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Comparison of the furnishings of ketamine and fentanyl-midazolam-medetomidine for sedation of rhesus macaques (Macaca mulatta)

BMC Veterinary Research volume 12, Article number:93 (2016) Cite this article

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Abstract

Background

This study assessed the effects of sedation using a combination of fentanyl, midazolam and medetomidine in comparison to ketamine. Rhesus Macaques (Macaca mulatta), (n = sixteen, five males and 3 females randomly allocated to each treatment group) received either ketamine (KET) (10 mg.kg−one) or fentanyl-midazolam-medetomidine (FMM) (10 μg/kg−1; 0.five mg.kg−one; xx μg.kg−1) both IM. Oxygen (100 %) was provided by mask and heart rate, blood pressure, respiratory charge per unit, EtCO2 and depth of sedation were assessed every 5 min for 20 min. Afterwards the last time signal, FMM monkeys were reversed with atipamezole-naloxone (0.ii mg.kg−i; 10 μg.kg−1). Recovery was scored using clinical scoring scheme. Differences in physiological parameters and quality of sedation were compared using Surface area Nether the Curve (AUC) method and either Mann-Witney or t-pupil tests.

Results

Heart rate (beats/min) (Ket = 119 ± eighteen; FMM = 89 ± 17; p = 0.0066), systolic blood pressure (mmHg) (Ket = 109 ± 10; FMM = 97 ± 10; p = 0.0313), and respiratory charge per unit (breaths/min) (Ket = 39 ± 9; FMM = 29 ± 10; p = 0.0416) were significantly lower in the FMM group. End-tidal COii (mmHg) did not differ between the groups (KET = 33 ± 8; FMM = 42 ± 11; p = 0.0462). Although some low of physiological parameters was seen with FMM, the variables all remained within the normal ranges in both groups. Onset of a sufficient caste of sedation for safe handling was more rapid with ketamine (KET = 2.nine ± 1.4 min; FMM = 7.9 ± i.2 min; p = 0.0009), but FMM recovery was faster (KET = 21.4 ± 13.four min; FMM = 9.1 ± 3.6 min; p = 0.0379) and of better quality (KET = 1.iii ± 0.9; FMM = vii.iv ± 1.9; p = 0.0009) most probably because of the effectiveness of the reversal agents used.

Determination

FMM provides an easily reversible immobilization with a rapid and good recovery quality and may bear witness a useful alternative to ketamine.

Background

Ketamine, a dissociative anaesthetic, is widely used for the chemical immobilization of not–man primates (NHPs). When administered alone it induces a cataleptic state allowing safe handling equally the biting reflex is inhibited [1, 2]. Protective airway reflexes are conserved and voluntary motion can all the same occur. Ketamine has some analgesic activity, allowing minor procedures such as skin suturing to be undertaken just information technology is not suitable as a sole agent for more invasive procedures. Ketamine is an NDMA receptor adversary, and and then should prevent "wind-up" associated with noxious stimuli [3], but this effect has never been assessed in NHPs. Several side effects have been described in primates and other species, including pain on injection, muscular and nervus damage at the site of injection [2, 4–6], and rarely, seizures [7–x]. Recovery delirium also occurs simply this can be reduced by addition of other agents. Despite these problems, ketamine is widely used in primates, primarily considering of its adept condom profile and relative lack of low of the cardiovascular and respiratory systems. For some procedures, a greater degree of analgesia and muscle relaxation would be advantageous. Although this can be achieved by the addition of medetomidine, as in other species, recovery is yet relatively prolonged even after reversal of the medetomidine with atipamezole [eleven]. Replacement of ketamine with agents that have less prolonged depressant furnishings, or are reversible with specific antagonists could therefore exist advantageous. In human medicine, the combination of fentanyl and midazolam has been widely used for witting sedation for minor procedures, and at higher dose rates for surgery [12–fifteen]. Combinations of opioids and benzodiazepines seem to be less effective in Rhesus macaques [sixteen], all the same in other species, addition of medetomidine to these combinations produces fully reversible anaesthesia [17–19] and an initial report suggests this combination tin can be used successfully in non-homo primates [xx].

This study compared the effects of a combination of fentanyl-midazolam-medetomidine (FMM), followed by reversal with naloxone and atipamezole, with ketamine (KET) in rhesus macaques.

