Effects of physical and chemical restraint on intravenous glucose tolerance test in crested black macaques (Macaca nigra).код для вставкиСкачать
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. REFERENCES Abdel el Motal, S.M.; Sharp, G.W.G. Inhibition of glucose-induced insulin release by xylazine. ENDOCRINOLOGY 11623372340,1985. Ausman, L.M.; Gallina, D.L. 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