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J Am Assoc Lab Anim Sci. Jan 2010; 49(1): 57–63.
Published online Jan 2010.
PMCID: PMC2824969

Comparison of the Effects of Ketamine, Ketamine–Medetomidine, and Ketamine–Midazolam on Physiologic Parameters and Anesthesia-Induced Stress in Rhesus (Macaca mulatta) and Cynomolgus (Macaca fascicularis) Macaques


This study compared the cardiovascular, respiratory, anesthetic, and glucocorticoid effects of ketamine alone with ketamine–medetomidine and ketamine–midazolam in rhesus and cynomolgus macaques. Macaques were given either intramuscular ketamine (10 mg/kg), intramuscular ketamine–medetomidine (3 mg/kg; 0.15 mg/kg), or oral midazolam (1 mg/kg) followed by intramuscular ketamine (8 mg/kg). The addition of medetomidine, but not midazolam, provided muscle relaxation and abolishment of reflexes that was superior to ketamine alone. In addition, medetomidine did not cause clinically relevant effects on cardiovascular and respiratory parameters when compared with ketamine. These 3 protocols did not have significantly different effects on fecal glucocorticoid metabolites. These results suggest that medetomidine can be a valuable addition to ketamine for healthy patients, whereas oral midazolam at the tested dose does not provide additional benefits.

Abbreviations: KetMed, ketamine–medetomidine, KetMid, ketamine–midazolam, NHP, nonhuman primates, PaCO2, arterial partial pressure of carbon dioxide, PaO2, arterial partial pressure of oxygen, SO2, oxygen saturation of hemoglobin, SaO2, arterial oxygen saturation, SpO2, peripheral oxygen saturation, T, time

Ketamine hydrochloride is commonly used as a sole anesthetic agent in nonhuman primates (NHP) but has several drawbacks that could be ameliorated by combining it with other agents. First, animals sedated with dissociative anesthetics retain their reflexes and can exhibit varying amounts of skeletal muscle movement and, rarely, seizure activity.46 This propensity raises concerns about personnel safety when working with animals carrying zoonotic infectious agents. In addition, excessive movement creates challenges when performing certain tasks such as tuberculosis testing or when monitoring animals for appropriate anesthetic depth during minor surgical procedures.55 Second, the analgesic properties of ketamine in NHP are unknown. Ketamine generally is considered to be satisfactory for somatic analgesia but inadequate for deep or visceral pain. However, analgesic effects can differ widely between species, and the few studies available show variable results even for minor procedures in NHP.21,28,53 In addition, ketamine is associated with pain on injection and volume-dependent tissue damage in many species7,17,18,46,55 and can cause severe psychomimetic side effects such as hallucinations and delirium in people.29,44 Although we cannot know whether ketamine causes excessive psychological stress in NHP, policies of the Public Health Service and Animal and Plant Health Inspection Services establish a precedent for assuming that procedures affect animals as they do human beings unless there is evidence to the contrary.3,43

Medetomidine and midazolam are 2 agents that are often combined with ketamine to improve anesthesia.15,24,27,33,40,49,50,54,58,59 Medetomidine is a selective α2-adrenergic agonist that is a racemic mixture of 2 optical enantiomers, the active dexmedetomidine and the inactive levomedetomidine. Although the primary benefit of α2 agonists is improved muscle relaxation, they also provide documented analgesic effects in many species, including humans and NHP.10,11,23,35,46,57 In addition, reversal of the medetomidine with atipamezole can decrease recovery time and reverse sedation if unacceptable side effects occur.55 As a benzodiazepine, midazolam can be expected to offer additional sedation and muscle relaxation to ketamine anesthesia.45 In addition, the use of medetomidine or midazolam may accommodate a decreased dose of ketamine, thus reducing tissue necrosis and inflammation.55

