure homeostasis. Their studies were carried
out in dogs anesthetized with chloralase and morphine without benefit

of other controls.

15

Also in 1958, Larsen (62) found only slight changes in heart rate
and blood pressure in the horse. Further studies by Larsen et a2.
(63) in 1959 revealed a tachycardia with 4 of 8 horses suffering
cardiac muscle necrosis. Blood pressure was not measured.

Hansson (45), in 1958, studied the effects of succinylcholine
in horses, calves, pigs and dogs. Injection of succinylcholine caused
a pronounced increase in blood pressure in the horse, no change in
blood pressure in the calf and inconsistent results in the dog and
pig. Changes in blood pressure were thought to be due to a direct
effect of succinylcholine on the vasomotor and cardiac center or
secondary to reduced ventilation.

Stevenson (92) reported in 1960 a rise in blood pressure in dogs
thought to be due to ganglionic stimulation and adrenaline release.

He also reported an increased concentration of potassium in plasma
after succinylcholine administration.

The same year Wahlin (97), using a drop counting method of blood
flow measurement devised by Lindgren (66), observed a fall in superior
mesenteric artery blood flow following succinylcholine administration.
He felt the fall in blood flow might have been associated with con-
traction of intestinal musculature.

Lupprian and Churchill-Davidson (67), studying the effect of
succinylcholine on cardiac rhythm in human patients, found an increase
in heart rate after the first dose, but a slowing of heart rate after
subsequent doses. The sinus bradycardia could be prevented in 68% of
the patients by atropine. Since atrOpine is believed to act princi-
pally at the sino-atrial node, they thought this was strong evidence

of vagal stimulation by succinylcholine.

16

Conversely, Barreto (6), in 1960, working with patients 4 weeks
to 16 years of age, anesthetized with ether or thiobarbiturate followed
by nitrous oxide and oxygen, found that the predominant response to
intravenously administered succinylcholine was a sinus tachycardia.

Also in 1960, Craythorne et a1. (28) found a bradycardia following
intravenous administration of succinylcholine to infants and children.
Patients were studied before operation, premedicated with atropine
or scopolamine and anesthetized with cyclopropane, nitrous oxide and
oxygen or ethyl ether. They theorized the cause of the bradycardia
may be due to stimulation of pulmonary chemoreceptors.

Williams et a1. (99), in 1961, using halothane anesthesia in man,
found that injected succinylcholine was followed by a moderate hyper-
tension and tachycardia while successive doses of succinylcholine
caused bradycardia. Administration of trimetaphan prevented the
action of succinylcholine on cardiac rhythm. This drug is thought to
block vagal transmission principally at the cardiac ganglion, which
means that succinylcholine acts at a site on the vagal pathway which
is at or proximal to the cardiac ganglion. They concluded that succinyl-
choline probably stimulates the sympathetic nervous system.

Adams and Hall (1), in 1963, using artificially ventilated spinal
cat preparations or cats anesthetized with thiopentone, nitrous oxide,
and oxygen, found that succinylcholine has both a nicotine and a
muscarine-like effect. In anesthetized cats, there was a sharp fall
in blood pressure followed by a rapid rise to above pre-injection
levels, with blood pressure stable two to three minutes later. If

atropine was given in sufficient quantity to block the vagus nerve,

17
then the initial sharp fall was abolished. Atropine and hexamethonium
completely abolished blood pressure change when given before
succinylcholine.

Galindo and Davis (40), in 1962, working with monkeys, explained
the slowing of the heart as a secondary reflex effect brought about
by a rise in blood pressure after the initial injection.

In 1963, Graf et al. (42) injected succinylcholine into anesthe-
tized man and produced a biphasic action. A sudden initial decrease
in peripheral blood flow and heart rate was followed by an increase
throughout the apnea period. They concluded that succinylcholine
seems to be a general vasodilator substance partially caused by a
local action on peripheral circulation. That is, the smooth muscle
bed of blood vessels may constrict and relax similarly to skeletal
muscle.

Dowdy (33), one year later, suggested the initial bradycardia
from succinylcholine injection was due to an acetylcholine-like
phenomenon at the receptor site of the cholinergic nerves. Acetyl-
choline and succinylcholine also stimulated autonomic ganglia and
this effect could proceed to stimulate the sympathetic ganglia of
myocardial nerves releasing catecholamines and resulting in stimula-
tion of beta effectors. Paradise (75) explained that ventricular
pacemaker fibers were innervated by sympathetic nerves which contain
acetylcholine. The acetylcholine acted on a storage depot of cate-
cholamines effecting their release which resulted in an increased
firing rate of ventricular pacemakers. Succinylcholine mimics this

acetylcholine action.

18

Conversely, Mathias and Evans-Prosser (70), in 1968, stated that
sympathetic stimulation plays no part in alteration of the cardiac
rhythm caused by succinylcholine. In certain circumstances, the
action of succinylcholine on cardiac rhythm is exerted reflexly by
stimulation of peripheral receptor organs (carotid sinus) and that
this effect may be blocked by the prior administration of a non-
depolarizing muscle relaxant.

In 1970, Zinn at al. (102), studying the effect of succinylcholine
on the cardiovascular system-of horses, concluded that the hypertension
seen is probably due to the combination of adrenaline release, hypoxia
and hyperpnea, muscle fasciculations, and ganglionic stimulation.

