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Thesis for the Degree of M. S.

MICHEGAN STATE UNIVERSITY A

DELBERT J. KRAHWINKEL JR.
1973 'f

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ABSTRACT

CARDIOPUEHOEARY.EFIECTS OP.!ENTANYL9DRDPERIDOL,
NITIOUS OXIDE, AND ATROPINE SULFATE IN DOGS

By
Delbert J. Krahwinkel Jr.

The cardiopulmonary effects of droperidol-fentanyl, nitrous oxide,
and atropine were evaluated and analyzed in 12 adult male Beagles.
The cardiovascular variables measured were: cardiac output, systolic
arterial pressure, diastolic arterial pressure, mean arterial pressure,
central venous pressure, heart rate, stroke volume, total peripheral
resistance, and packed cell volume. Respiratory measurements included
arterial and venous pH, P02 and P002, base.deficit, minute volume,
respiratory rate, and tidal volume. In addition, analgesia, response
to auditory stimuli, and muscle relaxation were subjectively evaluated.
All dogs were surgically prepared with a thermistor in the sorts for
measuring cardiac output by thermal dilution. Arterial and venous
catheters were inserted and a chronic tracheostomy was performed. Each
dog served as its own control and data obtained from unanesthetized,
unmedicated animals were compared with data recorded following administra-
tion of the test drugs.

The dogs were randomly divided into 3 groups of 4 dogs each.
Group I was given intravenous droperidol—fentanyl alone; Group II was

given droperidol-fentanyl intravenously with 671 nitrous oxide, and

Delbert J. Krahwinkel Jr.
Group III was given atropine sulfate intramuscularly followed by intra-
venous droperidol-fentanyl and 672 nitrous oxide.

Respiration was depressed in all 3 groups for 3 to 5 minutes
following injection of the droperidol-fentanyl. This resulted in a
respiratory and metabolic acidosis in all animals.

In addition, droperidol-fentanyl alone caused a decrease in systolic
pressure and a slight decrease in heart rate. These dogs were sensi-
tive to auditory stimulation. No cardiovascular changes were noted
when nitrous oxide was added in the Group II animals. Analgesia and
muscle relaxation.were improved over the Group I aninals. The pre-
medication of atropine sulfate in Group III resulted in increased
cardiac output, heart rate, and diastolic pressure. The subsequent
administration of droperidol-fentanyl-nitrous oxide caused a transient
increase in mean and systolic pressure. This latter anesthetic regime
along with assisted or controlled respiration provides an excellent

anesthetic state with minimal cardiopulmonary depression.

CARDIOPULMDNARY EFFECTS OF FENTANYLPDROPERIDOL,

NITROUS OXIDE, AND ATROPINE SULFATE IN DOGS

By
Delbert J. Krahwinkel Jr.

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

1973

(:0 /‘/»~‘,j’ 7 ‘2)

Dedicated to
my God
to Whom belongs the credit

for any and all talents
that I possess

ii

ACKNOWLEDGEMENTS

I would like to express my thanks to the many people who helped
make this research endeavor possible.

To Dr. Donald Sawyer for all his help in planning and conducting
the research as well as preparing this thesis. To Dr. George Eyster
for his advice and guidance particularly with the electronic instru-
mentation. To the other members of my committee, Dr. Gabel Conner
and Dr. Mark Heerdt, for the time they spent on my behalf. To Mrs.
Gayle Bender for all the hours she spent helping to conduct the
research and to analyze the results. To Miss Janice Fuller for the
expert typing of this manuscript, and to the Medical Media Center
of Michigan State University for the preparation of the charts and
graphs. Finally, to Dr. James Gibson for his advice on the statistical

analyses of this research.

iii

TABLE OF CONTENTS

INTRODUCTION . . . . . . . . . . . .

REVIEW OF LITERATURE . . . . . . . .

Effects on Systemic Cardiovascular Dynamics
Effect on Regional Blood Flow . .

Anti-Arrhythmic Effect. . . .

Effect on Vasoactive Substances

Effects on Respiration. . . .
MATERIALS AND METHODS. . . . . . . .

Animals 0 O O O O O O O O O O
Standardization and Training.
mterials O O I O I O O I O 0

Equipment . . . . . . . . .
Data Measurement Technic. .

Recording of Control Data . .
Drug Evaluation . . . . . .
Data Analysis . . . . . . .

RESWTS O O O O I O O O O 0 0 O O O 0
General Considerations. . . .
Group I: Innovar-Vet . . . .
Group II:
Group III:
DISCUSSION AND CONCLUSIONS . . . . .

Innovar-Vet o s o s s o a e s

Surgical Implantation and Preparation

Innovar-Vet with Nitrous Oxide.
Innovar-Vet with Nitrous Oxide and Atropine

SWY‘O o s s s s o o e s s e s o s

WCES O O O O O O O O O O O O 0

iv

Innovar-Vet with Nitrous
Innovar-Vet with Nitrous Oxide and Atropine

Oxide .

Page

(.0

\OQNNU

11

11
11
12
14
15
16

19
19

23
23
23
31
39
49
51
54
56
58

60

LIST OF TABLES
Table Page
1 Experimental design for the research project . . . . . . . 20
2 Cardiovascular data.with Innovar-Vet . . . . . . . . . . . 24
3 Respiratory data with Innovar-Vet. . . . . . . . . . . . . 25
4 Cardiovascular data with Innovar—Vet and nitrous oxide . . 32
5 Respiratory data with Innovar-Vet and nitrous oxide. . . . 33

6 Cardiovascular data with atropine, Innovar-Vet,
and nitrous oxide. . . . . . . . . . . . . . . . . . . . . 40

7 Respiratory data with atropine, Innovar-Vet, and
nitrous oxide. 0 O O O O O O O I O O O O O O O O O O I O O 41

Figure

10

11

12

13

14

LIST OF FIGURES

Catheters used for recording cardiac output and arterial
and venous pressure. . . . . . . . . . . . . . . . . . .

Illustration of the mechanical and electronic layout
for data recording . . . . . . . . . . . . . . . . . . .

Cardiac output, stroke volume, and heart rate with
Innovar-vet s s e s e s s a s o e o e o e s s o s e a s 0

Mean arterial pressure and total peripheral resistance
V1 th Innovar- ve t I I I I I I I I I I I I I I I I I I I I

Arterial blood gases with Innovar-Vet. . . . . . . . . .

Minute volume, respiratory rate and tidal volume with
Inncvat-Vet s e s s o s o o o o s s s e s s s s s o s s 0

Cardiac output, stroke volume, and heart rate with
Innova I'vet e e o s o e s e s s s s s s e s e s s o s o a

Mean arterial pressure and total peripheral resistance
With InnOVEI-vet and nitrous 031416 a s e s s s or o s e e

Arterial blood gases with Innovar—Vet and nitrous oxide.

ZMinute volume, respiratory rate, and tidal volume with
MOVIE-vet and nitrous OXIde. a e e e a e s e s s o s 0

Cardiac output, stroke volume, and heart rate with
atropine, Innovar-Vet, and nitrous oxide . . . . . . . .

Mean arterial pressures and total peripheral resistance
with atropine, Innovar-Vet, and nitrous oxide. . . . . .

Arterial blood gases with atropine, Innovar-Vet, and
n1 t rous ox 1d e I I I I I I I I I I I I I I I I I I I I I I

Minute volume, respiratory rate, and tidal volume with
atropine, Imovar-Vet and nitrous OXidI. s s s e e s s 0

vi

Page

13

22

26

27
28

29

34

35
36

37

43

44

45

46

INTRODUCTION

In 1949, Laborit of France conceived the idea that general anes-
thesia could be produced without profound depression of all cortical
and subcortical centers. He introduced a method of anesthesia based
on selective blocking of certain cellular, autonomic, and endocrine
responses. This new technique utilized a narcotic-tranquilizer combina-
tion to form a "lytic cocktail." When this method, called neuroplegia,
was combined with hypothermia, surgery could be performed without the
aid of other anesthetic agents. However, this resulted in marked circu-
latory depression. Consequently, the technique never gained wide
popularity.

The term neuroleptanalgesia was introduced in Europe by De Castra
and Mudeleer in 1959. They popularized the idea and stimulated interest
by using a potent psychomotor sedative with a powerful analgesic.

The search continued for a means of selectively blocking afferent
nervous systems involved in surgical stress. 'With the emphasis on
analgesia, Janssen (1963) introduced a series of highly potent meperidine-
derived analgesics from which evolved the narcotic, fentanyl. This
drug proved to be a very potent analgesic with minimal cortical and
cardiovascular depressant effects. Janssen simultaneously developed
a group of butyrophenone derivative tranquilizers. These potent
tranquilizers induced a state of "neurolepsis" by effectively suppres—
sing subcortical and autonomic activity. Droperidol was one of this

group.

2

When these 2 drugs were administered, a condition resulted in
which the patient was completely passive, unresistant to physical stress.
and analgesic. This stage was referred to as neuroleptanalgesia (NLA).
The combination of droperidol and fentanyl in a 50:1 ratio is the pri-
mary neuroleptanalgesic presently used. Innovar-Veta contains 20 mg of
droperidol and 0.4 mg of fentanyl per milliliter and is used in animals.
Innovarb is used in human medicine and contains 2.5 mg of droperidol
and 0.05 mg of fentanyl per milliliter. Innovar is used extensively in
human surgery for the poor-risk patient who cannot tolerate cardio-
vascular depression produced by most inhalant anesthetics. Many incon-
sistencies have been reported in the literature with reference to the
cardiopulmonary effects of NLA. Some investigators have reported a
significant decrease in blood pressure while others have reported no
decrease. Bradycardia was observed by some but not by others. Similar
differences have been noted in the effect on respiratory rate and tidal
volume.

The objective of this experiment was to evaluate the cardiovascular
and respiratory effects of Innovar-Vet in the dog when used alone and
with nitrous oxide and atropine sulfate. The reasons for the study
were (1) inconsistencies in the literature both in its effects on man
and dogs, (2) a lack of control measurements for comparison, (3) other
drugs were used in many experiments which may have affected the results,
and (4) a lack of a study using NLA alone and in combination with

nitrous oxide and atropine.

 

aInnovar-VetR, Pitman-Moore, Inc., washington Crossing, N.J.

bInnovarR', McNeil Lab, Ft. Washington, Penn.

REVIEW OF LITERATURE

Effects on Systemic Cardiovascular Dynamics

In order to study some of the basic effects of this combination of
drugs, investigations were conducted to evaluate effects of droperidol
and fentanyl separately. Yelnosky and Gardocki (1964) stated that each
drug exerted its own cardiovascular effect without any well-defined
antagonistic or potentiating interaction.

Gardocki and Yelnosky (1964) reported that fentanyl citrate given
to dogs anesthetized with pentobarbital produced changes which were
dose related. At low doses (0.0025 to 0.005 mg/kg), there was no sig-
nificant effect on blood pressure, heart rate or ECG. However, when
the dose was increased to 0.01 to 0.04 mg/kg, hypotension and brady-
cardia resulted. The bradycardia responded immediately to 0.1 to 0.5
mg/kg of atropine intravenously. At these high doses, ventricular
premature contractions were noted on one occasion and prolongation of
the P—R interval occurred during the periods of marked bradycardia.

No ectopic pacemaker activity was noted in any of the tests. Brady-
cardia was not as profound in vagotomized dogs, but there was no sig—
nificant difference in blood pressure. Hypotension occurred even when
the dogs were premedicated with antihistamine or 1 mg/kg IV atropine.
However, these agents markedly reduced the depressor effects of
histamine and acetylcholine. Response to intravenous epinephrine
indicated there was no sign of adrenergic blockade. Femoral artery
injections caused a decrease in vascular resistance. The doses of

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4
fentanyl used in this experiment represent 2 to 4 times the recommended
human dose but are much lower than the usual dog dose. This lack of
depression has been observed by Morrison (1969). Shepherd (1964)
reported that fentanyl tolerant dogs maintained normal myocardial
function with a greatly reduced oxygen consumption.

