FUNDAMENTAL

AND APPLIED

TOXICOLOGY

19,64-68 (1992)

Noninvasive Measurement of Blood Pressure in Conscious Cynomolgus Monkeys ANNE E. CHESTER,* ALBERT E. DORR,t KEVIN R. LUND,* AND LARRY D. WOODS *Institute of Toxicologic Sciences, tlnstitute for Research Data Management. and *Institute of Pharmacology. Syntex Research, 3401 Hillview Avenue, Palo Alto, California 94303

ReceivedJuly 22, 199I; acceptedDecember3, 1991

pressure in toxicological registration studies (Hassler et al., 1979). The same limitations apply to telemetry systems, plus, the blood pressure transmitters for large animals are still in relatively early development. The objective of the present studies was to evaluate the reproducibility and accuracy of a device available commercially (Dinamap monitor, Model 1846 SX/P) to noninvasively measure systolic (SP), diastolic (DP), and mean arterial blood pressure (MAP) and pulse rate (PR) in conscious cynomolgus monkeys. Additionally, a 15-min blood pressure recording session was compared to a 5-min recording session. Blood pressure was measured in untreated monkeys for 4 weeks for 15 min three days a week and for 5 min twice a day two times a week. In an additional preliminary study, monkeys were treated with standard drugs known to alter blood pressure. A restraining tube was used in all studies instead of a chair because of our inability to collect blood pressures when monkeys were chair restrained. Health problems are also associated with chair restraint of macaques (Morton et al., 1987). The Dinamap monitor cyclically inflates a cuff that encircles a limb or tail and then initiates a stepped deflation sequence. At the same time, the device records the oscillations of the arterial wall produced by the pulsatile blood flow. As the initial, occlusive pressure drops to equal the systolic blood pressure, oscillations reflecting deformation of the arterial wall begin. The mean arterial blood pressure is the maximum oscillation amplitude. The diastolic pressure is recorded when a sudden decrease in amplitude begins. The peripheral pulse rate is also recorded by the system. Dinamap monitors have been developed for use in humans and laboratory animals. The model designated for laboratory animals (Model 1255) is no longer being manufactured. Model 1255 was reported to accurately measure blood pressure in treated and nontreated conscious beagle dogs for toxicologic research (Pettersen et al., 1988), in treated and nontreated anesthetized dogs (Hamlin et al., 1982), and has been used in chaired pregnant rhesus monkeys (Golub and Anderson, 1986). Studies have compared the results from older Dinamap monitors to direct intraarterial methods in anes-

Noninvasive Measurement of Blood Pressure in Conscious Cynomolgus Monkeys. CHESTER, A. E., DORR, A. E., LUND, K. R., AND WOOD, L. D. (1992). Fundum. A&. Toxicof. 19, 64-68. Systolic (SP), diastolic (DP), and mean arterial blood pressures (MAP) and pulse rate (PR) were recorded on treated and untreated conscious cynomolgus monkeys by the oscillometric method (Dinamap 1846SX/P). Each monkey was placed in a restraining tube with the cuff placed on the base on the shaved tail. Measurements were taken on untreated animals once or twice a day for 4 weeks. The mean and standard deviations for SP, DP, MAP, and PR were approximately 121 + 17,60 f 14, and 84 + 17 mm Hg and 193 + 18 pulses/min, respectively. One male and one female cynomolgus monkey were treated with isoproterenol, norepinephrine, and nitroprusside. Blood pressure was measured indirectly with the cuff on the tail and directly with an indwelling catheter in the descending thoracic aorta. Although the oscillometric method was not as sensitive as the catheter, the oscillometric method detected a change in the same direction of SP, DP, MAP, and PR compared with the direct method for all drugs administered. The monitor was reliable and sufficiently accurate to conclude that it may be useful in toxicology studies for evaluation of blood pressure parameters in conscious cynomolgus monkeys. 0 1992 Societyof Toxicology.