The following year Leighton (65), using dogs anesthetized with
halothane, nitrous oxide and oxygen, studied the effect of succinyl-
choline on the cardiovascular system. A dose of 4 mg/kg resulted in
a fall in arterial pressure with no change in cardiac output. Blood
pressure, accompanied by an increase in heart rate, then rose higher
than preinjection levels. Bradycardia was not observed. Administra-
tion of atropine blocked blood pressure changes. Leighton then con—
ducted experiments showing the effect of alpha and beta adrenergic
blockade upon the biphasic response to succinylcholine. Norepinephrine
was injected and an increase in blood pressure noted. Then phenoxy-
benzamine (10 mg/kg) was administered followed by norepinephrine and
the absence of pressor action was noted. Then isoprenaline (beta
agonist) was given and an increase in heart rate noted. Propranalol
was then injected followed by isoprenaline and the response was

eliminated. Subsequent succinylcholine administration resulted in

19
hypertension without an overshoot. Leighton also studied the effect of
ganglionic blockade on the action of succinylcholine. After he
obtained a succinylcholine response, the right vagus was exposed and
stimulated producing cardiac standstill. Subsequent hexamethonium
administration followed by vagal stimulation resulted in normal heart
action. Succinylcholine given at this time produced a typical response
but with a marked overshoot. Leighton theorized that the initial fall
in arterial pressure must be due to an action on the peripheral
vasculature as cardiac output did not change. Ganglionic vagal block-
ade and adrenergic receptor blockade failed to prevent this response
to succinylcholine indicating that this response is not mediated
through the autonomic nervous system, nor is it the reflex result of
circulatory change elsewhere. In conclusion, Leighton noted that,
since atropine blocks the response completely, it would appear that
succinylcholine produces the effects which have been observed by an
action upon the muscarinic receptors in the peripheral vasculature.

A new concept explaining cardiovascular changes from succinyl-
choline injection was reported by Mori at al. (73) in 1973. They
injected succinylcholine into patients anesthetized with halothane
and found an arousal response in the electroencephalogram which was
accompanied by increases in heart rate and blood pressure. While
gallamine produced no arousal pattern in the electroencephalogram,
it did prevent the changes produced by a subsequent injection of
suxamethonium. It is postulated that the depolarizing drugs produce
an increased activity in the afferent discharge of the muscle spindles

which leads to the electroencephalogram arousal pattern. They

20
concluded that this arousing pattern may have some role in the tachy-

cardia and hypertension produced by these drugs.

Summary

The most debated controversy involving the effects of succinyl-
choline on the cardiovascular system involves the presence or absence
of hypertension. Graf (42), in his exhausting literature review,
found 63 references indicating succinylcholine is associated with
arterial hypertension, 16 references indicating hypotension, and 5
references indicating a biphasic response. The literature review for
the current study found 12 reports of hypertension after succinyl-
choline administration, 6 in human, 2 in horse, 2 in dog, and 2 in
cat. There were also 4 reports of hypotension in the human and one
report of hypotension in the cat. A biphasic response was seen 6
times, 4in human and once each in cat and dog. No response was seen
in man, twice in the horse, 3 times in the dog and once in a cat.
Explanations for increases in blood pressure include ganglionic
stimulation, a direct myocardial effect, stimulation of peripheral
receptor organs, a local action on peripheral circulation, a direct
effect on the cardiac center, an increase in PC02, and a reflex response
from the act of intubation. Bradycardia was thought to be due to a
muscarinic effect, stimulation of pulmonary chemoreceptors, or accumu-
lation of acetylcholine derived from succinylcholine.

The convincing experiment by Leighton (65) identified the
biphasic cardiovascular effect of succinylcholine in the dog. He
proposed that an effect on the peripheral blood vascular system

explained the initial hypotension seen after intravenous administration

21
of succinylcholine. Much of the confusion arising from the reports
of earlier workers (9,92,94) is due to their failure to record whether
the experimental animals used in their studies were atropinized.
Leighton systematically used atropine, ganglionic blockers, and alpha
and beta blockers to sort out the effect of succinylcholine from
secondary phenomena. In summary, the explanation for the action of

succinylcholine on the cardiovascular system is still in doubt.

MATERIALS AND METHODS

Animals

Eight conditioned purebred Beagle dogs, 4 female and 4 male,
obtained from a biological supply company,8 were utilized in this
study. The animals' ages ranged from 6 months to 1 year, and weights
ranged from 7 to 10 kg. Prior to the day of study, dogs were housed
separately in concrete kennels in accordance with Public Law 89-544.
The dogs were cleaned, watered and fed a balanced ration twice daily.
Pooled fecal samples were checked for evidence of internal parasites.
In addition to a physical examination, a blood sample was collected
so that complete blood counts, blood urea nitrogen determinations,
and serum glutamic pyruvic transaminase levels could be evaluated.
Dogs were vaccinated against canine distemper, canine infectious
hepatitis, and leptospirosis as puppies, and immunity against these
diseases was considered adequate. All laboratory tests were performed
at the veterinary clinical pathology laboratory, Michigan State

University.

 

8Laboratory Research Enterprises, Inc., 6251 South Sixth St.,
Kalamazoo, MI 49009.
22

23
Materials

Catheters used in the study included an end hole, 75 cm cardiac
catheter8 and a double lumen, 100 cm, 10 French cardiac catheter.b
The and hole catheter was used for collection of pooled venous blood
samples, recording of central venous pressure and for injection of
room temperature saline for determination of cardiac output. The
double lumen catheter was placed in the descending aorta, via the
carotid artery, and was used for collection of arterial blood samples
and recording of arterial pressure. The side hole position of the
double lumen catheter was occupied by a calibrated thermistorc
stabilized with epoxy cement by a local laboratory.d The thermistor
was used to monitor changes in blood temperature for determination
of cardiac output by thermal dilation technique.

A polypropylene tube was used for collection of end expiration
gas samples in order to monitor anesthetic concentration. The tube
was inserted into the lumen of an endotracheal tube near the plastic
adaptor and advanced to the tip of the endotracheal tube near the
thoracic inlet. A ten milliliter glass syringe with a threeeway

stopcock was used to collect gas samples.