Results

Sedation procedure

One female from the KET grouping started to recover 10 min after administration of the anaesthetic and was placed in a recovery muzzle. No physiological parameters were recorded after this time point, only the recovery fourth dimension and the cess of the recovery quality were assessed. All of the remaining primates were successfully immobilized later the administration of either KET or FMM.

Onset of sedation and recovery times

The onset of a sufficient degree of sedation for safe handling was significantly shorter in the KET grouping (2.9 ± 1.four min) than in the FMM group (vii.9 ± one.two min)(p = 0.0009). Recovery was significantly faster in the FMM group (9.1 ± 3.half dozen min) compared to the KET group (21.four ± 13.iv min) (p = 0.0379) (Fig. 1).

Fig. 1
figure 1

Onset of sedation and Recovery times in Rhesus macaques receiving ketamine (north = 8) or fentanyl-midazolam-medetomidine (north = 8) Induction times: Ketamine (KET) 2.ix ± i.4 min; Fentanyl-midazolam-medetomidine (FMM) vii.9 ± ane.2 min. Recovery times: Ketamine (KET) 21.4 ± 13.4 min; Fentanyl-midazolam-medetomidine (FMM) nine.1 ± three.6 min. An asterisk next to a p-value(*p) indicates a significantly differences

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Physiological parameters and depth of sedation

The physiological data are summarised in Table i. Area under the curves (AUCs) comparisons showed significant differences betwixt the two treatment groups. The eye rate (60 minutes) (p = 0.0066), Respiration charge per unit (RR) (p = 0.0416), systolic blood pressure (BPsyst) (p = 0.0313) and the cease-tidal CO2 (EtCO2) (p = 0.0462) AUCs were significantly lower in the FMM grouping. However, no significant difference was found in SpO2 betwixt the two groups (p > 0.one). The overall caste of sedation over the xx min process was deeper in the FMM group with a significantly higher score (p = 0.0009) than the KET group.

Table 1 Physiological parameters recorded over xx min for each treatment group

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Recovery quality

Recovery quality was significantly better in the FMM group after administration of reversal agents, than in the ketamine group, as assessed past both the visual analogue scale (VAS) and the recovery clinical scoring scheme (RCS) (Fig. 2). The Banal-Altman plots demonstrated a not-significant bias of 0.1437 and a reasonably good level of agreement between the two tests (Fig. three). However it also showed a non-homogeneous distribution of the plots that was probably due to the calibration difference between the VAS and the RCS. For the Kappa statistic analysis, the average of the two observers for each subject was used. The comparison of recovery grouping results gave a kappa statistic k = 0.662 with a significance of p = 0.01. According to usual interpretation of this result [21], there was a substantial agreement between the RCS and VAS.

Fig. ii
figure 2

Recovery quality results in Rhesus macaques receiving ketamine (n = viii) or fentanyl-midazolam-medetomidine (n = 8). The histograms stand for the hateful ± 95 % of confidence interval. The results are expressed every bit mean ± 1 SD. RCS: Ketamine 7 ± 2; Fentanyl-midazolam-medetomidine i ± one. VAS: Ketamine 6.2 ± 0.viii; Fentanyl-midazolam-medetomidine 2.2 ± 0.5. An asterisk next to a p-value(*p) indicates a significantly differences

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Fig. 3
figure 3

Bland-Altman plots comparing the quality of recovery in Rhesus macaques receiving ketamine (n = 8) or fentanyl-midazolam-medetomidine (n = viii). The differences between the scores for each method are plotted against the mean of the 2 methods. (b) = bias; (b + 1.96 due south; b – 1.96 s) = Agreement limits. The shaded lines represent the 95 % confidence intervals of the agreement limits

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Discussion

In this report the administration of the FMM combination to rhesus macaques provided a deeper and more reliable sedation and a ameliorate recovery score than ketamine sedation. The impacts of the two regimens on physiological parameters were consistent with the known properties and mechanism of activeness of the agents used.