Recently, Dixon et a1. (1970) found no alteration in ventricular
function in an isolated heart preparation. However, total peripheral
vascular resistance fell to 73% of control one minute after intravenous
administration of Innovar, then returned to 822 of control in 15
minutes. Peripheral vascular capacitance increased moderately.

In a similar experiment by Yelnosky et al. (1964), the effects of
droperidol were studied. Increasing doses (0.125 to 0.5 mg/kg) pro-
duced a sharp drop in blood pressure with complete or partial recovery
in one minute. Heart rate was not affected and there were no electro-
cardiographic abnormalities. .The effects on contractile force of the
heart were variable and of short duration. Yelnosky and Gardocki (1964)
showed that a combination of fentanyl and droperidol decreased blood
pressure and heart rate. Both effects occurred in 5 minutes, were
maximal in 10 to 20 minutes, and lasted as long as 30 minutes. Effects
‘were similar in vagotomized and intact dogs. This combination also
caused a partial blockade of the pressor effect of epinephrine. In
most instances, there was an increase in myocardial contractile force.
Intra-arterial injections of droperidol caused an immediate transient
increase in femoral artery blood flow with little change in perfusion
pressure. Doses of 0.5 mg/kg had little or no effect on cardiac output
but caused a decrease in blood pressure, total peripheral resistance,

and heart rate. Higher doses caused a lowered cardiac output as well.

5
Morrison (1969) observed a small reduction in pulmonary vascular
resistance and pressures in addition to its slight effect on the
systemic circulation.

In two separate experiments, Dobkin et a1. (1966) reported
extensive experiments in dogs using the 50:1 combination of droperidol
and fentanyl. Since a loss of consciousness was not produced, 662'
nitrous oxide was used to provide unconsciousness. This resulted in
a slight decrease in systolic and diastolic arterial pressure, mean
arterial pressure, and heart rate. Venous pressure rose slightly, and
there was no significant alteration in the electrocardiogram.

Dobkin at al. (1970) used premedication of 0.2 mg atropine subcu-
taneously followed by Innovar-nitrous oxide anesthesia in 60 human
patients. They reported no appreciable change in blood pressure, pulse
rate, or ECG. Cardiac index and stroke index decreased 28% and 152,
respectively. Peripheral vascular resistance increased 342 and left
ventricular work was reduced 32!. Atropine had no effect on pH, P002,
or P02, but during anesthesia pH increased and P002 decreased due to
hyperventilation. Metabolic acidosis did not develop in any patients.

Hamlin et a1. (1968) showed that Innovar-Vet, used simultaneously
‘with small doses of pentobarbital, produced a response similar to that
found in sleeping dogs. Depression of cardiac output was caused by
decreased heart rate, since stroke volume remained unchanged.

Abel and Waldhausen (1968) observed that chronic instrumented
dogs had a decreased heart rate, increased stroke volume, and unchanged
cardiac output. The addition of pentobarbital caused an increased
heart rate and decreased stroke volume.

Moran at at. (1972) reported on the cardiovascular effects of

Innovar-Vet-nitrous oxide (501) on chronically prepared dogs. They

6
found a decrease in mean arterial pressure secondary to a decrease in
total peripheral resistance, a nonsignificant increase in cardiac
output. Heart rate was not changed but all dogs were premedicated with
0.1 mg of atropine.

Several experiments with these drugs have been carried out in
human volunteers as well. In one of these by Corssen et a1. (1964),
the subjects received no premedication and drugs were administered
alone or in combination. Fentanyl alone caused a slight decrease in
pulse rate, but no consistent change in systolic or diastolic arterial
pressure, while droperidol alone caused a slight tachycardia, but no
blood pressure changes. When administered together, there was a non-
significant increase in heart rate and a nonsignificant decrease in
systolic blood pressure. Zaunder et al. (1965) studied human subjects
premedicated with atropine. The results showed an increase in cardiac
index and central venous pressure, a decrease in total peripheral
resistance, mean arterial pressure and pulse rate; stroke index,
stroke work and circulation time remained unchanged. The only sta-
tistically significant change was hypotension. In a third human study
with atropine premedication, Dobkin et al. (1964) found similar changes,
except that arterial pressure was less affected. In addition, the
electrocardiogram showed no abnormalities.

Grell et a1. (1970) reported no hypotension, arrhythmias or ECG
changes in 584 human patients anesthetized with fentanyl-nitrous oxide.
This observation is consistent with that of Heerdt (1970) in patients
anesthetized with Innovar~nitrous oxide for open-heart surgery.

In a study of the effects of fentanyl on isolated heart muscle,
Goldberg and Padget (1969) showed that fentanyl directly depressed the

contractile performance of heart tissue. There were decreases in peak

7
developed tension (tpd), maximum.rates of tension developed (dp/dt),
and relaxation (-dp/dt). Eisele and Smith (1972) studied the cardio-
vascular effects of 402 nitrous oxide in man and found an increase in
the catecholamine turnover and a direct depression of myocardial
function; mean arterial pressure was not affected since vasoconstric-

tion was present.

Effect on Regional Blood Flow

German and Craythorne (1969) reported that, in contrast to most
anesthetics, Innovar caused little or no depression on the hemodynamic
aspects of renal function. The increase in renal vascular resistance
observed with most anesthetics was not apparent with Innovar.

Freeman et a1. (1966) reported cerebral blood flow to be increased
up to 342 in one experiment utilizing cats. However, this was accomr
panied by activation of the EEG. Edmonds-Seal and Frye-Roberts (1970)
have shown depressant effects on cerebral flow.

As mentioned earlier, Gardocki and Yelnosky (1964) have indicated
that droperidol caused an increase in femoral artery flow while

Yelnosky et a2. (1964) reported fentanyl had no effect.

Anti-Arrhythmic Effect

The effectiveness of Innovar, or droperidol alone, in preventing
epinephrine induced arrhythmias has been reported by Dobkin and Byles
(1966), Hamlin et al. (1968), and Yelnosky et a1. (1964). However, in
dog experiments by Dobkin and Byles (1966) arrhythmias were only found
after administration of methoxamine, phenylephrine, mephentermine, and
metaraminol.

Antifibrillatory action has been attributed to Innovar anesthesia

in two studies of open-heart surgical procedures in human beings.

I!“

In

8
Corssen (1964) reported no ventricular fibrillation in 85 patients. In
the second series of 101 subjects, Corssen et a1. (1964) reported that
ventricular fibrillation occurred in 11, but 9 of these were due to
occlusion of coronary artery flow and sinus rhythm.was restored With a

single electroshock.

Effect on Vasoactive Substances

 

Brown at al. (1969) stated that Innovar produces a generalized
alpha adrenergic block which is useful in combating the arterial vaso-
constriction associated with hypovolemic shock. Chodoff and Domino
(1965) have shown that the adrenergic active drug, droperidol, effec-
tively blocks only the alpha effects of epinephrine and not those of
norepinephrine. In a study of numerous vasopressors, Dobkin and Byles
(1966) found that Innovar blocked the pressor response to norepinephrine
and methoxamine, reduced the pressor response to phenylephrine and
mephentermine, but had little effect on the response to metaraminol and
angiotensin. Shepherd (1964) stated that droperidol blocked the nor-
epinephrine pressor response and protected against traumatic shock.
Chodoff and Domino (1965) also found that this drug had no effect on
the depressor response of histamine or acetylcholine.

An extensive investigation by Dobkin et al. (1965) showed that
there was no gross alteration in the blood levels of histamine, sero-
tonin, epinephrine, or norepinephrine during long periods of Innovar-
nitrous oxide anesthesia in the dog. In a second study on human
surgical patients, Giesecke et al. (1967) found a significant increase
in the urinary excretion of epinephrine during the anesthetic, surgical,
and postsurgical periods, but no significant differences in norepinephrine
levels. They further stated that urinary levels paralleled those of

blood.

in.

9
Effects on Respiration

Schotz and Ziegler (1967) reported a respiratory and metabolic
acidosis in human patients given Innovar. These were premedicated with
atropine and pentobarbital. They theorized this was due to hypoxia and
hypercarbia associated with respiratory depression. Tarhan et a1.
(1971) observed significant decreases in P02, increases in P002, and
acidosis in human patients. Oxygen consumption was also significantly
decreased.

Teutenberg et a1. (1967) reported a decrease in both rate and
depth of breathing within 5 minutes following induction with Innovar-
nitrous oxide in human patients. These returned to control levels
within 15 minutes. Yelnosky et a1. (1964) showed a decrease in respira—
tory rate and an increase in tidal volume in dogs given droperidol
alone.

Gardocki and Yelnosky (1964) showed a decrease in minute ventila-
tion due to a decrease in both rate and tidal volume when fentanyl was
used alone. Maximal depression was seen within one minute with marked
recovery in 5 minutes. When the 2 drugs were combined, Yelnosky and
Gardocki (1964) found the effects to be similar to those induced with
fentanyl alone. That is, decreased respiratory rate and tidal volume
followed by recovery in 5 to 30 minutes to near control values.

Dobkin et a2. (1964) reported apnea in man within 5 minutes follow-
ing IV administration. Arterial pH decreased in 23 of 24 patients,
but the change exceeded 0.1 units in only 3 subjects. PCO2 increased
slightly in 22 of the 24, but all had assisted respirations due to the
apnea. Plasma bicarbonate did not change, so that there was no sig-
nificant evidence of a trend to metabolic acidosis. The P02 rose

considerably from.the administration of 402 oxygen. Cyanosis was

..r<

K

 

 

10
evident in a few subjects before respiration.was assisted. In dogs

given Innovar with 67% N 0, Dobkin and Byles (1966) reported a meta-

2
bolic acidosis which was not statistically significant. This change
was accompanied by a drop in P002 and an increase in P02 due to con-
trolled respiration. There was no change in hematocrit.

In summary, most NLA investigations have reported a decrease in
arterial pressure associated with a decrease in total peripheral
resistance. This is attributable to the alpha blocking effects of
droperidol. Cardiac output appears to be unchanged in experiments
where atropine is used to prevent bradycardia. Without atropine
fentanyl induced bradycardia does occur at anesthetic doses. Electro-
cardiogram.changes are minimal with combinations of droperidol and
fentanyl. Antiarrhythmic properties have been reported. Nitrous
oxide appears to have no cardiopulmonary effect except for a mild
vasoconstriction. Respiration is severely depressed by NLA, especially

during the first few minutes following IV injection. Metabolic and

respiratory acidosis can be prevented by controlling ventilation.

MATERIALS AND METHODS

Animals
Twleve, male, 1- to 2-year-old, conditioned Beagles (Cents
fhmiliaris) weighing 9 to 12 kilograms were obtained from a laboratory
animal dealer.a These dogs were housed in individual concrete cages
and exercised twice daily in accordance with Public Law 89-544 (The
Animal Welfare Act). Cages were cleaned twice daily and dogs fedb
once daily. Fresh water was provided ad Zibitum. All animals were

vaccinated against rabies, distemper and hepatitis and were free from

internal and external parasites.

Standardization and Training

0ne week prior to experimentation, blood was collected from each
dog and examined. Tests included total leukocyte count, differential
leukocyte count, hemoglobin, packed cell volume, total protein, blood
urea nitrogen, and serum glutamic pyruvic transaminase. All values
were within normal limits as reported by Michaelson et a1. (1966) for
the normal Beagle.

Two days before surgical preparation, each dog was brought to the

laboratory and a neck bandage applied as a conditioning procedure.

 

aLaboratory Research Enterprises, 6251 S. Sixth Street,
Kalamazoo, Mich. 49001.

bKen-L-Ration Meal, Quaker Oats Co., Chicago, 111. 60651.