 

aCournand Teflon Catheter #7550, U.S. Catheter and Instrument
Co., P.O. Box 787, Glen Falls, NY 12801.

bCournand Double Lumen Catheter, U.S. Catheter and Instrument
Co., P.O. Box 787, Glen Falls, NY 12801.

cVeco 32A7, Victory Engineering Corp., Victory Road, Spring-
field, NJ 07081.

dDept. of Physiology, Michigan State University, East Lansing,
MI 48824.

24
Development of hypothermia during the study was avoided by means
of a thermostatically controlled circulating water blanketa which was
used to insulate dogs from the surgery table. In addition, an elec-

tronic thermometerb was used to monitor esophageal temperature.

Equipment and Calibration

An eight channel photorecorder with oscilloscopeC was used to
monitor arterial pressure, central venous pressure and cardiac output.
Pressure transducersd used for monitoring arterial and venous pressure
were calibrated by means of integrated resistors contained by the
photorecorder. The arterial and venous catheters were connected to
the transducers and then to the preamplifiers of the photorecorder.
Electronic averaging was used to obtain mean values.

A three-channel graphic recordere was utilized for monitoring
presence of muscle twitch during the period of paralysis. Conversion
of the physical twitch to a visual tracing was by means of a force
displacement transducer.f The transducer was calibrated using inte-
grated resistors in the graphic recorder. One of the dog's posterior
limbs was stabilized with a modified Thomas splint apparatus which

was connected to the force displacement transducer by means of

 

aModel Kr13, Gorman—Rupp Industries Co., Belleville, OH.
bModel 41TF, Yellow Springs Instrument Co., Yellow Springs, OH.
cModel DR-8, Electronics for Medicine, White Plains, NY.

dModel P23Db, Statham Transducers, Inc., Hato Rey, Puerto Rico.
eModel 50 Polygraph, Grass Instrument Co., Quincy, MA.

fModel FTlO, Grass Instrument Co., Quincy, MA.

25

adhesive tape and 2.0 silk suture. The tape was used to form a loop
which in turn was taped to the tarsal area of the dog's leg. The
silk suture was used to connect the loop to the force displacement
transducer. Counter force was applied to the transducer until a
stable recording was maintained. To elicit a twitch, the peroneal
nerve was stimulated with a single rectangular stimulus of 0.1 milli—
second in duration, 15 volts in strength, at a rate of .5 pulses/second.

A gas chromatographa was used to monitor alveolar anesthetic
concentration. A 15 x 1/8 inch stainless steel screened 60/80 mesh
silica gel column was used. Column and detector temperature were
maintained at 165°C and 200°C, respectively. Gases used were hydrogen
at 50 psi flowing 60 ml/min, air at 50 psi flowing 300 ml/min, and
nitrogen at 60 psi flowing at lOO.ml/min. Calibration gas tanks were
prepared by adding liquid halothane to size E gas cylinders to yield
nearly complete saturated concentrations of anesthetic at atmospheric
pressure following the procedure of Sawyer at al. (84).

A blood gas analyzerb was used to monitor blood concentrations
of oxygen, carbon dioxide and hydrogen ion. Calibration of the blood
gas analyzer was checked before each sample, and base excess was come

puted by means of a nomogram.c Arterial blood was used for all analyses.

 

aGaschromatograph GC-M, 115 Frankfurter Ringer, Munich, Germany.
b
Denmark.

Model 72, EMD-RUPVEJ, Radiometer Copenhagen, Copenhagen,

cSiggaard-Anderson Alignment Nomogram, Radiometer Copenhagen,
Copenhagen, Denmark.

26
A semi-closed circle anesthesia machinea was used to deliver
halothane and oxygen to the experimental subjects. Ventilation was
controlled by a mechanical ventilatorb with end tidal carbon dioxide
concentration maintained at 5% by means of a carbon dioxide analyzer.c

Figure 1 shows a diagrammatic sketch of equipment arrangement.

Calculations

A thermal dilution technique was used for determination of
cardiac output. Room temperature saline was injected into the right
atrium and, after flowing through the pulmonary circulation, a fall
in temperature was recorded by the thermistor located in the descend-
ing aorta. Before each injection, blood temperature, injectate tempera-
ture and volume of injectate were recorded.

The change in temperature was visualized as a curve, the area
of which was measured as a triangle by planimetry.d Three separate
determinations of area were made with the average used in calculation
for cardiac output. Paper speed was verified by counting time lines.
Cardiac output was calculated by the following modified Stewart-

Hamilton formula (61):

 

aModel Rotameter, The Foregger Co., Inc., New York 18, NY.

bAnesthesia Ventilator Series 300/80, Ohio Chemical and
Surgical Equipment Co., Madison, WI.

cMedical Gas Analyzer, LB—2, Beckman Instruments, Fullerton,
CA 92634.

dK & E Compensating Polar Planimeter, Keuffel and Esser Co.,
New York, NY 10017.

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where CO

.<
II

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28

CO = v1 (Tb-Ti) (R) (F)
A

cardiac output in l/min

volume of the injectate in ml

temperature of the blood in degrees centigrade

temperature of the injectate in degrees centigrade

standard deflection due to 3 ohm resistor given in cm/C°

paper speed in cm/min

2
area under the curve in cm .

Cardiac index, stroke volume and total peripheral vascular resistance

were determined from cardiac output values.

Formulae utilized for these calculations included:

where CI

CO

BSA

SV

TVPR

._29
CI BSA
-C—0
SV - HR x 1000
_MAP-MVP
TPVR __-EET—-——

= cardiac index

= cardiac output in l/min
- body surface area in m2
= heart rate in beats/min
= stroke volume in ml

= total peripheral vascular resistance in peripheral
vascular resistance units (PRU)

= mean arterial pressure in mm Hg

= mean venous pressure in mm Hg.

