Comparison of the Anesthetic and Cardiorespiratory Effects of Medetomidine-Ketamine, Medetomidine-Butorphanol-Ketamine, and Medetomidine-Butorphanol-Midazolam in Ring-Tailed Lemurs (Lemur catta)
Ring-tailed lemurs, Lemur catta, are prosimian primates endemic only to the island of Madagascar. Due to an accelerating rate of natural habitat destruction, they are currently listed as vulnerable to extinction by the World Conservation Union (IUCN).8 Approximately 1,000 captive ring-tailed lemurs worldwide are currently registered with the International Species Identification System (ISIS).8,11 Scientific studies and health management practices aimed at conservation of this threatened species often necessitate the use of anesthetic agents for restraint. Unfortunately, information on the use of anesthetics in lemurs is scarce and mostly limited to brief mention of agents used for field capture, without reference to effectiveness or physiologic response.2,5,6 Very high doses of ketamine (30–35 mg/kg) or tiletamine:zolazepam (20 mg/kg) appear to be necessary for rapid immobilization of lemurs in the wild.5 At these concentrations 3–5-hours recovery times are to be expected (K.E. Glander, personal communication).
The purpose of our study was to evaluate three anesthetic drug combinations as potential replacements for ketamine and tiletamine:zolazepam use in captive and free-ranging lemurs. All three combinations include the potent alpha2-adrenergic receptor agonist, medetomidine, an effective sedative-analgesic agent commonly used in a variety of species.1,9 It is not, however, a complete anesthetic, and therefore must be combined with other drugs to potentiate its effects. Two combinations that have been evaluated extensively in carnivores9,12 and, to some extent, non-prosimian primates,7 are medetomidine-ketamine and medetomidine-butorphanol-ketamine. Medetomidine has been shown to significantly reduce the dosage requirement for ketamine in many species, including great apes,7 while the inclusion of butorphanol in the mixture has been shown to reduce the dosage requirement for medetomidine12. The combination, medetomidine-butorphanol-midazolam, eliminates the need for ketamine, and in dogs, has been shown to create an anesthetic state resembling that provided by inhalation agents.13
Twenty-three captive adult ring-tailed lemurs (ages 3–15 years) undergoing routine annual exams at the Duke University Primate Center were used in the study. Animals were randomly assigned to one of three groups: 1) MK (n=6), medetomidine (Domitor, Pfizer Animal Health, Exton, PA 19341), (40 or 60 µg/kg) three animals at each dose, + ketamine (Ketaset, Fort Dodge Animal Health, Fort Dodge, IA 50501) (3 mg/kg) with atipamezole (Antisedan, Pfizer) (0.2 mg/kg) reversal; 2) MBK (n=9), medetomidine (40 µg/kg) + butorphanol (Torbugesic, Fort Dodge Animal Health) (0.4 mg/kg) + ketamine (3 mg/kg) with atipamezole (0.2 mg/kg) and naloxone (Abbott Laboratories, Abbott Park, IL 60064) (0.02 mg/kg) reversal; and 3) MBMz, (n=8), medetomidine (40 µg/kg) + butorphanol (0.4 mg/kg) + midazolam (American Pharmaceutical Partners, Inc., Los Angeles, CA 90024) (0.3 mg/kg) with atipamezole (0.2 mg/kg), naloxone (0.02 mg/kg), and flumazenil (Romazicon, Roche Laboratories Inc., Nutley, NJ 07110) (0.02 mg/kg) reversal. Individual animals were netted and weighed prior to calculation of dosages. Drugs were mixed in the same syringe and injected into the cranial quadriceps muscle using manual restraint. The animals were then placed in transport kennels and allowed to sit in a darkened room for 10 min while the drugs took effect. Once immobilized, the animals were moved to an examination area for instrumentation.
Physiologic parameters were recorded every 5 min. Indirect mean arterial blood pressure (MAP) and heart rate (HR) were measured oscillometrically (Dinamap Model 8300, Critikon, 4710 Eisenhower Blvd., Tampa, FL 33614) with a size 2 cuff placed just above the tarsus over the anterior tibial or dorsal superficial pedal arteries. A lead II electrocardiogram was recorded continuously (Physio-Control Lifepak 6S Cardiac Monitor, Physio-Control Corp., Redmond, Washington 98052). Oxygen-hemoglobin saturation (SpO2) was assessed by pulse oximetry (Vet/Oxä 4403, Heska Corp., 1801-A Airport Rd., Waukesha, WI 53188), and end-tidal CO2 (ETCO2) and respiratory rate (RR) were measured by sidestream capnography (VetCap 7100, Heska Corp.). A femoral arterial blood sample was taken 30–60 min post-induction for measurement of blood gases and electrolytes using a portable i-STAT clinical analyzer and EG7+ cartridges (Heska Corp.). The following parameters were measured: pH, pCO2, pO2, hematocrit, sodium, potassium, and ionized calcium. HCO3 values were calculated. Animals received reversal agents after 50 minutes of consecutive measurements or when they became sufficiently alert that data collection was no longer possible, whichever came first.