11

12
Subsequently no dog bothered his implanted catheters postsurgically.

All dogs were trained to lie on a table in right lateral recumbency
to minimize excitement and anxiety during control recordings. This
15~minute daily training was initiated 7 days prior to experimentation.
Most dogs were unaccustomed to handling and objected to this procedure
for the first 2 or 3 days. With one exception, all dogs had adjusted
to lying quietly on the table with a technician scratching the ears.

One experimental run was postponed for 3 days until further training

was accomplished.

Materials

Silicone rubber tubing,a 1.01 mm ID x 2.16 an OD, was used for
venous catheters to be placed in the right atrium. These were 75 cm
long and had small silasticb blebs placed 15 cm from,one end to provide
anchorage within the jugular vein (Figure l).

A double lumen, 100 cm,number 10 French,cardiac catheterc was used
for the arterial pressure and cardiac output determinations (Figure 1).
The end-hole lumen was used to obtain arterial pressures and blood for
analysis. A calibrated thermistord was mounted in the side-hole posi-
tion with epoxy cement by a local laboratory8 for measurement of cardiac
output by the thermal dilution technic as described by Evonuk at al.

(1961).

 

aMedical Grade Silastic Tubing, Dow Corning Corp., Midland, Mich.
bSilastic Medical Adhesive, Dow Corning Corp., Midland, Mich.

cCorunand Double Lumen Catheter, U.S. Catheter and Instrument
Co., P.0. Box 787, Glen Falls, N.Y. 12801.

dVeco 32A7, Victory Engineering Corp., Victory Road, Springfield,
N.J. 07081.

eDept. of Physiology, Michigan State university, East Lansing,
Mich.

13

THREE — WAY STOP COCK

.g. “

   

END HOLE

l;

 
  
 

    

ELECTRICAL JACK

fl

 

 

 

 

 

 

BLEB

THERMISTOR
\i\3

 

 

SILASTIC
CATHETER

  

 

 

 

 

 

Figure l. Catheters used for recording cardiac output and arterial and venous
pressure. A double lumen 100 cm cardiac catheter (left) with thermistor for
measuring cardiac output and arterial pressure. A 75 cm silastic catheter (right)
for venous sampling and injection. Blobs were used to secure the catheter within
the jugular vein.

14
Surgical Implantation and Preparation

Animals were fasted 12 hours before surgery. Following atropine
sulfate medication (0.02mg/lb SQ), anesthesia was induced with 9 lag/kg
of thiamylal sodiuma and an 8 mm ID cuffed endotracheal tube inserted.
Anesthesia was maintained with 1.01 halothaneb delivered with 1 L/min
oxygen and 1 L/min nitrous oxide.

The ventral cervical area was prepared aseptically and a 5 cm
skin incision was made on the ventral cervical midline over the first
6 to 8 tracheal rings. The sternocephalicus and sternohyoideus muscles
were separated on the midline which exposed the trachea. The deep
cervical fascia was removed from the ventral surface of the tracheal
rings. A 1.5 x 2 cm oval window was cut in tracheal rings 3 through
6 using a No. 11 scalpel blade. A 1:10.000 epinephrine solution was
used to control hemorrhage from the tracheal mucosa. The skin was
then sutured to the severed tracheal rings using 3-0 silk sutures.
The ends of the skin incision were also sutured with 3-0 silk.

A venous cutdown was performed on the left jugular vein and the
venous catheter inserted. A 5 ml bolus of sodium diatrizoatec was
injected and observed through a fluoroscopec1 to confirm the position
0f the catheter tip in the right atrium. If necessary, the catheter
was repositioned and secured to preclude movement. The catheter was

authored to the sternocephalicus muscle with a 3—0 silk suture. The

 

 

aSurital, Parke, Davis & Company, Detroit, Mich. 48207.
bFluothane, Ayerst Lab, New York, N.Y. 10017.
cHypaque 501, Winthrop Lab, New York, N.Y.

ClModel HRT, General Electric Co. , Medical Systems Division,
Detrou, Mich. 48219.

15
catheter was filled with a heparinized saline solution (100 u/ml) and
the stopcock closed. An antibiotica saturated gauze sponge was placed
over the tracheostomy and the catheter loosely coiled around the neck.
A gauze and tape bandage was applied to the neck to keep the dog from
damaging the catheters. The dog was placed in a padded cage for
recovery.

Aqueous penicillin, 200,000 units, and streptomycin, 250 mg, were
administered once daily for the next 7 days. The bandage was changed
and the venous catheter flushed with the heparinized saline every 48
hours.

On the day of the study, the dogs were placed on a padded table
in right lateral recumbency and the right femoral area was surgically
prepared. The skin and subcutaneous area over the femoral artery was
infiltrated with 1 ml of 0.52 lidocaine hydrochlorideb solution. A
femoral artery cutdown was performed and the double lumen catheter

implanted as described by Rawlings et al. (1970).

£921.22;

An 8-channe1, photographic write-out recorderc was used for data
recording. Thermal dilution cardiac output curves were obtained by
connecting the arterial thermistor to a pressure preamplifier via a
Wheatstone bridge. The thermistor was also connected to an electronic
thermometerd by a two-way switch for measurement of blood temperatures.

Lead II of the electrocardiogram was recorded using an ECG preamplifier.

 

 

llF‘uracin Ointment, Norwich Pharmacal Co. , Norwich, N.Y. 13815.
belocaine, Astra Pharmaceutical, Worcester, Mass.
cModel DR-8, Electronics for Medicine, White Plains, N.Y.

dModel 41TF, Yellow Springs Instrument Co. , Yellow Springs, Ohio.

16
Pressure transducersa were calibrated before each experiment by
use of integrated resistors within the recorder. Arterial and venous
catheters were connected to the transducers and then to preamplifiers.
Electronic averagers were used to obtain mean values.

Arterial and venous blood gases were determined using a blood gas
analyzerb which was calibrated prior to each study. Calibration was
performed using known P02, PC02 and pH.

Respiratory measurements were obtained by the use of a vane
spzlrometerc and stopwatch. Minute volume along with respiratory rate
and the tidal volume were calculated.

Oxygen, nitrogen and nitrous oxide were delivered from an anesthetic
machine“1 to which was attached a non-rebreathing valve.e The concen-
trations of these gases were confirmed by the use of an oxygen
analyzerf which was calibrated utilizing room air and 100% oxygen.

The dogs were placed on a water blanketg to minimize hypothermia.
Arterial hematocrit values were obtained using the centrifuged micro-

hematocrit method .

Data Measurement Technic
Cardiac output was determined by injection of 3 ml of room

telnperature saline into the right atrium via the implanted venous

E

filodel P23Db, Statham Transducers, Inc., Hato Rey, Puerto Rico.
13Model 72 EMD-RUPVEJ, Radiometer Copenhagen, Copenhagen, Denmark.
cVolulneter, North American Drager Co., Telford, Penn.

dModel Rotameter, The Foregger Co. , New York, N.Y.
efStephen-Slater Valve, Ohio Medical Products, Madison, Wise.

fOxygen Analyzer, IMI Division, Becton Dickinson & Co., New
P°rt Beach, Calif.

8Model K913, Gorman-Rupp Industries Co., Bellville, Ohio.

17
catheter. The thermal curve was recorded by the thermistor in the
aortic arch, as reported by Evonuk at al. (1961). A 3 ohm.resistor
built into the Wheatstone bridge was used to produce a 0.1 C standardi-
zation deflection. The cardiac output was determined by using a
modified Stewart-Hamilton formula as worked out by Evonuk at al. (1961).

KVi (Tb-Ti)f
A

 

C.0. (L/mln) =

where:

K is calibration factor of the thermistor (mm deflection

per 0.1 C)
Vi is volume of the injectate (ml)
Tb is temperature of the blood (C)

T1 is temperature of the injectate (C)
f is recorder paper speed (cm/min)
A is area under the curve (sq.cm)

Heart rate was obtained by counting the pressure pulses on the
arterial pressure tracing. Stroke volume was calculated by dividing
the cardiac output by the heart rate.

Total peripheral vascular resistance was calculated and expressed

as PVR units using the following formula:

mean arterial pressure
cardiac output

PVR -
Arterial pressures were recorded as pulsatile and mean pressures.
Venous pressure was recorded only as the mean.
One milliliter arterial and venous blood samples were collected
in heparinized 3 ml plastic syringes. Within 1 minute, P02, P002 and
pHmwere determined. Capillary tubes were filled with arterial blood

for hematocrit determinations. Base deficit was calculated from.pH and

PC02 using a Siggaard-Andersen nomogram°

18

Degree of analgesia was determined by clamping a rear digit with
an Allis tissue forcep. Withdrawal of the leg was recorded as a 1+
reaction, withdrawal of the leg and raising the head as a 2+ reaction,
and additional movement as a 3+ reaction. Response to auditory stimuli
was determined by dropping an Allis tissue forceps from 30 cm onto a
Mayo stand 75 cm from the dog's head. Opening of the eyes was recorded
as a 1+ reaction, raising of the head as a 2+ reaction, and additional

movement as a 3+ reaction.

Recording of Control Data

Following calibration of equipment, the dogs were connected to
the recording devices (Figure 2).

The thermistor was connected to the electronic thermometer and
recorder. The arterial pressure catheter was flushed with heparinized
saline (100 u heparin/ml saline) and connected to a transducer. The
neck bandage was removed, the venous catheter flushed with heparinized
saline, and connected to a second transducer. Four limb ECG leads
were attached and secured with tape. The tracheostomy was cleaned
with saline and an 8 mm tracheostomy tubea lubricated with an anesthetic
Jellyb inserted. The cuff was inflated to prevent leakage and connected
to the anesthetic machine and spirometer via the non-rebreathing valve.
The dogs were then given 15 minutes to rest before control measurements
were taken.

A set of control values was recorded with the animals relaxed and

breathing room air. Air was delivered through the respiratory apparatus

 

aPortex Division, Smith Industries, Woburn, Mass.

blelocaine Jelly, Astra Pharmaceuticals, worcester, Mass.

19
by removing the breathing bag. Then each animal was given a mixture
of 33% oxygen in nitrogen delivered from the anesthetic machine for
15 minutes. A second set of control values was then taken with the

dogs breathing the increased oxygen concentration (Table 1).

DruggEvaluation

Following control recordings, Group I dogs were given 1 ml of
Innovar-Vet per 25 lb (11.4 kg) body weight diluted to 10 ml with
normal saline. This was given through the right atrial catheter over
a l-minute period. All variables were measured every 10 minutes fol-
lowing injection until recovery was apparent by the analgesia test.
Thirty-three percent oxygen in nitrogen was continued for the entire
anesthetic period (Table 1).

Group II dogs were administered the same dose of Innovar4Vet as
Group I, but nitrous oxide was substituted for nitrogen. Measurements
were made as in Group I with nitrous oxide being administered for the
anesthetic period (Table 1).

Group III dogs had 2 sets of control measurements, after which
0. 044 mg/ kg of atropine sulfate was injected intramuscularly. Fifteen
minutes later, the third set of control measurements was taken. They
were then given Innovar-Vet intravenously and oxygen-nitrous oxide
mixture by the same protocol as followed in Group II. Measurements

were made every 10 minutes until recovery was apparent (Table 1).

Data Analysis
Data analysis was accomplished utilizing the facilities and a
computer program of Michigan State University. Variables with sig-
nificant change (P<0.05) were determined by the use of Snedecor's

Fetest as explained by Lewis (1966). These variables were then

20

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21

analyzed by the Student's t-test to determine where the changes occurred

within the experimental design.
Means and standard errors were calculated for each variable within

the 3 groups. Data accumulated with the dogs breathing 33! oxygen were

used as control measurements.

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RESULTS

General Considerations
A.tota1 of 12 animals were used for the study, with 4 dogs
equally divided into 3 groups. In addition, 3 were used to develop
the technic and 1 died subsequent to an iatrogenic accident. One
dog was studied each week. Catheters and tracheostomies were removed
from all dogs following the study and the dogs were observed closely
for 3 days. All animals survived the study without observable

complications.