High ketamine liposolubility results in rapid bioavailability in the cardinal nervous system, resulting in rapid onset of action [22]. This rapid onset of sedation was observed in the present written report and is similar to that reported in previous studies [23–25]. Attainment of sedation sufficient for prophylactic handling was significantly shorter post-obit assistants of ketamine than following FMM, likely due to the dissimilar rates of absorption and distribution of the components of the combination. The onset of a sufficient degree of sedation to allow prophylactic handling later administration of FMM observed in this written report was longer than that reported by Votava et al., using a comparable sedation protocol [xx]. This departure may be due to differences in the doses of the agents used in the two studies and the use of hyaluronidase to speed absorption in Votava study. Recovery time in the FMM group was significantly shorter than the KET group, very likely due to the use of specific antagonists to opposite two of the components used for sedation [26, 27]. We chose not to administer flumazenil to reverse midazolam, since our experience has shown that midazolam has minimal sedative furnishings at the dose used in this species. In this study, because no post-procedural pain was anticipated, naloxone was used to contrary the effects of fentanyl. As an alternative, butorphanol, nalbuphine and buprenorphine have all been shown to be constructive antagonists [28–xxx]. This latter arroyo has the reward of providing continued analgesia following reversal of the fentanyl, because of assistants of agents with either grand agonist/μ antagonist activity, or fractional μ agonist actions. A duration of sedation prior to reversal of the FMM regimen of 20 min was chosen as it represented the mean time that NHPs tin be safely handled nether ketamine sedation [24, 25].

Anaesthetic agents decrease central nervous system activity and the assessment of somatic withdrawal reflexes is generally accepted as a means of assessing anaesthetic depth [iii]. Due to its mechanism of action, ketamine produces a unique cataleptic land, but one which can be considered equally calorie-free sedation based on the degree of suppression of reflex responses (eg withdrawal reflexes) [iii, 4]. Used lone, ketamine increases muscular tone in many species [31–33] but this effect is non as marked in non human primates as in other species [24]. Seizures [seven–10] and tissue necrosis [5, 6, 34] can also occur with ketamine injection. In this study, none of these complications occurred, however 1 of the female primates just remained in lateral recumbency for less than ten minutes post-injection and this has been observed in other studies [24, 25]. Several hypotheses such as the variation of the injection site with incomplete intramuscular assistants, individual variability or a possible acquired tolerance to ketamine [25] can explicate this observation. In this study, the FMM protocol provided a deeper sedation, comparable to surgical anaesthesia. Following completion of this study, nosotros have used the combination to enable intubation as jaw tone is markedly reduced and laryngeal reflexes absent-minded. Nosotros accept also repaired deep and superficial wounds, which resulted from fights betwixt cage-mates.

Pulse oximetry was used successfully to assess oxygen saturation, but this technique can exist compromised by poor peripheral tissue perfusion [two], such as can occur when alpha2 agonists are administered. This was not a problem in the current written report. Systolic claret force per unit area was measured by a non-invasive oscillometric method. The cuff used to measure the claret pressure followed the general recommendation that the cuff width should equal twoscore % of the limb circumference [35]. However, this method has been shown to underestimate systolic and diastolic blood pressures by between five and xx mmHg depending on the cuff location [36–38]. Adequacy of ventilation was assessed using capnography, since this allowed cess of respiratory rate and design and the EtCOii. The EtCO2 is unremarkably measured at the distal extremity of the endo-tracheal tube [39, forty], but in the present written report, the EtCOtwo was measured in the ventral meatus of the nose with a sample line linked to a side stream capnography device. This approach provided a good waveform and is a technique that could be used routinely for anaesthetic monitoring in this and other primate species

However validation of the approach should be performed equally published data comparing the technique are bachelor simply in people [41–44].

