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Effects of physical and chemical restraint on intravenous glucose tolerance test in crested black macaques (Macaca nigra).

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American Journal of Primatology 15:171-180 (1988)
TECHNICAL ARTICLE
Effects of Physical and Chemical Restraint on
Intravenous Glucose Tolerance Test in Crested
Black Macaques (Macaca nigra)
MITSUYA YASUDA, JOANN WOLFF, AND CHARLES F. HOWARD, JR.
Oregon Regional Primate Research Center, Beaverton, Oregon
The effects of physical and chemical restraint on glucose clearance and
insulin secretion were evaluated during intravenous glucose tolerance
testing in Mucuca nigru. Conscious monkeys placed in Plexiglas cylindrical restraining devices (CRD) appeared relaxed, but glucose clearance and
insulin secretion were impaired. A combination of midazolam with ketamine, compared to ketamine alone, did not cause detectable changes in the
intravenous glucose tolerance tests; midazolam also reduced adverse
reactions to ketamine and extended the duration of anesthesia. The
cylindrical restraining device can be convenient for examining monkeys,
but it is limited by its adverse affects on metabolic and hormonal
measurements in intravenous glucose-tolerance tests. Chemical restraint
using ketamine with midazolam was more effective than ketamine alone.
Key words: ketamine, midazolam, restraining device
INTRODUCTION
The intravenous glucose tolerance test (IV-GTT) has been used as a major
diagnostic tool [Howard, 1972; Howard, 1974; Howard et al., 19871. Physical or
chemical restraints [Honjo et al., 1976; Rosenblum et al., 1976; Hamilton &
Ciaccia, 1978; Tanaka et al., 19861 are usually necessary when conducting
glucose-tolerance tests in nonhuman primates. However, the stress of restraint
may affect the results [White et al., 19731. Stress can cause suppression of insulin
release [Porte & Robertson, 19731 or an increase in glucagon secretion [Bloom et
al., 19731. Chemical restraint is most feasible because the stress caused by
handling of the monkeys is minimized [Cohen & Bree, 19781. However, some
drugs, such as xylazine [Abdel el Motal & Sharp, 19851 or atropine [Daniel &
Henderson, 19751, inhibit glucose-inducedinsulin release, and glucose clearance is
reduced. Thus, it is important to choose suitable sedatives and t o handle monkeys
with minimal stress.
Ketamine hydrochloride, which is a cyclohexylamine analogue, has been used
for chemical restraint in IV-GTT because it does not affect glucose tolerance in
macaques [Castro et al., 1981; Kemnitz & Kraemer, 1982; Brady & Koritnik,
Received September 8, 1987; revision accepted January 17, 1988.
Address reprint requests to Dr. Mitsuya Yasuda, Oregon Regional Primate Research Center, 505 NW
185th Avenue, Beaverton, OR 97006.
0 1988 Alan R. Liss, Inc.
172 I Yasuda et al.
19851. Some monkeys, however, have displayed side effects to ketamine, i.e.,
excessive salivation, slow movements of limbs and hands, or uncoordinated eye
movement. Also, ketamine is a short-acting agent, and it is necessary to check that
the monkey is well sedated; additional ketamine doses are frequently needed.
Because long-term sedation by ketamine can be difficult to maintain, it became
necessary to explore alternate restraining methods that would not affect glucose
metabolism and would minimize stress. The present study was designed to
examine the effects of some physical and chemical restraint methods in terms of
their influences on the IV-GTT.
MATERIALS AND METHODS
Subjects
Seventeen nondiabetic crested black macaques (Macaca nigra) were studied;
these included eight males and nine females (3.7-7.7 kg body weight and 3-17
years of age). Monkeys were housed in individual cages. The room temperature
was maintained at 22 ? 1"C, and lights were on from 0700 to 1900 hours. Monkeys
were fed Purina 15 Monkey Chow@twice a day with fruit supplements. Water was
provided ad libitum. Food was withheld from monkeys a t 1600 hours, and the tests
were performed between 0900 and 1100 hours the next day. Each monkey was used
as its own control in chemical restraint; there were 6 to 15 days between tests on
each animal.