Chronic toxicologic studies in cynomolgus monkeys require noninvasive methods of measuring blood pressure that permit rapid, multiple measurements each day on large numbers of animals during studies that may last for up to 1 year. The invasive techniques commonly used in acute pharmacologic studies require anesthesia and are not applicable. The jacket and tethering system used in conjunction with chronic catheterization has been used in specialized cardiovascular toxicity studies to measure mean blood pressure in conscious rhesus monkeys and baboons (Cornish et al., 1989). The tethering system, however, adds disadvantages of requiring continuous infusion of heparinized saline, a potential for infection (Talan and Engel, 1990), and the need for specially trained technicians. The cost of materials and labor does not allow for the routine measurement of blood 0272-0590/92 $5.00 Copyright 0 1992 by the Society of Toxicology. All rights of reproduction in any form reserved.

64

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thetized and conscious human adults (Loubser, 1986) and infants (Park and Menard, 1987) and found that there was no difference between the Dinamap monitor and direct intraarterial pressures until the systolic pressure was greater than 160 mm Hg. MATERIALS

65

PRESSURE IN MONKEYS

AND METHODS

Materials The Dinamap monitor (Model 1846 SX/P, Critikon, Inc., Tampa, FL) was used with neonatal cuff sizes 3 and 4. The width of the cuff used on each monkey was approximately 60% of the circumference of the tail. The restraining tube (5.5 in. diameter X 2 feet in length) was cut from acrylic cast tubing with 0.25in. wall thickness (Commercial Plastics, Santa Clara, CA). Norepinephrine and nitroprusside were purchased from Sigma Chemical Co. (St. Louis, MO). Isoproterenol was purchased from Aldrich (Milwaukee, WI). Animals Feral cynomolgus monkeys were purchased from Hazleton Laboratory Animals (Alice, TX) and Charles River Primate Corp. (Port Washington, NY). After release from quarantine, the healthy monkeys were individually housed in the colony facilities for at least 4 weeks before assignment to the study. Food (Purina certified primate chow) supplemented with fruit was offered on a standard husbandry schedule. Water was provided ad libitum. The room in which the monkeys were housed was environmentally controlled. Methods Conscious untreated monkeys. SP, DP, MAP, and PR were recorded in four male and four female cynomolgus monkeys over a 4-week period, excluding weekends. During the week prior to the start of the study, monkeys were acclimated to the restraining tube. Each monkey was placed in a horizontal restraining tube with a cuff in place on the tail on at least 3 separate days for 5 min per day. The hair of approximately 2 in. at the base of the tail was clipped just prior to the first acclimatization session and thereafter as needed. During the study, each monkey was placed in a horizontal monkey restraining tube in a quiet room. A towel was placed over the head end of the tube to restrict vision. The blood pressure cuff was placed around the base of the tail. The Dinamap monitor was set to measure blood pressure and pulse rate every minute. On each monkey, measurements were attempted for 15-min periods during the morning on Mondays, Wednesdays, and Fridays and for 5-min periods in the morning and again in the afternoon on Tuesdays and Thursdays (7 sessionsper monkey per week; 28 sessions per monkey). If the monkey was not calm during the recording, the condition and/or the cause of the disturbance (for example, a nearby door being slammed) and the time of the disturbance was recorded. If measurements could not be obtained, a set of procedures was attempted in the following order: (1) reattaching the cuff, (2) moving the cuff slightly higher or lower, (3) repositioning the animal, and (4) using another size cuff. After 5 or 15 min, attempts to record blood pressure were halted. In a number of cases, however, two measurements were recorded for an animal with the same time to the nearest minute. In those situations, the second of two measurements was assumed to have been made 0.5 min later. Body weights were recorded on the first day of the study and weekly thereafter. Clinical observations were recorded at least weekly. Conscious treuted monkeys. Under general conditions described above, on 3 separate days during the week before drug was administered monkeys were acclimated to the restraining tube. Each monkey (one male and one female) was placed in a level restraining tube with a Dinamap monitor cuff placed on the base of the tail. The animals were in the tube for 1 hr the first day, 2 hr the second day, and 3 hr the third day. One monkey was dosed