29
Body surface area was determined from a nomogram (37).

Calibration of the gas chromatograph involved the injection of a
known concentration of halothane (0.80%) and determination of the
deflection on a recorder.8 The gas chromatograph was determined to
be linear over the span of concentrations used in the study and there-

fore a proportion was utilized to determine the unknown anesthetic

 

concentration.
unknown
- Alhalothane standard (%)]
anesthetic [standard deflection (mm)] [sample deflection (mm)]
concentration

Procedure

On the day of study a dog was selected at random and was brought
to the surgical preparation area. A 3 ml EDTA sample of venous blood
was drawn from the cephalic vein and taken to the clinical pathology
laboratory for evaluation. Using a gentle manner, the dog was then
anesthetized with halothane and oxygen delivered by mask. Preanesthe-
tics were not used. After intubation, anesthesia was maintained by l
to 1.5% halothane in oxygen delivered by a semi-closed circle anesthesia
machine.

After anesthetic stabilization the dog was transported by gurney
to the catheterization room. In order to prevent development of
accidental hypothermia, the dog was insulated from the gurney and
catheterization table by a circulating warm water blanket. After

surgical preparation of the lateral cervical area, exposure of the

 

aModel 1005, Beckman Instruments, Inc., Fullerton, CA.

30
jugular vein and common carotid artery was accomplished. A double
lumen cardiac catheter was placed in the descending aorta via the
carotid artery. Fluoroscopya was used to verify correct positioning.
The catheter was then double ligated in place to insure that movement
would not occur. The and hole cardiac catheter was then introduced
to the level of the right atrium via the jugular vein. Position was
verified by a 3 ml injection of radiopaque dyeb witnessed by fluoroscopy.
In order to prevent development of blood clots within the lumens of
catheters, heparinized saline was used as a periodic flushing agent.
At the conclusion of 30 minutes of catheterization procedure, the dog
was transported to the surgical laboratory.

Catheters were then connected to pressure transducers and control
values for arterial pressure and ventral venous pressure were
obtained. The arterial thermistor catheter was connected to a Wheat-
stone bridge which was in turn connected to a pressure preamplifier
which allowed visualization of cardiac output curves. The thermal
dilution technique was used for determination of cardiac output. The
dog's blood temperature was continuously recorded by an electronic
thermometer via the Wheatstone bridge. Lead II electrocardiogram‘was
continuously monitored, and heart rate was computed from the arterial
pulse tracing on the photographic printout.

In order to provide support and a stable base for the force dis-

placement transducer, a modified Thomas splint apparatus was fitted to

 

aModel HRT, General Electric Co., Medical Systems Division,
Detroit, MI 48219.

bHypaque 50%, Winthrop Lab., New York, NY.

31

a rear leg (16). The force displacement transducer was then connected
to the leg via adhesive tape and silk ligature with the resting'
tension adjusted so that during intermittent electrical stimulation,
a stable tracing was obtained. Alveolar concentration of halothane
was determined by gas chromatograph and maintained at 1.1 times the
minimum alveolar concentration (34) throughout the experimental pro-
cedure. Preparation procedure from induction of anesthesia to beginning
of experiment averaged 75 minutes in duration.

After control determinations of cardiac output, arterial pressure,
central venous pressure, total peripheral resistance, cardiac index
and heart rate, the dog was given either succinylcholine or gallamine
0.4 mg/kg intravenously via the lingual vein. Cardiac output determina-
tions were made at 5-minute intervals until the twitch response had
returned to 1/10 of control values. Blood pH was monitored from samples
drawn from the femoral catheter. If the hydrogen ion concentration
expressed in terms of pH was less than 7.30, correction was completed
before injection of the muscle relaxant to be tested. Metabolic acidosis
was corrected by the administration of 7.5% sodium bicarbonate solution
and respiratory acidosis was corrected by adjustment of the rate or
volume of the ventilatory pattern. A total of 8 dogs was involved in
the study. Each dog served as his own control as the procedure was

repeated after 2 weeks with the second relaxant.

Data Analysis
Analysis of data was accomplished through the facilities of the
computer laboratory of Michigan State University. An analysis of

variance (randomized complete block design) was used to compare

32
differences due to time. Data collection points analyzed were con—
trol, x +-one minute, x-+ 5 minutes, and x-+ 10 minutes. Tukey's
w-procedure (89) was used to test for differences between means. The

level of probability chosen for this study was 0.05.

RESULTS

General Considerations

Eight dogs were employed in the study. A total of 16 trials
was completed with each dog undergoing the experimental procedure
twice. Succinylcholine was used in the first trial followed in 2
weeks by the administration of gallamine.

Laboratory examination of each dog included a fecal examination
for parasites, a complete blood count, blood urea nitrogen determina-
tion and evaluation of serum glutamic pyruvic transaminase levels.
All values (Table 1) were within the normal range established for the

Beagle (19,27,96).

Table 1. Blood eValuations for 8 dogs prior to study

 

SGPT BUN WBC PCV Hb Protein
(S.F. units) (mg/100 ml) (cellB/mm3) (%) (gm/100 ml) (gm/100 ml)

 

16.2i3.2 15.3i2.6 12,462:3,488 4812‘ 16.811 5.510

 

Mean and standard deviation values from 8 dogs recorded from
jugular vein blood samples.

33

 

34

During the experimental procedure, dogs were placed on warm water
blankets in order to prevent accidental hypothermia. At each time
period the gallamine group averaged 35.4°C while the succinylcholine
group was slightly warmer (Table 2). The mean temperature at each time
period for either gallamine or succinylcholine was not significantly

different from their respective control means.