In addition to the physical benefits of medetomidine and midazolam, these drugs may help attenuate anesthesia-related stress responses. In dogs, medetomidine decreases the stress-related hormonal changes that occur with ketamine alone.1 Human physicians often use benzodiazepines to decrease psychotic events, anxiety, and nausea, particularly when ketamine is used.8,9,19,22,29,44 In NHP, premedication with midazolam may decrease the stress associated with injection and the possible psychologic effects associated with ketamine. These potential benefits are difficult to measure in animals, but various methods have been used in an effort to quantify the stress associated with anesthesia in NHP.2,14,51,63 Food intake and urinary cortisol are affected significantly by ketamine anesthesia in macaques.14,51 Fecal cortisol is gaining popularity as a noninvasive way to evaluate the hormonal impact of a variety of situations, including restraint and sedation.20,38,41,48,56,61,63 For example, fecal cortisol increased significantly in chimpanzees 2 d after sedation.63 Although cortisol was the first hormone measured in fecal samples, a fecal corticosterone assay has been developed that measures glucocorticoid metabolites in primate fecal samples with less variable results than those of fecal cortisol assays.60,62 Although any anesthetic episode may create stress, whether particular drugs or injections in an unsedated animal are exacerbating factors is unclear. We therefore used the glucocorticoid assay to compare 3 different anesthesia protocols.

The purpose of this study was to determine whether medetomidine or oral midazolam could provide a deeper level of anesthesia in macaques than ketamine alone with comparable safety. In addition, we sought to determine whether either of these medications, particularly premedication with midazolam, attenuated the glucocorticoid response associated with anesthesia.

Materials and Methods

Humane care and use of animals.

Animals were housed in an AAALAC-accredited facility and in compliance with the Guide for the Care and Use of Laboratory Animals.31 All research procedures involving animals were approved by the Institutional Animal Care and Use Committee at Emory University.


This study used 23 macaques scheduled for semiannual tuberculosis testing and physical exams. The population was composed of 5 male cynomolgus macaques (Macaca fascicularis), 8 male rhesus macaques (Macaca mulatta), and 10 female rhesus macaques. Ages ranged from 6 to 17 y, and all animals have been at the institution for at least 3 y. The animals were housed in stainless steel NHP cages with a squeeze-back mechanism in a room with a 12:12-h light:dark cycle. They were fed a standard commercial primate chow (LabDiet 5037, Purina, St Louis, MO) and filtered water was available ad libitum. Twelve animals were pair-housed with full contact between animals, and the remaining were single-housed in rooms with visual but no physical contact between conspecifics. Cages were not changed, nor was there any other experimental manipulation by laboratory personnel for any animal in the room during the week that the study was conducted.

Sedation procedures.

Animals were assigned randomly to 1 of 3 treatment groups (Figure 1). The doses for the ketamine–medetomidine (KetMed) group were chosen based on a previous study.55 For the KetMed group, atipamezole was administered after the arterial blood sample was obtained (described following). The 2 other groups were given an equivalent volume of normal saline to serve as a placebo reversal agent at a corresponding time. For the ketamine–midazolam (KetMid) group, cherry-flavored oral midazolam (Versed 2 mg/mL, Ranbaxy Pharmaceuticals, Jacksonville, FL) was administered 20 to 26 min before the ketamine injections. Oral midazolam was mixed with a cherry-flavored liquid drink (Kool-Aid, Kraft Foods, Northfield, IL) and frozen in paper cups the afternoon prior to the procedure, less than 24 h prior to administration. The 2 other groups received an equivalent volume of the frozen flavored drink without midazolam. To minimize the effect of natural daily cortisol fluctuations by limiting the time frames for sedation, the study was conducted on 3 consecutive Wednesdays at the same time each day. The animals were housed in 3 separate rooms, and an entire room was assessed each day. Treatments were randomized across days, investigators, rooms, sex, social housing status, species, and order of sedation.

Figure 1.
Experimental groups for sedation protocols.

Cardiorespiratory parameters.

When macaques became laterally recumbent after injection, they were moved to an adjacent room and immediately placed in dorsal recumbency for the study. Heart rate, respiratory rate, blood pressure, and peripheral oxygen saturation (SpO2) were measured at 0 (time 0, T0), 10 (T10), and 20 (T20) min. T0 measurements were recorded within 5 min of lateral recumbency, and T0 served as the reference time for subsequent measurements and data collection. Indirect blood pressure was obtained by using Doppler ultrasonography on the tail with a cuff width approximately 40% of the tail circumference. Because of the difficulty of obtaining a reliable blood pressure reading in 4 animals, values from those animals were obtained from a limb by using a cuff that was 40% of the limb circumference. The systolic blood pressure was measured twice and an average was determined. Pulse oximetry with the probe placed on the ear or the tongue, depending on where consistent readings could be obtained, was used to determine peripheral partial oxygen pressure (SpO2) and heart rate. A blood sample was obtained from the femoral artery at T20, and blood gases were measured immediately by using a portable machine (iSTAT, Heska, Loveland, CO). Animals were excluded from analysis for particular time points and blood gases if samples could not be obtained (for example the animal was too awake to allow safe sampling or a venous sample was obtained). In addition, due to inability to safely obtain a blood gas sample from half of the monkeys in the KetMid group, this group was not included for blood gas analysis.