Intravenous Glucose Tolerance Test
Regardless of restraint method, an overnight fasting blood specimen (1.5 ml)
was drawn by femoral or saphenous venipuncture, and 0.45 g of glucoselkg of body
weight (1 ml of D50W glucose solutionkg) was rapidly infused over 30 sec into the
saphenous vein. Time was noted a t the end of the injection, and 1.5 ml of blood
samples were collected from the femoral or saphenous vein at 15, 30, 45, and 60
min post injection.
Assays and Calculations
Blood samples were allowed t o clot a t room temperature for 45 min and were
then centrifuged a t 2,500 rpm for 10 min to obtain serum. Glucose was measured
on a Beckman Glucose Oxidase Analyzer (Fullerton, CA). Insulin was assayed
with an Amersham (Arlington Heights, IL) radioimmunoassay kit, which uses the
double antibody method [Hales & Randle, 1963; Howard, 1986al. Cortisol was
assayed by radioimmunoassay with the dextran-coated charcoal method [Krey et
al., 19751. A K value (percentage of glucose clearance per minute) was calculated
with the glucose values from 15 min to the point when glucose returned to baseline
values, usually by 45 min [Lundbaek, 19621. The insulin response in an IV-GTT
(AIRI) was defined as the insulin concentration at 15 min minus that in the fasting
(0 min) sample [Howard, 19821. Total insulin response [Fujita et al., 19751was the
area that is circumscribed by the insulin curve, i.e., the increment above fasting
level.
Restraint
Physical restraint methods were tested with a cylindrical restraining device
(CRD) constructed of clear acrylic plastic (Fig. 1); manual restraint was also used.
Monkeys were selected by measuring the width of the shoulder and the hip to
ensure adequate CRD size, i.e., small enough to prevent escape but large enough
for monkeys to rotate in the tube. Several sizes of CRD can be used for different
Restraint for Glucose Tolerance Test I 173
Clear Acrylic Plastic Tube
Heater Hose
Stand/
Fig. 1. Diagram of cylindrical restraining device (CRD)used in this study. Monkeys are inserted headfirst with
their arms behind the back. Size of this CRD is 60 cm in length and 14 cm in diameter. Heater hoses (1.6 cm in
diameter) are attached to protect the tube if dropped when inserting the monkey and to hold the CRD in place
on the stand. In later versions of the CRD, one end was cut diagonally so that monkeys could rest their heads
and breathe more easily.
sizes of monkeys [Sato et al., 19861. Monkeys were placed into the CRD with the
arms held behind them and the legs grasped to straighten the body. The CRD was
held vertically, and monkeys were inserted into the CRD head first [Lendon &
Dalgard, 19831 and maintained throughout the test period (see Fig. 1).Blood
collections were made by saphenous venipuncture.
Tests were also conducted on monkeys with manual restraint a t each occurrence of blood sampling or glucose injection. Monkeys were restrained by being
grasped with their arms firmly behind them in dorsal recumbency. Blood collections were performed by femoral venipuncture. Monkeys were returned to their
own cages after sampling or injection.
For chemical restraint, ketamine hydrochloride (KTM) (VetalarB, ParkeDavis, Morris Plains, NJ) alone or in combination with midazolam hydrochloride
(MDZ) (Versed@, Roche Laboratories, Nutley, NJ) (KTM + MDZ) was used.
Monkeys were restrained with 10 mg of ketamine/kg of body weight administered
intramuscularly; an additional 5 mg/kg of the substance was injected a t time
intervals necessary to maintain anesthesia. The same monkeys were also tested
with KTM + MDZ. Midazolam, 0.33 mgkg, was given intramuscularly 15 min
before the injection to ketamine; additional doses of 0.17 mg/kg were given when
adverse reactions of ketamine returned. Initial and additional doses of ketamine
were the same as in previous tests. The sedated animals were laid on the table in
the lateral position, and both forearms were fixed to the table with tape.
Behavioral Observations
Side effects of the drugs to chemical restraint were recorded throughout the
IV-G'M'. These included excessive salivation, nystagmus, and tongue movement
(involuntary, slow movement of the tongue with opening of the mouth). The test
period was divided into six intervals of 10 min. Whenever a behavior was observed
during a 10-min block of time, it was recorded. Once a behavior was noted in a
checklist, further instances of the behavior were not recorded until the beginning
of the next interval.