Group I: Innovar—Vet

Evaluation of Innovar-Vet alone was accomplished with 4 dogs whose
average body weight was 11.4 kg (10.5-13.6 kg). The cardiovascular
and respiratory data are presented in Tables 2 and 3, respectively.
Cardiac output, mean arterial pressure, heart rate, stroke volume,
total peripheral resistance, pHa, Pao2 and PaCOZ, respiratory rate,
tidal volume and minute volume are plotted in Figures 3 through 6.

The average duration of anesthesia was 42.5 minutes, at which time
all 4 animals had a 2+ pain response. Three of the 4 dogs had at
least a 1+ response for the entire study. The fourth had no pain
response during the study.

Cardiac output was not significantly changed (P>0.05) during the

study. Control value was 2.35 i 0.27 L/min with the dogs breathing

23

24

Table 2. Cardiovascular data with Innovar-Vet

 

 

 

 

 

 

 

CONTROLS TIME (MINUTES)
VARIABLE AIR 02 1o 20 30 4o 4
CO 2.41 2.35 2.38 2.23 2.44 2.13
(l/min ) .+. .30 i .27 i .21 i .24 i .31 i .27
SAP 133 130 118 109* 103* 106'
(mmHg) :3 :7 :6 :7 :4 :6
DAP 83 92 71 71 65 66
him Hg) : 7 : 9 : 4 : 8 : 3 : 2
MAP 100 105 94 91 85 88

'(mmHg) :6 :6 E :7 :9 :4 :5
>
HR 87 93 ml: 69 82 85 92
rlbeats/min) :13 :17 § : 7 : 8 : 9 : 5
O
CVP 3 3 2 4 3 3 2
(mmHg) :1 :2 :2 :2 i2 :1
SV 28 26 35* 27 29 23
(ml) ’1 3 i 2 i 2 i 2 i 3 i 2
TPR 42 44 39 41 36 42
(pm) i 3 i 3 i 4 i 4 i 5 i 4
PCV 37 37 37 37 36 35
PM) “:3 :4 :4 :4 :4 :44

 

 

 

 

 

 

 

Represents mean values and standard errors (1) from 4 dogs given Innovar—Vet
alone. Controls taken breathing room air and 33% oxygen. Experimental
values taken at 10 minute intervals following injection. CO8 Cardiac Output;
SAP = Systolic Arterial Pressure; DAP = Diastolic Arterial Pressure; MAP =
Mean Arterial Pressure; HR = Heart Rate; CVP = Central Venous Pressure;
SV = Stroke Volume; TPR = Total Periperal Resistance; PCV = Packed Cell
Volume. * Changes of P< 0.05 or greater from 02 control.

25

Table 3. Respiratory data with Innovar-Vet

 

 

 

 

 

 

 

 

 

 

 

 

 

CONTROLS TIME (MINUTES)
VARIABLE AIR 02 10 20 30 40
F
pHa 7.40 726* 732* 733* 7.341
i .02 i .01 i .01 i .01 : .02
pHv 7.36 7.25“ 729* 7.30* 7.33“
i .01 i .01 i .01 i .01 :t .01
9802 114 136 132 147 143
(mm Hg) i 17 i 16 i 14 i 14 i 15
onz 52 63 58 61 58
(mm Hg) i 6 i 4 i 11 i 2 i 8
Pacoz 26 ,_ 35 33 30 32
(mm Hg) : 2 “>‘ : 3 : 3 : 2 : 3
I
0:
BD 9 < 11 8 9 8
(meq/l) i 2 B i 1 i 2 i 1 : 1
z
2
PV co2 29 - 38 35 35 35
(mm Hg) 1‘ 1 i 3 i 2 i 3 i 3
ii 7.15 5.73 3.33 11.80 13.31
(l/min ) : 2.70 : 3.44 : 3.90 : 3.99 : 3.76
RR 123 76 92 129 140
(resp./min). i 34 i 43 i 42 i 41 i 35
V1- 75 78 93 90 97
(ml) : 5 : 10 : 7 : 3 : 3

Represents mean values and standard errors (1) from 4 dogs given Innovar-Vet

alone. Controls taken breathing room air and 33% oxygen.

Experimental

values taken at 10 minute intervals following injection. pHa = Arterial pH;
pHv = Venous pH; P502 = Arterial Oxygen Tension; Pv02 = Venous Oxygen
Tension; PaCOZ = Arterial Carbon Dioxide Toension; DD = Base Deficit;
PVCOZ = Venous Carbon Dioxide Tension; V = Minute Volume; RR =

Respiratory Rate;

= Tidal Volume.

* Changes of P< 0.05 or greater from 02 control.

 

 

 

 

 

 

 

 

.—
~ 5“.
C
E 2.5 J a:
\ <
= 5
8 a
2.0 -+
40 —
p.
u]
>
‘-'-‘ c:
g 30 _ g
> O
m 2
E
2. 11
110 — --
I00 -‘ Hr-
? 1-
LL]
5 90 - >
'5 c:
.8 <
O
E .Ib 2
Ji— 2
70 — "
60 4
l T l r I l
AIR 02 10 20 30 40
CONTROLS «IQ—TIME lminutes)—-.-

Figure 3. Cardiac output, stroke volume, and heart rate with Innovar-Vet.
Mean values and standard errors plotted for 4 dogs given Innovar-Vet alone.
Controls taken breathing room air and 33% oxygen. Experimental values
plotted at 10 minute intervals. CO = Cardiac Output; SV = Stroke Volume;
HR = Heart Rate

. MAP (mm Hg)

TPR (pm)

27

 

 

 

 

 

 

 

 

 

 

110 - ‘F

.—

LU

>

100 - E 7F 7'

>

O

2

.1- _Z_
90 '1
80 -
50 -

1..

Lu

>

2‘

40 -1 >

O

2

E
30 -1

r l I fit I 1
AIR 02 10 20 30 40
CONTROLS ‘—-——TIME (minutes)-—>

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Innovar-Vet. Mean values and standard errors plotted for 4 dogs given
Innovar-Vet alone. Controls taken breathing room air and 33% oxygen.
Experimental values plotted at 10 minute intervals. MAP = Mean Arterial
Pressure; TPR = Total Periperal Resistance

 

 

 

 

 

 

7.5 '-
1” 7.4 -
o. E
>
1:
§
7.3 — g
E
160 -—
150 -‘
140- I:
. >
f 130-1 E
E >
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“- 110-
100—
90.1
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3? E
E
c:
.5. 30 <
n 5
8 2
.~ H z
20
l l l l T l
AIR 02 10 20 30 40
CONTROLS |<———TIME (mantel—bl

Figure 5. Arterial blood gases with Innovar-Vet. Mean values and standard
errors plotted for 4 dogs given Innovar-Vet alone. Controls taken breathing
room air and 33% oxygen. Experimental values plotted at 10 minute intervals.
pHa= Arterial pH; P302 = Arterial Oxygen Tension; PaCOZ = Arterial Carbon
Dioxide Tension

I

INNOVAR VET

RR (respirations/min)
8 8
IFJIIJUJIIIIIJI
I I
INNOVAR VET
1g : J1 % S

 

 

3’

 

 

 

 

8

a
d
O
I

INNOVAR VET

 

 

I I I I I

AIR 02 20 30 40
CONTROLS I‘— TIME (minimal-4|

Figure 6. Minute volume, respiratory rate and tidal volume with Innovar-Vet.
Mean values and standard errors plotted for 4 dogs given Innovar-Vet alone.
Controls taken breathing room air and 33% oxygen. Experimental values plotted
at 10 minute intervals. \°I = Minute Volume; RR = Respiratory Rate;

VT = Tidal Volume

3"!

30
332 oxygen. Thirty minutes postinjection cardiac output increased 418
to 2.44 i 0.31 L/min and 2.13 i 0.27 lein (92) at 40 minutes. Heart
rate decreased from a control of 93 i 17 beats per minute to 69 _'l_-_ 7
(252) at 10 minutes and returned to control level at 40 minutes.
However, these changes were not significant (P>0.05). Total peripheral
vascular resistance and packed cell volume were not significantly
changed. Stroke volume increased from a control value of 26 i 2 ml
to 35 j; 2 m1 (351) at 10 minutes postinjection; this change was sta-
tistically significant (P<0.05).

Systolic arterial pressure was significantly decreased (P<0.05).
The change was not apparent until 20 minutes after injection and did
not return to control values during the 40-minute recording period.
Control was 130 j; 7 m Hg and decreased to 103 i 4 mm Hg (21%).
Diastolic and mean pressures were not significantly affected.

Arterial and venous pH were significantly changed. Arterial pH
decreased from a control of 7.40 _-l_-_ .02 to 7.25 i .01 (P<0.01) at the
lO-minute interval. It then stabilized at 7.32 to 7.34 (P<0.05) for
the remainder of the study. Venous pH followed a similar trend. The
greatest depression occurred at the lO-minute interval (7.25 1 .01).
The pH tended to rise during the remainder of the experiment but never
reached control values. All venous pH changes were highly significant
(P<0.01). The metabolic change was particularly evident at the 10-
minute interval when base deficit increased from a control of 9 j_l-_ 2
mEq to 11 j; l (181). The PaCO2 increased from a control of 29 i 1 mm
Hg to 38 _+_- 3 mm Hg (31%) at the lO-minute interval and remained at

354m Hg for the duration of the study.

 

£|Percent change from control.

31

The response to auditory stimulation was variable. One dog had
from O to 1+ response during the experiment, while another had 3+ most
of the time. The range for the other 2 dogs at most time intervals
was 1+ to 2+.

Nystagmus and muscle twitching were present in 3 of the 4 dogs.
Apnea occurred in 2 dogs 1 to 3 minutes following injection, and slow
respiration (5 respirations/min) with cyanosis present in a third
animal. Respiration was spontaneous and not assisted, and all animals
were breathing at a normal rate by 10 minutes postinjection. Panting
began after 10 minutes in 2 dogs and continued for the remainder of the
experiment. Borborygmus was present in 2 dogs, and defecation occurred
in another. Premature ventricular contractions (l per 4-5 normal

contractions) occurred in 1 dog 5 minutes following injection.

Group II: Innovar-Vet with Nitrous 95292

The combination of Innovar-Vet with 671 nitrous oxide and 33%
oxygen was evaluated with 4 dogs averaging 10.1 kg (9.1 to 10.9).

The cardiovascular and respiratory data are presented in Tables 4 and
5, respectively. Cardiac output, mean arterial pressure, heart rate,
stroke volume, total peripheral resistance, arterial pH, P002 and P02,
respiratory rate, tidal volume, and minute volume are plotted in
Figures 7 through 10.

The average duration of anesthesia was 70 minutes due to one
animal remaining anesthetized for 110 minutes. Data were analysed
only through 50 minutes since 3 animals recovered at that interval
(i.e., pain response of 2+ or more).

No cardiovascular variable was significantly changed (P>0.05) in

this group. Control cardiac output was 2.05;: .30 L/min with values

32

Table 4. Cardiovascular data with Innovar-Vet and nitrous oxide

 

 

 

 

 

 

 

 

 

 

 

 

CONTROLS TIME (MINUTES)
VARIABLE AIR 02 10 20 30 40 50 4
co 2.42 2.05 2.33 2.66 2.63 2.48 2.82
(”MM :.33 :.30 :.45 :.24 :21 :34 :58
SAP 114 120 117 116 122 111 117
(mmHg) : 4 :1 : 5 : 7 :13 : 6 : 7
DAP 83 74 67 70 84 81 84
(mm Hg) ’5 7 i 6 1‘ 6 i 7 i12 i 5 i 8.
MAP 94 98 :34 84 92 103 103 104
(mmHg) : 6 : 5 a : 8 :10 :13 : 9 :10
HR 98 92 E 69 80 86 93 108
“beats/min :14 :24 >. :12 :11 : 8 :10 :12
I:
CVP 2 3 g 5 4 3 3 2
(mm Hg) : 1 : 1 z : 1 : 2 : 1 : 1 : 1
Z

sv 30 26 33 35 34 27 27
(ml) :5 :5 :6 :5‘ :4 :4:5
TPR 40 49 44 34 37 41 39
(pru) -_+ 4 : 6 :16 : 4 : 5 : 3 : 5
PCV 36 37 36 37 37 36 37
(96) : 2 : 2 : 3 : 2 : 2 : 2 : 2
I

 

Represents mean values and standard errors (1;) from 4 dogs given Innovar-Vet

and nitrous oxide. Controls taken breathing room air and 33% oxygen.
Experimental values taken at 10 minute intervals following injection.

