Abstract

Alpha₂-agonists produce profound sedation and analgesia by virtue of their ability to modulate neurotransmitter release in noradrenergic and serotonergic pathways of the brain and spinal cord.¹ The most potent and highly selective of the alpha₂-agonists, medetomidine, has recently become available for use in veterinary medicine in the United States. Dexmedetomidine, the D-enantiomer of medetomidine, is currently being investigated for use in human medicine.² Medetomidine alone can be used effectively as a sedative-analgesic in a variety of species, but does not provide complete anesthesia. This has lead to experimentation with a variety of combinations of medetomidine and other classes of injectable agents, including tranquilizers, opioids, and dissociative anesthetics.^2,3 The combinations of medetomidine (30–100 µg/kg) and ketamine (1–8 mg/kg depending on species), and medetomidine (6–50 µg/kg) and Telazol (0.5–6 mg/kg) have been reported to be quite effective in a variety of nondomestic mammals.^4-6 Little is known, however, about the cardiopulmonary effects of these combinations, especially in nonhuman primates.

The purpose of our study was to compare the cardiopulmonary effects of combinations of medetomidine (30–40 µg/kg) and either ketamine (2 mg/kg) or Telazol (1.25 mg/kg) on maintenance isoflurane anesthesia in the chimpanzee.^6,7 In a previous report, we showed in both chimpanzees and gorillas that medetomidine-ketamine provided a rapid induction and smooth transition to a 1-hr period of isoflurane anesthesia.⁸ Blood pressure, heart rate, hemoglobin saturation, and end-tidal CO₂ remained within normal limits throughout this period, and reversal with atipamezole provided rapid and smooth recovery. As the use of medetomidine-Telazol is becoming more popular,⁶ we chose to extend our study by evaluating medetomidine-Telazol under the same conditions.

Thirteen chimpanzees (four juveniles, nine adults) undergoing routine annual (1997 and 1998) physical exams at the North Carolina Zoological Park were included in the study. Medetomidine (10 and 20 mg/ml) and ketamine (200 mg/ml) were purchased separately (Wildlife Laboratories, 1401 Duff Drive, Fort Collins, CO). Telazol (Fort Dodge Laboratories, Fort Dodge, IA) was reconstituted in H₂O (100 mg/ml). The drug combinations were mixed in the same syringe prior to being administered either by hand syringe or by dart (Telinject USA Inc., 9316 Soledad Canyon Rd., Saugus, CA). The combinations were allowed at least 5–10 min to take effect. Animals were then masked with 2–3% isoflurane (IsoFlo, Abbott Laboratories, N. Chicago, IL) in 100% oxygen to permit endotracheal intubation. Following intubation, animals were maintained with 0.5–2.0% isoflurane for the duration of the exam (in most cases 50–60 min) using a non-rebreathing anesthetic circuit. Lactated Ringer’s solution was administered at a rate of 10 ml/kg/hr. To assess the cardiovascular effects of the anesthetic protocols, indirect arterial blood pressure and heart rate were measured oscillometrically (Dinamap Model 8300, Critikon, 4710 Eisenhower Blvd., Tampa, FL) at 3-min intervals beginning at the point where animals became recumbent. To assess respiratory effects, hemoglobin saturation was measured indirectly by pulse oximetry (Model N20, Nellcor, 25495 Whitesell St., Hayward, CA), and end-tidal CO₂ and respiratory rate were measured by mainstream capnography (Model 1260, Novametrix, 3 Sterling Dr., Wallinford, CT). Arterial blood gases were measured with a pH and blood gas analyzer (StatPal SP2-A, PPG Ind., 11077 N. Torrey Pines Rd., La Jolla, CA). At the end of the procedure, isoflurane was discontinued, the animals were placed in a recovery cage, and 2 mg/kg atipamezole (Antisedan, Pfizer, Exton, PA) was immediately given i.m.