each day. Approximately 1 hr before the start of the experiment, each animal was sedated with 10 mg/kg ketamine. Using aseptic technique, an incision was made and the femoral artery was cannulated with PE 160. After advancing the cannula into the descending thoracic aorta, the skin was temporarily closed with monofilament nylon sutures. Immediately following the cannulation, the animal was placed in a restraint tube. The indwelling cannula was coupled to a pressure transducer (P23ID Gould Statham). SP, DP, MAP, and pulse rate were recorded continuously on a Gould Series 200 polygraph. Blood pressure was monitored via the direct method until the animal was conscious and blood pressure values had stabilized. Following stabilization, baseline values were collected for approximately 20 min by both the direct and the indirect methods. After baseline measurements were collected, each monkey was infused with isoproterenol (10 min at 0.02 pg/kg/min, followed by 10 min at 0.07 pg/kg/min, followed by 10 min at 0.2 1 &kg/min), norepinephrine ( 10 min at 0.1 &kg/min, followed by 10 min at 0.3 rg/kg/min, followed by 10 min at 1.O&kg/min), and nitroprusside (10 min at 1.Opg/kg/min, followed by 10 min at 3.0 pg/kg/min, followed by 10 min at 10.0 &kg/min). Between administration of each drug, values were allowed to return to a new baseline. Direct and indirect measurements of blood pressure and pulse rate were recorded simultaneously. Monkeys were sedated with ketamine for the removal of the cannulae and allowed to recover.

RESULTS Untreated Monkeys

No clinical observations or body weight data are presented since no changes were associated with the procedures. The oscillometric method successfully recorded a MAP in 1844 of 1849 attempts (99.7%) and a pulse rate in 1827 of 1849 attempts (98.8%). There were 1821 systolic and diastolic measurements recorded, which was 98.5% of the attempts made. The mean (and standard deviation) for each parameter measured is presented in Table 1. Monday, Wednesday, and Friday Data. For each 15 min recording session, the means and standard deviations of blood pressure and pulse rate for all measurements are presented in Table 1 and for each day are presented for males and females in Figs. 1 and 2, respectively. Tuesday and Thursday Data. For each 5-min recording session, the means and standard deviations of blood pressure and pulse rate for all measurements are presented in Table

TABLE 1 Means ? Standard Deviation Blood Pressure (mm Hg) and Pulse Rate (beats/minute)

MWFb TTH’ All data

Systolic

Diastolic

MAP’

Pulse rate

121 f 16 122 f 17 121 + 17

59* 13 62* 15 602 14

83 f 16 85 f 17 842 17

192 f 18 195 zk 18 193 f 18

’ MAP, mean arterial pressure. b MWF, Monday, Wednesday, and Friday data (n = 1237 to 1256 measurements per parameter). ’ TTH, Tuesday and Thursday data (n = 584 to 586 measurements per parameter).

CHESTER ET AL.

66 Monday,

Wedneadey,

Friday

Data

Tuesday,

- Males

Thursday

Data

- Males

50

0

5

10

15

20

25

0

30

5

1'0

1'5

2'0

2'5

3'0

Days

DEiYS

FIG. 1. Mean and standard deviation of blood pressure and pulse rate of four males taken on Mondays, Wednesdays, and Fridays. Recordings were collected for I5 min per day. (0) Systolic pressure, (Cl) diastolic pressure, (0) MAP, (X) pulse rate.

FIG. 3. Mean and standard deviation of blood pressure and pulse rate of four males taken on Tuesdays and Thursdays. Recordings were collected for 5 min in the morning and afternoon of each day. (0) Systolic pressure, AM; (0) systolic pressure, PM; (0) diastolic pressure, AM; @) diastolic pressure, PM; (0) MAP, AM; (+) MAP, PM; (X) pulse rate, AM; (+) pulse rate, PM.

1 and for each day are presented for males and females in Figs. 3 and 4, respectively.

The indirect method detected a change in the same direction of SP, DP, MAP, and PR compared with the direct method. With isoproterenol, both methods generally detected no change in the male and increased SP, DP, and MAP in the female and increased pulse rates in the male and female monkey. With norepinephrine, both methods detected increased SP, DP, and MAP and decreased PR in the male and female monkey. With nitroprusside, both methods detected decreased SP, DP, and MAP and increased PR in the male and female monkey.