CO = Cardiac Output; SAP = Systolic Arterial Pressure; DAP = Diastolic

Arterial Pressure; MAP = Mean Arterial Pressure; HR = Heart Rate; CVP = Central
Venous Pressure; SV = Stroke Volume; TPR = Total Periperal Resistance;

PCV = Packed Cell Volume. * Changes of P< 0.05 or greater from 02 control.

33

Table 5. Respiratory data with Innovar-Vet and nitrous oxide

 

 

 

 

 

 

CONTROLS TIME (MINUTES
VARIABLE AIR o2 10 20 30 40 50
:1
pHa 7.41 7.37 722* 726* 729* 730* 7.34
1.02 1.02 1.01 1.02 ‘ 21.01 :.01 1.04
pHv 7.39 7.34 720* 725* 726* 7.28 7.31
:03 1.02 1.02 _+_.02 1.02 :02 :03
P802 89 141 133 139 151 161 142
(mm Hg) :- 7 :17 2~_23 :16 :22 :18 116
P1702 43 52 69 101 78 91 76
(mm Hg) 1 3 1 2:13 % _+_ 6 :30 i 5 :20 :10
Z
pace2 29 29 d, 43 37 33 32 30
(mmHg) :4 :4 ._ :8 :6 +4 :4 i4
LU
>
so 6 10 flIc 14 13 14 10 9
(meq/l) :3 :3 § :4 :3 :3 :2 :3
o
Pvcoz 32 30 g 45 39 36 35 32
(mmHg) 1’2 :3 " :7 :4 i4 i4 1'5
0
v 6.12 4.33 1.37 4.31 3.67 4.31 4.89
I l/min) “.170 i 65 1.20 12.27 :156 1.39 _+_.82
RR 91 42 10 41 43 42 64
(resp/min) :37 i 6 1'. 2 -I_-27 -I_-_ 24 i 11 :1; 22
vT 79 104 151 142 105 128 99
(ml) :13 + 4 +17 +31 +12 +36 26

 

 

 

 

 

 

 

 

 

 

Represents mean values and standard errors (1;) from 4 dogs given Innovar-Vet
and nitrous oxide. Controls taken breathing room air and 33% oxygen.
Experimental values taken at 10 minute intervals following injection.

pHa = Arterial pH; pHv = Venous pH; PaOZ = Arterial Oxygen Tension;
PVOZ = Venous Oxygen Tension; PaCOZ = Arterial Carbon Dioxide

Tension; DD = Base Deficit; PVCOZ = Venous Carbon Dioxide Tension;

V = Minute Volume; RR = Respiratory Rate; VT = Tidal Volume

* Changes of P< 0.05 or greater from 02 control.

34

  
 

 

 

 

 

 

 

 

 

 

 

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fil-
3.0“—
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7: F 2 ~
8 as
E 25-— ,_
[U
8 >
m h-
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- >
2.0— o
z
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a 0N
110— Q- 2
E _ on
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I — J; O
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30— c:
>
<
m >
O
z
E
20
T I I T I I I
AIR 02 10 20 30 40 50
CONTROLS l“—TIME (minutes)———->

Figure 7. Cardiac output, stroke volume, and heart rate with Innovar-Vet
and nitrous oxide. Mean values and standard errors plotted for 4 dogs given
Innovar-Vet and nitrous oxide. Controls taken breathing room air and 33%
oxygen. Experimental values plotted at 10 minute intervals.

CO = Cardiac Output; SV = Stroke Volume; HR = Heart Rate

 

MAP (mm Hg)

TPR (pru)

35

 

 

 

 

 

 

 

 

 

 

 

 

 

120 —
110 — T F
o
N
100 — 2
03
j.
“J
>
90 — 3::
>
o
2
E
80 —
60—4 T
o
N
Z
50-— as
j.
I.“
>
m
40— §
0
Z
3
30—
.J—
F I I I I I I
AIR 02 10 20 30 40 50
CONTROLS I<———- TIME (minutes) ——>

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Innovar-Vet and nitrous oxide. Mean values and standard errors plotted
for 4 dogs given Innovar-Vet and nitrous oxide. Controls taken breathing
room air and 33% oxygen. Experimental values plotted at 10 minute intervals.
MAP = Mean Arterial Pressure; TPR = Total Peripheral Resistance

7.5 -‘

36

INNOVAR VET 8. N20

 

  
 

 

 

 

 

 

O
N
a 2
In 40- a
E I:
a > J
N C
8.. S
c. 30‘ O
z
E
20
94
180—1 2
E : ..
E 7" E
5130- >
'7 I:
N
o -— <
0
. ._ g
— z
80-1 E
I I I T I I
AIR 02 10 20 30 40 50
CONTROLS I 4— TIME Iminutal-——->l

Figure 9. Arterial blood gases with Innovar-Vet and nitrous oxide. Mean
values and standard errors plotted for 4 dogs given Innovar-Vet and nitrous
oxide. Controls taken breathing room air and 33% oxygen. Experimental
values plotted at 10 minute intervals. pHa= Arterial pH; P302 = Arterial Oxygen
Tension ; PaCOZ = Arterial Carbon Dioxide Tension

 

 

\9 II/m'nl

RR (respirations/min)

Vt (ml)

37

 

 

 

 

 

 

 

 

o
7.0 "‘ ZN
‘I"
a «a
p.
—‘ LU
>
4.0 2 a:
<
7 B
_ z 1-
E
1.0
—1
I o
N
—* Z
90 — .5
T I-
—- LU
_ >
‘ 5
40 — >
- o
._ 2
E
*1 94
160 — z
- a
T‘ l-
- m
_. >
110 — o:
-‘ §
‘ S
'4 z 7
6° I I I I T I I
AIR 02 10 20 30 40 50
CONTROLS ‘— TIME (minutes)—>

Figure 10. Minute volume, respiratory rate, and tidal volume with
Innovar-Vet and nitrous oxide . Mean values and standard errors plotted for
4 dogs given Innovar-Vet and nitrous oxide. Controls taken breathing room
air and 33% oxygen. Experimental values plotted at 10 minute intervals.

\7 = Minute Volume; RR = Respiratory Rate; V1- = Tidal Volume

38
postinduction ranging from 2.23 -_l-_ .45 L/min at 10 minutes to 2.82 _-I_-_
.58 L/min at 50 minutes (maximum of 372 increase from control). Mean
arterial pressure was 98 *_l-_ 5 1n Hg at control and ranged from 84 -_l-_ 8
mHgat 10minto 104:10mHgat 40min (maximat 14! change
from control). The slight hypotension was most prominent at the 10-
minute interval and returned to above control levels by 30 minutes.
Heart rate decreased 25! initially from 92 j; 24 beats/min to 69 +_ 12
at 10 minutes and returned to 80 _-l_- 11 by 20 minutes. Stroke volume
increased during the experiment and total peripheral resistance
decreased 31% from 49 i 6 units to 34 j; 4 at 20 minutes. Total
peripheral resistance was 44 -_I-_ 16 at 10 minutes due to 1 dog having
an extremely low cardiac output (1.07 L/min).

Bradycardia occurred in 2 of the 4 dogs for 2 to 3 minutes
following induction. Numerous premature ventricular contractions
(30-402 of total) occurred in 1 dog at the lO-minute interval.

Arterial pH decreased from control of 7.37 _-l_-_ .02 to 7.22 i .01
at 10 minutes, 7.26 i .02 at 20 minutes, and 7.29 i .01 at 30 minutes.
All these changes were highly significant (P<.01). It was 7.30 1;

.01 at 40 minutes (P<0.05) and had returned to 7.34 1; .04 at 50
minutes. The venous pH followed a similar trend with the most severe
decrease (P<0.0l) occurring at the lO-minute interval.

Ten minutes following the injection of Innovar-Vet, PaCO2
increased 481 to 43 _-l_-_ 8 mm Hg and returned to near control (29 i
4 m Hg) at the 50-minute interval. Base deficit returned to control
levels at 40 minutes postinduction. Administration of 332 oxygen
caused a significant increase'in PaO2 (P<0.05) in both the control

and experimental time intervals.

 

39

Increasing the inspired concentration of oxygen caused a decrease
in minute volume and respiratory rate. Administration of Innovar6Vet
and nitrous oxide caused a further decrease. The respiratory rate
decreased 54! from 91 1'37 respirations/min breathing room air to
42 1:6 respirations/min breathing 332 oxygen. Ten minutes postinduc-
tion the rate was 10:1'2 respirations per minute. Respiratory rate
returned to control levels after 20 minutes. Decreased respiratory
rate was accompanied by increased tidal volume.

Analgesia was better in this group. Zero to 1+ pain response

 

was present in all 4 dogs up to the SO-Udnute interval, at which time

 

3 of the 4 dogs recovered, despite a 67% N20 breathing mixture.
Response to auditory stimuli was greatly reduced. No animal exhibited
more than a 1+ response at any time interval of the experiment

breathing N O.

2
Nystagmus was present in 2 of the 4 animals during the experi-
ment. Apnea occurred in 2 dogs following the injection of Innovar-
Vet and persisted for 3 minutes. This was accompanied by transient
cyanosis. Panting did not occur in any animal and only 1 had evidence

of muscle tremors. Muscle relaxation, judged subjectively, was good

in all 4 animals.

Group III: Innovar-Vet withrNitrous Oxide:ggd Atropine
Innovar-Vet with nitrous oxide anesthesia and atropine premedi-
cation was studied in 4 dogs averaging 11.3 (10.9 to 11.8) kg. Cardio-
vascular and respiratory data are presented in Tables 6 and 7,
respectively. Cardiac output, mean arterial pressure, heart rate,
stroke volume, total vascular resistance, arterial pH, P02 and P002,

‘respiratory rate, tidal volume, and minute volume are plotted in

40

Table 6. Cardiovasqu data with atropine, Innovar-Vet, and nitrous oxide

 

 

 

   

 

 

CONTROLS CONTROLS TIME (MINUTES)
VARIABLE AIR 03—1 02 10 20 30 40 50 60
CO 2.13 1.82 3.32 *1 3.33 * 3.28 * 311 * 2.95 * 2.32 r 2.79 *
l1/min) : .16 : .12 : .81 : .39 : .43 t .28 2t .53 2t .32 i .35
SAP 125 118 119 140:. 129 126 123 121 127
(mmHg):7 :10 :5 :4 :1 t8 :4 :4 :3
DAP 79 67 103* 115* 99* 95* 103* 98* 100*
ImmHgl:6 :3 :3 :7 :3 :5~:3 :6 :4
0
MAP 102 96 113* z" 126:. 115* 111* 116* 112* 114*
(mm Hg) : 6 : 4 w : 4 a : 5 : 2 : 1 : 3 : 4‘ : 2
HR 73 61 5 205* I: 163;:« 153;. 140:. 133:. 133:. 133;.
luau/min : 6 : 7 g :10 >, _12 _ 9 8 - 9 6 : 3
I- I
CVP 4 4 < 2 g 2 1 1 1 2 1
(mm Hg) : 1 : 1 : 1 o : 1 : 1 : 1 : 1 : 2 : 1
Z
sv 30 31 17* E 21* 22* 231 22* 22* 21*
(ml) 2€313 t4 t3t31214i3t3
TPR 47 52 39 40 37 36 44 42 42
(Dru) : 4 : 3 : 7 : 5 : 4 :t 3 :t s : 5 : 4
PCV 42 44 ~ 43 42 43 42 41 41 39
1%) I) : 4 : 5 : 4 : 1 : 1 : 2 : 1 : 1 : 1

 

 

 

 

 

 

 

 

 

 

 

 

 

Represents mean values and standard errors (1) from 4 dogs given premedication
of atropine followed by Innovar-Vet and nitrous oxide. Controls taken breathing
room air and 33% oxygen. Experimental values taken at 10 minute intervals
following injection. CO = Cardiac Output; SAP = Systolic Arterial Pressure;
DAP = Diastolic Arterial Pressure; MAP = Mean Arterial Pressure; HR '-

Heart Rate; CVP = Central Venous Pressure; SV - Stroke Volume; TPR .