Table 2. Mean temperatures of 8 dogs given either gallamine or

 

 

succinylcholine
Control x + l min x + 5 min x + 10 min
(°C) (°C) (°C) (°C)
Gallamine 35.4il.3 35.4il.3 35.4il.3 35.4il.3
Succinylcholine 36.130.85 36.2i0.85 36.3il.0 36.3il.O

 

Mean and standard deviation of esophageal temperature values.
X equals time of injection of muscle relaxant.

Within 45 seconds after injection of either relaxant, muscle paraly-
sis was complete. The duration of paralysis was monitored by two
criteria: when the twitch response had returned to 1/10 of control
values and when the twitch response had returned to maximum. Cardio-
vascular variables were monitored up to the return of 1/10 of control
twitch. Table 3 displays the mean duration of paralysis for succinyl-
choline and gallamine.

End tidal halothane concentration was monitored to insure paral-
lelism of anesthetic depth among the dogs studied. Table 4 displays

mean end tidal anesthetic concentration for the 2 groups of dogs.

35

Table 3. Duration of paralysis of 8 dogs given either gallamine or

 

 

succinylcholine
Return to Return to
1/10 twitch (min) complete twitch (min)
Gallamine 26¢7 40111
Succinylcholine 22i12 37:19

 

Mean and standard deviation values for 2 groups of 8 dogs measured
at 1/10 and complete return of control twitch.

Table 4. Mean end tidal halothane concentration of 8 dogs given either
gallamine or succinylcholine

 

% halothane

 

Gallamine group l.lli.06

Succinylcholine group 1.14i.11

 

Mean and standard deviation values for 2 groups of 8 dogs.

Serum potassium levels were monitored from samples drawn before,
during, and after administration of a muscle relaxant. Specific times
were: 1) preanesthesia, 2) anesthetized but before injection of
relaxant, 3) 15 minutes after injection of a relaxant, and 4) 2 weeks
after the experimental procedure. Only 6 dogs were included in this

phase of the experiment due to incomplete data from 2 of the dogs. In

36
the gallamine group of dogs, preanesthetic serum potassium levels
were not significantly different from any other time periods.
However, the mean of the 2 week potassium serum sample was signifi-
cantly different from the anesthetized preinjection sample mean and
the 15 minute postinjection sample mean. In the succinylcholine
experiment, the preanesthesia sample was significantly different from
the 15 minute postinjection sample and the 2 week sample. All other

sample comparisons were homogeneous (Table 5).

Table 5. Mean serum potassium concentrations from 8 dogs given either
gallamine or succinylcholine

 

 

Time
15'minutes
Preanesthesia Preinjection Postinjection 2 weeks
(111qu 1) (Inqu 1) (111qu 1) (Inqu 1)
Gallamine 3.8:.42 3.51.37 3.4:.62 4.2:.37
Succinylcholine 4.2:.45 3.3:.36 4.1:.63 4.3:.24

 

Mean and standard deviation values for 8 dogs from blood samples
taken prior to induction of anesthesia, before injection of muscle
relaxant, 15 minutes after injection of muscle relaxant and 2 weeks
after the experimental procedure.

Cardiovascular Effects of Gallamine
After intravenous administration of gallamine, cardiac output and
heart rate exhibited slight increases. Specifically, cardiac output
increased 5% at x + l, 7% at x 4-5, and 7% at x +-10 when compared with

control values. Heart rate was increased 7% at x +-l, 4% at x +-5, and

 

37
3% at x + 10 when compared with control values. Stroke volume decreased
5% at x + 1, then slightly increased at the next 2 data points, while
mean arterial pressure increased 12% at x + 1, then slightly decreased
to 8% above control for the next 2 data points.

Cardiac index and central venous pressure exhibited opposite move-
ments as cardiac index increased slightly, while central venous pressure
slightly decreased. Total peripheral resistance slightly increased at
x + l, but then gradually declined toward control values.

Analysis of variance revealed that the slight variations from
control were not significant at the 0.05 level; however, there was a
significant difference between values from individual dogs. The identi-
fication of the source of variation may explain the occurrence of large
standard deviation found with certain variables. Table 6 displays the

cardiovascular changes from injection of gallamine.

Cardiovascular Effects of Succinylcholine ‘

Intravenous administration of succinylcholine resulted in a 9%
increase in cardiac output at x4+ 1 minute, followed by a gradual
reduction to control values over the next 10 minutes.

Heart rate also initially increased and was followed by a slow
return to control values. In a manner similar to the change in cardiac
output, mean arterial pressure exhibited the greatest increase at
x + 1 minute (24%), only to return to control values at the 5 minute
mark.

Mean central venous pressure, stroke volume and cardiac index
exhibited small changes from control values with mean venous pressure
and cardiac index increasing slightly and stroke volume decreasing at

x +-l minute.

 

38

Table 6. Mean cardiovascular variables from 8 dogs given 0.4 mg/kg

 

 

gallamine
Time (min) c x+1 x+5 x+10
CO (l/m) 1.38:27 1.44:.26 1.47:.43 1.48:.38
CI 2.94:.52 3.05:.52 3.12:.50 3.14:.47
HR (beats/min) 94:22 101:15 98:22 97:21
SV (ml) 15:5 15:4 16:6 16:5
TPR (PRU) 42:9 46:10 44:11 44:9
MVP (mean mm Hg) 5:2 4:2 4:1 4:2
MAP (mean mm.Hg) 62:9 69:13 67:12 66:11

 

Mean and standard deviation values for 8 dogs for each variable
recorded immediately before and at 1 minute, 5 minutes, and 10 minutes
after injection of gallamine.

CO - cardiac output; CI . cardiac index; HR = heart rate; SV =

stroke volume; TPR = total peripheral resistance; MVP = mean venous
pressure; MAP . mean arterial pressure.