Treated Monkeys The oscillometric method recorded blood pressures and pulse rates every 1 min throughout the dosing of the male and female, except once when a systolic and diastolic pressure were not recorded. The mean difference in blood pressure and pulse rate with respect to baseline for each method is summarized in Table 2.

Tuesday, Monday,

Wednesday,

Friday

Data

Thursday

Data

- Females

- Females 250 a25o

200

m z

0 I,150 E

150

5 3 iTi

100

100

50

50 0

0

5

10

15

20

25

30

Days FIG. 2. Mean and standard deviation of blood pressure and pulse rate of four females taken on Mondays, Wednesdays, and Fridays. Recordings were collected for 15 min per day. (0) Systolic pressure, (Cl) diastolic pressure, (0) MAP, (X) pulse rate.

5

10

15

20

25

30

WS

FIG. 4. Mean and standard deviation of blood pressure and pulse rate of four females taken on Tuesdays and Thursdays. Recordings were collected for 5 min in the morning and afternoon of each day. (0) Systolic pressure, AM; (0) systolic pressure, PM; (Cl) diastolic pressure, AM; (m) diastolic pressure, PM; (0) MAP, AM; (+) MAP, PM; (X) pulse rate, AM; (+) pulse rate, PM.

BLOOD

67

PRESSURE IN MONKEYS

TABLE 2 Mean Differences from Predose or Baseline of Blood Pressure (mm Hg) and Pulse Rate (Beats/Minute) SP D

DP IN

MAP

D

IN

PULSE

D

IN

D

IN

95 f 2 2 -1 -3

80+ 10 -10 -2 -11

142?

97 IL 2 2 16 29

79*

147 of 26 5 -14 -34

160 + 17 -20 -34 -52

91 fl -3 -18 -24

71 f 10 -8 -20 -27

140*

138?

7 36 55

8 35 60

89 + 4 8 6 4

72*

12 10 5 11

177+ 7 19 22 12

196k 5 11 13 16

95 * 4 0 0 8

87k 18 -16 -10 7

191 ix 13 0 -8 -28

204 + 8 -10 -25 -43

87 + 4 1 -6 -17

73+ 9 -1 -4 -14

189k 11 11 6 11

191 + 6 I 13 21

Male Isoproterenol Predose 0.02 rg/kg/min 0.07 &kg/min 0.21 rg/kg/min

127k

Baseline 0.10 pg/kg/min 0.30 pg/kg/min 1.OOpg/kg/min

124+

3

2 -4 -7

113 f 3 -6 -6 -11

79 f 2 2 1 -1

108 + 5 1 15 27

83 + 2 1 11 19

54*

7 -5 0 -6

6

8 36 57

1402

6

4 31 64

Norepinephrine 3

6 27 48

54?

6 3 12 20

7 0 13 24

Nitroprusside Baseline 1.O &kg/min 3.0 pg/kg/min 10.0 rg/kg/min

121 + 12 -7 -32 -40

106 + 9 -7 -21 -38

76 + 5 -1 -11 -16

47f

6

-2 -11 -16

8

8

Female Isoproterenol Predose 0.02 pg/kg/min 0.07 pg/kg/min 0.21 pg/kg/min

123rt

5 9 5 5

111 f4 9 5 21

73 XII3 6 6 3

55*

9 7 -I 3

Norepinephrine Baseline 0.10 &kg/min 0.30 &kg/min 1.OO&kg/min

129+

6

0 -2 15

126 f 8 -8 -7 10

77 f 3 1 2 6

61 ?23 -9 -5 3 Nitroprusside

Baseline 1.O &kg/min 3.0 pg/kg/min 10.0 pg/kg/min

118+

5 1

-8 -24

108 + 8 3 -2 -18

71 +4 2 -4 -13

53 f 10 -2 -4 -8

Note. SP, systolic blood pressure; DP, diastolic blood pressure: MAP, mean arterial pressure; D, direct method; IN, indirect method.