Total Peripheral Resistance; PCV = Packed Cell Volume.

* Changes of P<0.05 or greater from 02 control before atropine.

" Changes of P< 0.06 or greater from 02 control after atropine.

41

Table 7. Respiratory data with atropine, Innovar-Vet and nitrous oxide

 

 

 

 

 

CONTROLS CONTROLS TIME (MINUTES)
VARIABLE AIR O2 O2 10 20 30 40 50 60
pH. 7.42 7.39 7.36 7.23 t. 7.32 * 7.31 - 730* 7.30 * 7.34
: .01 : .01 : .01 .01 : .03 i .02 : .03 : .03 : .04
pHV 7.39 7.36 7.30 7.24 * 7.31 7.30 7.30 * 7.28 * 7.33
: .02 : .01 : .04 .02 : .03 : .02 : .02 : .02 : .02
P802 79 154 153 173 164 165 159 164 170
(mmHg) 2‘ 7 i 12 : 12 23 i 20 i 20 t 23 i 13 i 13
9,02 40 51 59 o 82 77 81 80 83 81
(mmHg) : 5 : 5 : 9 z“ : 12 : 12 :16 :16 :16 : 17
9,062 33 30 g 32 '3 43 34 36 37 35 29
(mmHg):3 :3§:25:5 :6 :6 :6 :7 :3
>
80 3 5 E 7 0': 10 8 s 9 9 9
(moq/ll : 2 : 2 < : 1 g : 2 : 2 : 2 : 2 : 2 : 3
Pvcoz 38 37 35 g 45 37 37 38 39 35
lmmHg):2:4 :3E:4 :5 :5 :6 :5 :4
o
V . 4.15 3.52 16.08 3.20 17.19 14.13 16.07 12.12 10.33
“mm : .92 : .63 :11.02 : 5.59 :435 : 4.28 : 5.10 : 5.71 : 5.23
RR 60 43 94 46 136 141 148 91 57
(resp/minl : 20 : 16 : 38 : 22 : 22 : 38 : 48 : 43 : 21
V1 82 93 130 159 126 111 127 143 163
ir(ml) :13 :11 :39 :37 :29 :33 :33 130 :23

 

 

 

 

 

 

 

 

 

 

 

 

 

Represents mean values and standard errors (5;) from 4 dogs given premedication of atropine
followed by Innovar-Vet and nitrous oxide. Controls taken breathing room air and 33%
oxygen. Experimental values taken at 10 minute intervals following injection. pHa = Arterial
pH; pHv - Venous pH; P802 = Arterial Oxygen Tension; PVOZ = Venous Oxygen Tension;
P8002 = Arterial Carbon Dioxide Tension; DD = Base Deficit; PVCOZ = Venous Carbon
Dioxide Tension; V - Mnute Volume; RR = Respiratory Rate; V1- - Tidal Volume

' Changes of P< 0.05 or greater from 02 control before atropine.

" Changes of P< 0.05 or greater from 02 control after atropine.

42
Figures 11 through 14. The average duration of anesthesia was 80
minutes, but data were analyzed only through 60 minutes since 2 animals
were responsive at that time.

The cardiac output increased 822 from a control of 1.82 i .12 L/min
to 3.32 i .81 L/min (P<0.05) 15 minutes after the administration of
atropine. The high cardiac output was maintained over the 60-minute
period and was not affected by the Innovar-Vet and nitrous oxide. The
increase in cardiac output was due to an increase in heart rate.
Control heart rate was 61 i 7 bpm, which was increased 236% by atropine
to 205 j; 10 bpm. This highly significant Change (P<0.01) was evident
for the entire study. When Innovar-Vet and nitrous oxide were adminis-
tered, heart rate decreased slightly to 168 j; 12 bpm and steadily
decreased to 133 -_I-_ 3 bpm at the 60-minute interval. The increase in
heart rate was accompanied by a change in stroke volume which decreased
45! from a control value of 31 :_l-_ 3 ml to 17 _-l_- 4 ml 15 minutes following
atropine (P<0.05). This increased 32% to 21 j; 3 ml 10 minutes after
the administration of the anesthetic agents.

Mean arterial pressure increased 181 from a control of 96 i 4 m
Hg to 113 _t 4 mm Hg after atropine. This increased an additional 312
to 126 i 5 mm Hg following Innovar—Vet and nitrous oxide and maintained
at 111 to 116 mm Hg for the remainder of the experiment. All (these
changes were highly significant (P<0.01) .

Systolic pressure was significantly affected only at the lO-minute
interval. The control values were 118 _-l_-_ 10 mm Hg before atropine,

119 j; 5 mm Hg 15 min after atropine and then increased by 192 to 140
_‘t 4 mm Hg at the lO-minute interval (P<0.01). Diastolic pressure
followed the same trend as mean pressure. Control was 67 i 3 mm Hg

and increased 542 to 103 j; 3 mm Hg after atropine. Values during

43

 

 

O

T z"

.. ID
5 3.5-1 .— _

u.)

5 - 9 >

<

8 2.5— g ‘L g

--1 I\I < z

E

1.5

 

T 94
T“ z
—‘ a
200_'I l-
_ I.“
>
_ Ir
- — g
g T E -
G.
v —‘ g
m —1
j.
I __ <
100‘-1
-—1

 

 

I\{
._ H

 

SV (ml)
N
O
I
ATROPINE
I—e—I
INNOVAR VET 81 N20

 

'° 1 I I I I I I T 7
AIR 02 02 10 20 30 40 50 60
CONTROLS l<——TIME IminumI-—-D- I

Figure 11. Cardiac output, stroke volume, and heart rate with atropine,
Innovar-Vet, and nitrous oxide. Mean values and standard errors plotted
for 4 dogs given Innovar-Vet and nitrous oxide with atropine premedication.
Controls taken breathing room air and 33% oxygen. Experimental values

plotted at 10 minute intervals.
CO = Cardiac Output; SV = Stroke Volume; HR = Heart Rate

44

 

 

 

 

 

9..
130-4 z
a!
s
.. 120— >
O
I w I:
E Z >
5110— g g
l g. —
§ <
100—
90
60*—
9.
Z
. .3 --
’2‘ 507 g 5
.9.- 8 >
E E a:
I- 40- 4: g
o J-
2
E
30 T I I r I I T I I
AIR 02 o2 10 20 30 40 50 60
CONTROLS +——TIME (misuse—b

Figure 12. Mean arterial pressures and total peripheral resistance with
atropine, Innovar-Vet, and nitrous oxide. Mean values and standard errors
plotted for 4 dogs given Innovar-Vet and nitrous oxide with atropine
premedication. Controls taken breathing room air and 33% oxygen.
Experimental values plotted at 10 minute intervals.

MAP = Mean Arterial Pressure; TPR = Total Peripheral Resistance

Pacoz (mm Hg) pHa

P302 (mm Hg)

 

 

 

 

 

 

 

45
7.5 fl
0
. N
w z
7.4— I\ g «I!
8 I '5
P >
< a:
7.3 -— g
o
g i.)
7.2 "
O
N
Z
40 2 f
‘5‘ m
E >
3 I c
30 -— ,_ g
< O
2
E
20
190— 99
_j Z
_ E :3
160— E f g
_ g a
— z s
130— g
‘7 E
100—
7” '—l: I I I I I I I I
AIR 02 02 10 20 30 40 50 60
CONTROLS «Q—TIME (minutes)—+l

Figure 13. Arterial blood gases with atropine, Innovar-Vet. and nitrous
oxide. Mean values and standard errors plotted for 4 dogs given Innovar-
Vet and nitrous oxide with atropine premedication. Controls taken breathing
room air and 33% oxygen. Experimental values plotted at 10 minute intervals.
9H3: Arterial pH; P802 = Arterial Oxygen Tension; P8002 = Arterial Carbon
Dioxide Tension

46

 
 
 

 

 

 

 

 

27.0 —
—I 4.
22.0 3
: 9‘ r T
I z
.75 17.0 __ L a
g I 1- -
o; - ‘S’
12.0 — T
a m o:
_. g <
a 8 5
7 o : m 2
. _ .- E J
“ < I ’ _)
2 0 _‘ E i .1.

RR (respirations/min)

Vt (ml)

 

 

 

 

 

if

 

 

 

 

 

—1 T
170—4
:1 O
N
— 2
120— '3
w I-
: g 1
-—I E m
70: (.5 g
_. :5 3
_ < z
20
_ 94 q
2 z I
160— o
: l—
u.)
: g >
110- a g L
-— o
— I-
~ i/f <
60
I I I I I l I I I
AIR 02 02 10 20 30 40 50 60
CONTROLS I + TIME (minuml—h-I

 

Figure 14. Minute volume, respiratory rate, and tidal volume with atropine,
Innovar-Vet and nitrous oxide. Mean values and standard errors plotted for
4 dogs given Innovar-Vet and nitrous oxide with atropine premedication.
Controls taken breathing room air and 33% oxygen. Experimental values
plotted at 10 minute intervals.
\°/ = Minute Volume; RR = Respiratory Rate; VT = Tidal Volume

47
anesthesia ranged from 95 to 115 m Hg. These changes were also highly
significant (P<0.01).

Although not a significant change, total peripheral resistance
decreased by 252 following atropine from 52 i 3 units to 39 _-l_-_ 7 units.
Administration of the anesthetic agents had no further effect.

Atropine had no significant effect on arterial pH. However,
administration of Innovar-Vet and nitrous oxide caused a decrease from
7.36 i .01 to 7.23 _-l_-_ .01 at the lO—minute interval (P<0.01). By 20
minutes it had returned to 7.32 i .03 (P<@.05) and gradually returned

to control values at 60 minutes.

 

The Paco2 increased by 342 from an atropine control of 32 i 2 In
fig to 43 j; 5 mm Hg at the lO-minute interval. By 20 minutes, it had
returned to 34 i- 6 mm Hg. The base deficit after atropine was 7 i
l mEq/L and increased to 10 i 2 mEq/L 10 minutes after the anesthetics
were administered. This stabilized at 8 to 9 mEq/L for the remainder
of the experiment. None of these changes were significant. The
administration of 332 oxygen caused a highly significant increase

(P<0.01) in PaO from 79: 7 mm Hg to over 150 mm Hg.

2
Atropine caused a nonsignificant increase in minute volume from

a control of 3.52 i .68 L/min to 16.08 1; 11.02 L/min. This high minute

volume remained for the entire experiment. This increase was attributed

to nonsignificant increases in both respiratory rate and tidal volume.
Apnea occurred in 2 of the 4 dogs , which lasted for 2 to 3 minutes.

Two dogs began panting at the 10-minute interval and continued for the

entire experiment. Muscle tremors involving the head and neck occurred

in 2 dogs near the end of the experiment. Muscle relaxation was good

and flatulence was evident in 3 of the dogs.

48
Slight (1+) response to auditory stimuli was present in 1 dog for
the entire trial. Complete analgesia (0 pain response) was evident in

3 of the 4 animals.