Depth and duration of anesthesia.

Induction time was calculated as the time from anesthetic injection until the time the macaque was laterally recumbent. The time for recovery was determined for the KetMed group and was calculated as the time from the injection of the reversal until the animal was sitting upright. The parameters for the depth of anesthesia were measured at times T0, T10, and T20 concurrently with cardiorespiratory parameters. The measurements included reflexes (pedal and palpebral) and myorelaxation (jaw tone, spontaneous movement, limb manipulation). The pedal reflex was assessed by pinching a toe with hemostats and the palpebral by applying light digital pressure to the medial canthus. For limb manipulation, the observer lifted the limb with 1 hand and let it fall into his other hand. Animals were assigned a score by the same blinded observer for all parameters (Figure 2), with some of the parameters based on a scoring system from a previous study for comparison.55

Figure 2.
Scoring system for parameters of anesthetic depth. In addition, animals received a score of 1 if they were too awake to the test to be performed.

Fecal collections.

For all fecal sample collections, pans were cleaned between 1600 and 1700, and feces were collected the following morning between 0700 and 0800. Presedation samples were collected the day prior to anesthesia. Postsedation samples were collected 24 to 36 h after sedation. Lake pigments (FD and C Yellow Alum 5 24% to 28% or Blue 1 Alum 11% to 13%, Sensient Food Colors North America, St Louis, MO) were used to identify fecal samples in pair-housed animals. Fruit treats with approximately 200 mg pigment were given every 12 h starting 36 h before each fecal collection, with the last pigment given 12 h prior, for a total of 3 administrations per collection. All other animals in the same treatment day were given fruit without pigment at corresponding times. To avoid an additional source of stress, paired animals were not separated to receive treats. They were observed until they had consumed the entire treat to ensure that the appropriate animal ate the pigment. The same person distributed all of the treats and collected all of the fecal samples. Samples were not collected if there was evidence of urine contamination. As noted in prior studies, blue pigments were distinct by visual inspection but the yellow pigments required the use of a microscope for identification.52 Samples were stored at –80 °C until analysis.

Fecal corticosterone radioimmunoassay.

Samples were submitted to the Laboratory of Reproductive Ecology and Environmental Toxicology (Emory University). The corticosterone assay is a modification of a commercially available kit (125I Double Antibody Corticosterone Kit, MP Biomedical, Solon, OH). Corticosterone standards were diluted 1:3 with working buffer (0.1% gelatin in PBS) to give concentrations of 0 to 1670 pg/mL for standards. In addition, controls were diluted 1:3, giving high and low ranges of 1115 to 2359 pg/mL and 314 to 516 pg/mL, respectively. Samples (0.1 mL) were dried down in a 37 °C warm bath and then reconstituted with working buffer (0.25 mL). On reconstitution, 0.1 mL of each sample was aliquotted in duplicate to appropriate tubes. Standards and controls were apportioned the same way, and 0.3 mL buffer only was placed in each of 2 tubes for measuring nonspecific binding. Corticosterone 125I tracer (0.050 mL) was added to all tubes (total count, nonspecific binding, standards [1:3], controls [1:3], and samples [1:3.5]). Next, 0.2 mL corticosterone antiserum (diluted 1:3 with working buffer) was added to standards, controls, and samples. After all tubes were vortexed for 10 s and incubated at room temperature for 2 h, 0.5 mL diluted (1:3) precipitating reagent was added to all tubes except total counts. Tubes were incubated at room temperature for 15 min, centrifuged for 30 min, and decanted, blotted, and counted for 5 min in a gamma counter (RIAStar, Packard, Downers Grove, IL) by using RIASmart and Expert QC software (Packard).