Total peripheral resistance increased 15% at x + 1 minute, return-
ing to control at x + 5 minutes.

At the 0.05 level of significance, analysis of variance (randomized
complete block design) revealed that changes observed for heart rate
and mean arterial pressure were significant. Changes observed in car-
diac output, cardiac index, stroke volume, mean central venous pressure
and total peripheral resistance were not significant.

Comparisons of means by Tukey's w—procedure (89) revealed that

control and x + 1 minute means for heart rate and mean arterial pressure

 

 

39
were significantly heterogeneous. Other comparisons between means
involving these two variables were not significant.

There was significant variation between dogs as shown by analysis
of variance (P<0.05). This identifies a source of variation which
might be mistakenly attributed to an action of succinylcholine.

Table 7 displays cardiovascular data from injection of

succinylcholine.

Table 7. Mean cardiovascular variables of 8 dogs given 0.4 mg/kg

 

 

succinylcholine

Time (min) C x + l x + 5 x + 10
CO (l/m) 1.58:.40 1.73:.33 1.71:.32 1.57:.26
CI 3.36:.79 3.67:.74 3.63:.75 3.30:.52
HR (beats/min) 113:22 125:ll* 119:13 116:14
SV (ml) 15:4 14:2 15:3 14:3
TPR (PRU) 51:10 59:20 49:11 52:12
MVP (mean mm Hg) 4:3 5:4 4:3 3:3
MAP (mean mm Hg) 82:12 103:24* 85:5 83:12

 

Mean and standard deviation values for 8 dogs for each variable
recorded immediately before and at 1 minute, 5 minutes, and 10 minutes

after injection of succinylcholine.

CO = cardiac output; CI = cardiac index; HR = heart rate; SV =
stroke volume; TPR I total peripheral resistance; MVP = mean venous

pressure; MAP - mean arterial pressure.

*
Statistically significant difference when compared with control
(P<0.05).

 

DISCUSSION

This study was undertaken to eliminate some of the doubts veteri-
nary practitioners may have concerning the use of muscle relaxants in
conjunction with halothane anesthesia. Muscle relaxants have not
been used in veterinary medicine partially due to a lack of informa-
tion on the cardiovascular effects in the dog. Indeed, the reports
of death involving the use of succinylcholine in the horse may have
frightened some veterinarians from considering the use of muscle
relaxants as an adjunct to anesthesia.

With the present study halothane anesthesia was chosen because
it is widely used in veterinary anesthesia. Atropine preanesthesia
was not utilized in order to eliminate a possible source of extraneous
effect on the autonomic nervous system.

Temperature was controlled by means of circulating water blankets
in order to eliminate the possibility of accidental hypothermia.
However, even with stringent preventive measures, a moderate degree
of hypothermia did develop. Several investigators (10,22,68,101) have
reported an effect from hypothermia on the duration and magnitude of
neuromuscular blocking drugs. Bigland et al. (10) found an increased
duration and magnitude at the motor end plate from succinylcholine and
a decreased duration of action from the non-depolarizing drug d-

tubocurare. Supporting results were found by Cannard (22) and Zaimis

40

 

 

41
(101) when studying the effect of lowered muscle temperature on the
action of neuromuscular blocking drugs in man. They found that
lowering muscle temperature to 26°C increased the magnitude and pro-
longed the duration of the blockade produced by succinylcholine. Hypo-
thermia for the current study was not less than 36°C and consequently
probably played no significant role in the duration of action of
succinylcholine or gallamine.

The acid-base status of each dog was monitored by analysis of
arterial blood samples collected prior to injection of a muscle
relaxant. If blood pH was below 7.30, proper corrective techniques
were instituted before injection of the relaxant. In work involving
cats, acidosis has been shown to have little effect or even accelerat-
ing recovery from the neuromuscular block of gallamine (48). Conversely,
respiratory alkalosis has been reported to prolong neuromuscular block
from.gallamine (56). In cats given succinylcholine (48), respiratory
acidosis antagonized the block and speeded recovery, while respiratory
alkalosis slightly potentiated the paralysis. Metabolic acidosis
and alkalosis did not modify the duration or intensity of neuromuscular
paralysis. The possible mechanisms of action for effects from changes

in pH include: 1) an increase in PCO will increase blood pressure and

2
blood flow which may reduce blockade and shorten recovery; 2) the
activity of the drug is inversely proportional to that fraction bound
to protein and alterations in plasma pH modify the ability of plasma
proteins to take up certain drugs, 3) finally, a change in ionization

could occur at receptors whtn pH is altered. Although the duration of

block from succinylcholine in the dog is variant from the cat, alterations

42
in duration of paralysis from changes in pH should be similar. In the

current study, any deviations in pH and P00 were corrected prior to

2
injection of the muscle relaxant.

The effect of halothane on the heart and circulation is well
documented (12,20,4l,49,51,52,80,85). In order to maintain the same
conditions for each group of dogs, end tidal halothane concentration
was closely monitored. Hypotension and muscle relaxation will result
from.increasing concentrations of halothane. It is not unrealistic to
think that early reports of hypotension from muscle relaxants might
have been due in part to deep levels of anesthesia. Black (12)
recently listed five possible mechanisms to explain the occurrence
of hypotension during halothane anesthesia: l) by suppressing auto-
nomic nervous activity, 2) by causing peripheral vasodilation, 3) by
altering the ability of baroreceptor reflexes to compensate for
changes in blood pressure, 4) by inhibiting the vasomotor center and,
finally, 5) by modifying the contractile force of the heart. Raventos
(80), in the initial study of the cardiovascular effects of halothane,
proposed that hypotension was due to mesenteric ganglionic blockade.
Hughes (49) ventilated closed chest dogs with 1 and 2% halothane and
noticed falls of arterial blood pressure similar to those following
hexamethonium. This was without comparable reduction in peripheral
vascular resistance or comparable impairment of either the cardiac
slowing induced by vagal nerve stimulation or the contractions of the
nictitating membrane induced by preganglionic cervical sympathetic

nerve stimulation. This indicates that ganglionic blockade does not

fully explain the hypotension produced by halothane. Burn et al. (20)

 

 

43
found little evidence of neural blockade in the superior cervical
ganglia of the cat and also demonstrated a blood pressure fall in an
eviscerated animal. Thus hypotension may be due to depression of
central autonomic centers. The most plausible explanation for the
effects of halothane is a combination of factors.