The significant differences in cardiovascular and respiratory parameters between the sedation protocols in this study are consistent with the mechanism of activity of the agents used. Ketamine has a minimal touch on on the respiratory arrangement with minimal modification of the ventilation parameters [3]. The breathing charge per unit observed and EtCO2 were similar to those described in a previous study in rhesus macaques just the EtCO2 values recorded were lower [23, 45]. Ketamine affects the cardiovascular system by stimulating the sympathetic pathway and increasing circulating catecholamine concentrations [three]. Centre rate and systolic blood pressure effects were also consequent with the literature [20, 23, 45, 46]. Due to the known mechanisms and interactions of the individual components of the regimen, it was expected the FMM protocol would have more than negative influences on cardiovascular and respiratory functions. Midazolam, has allaying and anxiolytic effects merely minimal effects on cardio-respiratory physiology [3, 4], however medetomidine and fentanyl both depress these organization and their effects are potentiated when they are combined [3]. Although FMM produced a significant decrease of heart charge per unit, systolic blood pressure level and respiratory function, these values stayed within adequate ranges for deeply sedated primates [one, 3]. In that location appears to be no previously published information on the impact of fentanyl-midazolam-medetomidine on these parameters in macaques, but the bradycardia noted in this study was similar to that reported by Votava et al. [xx]. This combination has varying effects in other species. In rats, rabbits, Mongolian gerbils and chinchillas, bradycardia is a consistent finding, whereas furnishings on claret pressure level varied. In dissimilarity to other species in which moderate hypotension was reported, rats developed moderate hypertension [17].

The quality of the recovery was assessed past two methods, a clinical scoring scheme (RCS) and a visual analogue calibration (VAS). The VAS is a subjective single-particular test that in this study was used only to appraise the quality of recovery. VAS assessments are widely used to assess hurting [47], feet [48] and other items [49, 50]. Such systems have the advantage of being quick and easy to perform and also to have good reliability [51]. The clinical scoring scheme used in this study was the first effort to construct and employ a multiple-item test to assess recovery in non-human primates. The scale used was based on the Pediatric Anesthesia Emergence Delirium Scale (PAED) [52, 53]. The items chosen to build the RCS were based on their abilities to evidence modification in cases of excitation or poor recovery and on the facility to observe these modifications. The 2 methods of assessment demonstrated a strong correlation and a strong agreement with a non-significant bias. The video extracts, used for the scoring the quality of recovery, focused on the period around start attempt to sit. This catamenia can be considered a critical betoken in recovery as excitation, ataxia or hallucination tin lead to injury [3, 54]. The study results showed that the recovery quality was significantly ameliorate in the FMM treatment group. In that location are several possible explanations for this consequence. The utilize of specific antagonists in the FMM group may have reversed not simply the allaying effects of the iii components but also their side effects [26, 27]. The poor quality recovery in the ketamine group may have been the results of ketamine's dissociative effects [iii]. Previous studies in dogs and cats, using ketamine, did non report a difference in the quality of recovery compared to other anaesthetic protocols [55, 56]. Withal the administration of ketamine to children and horses prior the end of anaesthesia resulted in a decrease in the quality of recovery in comparison with the use of α2-agonists, benzodiazepine or acepromazine [57, 58].

Decision

In determination, this report demonstrated the efficacy of the combination of fentanyl, medetomidine and midazolam to immobilise rhesus macaques. This regimen offers a potentially useful alternative to ketamine, since specific antagonists can chop-chop reverse it, and this results in a better quality of recovery.

Methods

Animals

The animals were purpose bred for inquiry in the UK, and were supplied from the Centre for Macaques to Newcastle Academy. Animals were housed in a Home Office (United Kingdom authority) accredited facility and in compliance with the Animal Scientific Procedure Act 1986 and the European Directive 2010/63/EU. Rhesus macaques aged from 3 to 10 years and weighing from 4 to 17.7 kg (n = 16, ten males and 6 females) scheduled, in November 2014, for almanac wellness checks and tuberculosis testing were used in this report. The animals were housed at Comparative Biology Center (Newcastle Academy, United kingdom of great britain and northern ireland), in indoor pens with a solid flooring and windows allowing a view on the other pens and the corridors. A minimum flooring surface area 4.xl m2 was provided for each animal or pair of animals. A smaller pen with a squeeze-back system was located between each housing pen. Enrichment devices and substrate for foraging were provided. Animals were maintained on a lite:dark cycle of 12 h:12 h. at a temperature of 22 °C and with 15 air changes per hour and a relative humidity of 24 %. Primates were fed with adjusted old world primate nutrition (Special Diets Service, Witham, Britain) and received tap water ad libitum at the fourth dimension of the study. Forage mix was provided daily to all animals (LBS Biotechnology, Great britain). Except for two males, all the primates were paired-housed. The single housing was due to infrequent circumstances unrelated to the research protocols. The primates had not been sedated or anaesthetised during the 2 weeks prior the start of the report.