Statistical analysis.

Analyses were performed by using the SigmaStat 2.03 software package (Jandel, San Rafael, CA). Heart rate, respiratory, rate and blood pressure were compared between groups at each time point, and induction times were compared between groups by using 1-way ANOVA with posthoc Tukey tests as needed. Arterial partial pressure of carbon dioxide (PaCO2) and PaO2 were compared between the KetMed and Ket groups by using Student t tests. Two-way ANOVA with a repeated measure on 1 factor was used to compare SaO2 and SpO2. Scores for depth of anesthesia were evaluated between groups at each time point by using Kruskal–Wallis ANOVA, with Dunn posthoc analysis when needed. To evaluate fecal glucocorticoid metabolite levels, 1-way ANOVA was used to compare the percentage change from baseline between groups. A P value of less than 0.05 was considered significant. Data are expressed as mean ± SEM.


Sedation procedures.

All of the macaques readily accepted the frozen premedication and placebo formulations, and observers verified that the items had been ingested prior to injection for sedation.

Cardiorespiratory status.

Compared with that in the Ket group, PaCO2 was significantly (P = 0.005) higher for the KetMed group (Table 1). Heart rate was significantly lower for the KetMed group than the other 2 groups at T0 (F[2,20]=11.458, P < 0.001; Table 2), T10 (F[2,19]=11.052, P < 0.001), and T20 (F[2,15]=10.162, P = 0.002). The groups showed no significant differences at any time point for PaO2, respiratory rate, or blood pressure. The SpO2 was significantly (F[1,15]=20.579, P < 0.001) lower than the SaO2 with no treatment effect.

Table 1.
Respiratory parameters
Table 2.
Cardiovascular parameters for the 3 sedation protocols

Depth and duration of anesthesia.

Induction time (mean ± SEM) did not differ significantly among groups (KetMed = 3.1 ± 0.4 min, KetMid = 3.7 ± 0.7 min, Ket = 3.7 ± 1.1 min). For the KetMed group, time for recovery after anesthetic reversal was 8.7 ± 1.8 min. For measurement of anesthetic depth (Table 3), scores for jaw tone were significantly higher (indicating less movement) for KetMed macaques than other treatment groups at T0 (P = 0.002), T10 (P < 0.001), and T20 (P < 0.001). In addition, the KetMed group had significantly higher scores than the other 2 groups for spontaneous movement at T10 (P = 0.002) and T20 (P < 0.001) but not at time T0. Palpebral reflex scores were significantly higher for KetMed than KetMid at T0 (P = 0.012) and higher for KetMed than both other groups at T10 (P < 0.001) and T20 (P < 0.001). Limb manipulation scores were higher for KetMed than KetMid at T0 (P = 0.004) and T10 (P < 0.001) and higher than both groups at T20 (P < 0.001). Pedal reflex scores were higher for KetMed than KetMid at T0 (P = 0.005) and T10 (P < 0.001), but there was no significant difference at T20.

Table 3.
Scores for depth of anesthesia

Fecal corticosterone assay.

The percentage increase for fecal glucocorticoid values after sedation was 0.09% ± 0.18% (n = 6) in the KetMid group, (0.40% ± 0.34% (n = 6) in KetMed animals, and 0.21% ± 0.14% (n = 7) in the macaques given Ket only; these values were not statistically different. Two macaques were excluded from sample collection because they were pair-housed and 1 ate part of a pigment-containing treat intended for the other and because a urine-free sample could not be obtained at 1 time point.


In this study, the combination of ketamine and medetomidine provided deeper anesthesia more reliably than did ketamine alone, without negative effects on cardiorespiratory status or induction and recovery times. The induction times and prompt recovery after reversal of medetomidine of the current study are consistent with findings of previous studies.55 The ketamine–medetomidine combination is reported to last approximately 71 min without reversal, but animals in this study recovered after an average of approximately 8 min after reversal.55 During the 20- to 25-min observation period of our study, KetMed provided greater muscle relaxation and less reflex movement than did ketamine alone. The greater number of parameters with significant differences at 20 min is likely due to the short-acting nature of ketamine. In addition, scores for KetMed at T0 and T10 were higher for some parameters but were skewed by 1 macaque that did not become as sedate as the rest of the group. This unexpected response to medetomidine could be due to either individual variation or inadvertent subcutaneous administration. The absorption of α2 drugs from subcutaneous tissue is unpredictable, and delayed absorption would explain how this animal's scores became progressively higher.46 Another possibility is that our scoring system is not sensitive enough to detect a difference. However, if the data are considered as a whole, an idiosyncratic response of 1 subject is more likely.