Neuromuscular transmission is also affected by halothane. Karis
et al. (52) state that even though muscular relaxation is mainly
attributable to the central effect of halothane, the peripheral action
which involves a reduction in sensitivity of the postjunctional membrane
is not negligible and could be significant when neuromuscular trans-
mission is impaired by disease or curare-like agents. When halothane
was studied in the amphibian nerve-muscle preparation (41), the block-
ing concentrations of halothane were found to be 1.5% for the nerve
stimulated twitch, 4% for the axonal conduction, and 4% for the
directly stimulated muscle. From these results, it was concluded
that the peripheral blockade produced by halothane occurs at the
neuromuscular junction. By the use of the microelectrode penetration
of single fibers, it was demonstrated that, at the neuromuscular
junctions, the postjunctional membrane is the synaptic structure
most sensitive to the action of halothane. In the current study,
halothane concentration was maintained at a mean of 1.11% for the
gallamine group and 1.14% for the succinylcholine group, thereby
limiting any effect on neuromuscular transmission.

The duration of neuromuscular block was monitored by a mechanical
recording of twitch using a method proposed by Bowen (16). There is

some controversy involving the ideal method of recording muscle

44
activity; however, Katz (53) compared electrical and mechanical methods
of recording spontaneous and evoked muscle activity and concluded that
a mechanical recording of twitch is an acceptable way of monitoring
neuromuscular block.

The primary objective of this study was to report on the cardio-
vascular effects of gallamine and succinylcholine administration to
dogs anesthetized with halothane. Ideally, one would like to see a
minimal or possibly a slight positive effect on the cardiovascular
system from the administration of these two drugs. In general, the
administration of the muscle relaxants, as defined in terms of this
study, had minimal effect on cardiovascular variables.

,Cardiac output increased slightly after administration of gallamine,
maintaining the increase throughout the evaluation period, while
succinylcholine exhibited a slight increase at the first data point
but slowly returned to control values over the next two data points.
These changes were not significant at the 0.05 level.

Clinically, a small increase in cardiac output could be bene-
ficial, principally to counteract cardiovascular depression commonly
seen during general anesthesia. The changes in cardiac output can
be related to small increases in heart rate. After gallamine adminis-
tration, heart rate increased 7% over control values. This result
agrees with other reports in quality but not quantity. Increases as
high as 40% have been reported (57) with an average increase of 25%
(69,98). Changes in heart rate due to gallamine have been related to
a vagal blocking action similar to atropine (23,31,82,83), myocardial

stimulation (87), or positivezchronotrOpic effect secondary to local

45
catecholamine release (18). The lack of marked increases in heart rate
during the present study may reflect increased attention to providing
a stable animal before and during action of gallamine. Increased levels
of CO2 in the blood may occur during anesthesia and subsequently may
increase heart rate. Another possible explanation is that many of the
cited studies were performed clinically on human subjects. If the
level of anesthesia was not deep and the cerebral cortex active, the
sensation of total paralysis may have stimulated the release of
epinephrine and subsequently a chronotropic effect on the heart. The

current study controlled the blood PCO and anesthetic level in order

2
to mitigate the above effects. As a result, a modest increase in heart
rate occurred which was analyzed as being not significant.

In contrast, the small increase in heart rate from succinylcholine
was found to be significant. Increases in heart rate have been found
by other investigators who have related their findings to: l) a nico-
tinic action of succinylcholine (1,13,54), 2) vagal stimulation and
reflex stimulation of peripheral receptor organs (70), and 3) an arousal
response in the electroencephalogram from afferent discharge of muscle
spindles (73). The nicotinic action of succinylcholine has been
well documented (91,92,93) by investigators who utilized the ganglionic
blockers hexamethonium and tetraethylammonium chloride to prevent
increases in heart rate after injection of succinylcholine. Reflex

stimulation of the carotid sinus precipitated by a vagal type action

would increase heart rate. Indeed, Mathias et a1. (70) state that

 

"it is generally considered that the action of succinylcholine on the

heart is identical to that of vagal stimulation." This would explain

 

46
the often seen biphasic nature of succinylcholine's action on cardiac
rhythm, i.e., initial slowing followed by tachycardia.

A new explanation for the action of succinylcholine on cardiac
rhythm was introduced by Mori et a1. (73) in 1973. They postulated
that the depolarizing drugs produce an increased activity in the
afferent discharge of the muscle spindles which leads to the electro-
encephalogram arousal pattern. This arousing pattern may have some
role in the tachycardia produced by succinylcholine. Whatever the
effect of succinylcholine, much of the confusion of its effect is
probably due to similarity between the succinylcholine and acetyl—
choline molecules. This similarity makes it difficult to determine
the exact mechanism or mechanisms of action, there being a different
effect at different sites (the heart cell, the ganglion, the motor
and plate). Evidence for postganglionic stimulation is found in the
development of hypertension and tachycardia after the administration
of large doses of succinylcholine.