Sedation protocols

Animals (five males and 3 females per group) were assigned randomly to receive either ketamine (KET) or Fentanyl-Midazolam-Medetomidine (FMM). Animals were fasted at least 4 h prior to the administration of the sedative agents. Both sedation protocols were administered by intramuscular injection in the femoral quadriceps, the femoral biceps or the gluteal maximus. Ketamine (Ketaset 100 mg/ml Solution for Injection, Zoetis, London, United Kingdom) was administered at the dose of ten mg.kg−i [23, 24]. For the FMM protocol, the dose each drug was determined based on a pilot study (data non reported here). Fentanyl (Fentanyl 50 micrograms/ml, Martindale Pharmaceutical, Romford, Britain), midazolam (Midazolam 5 mg/ml, Hameln pharmaceutical ltd, Gloucester, United Kingdom) and medetomidine (Domitor ane mg/ml, Vetoquinol United kingdom of great britain and northern ireland ltd, Buckingham, Britain) were administered at 10 μg.kg−1, 0.five mg.kg−1 and xx μg.kg−1, respectively. Due to the high injection volume 2 injection sites were used. Midazolam and medetomidine were mixed in the same syringe and injected separately from the fentanyl. When primates lost their righting reflex and could be safely handled, they were carried to a room outside of the NHP unit. At the finish of the process, primates in the KET group were placed in a recovery cage and monitored until the return of the righting reflex. In the FMM group, naloxone at x μg.kg−1 (Naloxone 400 micrograms/ml Solution for injection/infusion, Hameln pharmaceutical ltd, Gloucester, Uk) and atipamezole (Antisedan 5 mg/ml, Vetoquinol UK ltd, Buckingham, United Kingdom) at 0.22 mg.kg−ane were mixed in the same syringe and administered past intramuscular injection 20 min afterward the onset of sedation. Then primates were transferred to a recovery cage and monitored until the return of the righting reflex.

Sedation support and monitoring

Physiological parameters and depth of the sedation were measured every 5 min for 20 min procedure consisting of venous blood sampling, dental examination, an intradermal tuberculosis exam and a complete concrete exam. Animals were placed in lateral recumbency, covered with a forced-air warming blanket ready at 38 °C (Bair hugger model 505, Augustine Medical, USA) and received 100 % oxygen supplementation using a confront mask (2 to 4 litres per min). A Vitalogik 4500 monitoring system (Charter-Kontron Ltd, Milton Keynes, United Kingdom) was used to measure out vital signs. Heart charge per unit (Hour) and oxygen saturation (SpOtwo) were assessed using an absorbance pulse oxymeter probe placed on a finger. Blood pressure was assessed using an oscillometric method with a claret pressure cuff (Critikon Dura-Cuf, GE Healthcare, Hatfield, United Kingdom) appropriate for the size of the animal. The cuff was placed on the opposite arm to that used for pulse oximetry to record the blood pressure from the brachial artery. Two measures were taken at each time point and the mean calculated. The respiration rate (RR) and the end-tidal CO2 (EtCOii), were measured by the side stream gas analyser integrated in the electronic monitoring system. The gas sampling charge per unit was 50 ml/min. A soft neonatal feeding tube with one.7 mm of diameter and 38 cm of length (100 % latex-free Premature Infant Feeding tube, Bard Ltd, Crawley, Uk) attached to the gas sampling line was lubricated with lidocaine gel (Anbesol teething gel, Alliance pharmaceutical, Chippenham, United Kingdom) and gently advanced to a depth of 3 cm into the ventral meatus of i of the nostril (Fig. iv). This operation was repeated at each time point. The depth of the sedation was assessed by a clinical scoring scheme adjusted from previous publications (Table 2).