Our results pertaining to depth of anesthesia are consistent with the mechanism of these drugs and in agreement with prior studies.55 When used as a sole agent, ketamine generally is expected to cause variable unconsciousness and stage 2 anesthesia in most species.36,46 Even though ketamine usually provides more reliable sedation in NHP than other species, all animals still retain their reflexes. In addition, some subjects have pronounced movement or need frequent redosing. In contrast, α2 agonists cause CNS depression and muscle relaxation. These results are consistent with another study55 that found improved muscle relaxation in macaques by adding medetomidine. Although the authors of another study67 concluded that ketamine–medetomidine did not provide reliable sedation in rhesus macaques, they used much lower doses of medetomidine and similar doses of ketamine as those we used here.

In contrast to adding medetomidine, the addition of midazolam did not improve muscle relaxation. In fact, 4 of 8 animals in the KetMid group were too awake at various time points to yield samples for cardiovascular parameters or blood gases. This situation indicates that the midazolam dose (1 mg/kg) at the route of administration (oral) we used may not provide adequate sedation. Our observed lack of efficacy of midazolam likely is not due to degradation because the drug is stable when frozen for at least 24 h.68 We chose this dose because it had been used in a previous study without negative consequences.47 Although that study noted that oral ketamine and midazolam did not reliably provide good sedation, we expected that we could achieve better sedation by using intramuscular ketamine.47 In addition, the commercially available pediatric solution is palatable, but increasing the dose significantly increases the volume required because of its low concentration. Although our midazolam dose was higher than both the oral dose in children and the intramuscular dose in NHP, the increase does not appear to have been sufficient to overcome the decreased oral bioavailability of this drug in macaques.42 Potentially, doses as high as 3 mg/kg may be useful before sedation in NHP and warrant further study.16,47

Similar to other studies in primates, the reduced heart rate caused by medetomidine did not have a clinically relevant effect on blood pressure, and the average blood pressure for all groups was within reported normal ranges for macaques. Systolic blood pressures in lightly anesthetized macaques have ranged from 95 to 164, but averages were less than 140.12,25,64 Depending on the species, the initial vasoconstriction from medetomidine causes a normal to high blood pressure, but the reflex bradycardia leads to normal to low blood pressure. Although we noted reflex bradycardia in our study, the resulting blood pressure was not significantly different from that with ketamine alone. In contrast to medetomidine, ketamine has cardiovascular stimulating effects that can increase heart rate and blood pressure, but previous studies30 have shown that ketamine alone does not significantly alter mean arterial pressure in rhesus. The combination of ketamine and medetomidine maintained normotension when tested in tamarins, ring-tailed lemurs, and patas monkeys.32,49,65 In addition, a prior study67 in macaques showed that ketamine–medetomidine caused blood pressures similar to that of ketamine, but lower doses of medetomidine were used. Medetomidine reportedly decreases blood pressure in some NHP,5,11 but it was given intravenously and as the sole agent in those studies, and ketamine may ameliorate the hypotensive effects of medetomidine.

The indirect technique used to measure blood pressure in this study likely underestimated actual values. We chose indirect methodology to make efficient use of time because of the short-acting nature of ketamine. We followed the standard recommendations for a cuff size that has a width that is 40% of limb circumference.13,26 We chose the tail because this location was previously described for the published ranges for blood pressure, although limbs are used often in practice.12,25,64 In humans, systolic blood pressure values obtained by using indirect methods in normotensive and hypertensive patients can be approximately 20 mm Hg lower than those obtained by using direct techniques, even with recommended the cuff size.37 This outcome is consistent with studies in macaques, which indicate that indirect methodology often underestimates blood pressure measurements by direct methods by 5 to 20 mm Hg.12,64 Furthermore, because these effects can be more pronounced with vasoconstriction, the blood pressure values obtained from the KetMed group may have been affected differentially and underestimated.