DISCUSSION AND CONCLUSIONS

The results of this experiment did not completely agree with those
reported by other investigators as cited in the literature. Some of

the differences may be related to the influence of other anesthetic

agents used concomitantly with droperidol-fentanyl in some animal

studies. Also, drug doses used experimentally varied greatly from

 

I m “F13-
'!

those used clinically. Bolus intravenous injection (i.e., given in
less than 1 minute) used in some of the experiments may depress the
cardiovascular system much more than a slow injection. Effects of
drugs in human beings cannot always be equated to changes observed in
animals. Experimentally, healthy animals have been used, while clini-
cally this anesthetic has been used principally for the poor-risk
patient. Finally, very few laboratory investigations utilized cone
sistent control data.

There is considerable discrepancy in the literature concerning
the adrenergic blocking effects of Innovar and, more specifically, the
effects of droperidol. Some of this may have resulted from an alpha
blocking contaminant in the original drug mixture. Edmonds-Seal and
Frye-Roberts (1970) stated that alphaeadrenergic blockade has been
over-emphasized and this effect was inconsistent with other well docu-
mented studies. The antiarrhythmic effects of the droperidol may
indicate some type of beta blocking as well. When all aspects are
considered, droperidol-fentanyl cannot be classified as a typical
adrenergic blocking agent.

49

50

The increased excretion of epinephrine as found by Giesecke et
al. (1967) may help explain the observed cardiovascular stability even
in the presence of alpha adrenergic blockage which may be produced by
droperidol. Possible explanations for this increased excretion of
epinephrine may be due to stimulation of the adrenal medulla by a
central mechanism or an increase in excretion secondary to the alpha
blocking effect of droperidol. This alpha block may also account for
the increase in contractile force which was reported following the
administration of droperidol. The ionotropic effect may have been
caused by the increased epinephrine levels.

Fentanyl has been shown to increase vagal stimulation of the
heart. The resulting bradycardia can be effectively counteracted by
anticholinergic drugs. The hypotensive effects of fentanyl were due
to a negative ionotropic effect which was indicated by Goldberg et a1.
(1969) in isolated myocardial preparations. This resulted in a decrease
in the active state of the myocardium. Clinically, this may be
obscured by sympathoadrenal stimulation.

The dogs used for this study were a very homogeneous group which
helped reduce variable factors. All 12 were purebred Beagle half—
brothers of the same age and near the same weight. Their genetic
background was computerized to detect and eliminate any animals whose
parents exhibited defective traits. They were all acclimated to their
surroundings for 2 months before the experiment began.

Since data were to be gathered on the conscious unmedicated dog,
it was necessary that they be conditioned for this procedure. In order
to minimize excitement and provide a stable control period, each dog
was trained to lie on a table in lateral recumbency. No dog was used

until it would do this for long periods of time without apprehension.

 

51

If a dog was particularly nervous on the day of the experiment, he was
either given time to sufficiently quiet down or the procedure was post-
poned to another day.

The instrumentation used was particularly successful. A total of
19 variables were measured with a minimum of physiological disturbance.
The chest was not opened for instrumentation as is commonly done; there-
fore, intrathoracic dynamics were not altered. The only significant
physiological change was due to the tracheostomy. Since a large
volume of the dog's normal anatomical dead space.was bypassed, the

control PCO2 readings were lower than those reported for normal dogs.

 

All dogs began the experiments with increased base deficits (5
to 10 mEq/L). This was due to the dogs compensating for the mild
respiratory alkalosis with a mild metabolic acidosis. This combina-
tion resulted in control pHs being within the normal range.

Since Groups II and III were to be evaluated experimentally
breathing 67X nitrous oxide and 332 oxygen, it was decided that con—
trol and experimental measurements would be taken with all the dogs
breathing 332 oxygen. Therefore, control measurements were taken with
all dogs breathing 672 nitrogen and 332 oxygen. In addition, the
entire Group I experiment was run using this breathing mixture. Thus
inspired 02 content was equal in the control and study periods. As.a
result, the only significant change detected between the air controls
and the oxygen controls in the 3 groups was the increase in arterial

and venous P02.

Innovar-Vet
The duration of anesthesia with Innovar-Vet alone was very

constant. No dog recovered in less than 40 minutes and none stayed

52
anesthetized for more than 50 minutes. This is more constant than has
been reported by Krahwinkel et a1. (1972) for intramuscular Innovar-Vet,
but is consistent with that reported by Krahwinkel and Sawyer (1972)
for intravenous administration. It was decided that evidence of
recovery would be when the dog showed a 2+ pain response (lift head)
to toe clamping.

Innovar-vet alone caused statistically significant cardiovascular
changes only in systolic pressure. Cardiac output was very stable and
did not change from control. This is consistent with the observations
of Abel and waldhausen (1968) in chronic instrumentated dogs. Systolic
arterial pressure decreased significantly and was probably due to alpha
block by the droperidol fraction as indicated by Yelnosky et a1. (1964).
Although the diastolic and mean pressures both decreased, these changes
were not statistically significant due to the small sample size.
Although the heart rate decreased from 93 i 17 to 69 j; 7, this was
not statistically significant. However, on a larger sample size it
may have been and could be attributed to the effect of the fentanyl
component. Yelnosky and Gardocki (1964) showed that this bradycardia
would occur in vagotomized dogs, but Dobkin et a1. (1970) were able to
block the induced bradycardia with atropine.

When heart rate decreased, stroke volume increased which maintained
cardiac output constant. This was apparently due to increased filling
time evoking a Starling response as illustrated by Burton (1965).
Peripheral vascular resistance was not significantly changed in this
group.

A transient acidosis was induced with Innovar-Vet. This was due
to a combination of respiratory and metabolic acidosis. The respiratory

depression immediately following admdnistration of Innovar-Vet resulted

 

53
in increased P602 and decreased P02. These values had returned to near
normal by 10 minutes postinjection when the first measurement was made.
Schotz and Ziegler (1967) reported a similar respiratory and metabolic
acidosis in spontaneously breathing human patients, but they theorized
this to be due only to respiratory depression with hypercarbia and
hypoxemia. However, Dobkin et a2. (1964) were not able to detect any
plasma bicarbonate change in human patients being ventilated. In poor-
risk patients, sodium bicarbonate should be administered and respira-
tion controlled or assisted to counteract this acidosis.

Respiration was definitely depressed by Innovar-vet. This was

 

evidenced by apnea and cyanosis immediately following injection.

Since measurements were not recorded for analysis until 10 minutes
after injection, the peak respiratory depression was observed but not
recorded. This peak depression occurred 1 to 2 minutes after injection
and persisted for approximately 5 minutes. By the time the lO-mdnuta
measurements were taken, respiration was improved but had not reached
control values. .

Mbst dogs responded to auditory stimulation. This constitutes a
profound problem with this anesthetic since Operating rooms are usually
noisy. This finding is consistent with the reports of Some and Shields
(1964).

Other evidences of central nervous system.stimulation were nystagmus
and muscle twitching. These are most likely due to an effect of fentanyl
on the brain as reported by Some (1971). Panting, which occurred in
2 of the 4 dogs, has been noted by Krahwinkel et al. (1972), and has
been theorized to be due to the effect of fentanyl on the thermoregu-

latory centers of the brain.

54
Innovar-Vet with Nitrous Oxide

Anesthetic duration was increased with nitrous oxide by 10 minutes
compared to Innovar-Vet alone. This can be accounted for by the anal-
gesic properties of nitrous oxide. One dog had a prolonged effect from
this combination, resulting in 110 minutes of anesthesia. He appeared
to be conscious for the final 60 minutes, but did not respond to the
pain stimuli . F

The cardiovascular system was less affected with the combination

of Innovar-vet and nitrous oxide than with Innovar-Vet alone. This

— “’4.

was evidenced by the fact that no cardiovascular variable was signifi-

 

cantly affected. This is contrary to Dobkin et a1. (1964), who found~
slight hypotensive and bradycardia effects in dogs given the same
mixture.
Cardiac output was increased with nitrous oxide, although the
change was not significant. Control was 2.05;: 0.30 L/min and, at
30 minutes, output had increased to 2.83 t 0.21 L/min. There was no
change in arterial pressure at any time. Since hypotension was present
in Group I and not in Group II, there is the possibility of a pressor
effect caused by nitrous oxide, as was reported in man by Eisele and
Smith (1972). These findings are contradictory to Dobkin and Byles
(1966), who reported that Innovar-Vet and nitrous oxide caused a decrease
in arterial pressure and in heart rate in dogs. Total peripheral
resistance was not significantly decreased when all 4 dogs in this
group are analyzed. However, if the one dog with a very high resistance
(92 units) is removed, the change is highly significant (P<0.025).
Increased cardiac output and lack of hypotension suggests that
nitrous oxide may be vasoactive. Moran at al. (1972) found a similar

increase in cardiac output in dogs.

55
Similar to the results found in Group I, the only respiratory
variables with significant changes were those of arterial and venous
pH. The change had metabolic and respiratory factors similar to Group
I. These highly significant changes (P<0.01) persisted longer, sug-
gesting that the respiration was depressed for a longer period than in

Group 1. Both PCO and base deficit were increased and changes were

2
greater than in Group I.

Increasing the inspired oxygen concentration from room.air to 33!
produced a slight decrease in minute volume. This was concurrent with
an increase in P02. Comroe (1965) reported the same effect in conscious
man when breathing mixtures when changed from.room air to oxygen.

Respiration was depressed by Innovar-Vet and nitrous oxide as
evidenced by a decrease in minute volume. This was due to a decrease
in respiratory rate (from 42 to 10), but by 20 minutes returned to
control values. However, when the rate decreased, tidal volume increased
(from 104 ml to 151 ml). This is in partial agreement with Teutenberg
et al. (1967), who reported a decrease in rate and depth in human
patients given this mixture. Those values returned to normal in 15
minutes.

The combination of Innovar-Vet and nitrous oxide provided better
analgesia than Innovar-Vet alone, as evidenced by the analgesic scores.
Nitrous oxide alone will not provide anesthesia but is a good analgesic
at 672. It also provided good muscle relaxation and muscle tremors
were eliminated.

The response to auditory stimuli was greatly reduced from Innovar-

Vet alone. Also, panting was not present in any of the dogs of this

group but was present in 2 of 4 in Group I.

56
Innovar-Vet with Nitrous Oxide and Atropine
The anesthetic duration on this group was 10 minutes longer than
for the group without atropine. The extended anesthetic duration may
have been due to individual animal differences or a direct effect of
atropine. These effects were not distinguished in this study.

Atropine caused an 822 increase in cardiac output. The change was

 

due to a 2002 increase in heart rate from control values accompanied by E”
a 75% decrease in stroke volume. The increase in cardiac output is ;
consistent with the findings in man by Berry et al. (1958). Diastolic

pressure was also significantly increased by atropine, but systolic was _ E

not. This resulted in an increase in mean arterial pressure. Eger
(1962) reported from studies with human patients that atropine caused
an increase in cardiac output without a change in stroke volume and that
any tendency towards arterial hypertension was offset by a decrease in
peripheral resistance.
Atropine also seemed to have a stimulatory effect on respiration
as minute volume increased, but no changes were noted in blood gas
values. Due to a very large standard error of the mean, this change
in minute volume was not significant.
Cardiac output did not change with the subsequent administration
of the anesthetic drugs. However, mean and systolic pressure were
transiently increased. The change was significant at 10 minutes but
had returned to control levels by 20 minutes. The mechanism of this
pressor effect is difficult to explain, since total peripheral
resistance was unchanged when compared to the preanesthetic control.
Acidosis occurred with this group as in Groups I and II, but was
of shorter duration. This was possibly due to the higher cardiac output

providing better perfusion and returning the pH to normal levels sooner.

57

Respiration was definitely depressed by this combination of drugs
for approximately 5 minutes. By the 10~minute sampling period, respira-
tion had returned to near control, but the P002 and base deficit were
elevated. Therefore, as in Groups I and II, the true picture of respira-
tory depression is not apparent in the results.

Analgesia and auditory responses were similar to those of Group
II. Muscle relaxation was also comparable to Group II. Two dogs panted
from this group, compared to none in Group II. This may be due to the
respiratory effects of the atropine as cited by Eger (1962).