DISCUSSION To determine the reliability of the monitor, SP, DP, MAP, and PR were recorded over a 4-week period on untreated conscious cynomolgus monkeys. The monitor consistently obtained highly reproducible blood pressure and pulse rate. Due to the negligible differences between the means and the standard deviations of the data collected on Mondays,

Wednesdays, and Fridays and the data collected on Tuesdays and Thursdays, a 5-min recording session was established as sufficient to collect reproducible data. The measurements collected by the Dinamap monitor were slightly lower than values collected in our catheterized monkeys. Mean arterial pressure averaged 84 mm Hg by the Dinamap monitor and 96 mm Hg by intraarterial catheter. Mean arterial pressures were reported from 110 to 114 mm

68

CHESTER ET AL.

Hg in conscious, chronically instrumented chaired cynomolgus monkeys (Lacour et al., 1989). The oscillometric method, however, measures blood pressure in a smaller artery than that measured by an indwelling aortic catheter and the oscillometric detection device is distant from the monitored artery. Consequently, the two methods would not be expected to yield identical values. To determine the accuracy of the Dinamap monitor, therefore, the change in blood pressure from predose values obtained by the indirect method was compared with the changes in values collected by the direct method. Although the monitor was not as sensitive as the catheter, the Dinamap monitor detected a change from predose values in the same direction of SP, DP, MAP, and PR compared with the direct method for all drugs administered. The differences appeared relatively minor and may be due to the small sample size, the difference in the size of the arteries monitored, or the method of detection. The monitor was reliable and sufficiently accurate to conclude that it may be useful in toxicology studies using cynomolgus monkeys. The advantages of this model include measurement of SP, DP, and MAP, availability of a wide variety of cuff sizes, automatic inflation of the cuff, objective reading of pulses, simple calibration, immediate printout of results with the time of day to the nearest minute, computer/printer access, extensive training of personnel is not required, and it is relatively inexpensive. As a noninvasive method, blood pressure can be measured repeatedly with no surgical intervention.

REFERENCES Cornish, K. G., Barazanji, M. W., Yong, T., and Gilmore, J. P. (1989). Volume expansion attenuates baroreflex sensitivity in the conscious nonhuman primate. Am. J. Physiol. 251, R595-R598. Golub, M. S., and Anderson, J. H. (1986). Adaption of pregnant rhesus monkeys to short-term chair restraint. Lab. Anim. 36, 507-5 11. Hamlin, R. L., Kittleson, M. D., Rice, D., Knowlen, G., and Seyffert. R. (1982). Noninvasive measurement of systemic arterial pressure in dogs by automatic sphygmomanometry. Am. J. Vet. Res. 43, 127 1-1273. Hassler, C. R., Lutz, G. A., Linebaugh, R., and Cummings, K. D. (1979). Identification and evaluation of noninvasive blood pressure measuring techniques. Toxicol. Appl. Pharmacol. 41, 193-20 1. Lacour. C., Cazaubon, C., Roccon, A., Segondy, D., Wagnon, J., and Nisato, D. (1989). Effects of a renin inhibitor, SR 43845, and of captopril on blood pressure and plasma active renin in conscious sodium-replete macaca. J. Hypertens. I, S33-S35. Loubser, P. G. (1986). Comparison of intra-arterial and automated oscillometric blood pressure measurement methods in postoperative hypertensive patients. Med. Instrum. 20, 255-259. Morton, W. R., Knitter, G. H., Smith, P. M., Susor, T. G., and Schmitt, K. (1987). Alternatives to chronic restraint of nonhuman primates. J. Am. Vet. Med. Assoc. 191, 1282-1286. Park, M. K., and Menard, S. M. (1987). Accuracy of blood pressure measurement by the Dinamap monitor in infants and children. Pediatrics 79, 907-9 14. Pettersen, J. C., Linartz, R. R., Hamlin, R. L., and Stall, R. E. (1988). Noninvasive measurements of systemic arterial blood pressure in the conscious beagle dog. Fundam. Appl. Toxicol. 10, 89-97. Talan, M. I., and Engel, B. T. (1990). An improved method for recording blood pressure in the tethered monkey. Am. J. Physiol. 258, RI 5 12R1515.

Noninvasive measurement of blood pressure in conscious cynomolgus monkeys.

Systolic (SP), diastolic (DP), and mean arterial blood pressures (MAP) and pulse rate (PR) were recorded on treated and untreated conscious cynomolgus...
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