Compared with ketamine, ketamine–medetomidine had no clinically relevant effect on PaO2 and PaCO2. The KetMed group showed a trend toward increasing PaCO2 compared with the Ket group (Table 3), but all values were within the normal range of 35 to 45 mm Hg. Although the PaO2 values were not significantly different between these groups, both included animals with hypoxemia of potential clinical significance. The normal PaO2 for an animal spontaneously breathing room air is 80 to 110 mm Hg, with hypoxemia generally defined as less than 70 to 80 mm Hg.39 Both groups had 1 animal with values in the 60s, and PaO2 less than 60 mm Hg is commonly selected value for symptomatic therapy.26 Medetomidine alone usually does not significantly affect blood gas values and causes less respiratory depression than isoflurane. However, medetomidine tends to cause mild hypoxemia (60 to 70 mm Hg) and elevated PaCO2 when combined with other drugs such as ketamine.36 In some species, ketamine alone also can induce transient hypoxemia.36 Previously reported values for PaCO2 and PaO2 in rhesus macaques after 30 min of ketamine anesthesia were similar to those in our study and were not significantly different from values in monkeys sedated with pentobarbital and propofol.30 The respiratory effects we observed are commonly associated with injectable anesthesia and are typically well tolerated in healthy animals. We do not know whether animals would have developed progressive hypoxia or hypercapnia after 20 min. As with any injectable anesthetic protocol, the clinician should consider providing supplemental oxygen or measure blood gases during prolonged injectable anesthesia.

Arterial blood gases, particularly PaO2 and PaCO2, were measured in our study because of the insensitivity and inaccuracies that can be associated with SpO2. The percentage of oxygen saturation of hemoglobin (SO2) is not as sensitive as PO2 because of the sigmoidal relationship between these values, such that small changes in SO2 above 90% correlate with much larger changes in PO2. For example, a PO2 of 100 mm Hg correlates with an SO2 of 98%, whereas a PO2 of 60 mm Hg correlates with an SO2 of 90%. SpO2 can be inaccurate due to diverse factors, including tissue characteristics, pulsatile flow patterns, motion, and characteristics of the particular machine and the formula it uses to calculate the value.26 The accuracy is best within the range of 80% to 95%, and when inaccurate, the readout usually is lower than the actual value.26 In addition, vasoconstriction can alter pulse oximetry accuracy,26 so we predicted that SpO2 would be particularly unreliable in the KetMed group. However, in our study SpO2 was consistently lower than SaO2, with no effect of treatment group.

With regard to fecal corticosterone levels, variation between subjects was considerable, and the groups did not vary significantly. Reasons for this negative finding include the lack of a true difference, insensitivity of the assay to differences among the anesthetic protocols and inherent sampling errors for larger animals, which produce feces less frequently than do rodents (for which the test was developed). Given the lack of relaxation with midazolam in our study, the dose likely was insufficient to affect glucocorticoid production and excretion. The time frame we used for fecal sample collection should provide the most accurate reflection of the glucocorticoid levels associated with sedation, based on both laboratory and field studies.6,63 The pigments used to identify the sources of the samples have been used in prior studies and should not have interfered with the test.52 Attempts were made to minimize variability with sample collection, but further studies are required to determine whether this test is useful for comparing anesthetic protocols in larger species such as primates.

The results of our study suggest that the addition of medetomidine can provide considerable benefits to ketamine anesthesia for healthy macaques. In addition, lower doses of medetomidine are clinically useful in combination with higher doses of ketamine or with other sedatives and analgesics.32,34,35,49,65 Potentially, these drugs might even be administered orally, but preliminary studies have shown mixed results.47,66 Ketamine is widely used as a sole agent because it provides safe, often reliable short-term anesthesia in NHP. Although combination with medetomidine will not replace the use of ketamine only, medetomidine–ketamine may be particularly useful for minor surgical procedures or those of variable duration, such as digit amputations and radiographs. In addition, medetomidine may be a useful adjunct to anesthesia as a continuous-rate infusion because perioperative use of dexmedetomidine in humans decreases anesthetic requirement, opioid use, and even mortality and ischemia associated with some procedures.23 Injectable midazolam has been a valuable adjunct to ketamine in NHP, and further research is needed to determine potential benefits of oral midazolam.4


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