All three anesthetic combinations produced heavy sedation within 3–5 minutes after injection and complete immobilization within 10 min. Their duration of effect, however, varied dramatically. Median working time (time beyond initial 10-minute induction) was 6 minutes (range: 3–16) for the MK group, and 19 minutes (range: 16–47) for the MBK group. Within 5 minutes of being instrumented, five of six animals in the MK group had sufficient voluntary movement and chewing activity that procedures had to be terminated. They were also very rigid and roused more easily than those in the other two groups. MBK animals were relaxed and sedate enough to perform quick procedures within the first 10 min of working time; however, they began to recover quite rapidly shortly thereafter. In marked contrast, the median working time for the MBMz group was 50.5 min (range: 20–58). Six of the eight animals in the group exceeded 50 minutes, at which time they were reversed. These animals had excellent muscle relaxation and more than adequate sedation to perform complete physical exams and dental work over the 50 min of working time.
The cardiorespiratory effects of each of the three drug combinations were very similar. Median HR immediately after instrumentation (t=0) was 154 beats/min (range 100–172) for the MK group, 133 beats/min (range: 88–148) for the MBK group, and 118 beats/min (range: 94–137) for the MBMz group. Median HR remained constant within groups throughout the procedures. No arrhythmias were observed in any of the animals. Median MAP values at t=0 were 115 mm Hg, 106 mm Hg, and 120 mm Hg for the MK, MBK, and MBMz groups, respectively. MAP decreased steadily in all three groups during the first 20–30 min before stabilizing around 70–90 mm Hg. Median RR at t=0 was 58 breaths/min (range: 35–90), 50 breaths/min (range 36–76), and 49 breaths/min (range 25–59) in the MK, MKB, and MBMz groups, respectively. Median ETCO2 at t=0 was somewhat higher in the MBK group relative to the other two groups; 50 mm Hg (range 28–55) for the MBK group compared to 39 mm Hg (range: 37–44) for the MK group, and 40 mm Hg (range 32–46) for animals receiving MBMz. Median ETCO2 values remained consistent within a given group throughout each procedure. SpO2 values at t=0 were 94% (range: 93–99), 95% (range: 88–100), and 96% (90–98) in the MK, MBK, and MBMz groups, respectively. Median values for each group remained within the 94–99% range at each time point throughout the procedures. PaO2 values were within the range of 80–111 mm Hg, 57–109 mm Hg, and 67–91 mm Hg in the MK, MBK, and MBMz groups, respectively, in good agreement with predicted PaO2 values based on SpO2 readings. Measured PCV, Na+, K+, and Ca2+ values were similar among all three groups, ranging from 41–53%, 146–153 mmol/L, 3.3–4.6 mmol/L, and 0.99–1.23 mmol/L, respectively. Measured pH and HCO3- values were also similar among groups, ranging from 7.29–7.4 and 20–27 mmol/L, respectively.
All animals in each of the three groups were given reversal agents irrespective of their level of sedation. Atipamezole and naloxone were administered by intramuscular injection and flumazinil by intravenous injection. Significant differences in the quality of recovery were observed between animals in the three groups. Animals in both the MK and MKB groups appeared dazed, showed uncoordinated, jerky muscle movements, and salivated excessively for up to 45 min post-reversal. In contrast, animals in the MBMz group exhibited normal posture, coordination, and grooming behavior within 10 min of reversal.
From a physiologic standpoint, all three drug combinations may be considered safe to use, and recovery times for each combination were much shorter than those reported for ketamine and tiletamine: zolazepam in arboreal primates.4,6,10 From a practical standpoint, however, only the MBMz combination can be considered a reasonable substitute, as it was the only combination that provided the working time typically needed to perform routine field procedures. The short duration of action of MK in lemurs relative to larger primates,7 is likely explained by the fact that smaller primates have a higher metabolic rate3. The effectiveness of MBMz can be explained by the synergy of three different receptor agonists (alpha2-adrenergic, opioid, and GABAA) working together to provide controllable (and reversible) CNS depression. Further experiments are required to evaluate the effectiveness of MBMz in the field.
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