Fig. 4
figure 4

Respiration monitoring. A soft lubricated tube was inserted in the ventral meatus of ane of the nostril. The tube was linked to a side-stream capnograph providing the visualization of a waveform and finish-tidal CO2 value

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Table 2 Sedation Depth Scoring System. A college score indicates a deeper sedation

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Onset of sedation and recovery times

All of the sedation procedures were videotaped and analysed at a later date. This enabled blinding of the assessor to the treatment given. The time from administration of the allaying to the time at which it was considered that an animal that could exist safely handled was recorded. The recovery fourth dimension was the time betwixt the end of the twenty min procedure and the render of the righting reflex. The stop of the procedure was comparable with the injection of the antidote mix in the FMM group

Recovery quality assessment

Samples of the video-recording from 2 min before to 2 min afterwards the offset effort to sit were selected and the quality of recovery assessed by two treatment-blinded observers using 2 methods. A recovery clinical scoring scheme (RCS) consisting of a multiple-particular list (Tabular array 3) and a visual analogue scale (VAS), with a 10 cm line anchored with "all-time possible recovery" and "worst possible recovery" were used for this assessment. In both scoring schemes, a high score indicated a poor recovery. The observers were veterinary technicians with extensive experience of working with NHPs. Depending on the numeric consequence, each recovery was classified using the categories in Table 4.

Table three Recovery Clinical Scoring Scheme. Organisation based on xv points with the principle that a higher score indicates a poorer recovery

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Table 4 Recovery quality category

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Statistical analysis

For the HR, BPSyst, RR, EtCO2, SpO2 and sedation depth, Area Under the Curves (AUCs) were estimated using the trapezoidal method [59, threescore]. The AUCs normality distribution was assessed using the Shapiro-Wilk test. Student's t test was performed where information were normally distributed; otherwise the Mann–Whitney U test was used.

A Isle of mann–Whitney U examination was used to compare sedation times and recovery times between the two groups and the RCS and the VAS sedation recovery scores. Bland-Altman plots and Kappa statistic methods were used to assess the agreement between the VAS and RCS results.

Statistical analyses were performed with SPSS statistic software (vers. 22, IBM, USA) and Excel (vers. xiv.3.0, Microsoft, USA). A p-value < 0.05 was considered statically significant

Abbreviations

AUC, expanse under the bend; BPsyst, systolic blood pressure; EtCO2, endt-tidal COii; FMM, Fentanyl-Midazolam-Medetomidine; HR, eye rate; IM, intramuscular; KET, ketamine; NHPs, non-human primates; PAED, pediatric anesthesia emergence delirium scale; RCS, Recovery Clinical scoring scheme; RR, respiration rate; VAS, visual analogue scale

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Acknowledgement

Authors tank the primate intendance staff of the comparative Biological science Eye and research administration of the Establish of Neuroscience for their support in the accomplishment of this work. HGMJB would like to thanks Dr Matthew C. Leach for his advices and assistance in data statistical assay.

Funding

No funding was obtained to support this report

Availability of data and material

The information supporting these research findings are contained within the manuscript.

Authors' contribution

HB, YE, SO and PF developed the experimental pattern of the study, performed the sedations, prepared and interpreted data, created tables and figures, drafted and finalized the manuscript. The final version of the manuscript was read and approved past all authors of this study.

Competing interest

None of the authors of this newspaper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper. The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

The use of these animals for research was authorised past the U.k. Dwelling house Part (PPL60/4560; PPL70/7976; PPL60/4041; PPl60/4095), and the Newcastle Animal Welfare and Ethical Review torso. The anaesthetic procedures did not require specific ethical approval equally they were undertaken under the Veterinary Surgeons Act 1966.

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Affiliations

  1. Comparative Biological science Centre, Newcastle Academy, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK

    Henri Chiliad. K. J. Bertrand, Yvette C. Ellen, Stevie O'Keefe & Paul A. Flecknell

  2. Faculty of Veterinary Medicine, Academy of Liège, Boulevard de Colonster, Liège, 4000, Belgium

    Henri Chiliad. M. J. Bertrand

  3. School of Veterinary Medicine and Scientific discipline, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, Great britain

    Yvette C. Ellen

  4. Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK

    Paul A. Flecknell

Corresponding author

Correspondence to Henri G. Grand. J. Bertrand.

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Bertrand, H.G.1000.J., Ellen, Y.C., O'Keefe, South. et al. Comparison of the effects of ketamine and fentanyl-midazolam-medetomidine for sedation of rhesus macaques (Macaca mulatta). BMC Vet Res 12, 93 (2016). https://doi.org/10.1186/s12917-016-0721-9

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  • DOI : https://doi.org/ten.1186/s12917-016-0721-9

Keywords

  • Sedation
  • Ketamine
  • Fentanyl
  • Midazolam
  • Medetomidine
  • Recovery macaque

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