The present study did not show a slowing of heart rate followed
by an increase in rate to above control levels. Atropine was not
used so that any muscarinic effect of succinylcholine should have been
apparent. The noted increase in rate could neither be explained in
terms of reflex action as an initial bradycardia was not seen. An
asphyxial response aggravated by muscular activity can also not be
used to explain the tachycardia as blood PC02 and P02 were closely
monitored as the animal was artificially ventilated. In order to
achieve ganglion stimulation, doses larger than those used in this

experiment would seem to be needed. We are left with the possibility

47
that muscle fasciculation and resultant afferent discharge of muscle
spindles may somehow play a role in the occurrence of tachycardia.

In a manner similar to heart rate, mean arterial pressure increased
after injection of gallamine and succinylcholine with the increase in
pressure after the latter significant. Increases in mean arterial
pressure can be caused by increases in peripheral resistance or
increased cardiac output. Succinylcholine is thought to increase mean
arterial cardiac output. Succinylcholine is thought to increase mean
arterial pressure through stimulation of autonomic ganglia (9,13,54,92,
93,102). However, at least one report (41) points out that ganglionic
stimulation should include vasoconstriction of skin and splanchnic
areas and this is not the case. Other explanations for the action of
succinylcholine on blood pressure include a hypotensive muscarinic
effect on receptors in the peripheral vasculature (41,63), a hyper-
tensive response to asphyxia (91,50), and vagal stimulation from an
acetylcholine-like action (9,64,67).

The action of gallamine on blood pressure can be related to
cardiovagal block (83), myocardial stimulation (17,18) and a slight
sympathetic ganglionic block (86,93). A convincing study by Brown
et al. (18) utiliZing cats'and guinea pigs enforces the theory of
myocardial stimulation to increase blood pressure. They used reser-
pinized atria and inhibited the response to gallamine almost completely
with any residual effect abolished by propranolol. Recently, Reitan
(81), working with anesthetized man, could not demonstrate any iono-
tropic action of gallamine. The current study found only a small

nonsignificant increase in blood pressure. One possible explanation

48
is that experimental technique has improved. Original workers used a
kymograph to record changes in pressure with little attention to main-
taining a stable environment. Modern experiments utilize accurate
pressure transducers with a supporting role from.blood-gas monitors,
thermistors, and anesthetic concentration analyzers. Another factor
which contributed to conflicting results is the number of different
species which have been used. Almost all domestic animals plus man
have contributed to knowledge about the action of gallamine and succinyl-
choline. This fact cannot help but introduce an enormous degree of
variation. The reason the current study did not produce striking
changes in heart rate and arterial pressure may be due to closer
monitoring of control variables.

Other cardiovascular variables did not change significantly after
injection of succinylcholine or gallamine. Mean central venous pressure,
stroke volume, total peripheral resistance and cardiac index were all
homogeneous with respect to their control values.

It is interesting to note that a nonsignificant rise in total
peripheral resistance did occur during the succinylcholine trial.

This might possibly be related to muscle fasciculations during the
depolarization stage of paralysis, as the modest increase in resistance
(15%) was not present at the 5 minute mark.

Succinylcholine-induced increased serum potassium has been
reported by many investigators as a complication of the clinical use
of succinylcholine (11,26,95). In order to determdne if succinylcholine
administration causes a rise in serum concentration, blood samples

were collected prior to induction of anesthesia before injection of

49
the muscle relaxant, 15 minutes after injection, and 2 weeks after
the experimental procedure. The interesting result was that the
sample collected from the anesthetized dog before injection of succinyl-
choline was significantly lower than the preanesthesia sample, the
postinjection or the Zdweek sample. Therefore, injection of succinyl-
choline raised serum potassium an average 0.8 mEq/l. Administration
of gallamine did not produce a similar response. Succinylcholine is
thought to change cell membrane permeability for potassium with a
resulting loss of potassium from the cell, a decrease in resting
membrane potential, and an increase in serum potassium (54). The
cat has shown a similar response to succinylcholine (76). Although
the increase in the current study was statistically significant, it
was not clinically significant.

In the present study the duration of action of succinylcholine
was longer than the duration of action seen in man, cat or horse.
Possible explanations include decreased plasma pseudocholinesterase,
atypical plasma pseudocholinesterase or a phase II (desensitization)
block (100).

Decreased plasma pseudocholinestersase may be the result of
hepatic disease as plasma pseudocholinesterase is synthetized by the
liver. In the current study, there was no evidence of liver necrosis
as determined by serum glutamic pyruvic transaminase levels. Atypical
plasma cholinesterase is a hereditary defect in man (100) which has
not been reported in the dog. The occurrence of a desensitizing or
phase II block after one dose of succinylcholine in the dog should be
considered (90). This type of block occurs in man after repeated

doses of succinylcholine (100).

50

The rate of elimination of muscle relaxants also has an important
role in determining duration of action. The nearly complete ioniza-
tion of gallamine limits the ability of this relaxant to cross cell
membranes resulting in limited distribution. Consequently, renal
tubular reabsorption of the relaxant is prevented after being filtered
in the glomerulus. In addition, only a small fraction of gallamine
molecules are bound to protein and most are free to pass with the
plasma filtrate enhancing renal elimination of the drug.

In contrast, elimination of succinylcholine in most species
depends on 1) clearance from the active site by diffusion or by local
hydrolysis in the capillary and 2) removal by muscle blood flow (100).
Factors which affect these points include hepatic disease (100),

body temperature (101), preanesthetic medication, and cardiac output.

CONCLUSIONS

The intravenous administration of succinylcholine or gallamine
following the criteria defined in this study does not adversely
affect cardiac output, mean arterial pressure, heart rate, stroke
volume, mean venous pressure, total peripheral resistance, or cardiac
index. The use of these agents as an adjunct to anesthesia in the

dog should be encouraged in contemporary veterinary practice.

51

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