Medetomidine-ketamine (M-K) provided sedation within 2–5 min (3.0±1.6 min) and light anesthesia within 3–15 min (juveniles 3.7±1.25 min; adults 11±3.8 min). We found it to be very important that animals be left alone for the initial 10 min, as attempts to move them prior to this could result in rapid arousal. Medetomidine-Telazol (M-TZ) also provided sedation within 2–5 min (3±1.2 min), but a deeper plane of anesthesia was reached more rapidly (7.25±2.25 min). Animals induced with M-TZ were not easily aroused. Once the M-K or M-TZ had taken effect, only 3–5 min of 2–3% isoflurane by mask was required for intubation. Once intubated, an adequate plane of anesthesia (determined as the minimum concentration required to prevent purposeful movement in response to ultrasonic teeth cleaning) was maintained with 1.2±0.7% isoflurane in M-K animals and 0.8±0.2% in M-TZ animals.

Both M-K and M-TZ animals had elevated blood pressures immediately following induction. Average mean arterial pressures were 121±8 mm Hg for M-K animals and 119±11 for M-TZ animals. Blood pressure decreased steadily over the first 10–15 min and then stabilized. At 50 min, M-K animals had, on average, higher mean arterial pressures (89±15 mm Hg) than did M-TZ animals (73±7 mm Hg). Pulse pressure (the difference between systolic and diastolic pressure, a function of stroke volume and vessel compliance) remained essentially constant throughout the procedures and were nearly identical for both groups (at 50 min: M-K, 58±8 mm Hg; M-TZ, 59±11 mm Hg). Heart rates immediately after induction were similar in both groups (M-K, 78±11 beats/min; M-TZ, 83±12 beats/min), and declined gradually over time (at 50 min: M-K, 67±7 beats/min; M-TZ, 68±14 beat/min). Spontaneous respiratory rates remained elevated (at 50 min: M-K, 31±8; M-TZ, 24±5) and constant throughout the procedures. End-tidal CO₂ levels were on average between 37 and 44 mm Hg for both groups and hemoglobin saturation levels were consistently between 93–100%. Arterial blood gas values were within normal limits for those animals tested (four chimpanzees).

Speed and quality of recovery differed markedly between M-K and M-TZ animals. First signs of recovery in both groups occurred within 8–10 min following atipamezole injection. Extubation occurred at this time. M-K animals were fully recovered (standing, alert, vocalizing, climbing) within 10–13 min. M-TZ animals, in contrast, took much longer (3±2 hr) to reach the same end point, and showed signs of extreme drowsiness, dizziness, ataxia, and GI disturbance (vomiting, lack of appetite). Flumazenil (0.025 mg/kg i.v.) was administered to five M-TZ chimpanzees, and though it did transiently increase alertness, it did not significantly enhance the speed or quality of recovery.

Our results provide some insight into the cardiopulmonary consequences of the use of medetomidine-ketamine-isoflurane and medetomidine-Telazol-isoflurane anesthesia in the chimpanzee. Most notably, even at high doses in the chimpanzee, medetomidine, when combined with either ketamine or Telazol, does not appear to provoke the extreme bradycardia that is characteristic of its use in other species. Thus, both M-K and M-TZ given intramuscularly provide a rapid and safe induction in chimpanzees, and allow for a smooth transition to inhalation anesthesia. The cardiovascular data obtained (similar heart rates and pulse pressures in both groups, but significantly lower blood pressures in the MTZ-isoflurane anesthetized animals) suggested that the different drug combinations have similar effects on cardiac output but different effects on systemic vascular resistance. M-TZ appears to potentiate the vasodilatory effects of isoflurane. Our data also suggest that M-TZ has a more potent effect on reducing the MAC (minimum alveolar concentration) value for isoflurane. Thus, though both combinations may be considered safe, M-TZ-isoflurane anesthesia may put animals at risk of severe hypotension if close attention is not paid to the maintenance concentration of isoflurane. This is especially true if changes in posture (such as those required for chest films) occur while the animals are anesthetized. By far, the most dramatic difference between the two anesthetic regimes is the quality of the recovery. M-K recoveries are typically complete within 15–20 min and are without adverse side effects. M-TZ recoveries, on the other hand, may be quite prolonged and accompanied by adverse CNS and GI effects.

Acknowledgments

We thank Wildlife Laboratories for providing concentrated medetomidine, and Dr. W. Karesh and Rochel Laboratories for supplying flumazenil.

Literature Cited

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