174 I Yasuda et al.
n
5
2oor
CRD
o Manual
150
\
rn
0
u
50
I
2501
I
I
1
T
200
.-c
5 100rn
-C
50
~
OL
b
1
I
I
I
15
30
45
60
Time (minutes)
Fig. 2. Glucose clearances and insulin responses in normal monkeys restrained with cylindrical restraining
device (CRD) or by manual handling in intravenous glucose tolerance test. Points are the mean SEM;* = P
< .05, ** = P < .01.
*
Statistical Analysis
All values in the text and tables are the mean SEM. Data were compared
with the Student’s t-test; a P value of .05 or less indicated significance. x2 was used
to test for differences in the frequency of behavioral observations.
*
RESULTS
Experiment 1: Physical Restraints
Nine nondiabetic monkeys were examined with IV-GTT with manual restraint
or CRD. Glucose-clearance curves and insulin responses in IV-GTTs with physical
restraint are shown in Fig. 2. The K values, AIRI, and total insulin response are
listed in Table I. Glucose levels of the monkeys restrained with CRD remained
significantly higher a t 30,45, and 60 min than those manually restrained (P for all
< .05). K values were significantly lower with CRD than with manual restraint
(P < .01). The insulin response at 15 min was attenuated, but not significantly.
Restraint for Glucose Tolerance Test / 175
200r
n
5
0
Ketamine
+ Midazolam
150-
\
E!
Y
8
loo-
0
0
a
=]
50-
OL
’
4001
OL
b
I
I
I
I
T
1
I
I
I
15
30
45
60
Time (minutes)
Fig. 3. Glucose clearance and insulin response in normal monkeys anesthetized with ketamine or ketamine +
midazolam in intravenous glucose tolerance test. Points are the mean ? SEM;* = P < .02.
Insulin levels remained significantly higher at 45 and 60 min with CRD than with
manual restraint (P for both < .05), but the total insulin response and AIR1 were
not significantly different.
Because there were apparent differences in IV-GTT, the effects of CRD
restraint alone were examined on seven nondiabetic monkeys. Monkeys were
placed in the CRD without sedation for 60 min. Mean values of glucose, insulin,
and cortisol are given in Table 11. The glucose levels at 15,30,45,and 60 min were
significantly higher than the levels of zero sample during CRD restraint (P for all
<.05). The insulin levels were slightly increased (P < .02), but a significant
difference was found only a t 30 min. Differences in glucose, insulin, and cortisol
levels between zero samples and other samples were not statistically significant
with manual restraint. Baseline cortisol values were established by collecting
blood with manual restraint within 3 min after entrance into the monkey area a t
0700 hours. Zero values measured during testing by 0900 hours were significantly
greater than baseline values of 45 f 2 pg/dl (P < .001). The cortisol levels at 30,
45, and 60 min were significantly higher than that of zero sample with CRD (P for
all <.05).
176 I Yasuda et al.
TABLE I. Effects of Physical Restraints on Intravenous Glucose Tolerance Test*
K value (%/mid
AIRI (kU/ml)
Total insulin remonse (uU . midml)
Manual
restraint
(n = 9)
CRD
restraint
(n = 4)
5.64 k 1.09
195 ? 22
4233 k 489
2.04 2 0.38
136 2 59
5882 ? 1262
Significance
P < 0.01
N.S.
N.S.
~~
*See text for explanation of abbreviations.
TABLE 11. Effects of Physical Restraints on Repeated Blood Sampling?
Time
(min)
Glucose (mgldl)
IRI (pU/ml)
Cortisol (kg/dl)
0
15
30
45
60
0
15
30
45
60
0
15
30
45
60
Manual
(n = 7)
53
55
57
58
55
10
14
15
16
18
108
111
111
108
110
t 2
2
2
?
?
f
k
2
2
*
?
f
lr
2
2
3
3
4
4
2
3
2
3
4
6
6
5
5
6
CRD
(n = 7)
49 k 4
59 f 4*
66 2 5**
67 t 3***
67 ? 3***
11
2
16 f 2
19 f 3**
19 ? 4
18 ? 2
112 & 5
115 k 5
120 5 6**
124 2 7*
127 f 7***
*
tSee text for explanations of abbreviations.
*Significantly different from zero sample, P < .05.