This combination of Innovar—Vet and nitrous oxide appears to be
a safe anesthetic. The cardiovascular system is mdnimally affected,
whereas most general anesthetics depress both the cardiovascular and
respiratory systems. Respiration should be assisted during the first
5 to 10 minutes since this was the period of profound respiratory
depression. In addition, in poor-risk clinical cases, it would be
advisable to administer sodium bicarbonate to counteract the metabolic
acidosis. Innovar-Vet should be administered slowly and to effect over
several minutes with the dose not to exceed 1 ml/25 lb (11.4 kg).

Atropine should be used as a preanesthetic to prevent the initial
bradycardia and premature ventricular contractions. This transient

bradycardia is not present in all animals but should be prevented.

 

SUMMARY

The cardiopulmonary effects of droperidol-fentanyl, nitrous oxide,
and atropine were evaluated and analyzed in 12 adult male Beagles.
The cardiovascular variables measured were: cardiac output, systolic
arterial pressure, diastolic arterial pressure, mean arterial pressure,

central venous pressure, heart rate, stroke volume, total peripheral

 

resistance, and packed cell volume. Respiratory measurements included
arterial and venous pH, P02 and PC02, base deficit minute volume,
respiratory rate, and tidal volume. In addition, analgesia, response
to auditory stimuli, and muscle relaxation were subjectively evaluated.
All dogs were surgically instrumented with a catheter in the aorta for
measuring cardiac output by thermal dilution. Arterial and venous
catheters were inserted and a chronic tracheostomy was performed.
EAch dog served as its own control and data obtained from the unanesthe-
tized, unmedicated animals were compared with data recorded following
administration of the test drugs.

The dogs were randomly divided into 3 groups of 4 dogs each.
Group I was given intravenous droperidol-fentanyl alone; Group II was
given droperidol-fentanyl with 672 nitrous oxide, and Group III was
given atropine sulfate as premedication followed by droperidol-fentanyl
and 672 nitrous oxide.

Respiration was depressed in all 3 groups for 3 to 5 minutes
following injection of the droperidol-fentanyl. This resulted in a
respiratory and metabolic acidosis in all animals.

58

 

59

In addition, droperidol—fentanyl alone caused a decrease in systolic
pressure and a slight decrease in heart rate. These dogs were sensitive
to auditory stimulation. No cardiovascular changes were noted when
nitrous oxide was added in the Group II animals. Analgesia and muscle
relaxation were improved over the Group I animals. The premedication
of atropine sulfate in Group III resulted in increased cardiac output,
heart rate, and diastolic pressure. The subsequent administration of
droperidol-fentanyl-nitrous oxide caused a transient increase in mean
and systolic pressure. This latter anesthetic regime along with

assisted or controlled respiration provides an excellent anesthetic

v.

 

state with mdnimal cardiopulmonary depression.

Hillsidvflp H'- u."

REFERENCES

REFERENCES

Abel, F. L., and Waldhausen, J. A.: Effects of anesthesia and arti-
ficial ventilation on caval flow and cardiac output. J. Appl. Ew'
Physiol., 25, (November, 1968): 479-484.

Berry, J. N., Thompson, H. K., Miller, D. E., and McIntosh, H. D.: I
Observations of reduction of stroke volume and central venous .

pressure induced by atropine in man. Clin. Res., 6, (1958):

216. .

5"]. i‘ .

Brown, A. 8.: Neuroleptanalgesia. Int. Anesth. Clin., 7, (Spring,
1969): 159-175.

 

Burton, A. C.: Physiology and Biophysics of’the Circulation. Year
Book Medical Publishers, Chicago, 1965: 141-145.

Chodoff, P., and Domino, E. H.: Comparative pharmacology of drugs
used in neuroleptanalgesia. Anesth. and Analg., 44, (Sept.-
Oct., 1965): 558-563.

Comroe, J. H.: Physiology of Respiration. Year Book Medical Publishers,
Chicago, 1965: 39-57.

Corssen, C.: Neurolept-Analgesia. Univ. of Michigan Med. Center. J.,

Corssen, P., Chodoff, R., Domino, E. P., and Kahn, D. R.: Neurolept-
analgesia and anesthesia for openrheart surgery. J. Thorac.
Cardiovasc. Surg., 49, (June, 1965): 901-920.

Corssen, P., Domino, E. P., and Sweet, R. F.: Neuroleptanalgesia and
anesthesia. Anesth. and Analg., 43, (Nov.-Dec., 1964): 748-763.

Dixon, S. H., Nolan, 8. P., Steward, S., and Morrow, A. G.: Neurolept-
analgesia: Effects of Innovar on myocardial contractility,
total peripheral vascular resistance, and capacitance. Anesth.
and Analg., 49, (1970): 331-335.

Dobkin, A. B., and Byles, P. H.: Comparison of anesthesia with Innovar,
Halothane, and Methoxyflurane-nitrous oxide. Acts Anaesth.
Scand. Suppl., 18, (1966): 1-43.

Dobkin, A. B., Byles, P. H., and Cho, M. H.: Neuroleptanalgesies: 3.
Effect of Innovar-nitrous oxide anaesthesia on blood levels of
histamine, serotonin epinephrine, and norepinephrine, and on
urine excretion. Can. Anaesth. Soc. J., 12, (July, 1965): 349-360.

60

61

Dobkin, A. B., Israel, J. S., and Byles, P. H.: Innovar-nitrous oxide
anesthesia in normal man: Effect on respiration circulatory
dynamics, liver function, metabolic functions, acidrbase balance,
and psychic responses. Can. Anaesth. Soc. J., 11, (Jan., 1964):
41-71.

Dobkin, A. B., Lee, P. K. Y., and Byles, P. H.: Neuroleptanalgesia:
2. Laboratory evaluation of combination of analgesics and
neuroleptics with nitrous oxide. Can.~Anaasth. Soc. J., 12,
(Jan., 1965): 38-66.

Dobkin, A. B., Pieloch, P. A., Israel, J. 8., and Neville, J. F.: p“
Circulatory and metabolic effects of Innovar-fentanyl-nitrous '
oxide anesthesia for major abdominal surgery in man. Anesth.
and Analg., 49, (1970): 261-267.

Edmonds-Seal, J., and Prys-Roberts, C.: Pharmacology of drugs used in
neuroleptanalgesia. Brit. J. Anaesth., 42, (March, 1970):
207-216.

 

Eger, E. I.: Atropine, scopelamine and related compounds. Anesthesiology,
23, (May-June, 1962): 365-383.

Eisele, J. H., and Smith, N. T.: Cardiovascular effects of 40 percent
nitrous oxide in man. Anesth. and Analg., 51, (Nov.-Dec., 1972):
956-962.

Evonuk, E., Imig, C. J., Greenfield, N., and Eckstein, J. H.: Cardiac
output measured by thermal dilution of room temperature injectate.
J. Appl. Physiol., 16, (1961): 271-275.

Freeman, J., Ingvar, D. H., and Nilsson, E.: Cerebral blood flow in
neuroleptanalgesia. Acta Anaesth. Scand. Suppl., 25, (1966):
292.

Gardocki, J. P., and Yelnosky, J.: A study of some of the pharmaco-
logic actions of fentanyl citrate. Toxicol. Appl. Pharmacol.,
6, (1964): 48-62.

Giesceke, A. H., Jenkins, M. T., Crout, J. R., and Collett, J. H.:
Urinary epinephrine and norepinephrine during Innovar-nitrous
oxide anesthesia in man. Anesthesiology, 28, (July-Aug., 1967):
701-704.

Goldberg, A. H., and Padget, C. H.: Comparative effects of morphine
and fentanyl on isolated heart muscle. Anesth. and Analg., 48,
(Nov.-Dec., 1969): 978-992.

Gorman, H. Mg, and Crayghorne, N. W. B.: The effects of a new neuro-
leptanalgesic (Innovar) on renal function in mane Acts Anaesth.

Grell, F. L., Koons, R. A., and Benson, J. S.: Fentanyl in anesthesia:
A report of 500 cases. Anesth. and Analg., 49, (July-Aug.,
1970): 523-532.

62

Hamlin, R. L., Finaven, S. M., and Smith, C. R.: Pentanyl citrate-
droperidol and pentobarbital for intravenous anesthesia in dogs.
J.A.V.MtA., 152, (Feb. 15, 1968): 360-364.

Heerdt, M.: personal communication, 1970.

Janssen, P. A., Niemegeers, C. J., Schellekens, K. H., Verbruggen, P.
J., and Van Nueten, J. M.: The pharmacology of dehydrobenz-
peridol (R-4749), a new potent and short acting neuroleptic
agent chemically related to Haloperidol. Arzneimittel-forsch.,
13, (1963): 205-211.

._I
Krahwinkel, D. J., Evans, A. T., and Sawyer, D. C.: Clinical-use of E"
neuroleptanalgesia in the canine. Practicing Vet., 44, (June- '

July, 1972): 14-15.

-' "_r. 1".» .J

Krahwinkel, D. J., and Sawyer, D. C.: Neuroleptanalgesia and neurolept-
anesthesia. J.A.A.H.A., (October, 1972): 368-370.

 

I'luJLJ'x .-

Lewis, A. H.: Biostatistics. Reinhold Publishing Corp., New York,
1966: 72-82.

Michaelson, S. M., Scheer, H., and Gilt, S.: The blood of the normal
Beagle. J.A.V.M.A., 148, (March, 1966): 532-534.

Moran, J. E., Rusy, B. P., Vongvisces, P., and Lattansnd, 8.: Effects
of halothane-oxygen and InnovarR - nitrous oxide - oxygen on
the maximum acceleration of left ventricular ejection and the
tension-time index in dogs. Anesth. and Analg., 51, (Mhy-June,
1972): 350—354.

Morrison, J. D.: Drugs used in neuroleptanalgesia. Int. Anesth.
Clinics, 7, (Spring, 1969): 141-157.

Rawlings, C. A., Krahwinkel, D. J., and Anstadt, G. L.: Surgical
catheterization of the femoral artery and vein. VMVSAC,
(August, 1970): 777-781. "

Schotz, S., and Zeigler, M. L.: Neuroleptanalgesia with Innovar:
Controlled technic with a dilute intravenous drip. Anesth.
and Analg., 46, (January-Feb., 1967): 69-75.

Shepherd, N. W.: The chemistry and pharmacology of droperidol, pheno-
peridine and fentanyl. In The Application of'Neuroleptanalgasia
in Anesthetic and Other Practice. Pergamon Press, London,

1964: 1-17.

Soma, L. R.: veterinary Anesthesia, lst ed. Williams and Wilkins Co.,
‘ Baltimore, Md., 1971: 131-133.

Soma, L. R., and Shields, D. R.: Neuroleptanalgesia produced by
fentanyl and droperidol. J.A.V.M.A., 145, (Nov., 1964):
897-902.

63

Tarhan, S., Moffitt, B. A., Lundborg, R. 0., and Frye, R. L.: Hemo-
dynamic and blood-gas effects of Innovar in patients with
acquired heart disease. Anesthesiology, 34, GMarch, 1971):
250-255.

Teutenberg, H.‘W., King, J. B., and Massion, W. H.: Neurolept analgesia:
A clinical evaluation of 106 cases. J. Oklahoma State Med.
Assoc., (April, 1967): 178-182.

Yelnosky, J., Katz, R., and Dietrich, E. V.: A study of some of the
pharmacologic actions of droperidol. Toxicol. and Appl.
Pharmacol., 6, (1964): 37-47. Fflfl

Yelnosky, J., and Gardocki, J. F.: A study of some of the pharmaco-
logic actions of fentanyl citrate and droperidol. Toxicol. and
Appl. Pharmacol., 6, (1964): 63-70.

Zaunder, H. L., Del Guercio, L. R. H., Feins, N., Barton, N., and
Steward, W.: Hemodynamic during neurolept analgesia.
Anesthesiology, 26, (March-April, 1965): 266. u_.

 

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