**Significantly different from zero sample, P < .02.
***Significantlydifferent from zero sample, P < .01.
Experiment 2: Chemical Restraints
Eight nondiabetic monkeys were examined with IV-GTT with KTM or KTM +
MDZ. Glucose-clearance curves and insulin responses in IV-Gl"s with chemical
restraint are shown in Fig. 3. The K values, AIRI, and total insulin responses are
listed in Table 111. None of the average glucose levels from 0 to 60 min with KTM
+ MDZ was significantly different from that with KTM, and K values showed no
significant difference between the two chemical restraining methods. Although the
average AIRI and total insulin responses were slightly greater with KTM + MDZ
than with KTM alone, the only significant difference between KTM and KTM +
MDZ was a t 45 min. Acute insulin responses were not statistically different, but
the secondary responses were prolonged with both chemical restraining methods,
compared with manual restraint.
Effects of KTM and KTM + MDZ are given in Table IV, and behavioral
observations made during chemical restraint are presented in Fig. 4. Intramuscular administration of 10 mgkg of ketamine produced an average restraining period
of 33 ? 2 min, and the total amount of KTM necessary for a single IV-GTT
averaged 19 mgkg. When the same initial amount of ketamine was administered
in combination with 0.33 mgkg of midazolam, the duration of restraint was
Restraint for Glucose Tolerance Test / 177
TABLE 111. Effects of Chemical Restraints on Intravenous Glucose Tolerance Test*
KTM
(n = 8)
K value (%/mid
AIR1 (pU/mV
Total insulin resuonse (uU . midml)
-
KTM
(n
4.03 t 0.33
269 f 39
7603 ? 1052
+ MDZ
=
8)
3.56 ? 0.44
292
41
8251 t 960
*
Significance
N.S.
N.S.
N.S.
*See text for explanations of abbreviations.
TABLE IV. Duration of Anesthesia and Dosage of Ketamine in Intravenous Glucose
Tolerance Test (IV-GTT)*
KTM
(n = 8)
Duration of anesthesia" (min)
Total dosage of ketamine (mgikg)
KTM
(n
33 ? 2
19 t 1
+ MDZ
=
8)
>57 f 7 b
13 t 1
Significance
P < .02
P < .05
*See text for explanations of abbreviations.
"Time in minutes estimated from initial dose of 10 mgkg of ketamine to the time when monkeys started moving
slightly.
bBecause some monkeys were still sedated at the end of IV-G?T fn = 3),duration of anesthesia for them was
calculated from the initial injection to the end of the IV-G'IT.
Ketamine -tMidazolam
Ketamine
RSalivation
ITongue Movement
INystagmus
0-9
20-29
40-49
Time (minutes)
Fig. 4. Adverse reactions occurred during anesthesia with ketamine or ketamine + midazolam. Each column
indicates the number of the animals that showed the symptoms. Total reactions over 60 min for ketamine vs.
ketamine + midazolam were all significantly different salivation (P < .001,x2 = 64.1); tongue movement
(P< .001,x2 = 67.7); nystagmus (P< ,001,x2 = 46.4).
*
significantly extended to more than 57
7 min (P < .02). Consequently, the
amount of ketamine that was necessary for the test was significantly reduced to 13
mgkg (P < .05). Average dosage of midazolam used in IV-GTTs was 0.39 2 0.03
mgkg; additional doses were not necessary in five of the eight monkeys. Salivation, nystagmus, and tongue movement were noticeable adverse reactions when
monkeys were restrained with KTM alone; these symptoms occurred in all the
178 / Yasuda et al.
monkeys throughout most of the test. Total frequencies of salivation, nystagmus,
and tongue movement were all significantly less when monkeys were anesthetized
with KTM + MDZ than when they were anesthetized with KTM (P for all <.001;
x2 > 46). Further, no adverse reactions were observed in two of the eight monkeys.
DISCUSSION
Intravenous glucose tolerance tests have been used to detect and monitor
diabetes mellitus in Mucucu nigru [Howard, 1972; Howard, 1986al and numerous
other nonhuman primates. Monkeys have been restrained either by manual
handling or by injection of ketamine hydrochloride during IV-GTTs. It has been
reported that ketamine had no effect on the results of IV-G'M' [Castro et al., 1981;
Kemnitz & Kraemer, 1982; Brady & Koritnik, 19851.
The CRD is a convenient means for handling monkeys during short-term
procedures. Blood sampling from femoral veins, intravenous administration into
saphenous veins, oral administration, and tuberculin test can be done by a single
person using the CRD [Lendon & Dalgard, 19831. Brief restraint (20 min) with
CRD has no detectable effect on hematological or biochemical values [Sato et al.,
19861 in Mucucu fascicularis. However, glucose clearances were markedly depressed with CRD restraint in IV-G'M' in the current work. White et al. [19731
reported that glucose levels in stressed guenon monkeys (Cercopithecus pygerythrus) rose higher than levels in unstressed monkeys in IV-GTT. Stress probably
caused catecholamine release from the adrenal medulla, which suppressed insulin
secretion [Porte & Robertson, 19731 and was followed by altered glucose metabolism [Howard, 19751.
Less insulin was secreted during the first 15 min of CRD restraint, but
thereafter blood levels of insulin remained higher than when monkeys were
captured repeatedly. As a result, monkeys restrained with CRD produced approximately equal amounts of insulin against the glucose load, compared with results
with manual restraint. Based on total insulin, monkeys restrained with CRD did
not seem to be stressed more than with manual restraint; however, glucose
clearance was markedly depressed. Further, monkeys monitored over 60 min
without glucose injections revealed glucose and cortisol increases with CRD, but
not with manual restraint. Restraint with CRD apparently caused some stress, but
the degree was not enough to suppress insulin release. Ausman and Gallina [19781
reported that K values of trained conscious squirrel monkeys (Suimiri sciureus)
were markedly higher than those of untrained conscious monkeys. Monkeys used
in this experiment were accustomed to manual restraint, but not to CRD. Monkeys
trained and acclimated to CRD might sustain less stress than was encountered in
this study, and glucose clearance might be closer to that attained with manual
restraint.
Chemical restraint with ketamine has been used for IV-GTT in primates
[Kemnitz & Kraemer, 1982; Hansen & Bodkin, 1986; Howard et al., 1986bl. In this
study, a combination of ketamine and midazolam was compared with ketamine
alone. Results on glucose clearance and insulin release during the IV-G'M's were
similar. Insulin responses were prolonged with both of the chemical restraining
methods as compared to responses with manual restraint. This finding resembles
the results obtained by Brady and Koritnik 119851 in African green monkeys.
Because the monkeys used for chemical restraint were older (8.6 years of mean
age) than those used for physical restraint (mean age of 5.6 years for manual and
5.7 years for CRD restraint), insulin secretory results may not be comparable
between the two methods.
Midazolam administered in combination with ketamine minimized salivation,
Restraint for Glucose Tolerance Test I 179
nystagmus, and tongue movement, known adverse reactions with ketamine sedation in primates [Green et al., 19811. The duration of action was also significantly
extended. Because midazolam hydrochloride is a benzodiazepine derivative and has
tranquilizing properties, it has muscular relaxant and anticonvulsant actions
[Green et al., 19811 that reduce some of the untoward effects of ketamine.
Chemical restraint combining anesthesia with ketamine and midazolam
appears most useful for IV-GTT in primates, especially when there are long-term
procedures such as intravenous catheterization in frequent sampling IV-GTT
[Toffolo et al., 19801.
Primates also should be restrained physically even under anesthesia to
prevent accidents resulting from unexpected emergence from anesthesia. CRD
restraint offers several advantages; monkeys can be easily and safely observed
through clear acrylic material and can be rotated to the lateral position when
salivation occurs. CRD could be a convenient restraining device when combined
with chemical restraint.
CONCLUSIONS
1. Glucose clearance and insulin secretion appeared to be impaired with the
use of CRD for restraint in IV-GTT.
2. Prolonged restraint with the CRD caused elevations of glucose and cortisol
values in conscious monkeys.
3. Chemical restraint with the use of ketamine or ketamine plus midazolam
had minimal effect on glucose clearance and insulin response in IV-GTT.
4. The addition of midazolam reduced adverse reactions of ketamine and
extended the duration of anesthesia.
5. This drug combination may be useful for other procedures and should be
investigated further.
ACKNOWLEDGMENTS
The authors express appreciation to Jack Wolff for construction of the CRD and
stand. This is publication no. 1547 from the Oregon Regional Primate Research
Center, supported by Animal Resources Branch grant RR-00163 and General
Research Support Grant RR-05694, both from the Division of Research Resources,
NIH. Work from this laboratory was supported by USPHS grants DK-21982,
DK-35870, and RR-05694 and by the Sankyo Co., Ltd., Japan.
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