Evaluation of the anaesthetic effects of medetomidine and ketamine in rats and their reversal with atipamezole

ObjectivesTo compare the anaesthetic effects of varying doses of medetomidine (MED) combined with ketamine (KET) in rats, and to determine the efficacy of atipamezole (ATI) in the reversal of these effects using electroencephalogram (EEG) and assessment of clinical parameters.Study designProspective, randomized experimental trial.AnimalsTwenty-one male Sprague–Dawley rats weighing 300–398 g and aged 8–11 weeks old.MethodsThree groups received intraperitoneal injections of MED (0.2, 0.4 or 0.8 mg kg^?1) with KET (60 mg kg^?1) (MED-200, MED-400 and MED-800). Atipamezole, at doses five times higher than the previous dose of MED, was then administered intraperitoneally 70 minutes after MED-KET injection. The EEG band powers and spectral edge frequencies (SEFs), respiratory rates, reflex scores to toe-web clamping and behavioural changes were measured. Correlations between EEG parameters and reflex scores were also evaluated.ResultsThe duration of surgical anaesthesia was directly proportional to the dose of MED. Lower frequency bands (δ1 to α2) increased in all groups, and these changes were reversed by ATI. Minimal changes were observed in the higher frequency bands (β1 to γ), but their powers were increased by ATI. The SEFs were decreased in all groups, and they were reversed by ATI. While α1 band power and SEF95 showed strong correlations with the depth of anaesthesia, their changes appeared before the measured decreases in reflex score. Recovery from anaesthesia was extended by increasing the dose of MED.Conclusions and clinical relevanceSpectral EEG parameters may not accurately predict the depth of surgical anaesthesia because they had already changed during the induction of surgical anaesthesia. The ATI dose used in the present study may not be enough for complete reversal of anaesthesia induced by MED-KET.     

Comparative study of three intramuscular anaesthetic combinations (medetomidine/ketamine, medetomidine/fentanyl/midazolam and xylazine/ketamine) in rabbits

OBJECTIVE: To compare the quality of surgical anaesthesia and cardiorespiratory effects of three intramuscular (IM) anaesthetic combinations in rabbits. STUDY DESIGN: Prospective randomized cross-over experimental study. ANIMALS: Nineteen adult female chinchilla mixed-bred rabbits weighing 3.9 +/- 0.8 kg. METHODS: Rabbits were given one of three IM anaesthetic combinations: 0.25 mg kg(-1) medetomidine and 35.0 mg kg(-1) ketamine (M-K), 0.20 mg kg(-1) medetomidine and 0.02 mg kg(-1) fentanyl and 1.0 mg kg(-1) midazolam (M-F-Mz) and 4.0 mg kg(-1) xylazine and 50 mg kg(-1) ketamine (X-K). The effects of anaesthesia on nociceptive reflexes, circulatory and respiratory function were recorded. Statistical analyses involved repeated measures anova with paired Student's t-test applied post hoc. P-values <0.05 were considered as significant. RESULTS: Reflex loss was most rapid and complete in M-K recipients, whereas animals receiving M-F-Mz showed the longest tolerance of endotracheal intubation (78.1 +/- 36.5 minutes). Loss of righting reflex was significantly most rapid (p < 0.05) in the X-K group (114.7 +/- 24.0 minutes). Surgical anaesthesia was achieved in 16 of 19 animals receiving M-K, in 14 animals receiving M-F-Mz, and in seven animals with X-K, but only for a short period (7.1 +/- 11.6 minutes). This was significantly (p < 0.001) shorter than with M-K (38.7 +/- 30.0 minutes) and M-F-Mz (31.6 +/- 26.6 minutes). Heart rates were greatest in X-K recipients; lowest HR were seen in animals receiving M-F-Mz. Mean arterial blood pressure was significantly higher (about 88 mmHg) during the first hour in the M-K group. During recovery, the greatest hypotension was encountered in the X-K group; minimum values were 53 +/- 12 mmHg. Six of 19 animals in the M-F-Mz group showed a short period of apnoea (30 seconds) immediately after endotracheal intubation. Respiratory frequency was significantly lower in this group (p < 0.001). Highest values for arterial carbon dioxide partial pressures (PaCO(2)) (6.90 +/- 0.87 kPa; 52.5 +/- 6.5 mmHg) occurred after induction of anaesthesia in group M-F-Mz animals. There was a marked decrease in PaO(2) in all three groups (the minimum value 5.28 +/- 0.65 kPa [39.7 +/- 4.9 mmHg] was observed with M-K immediately after injection). Arterial PO(2) was between 26.0 and 43.0 kPa (196 and 324 mmHg) in all groups during O(2) delivery and decreased - but not <7.98 kPa - on its withdrawal. Immediately after drug injection, pH(a) values fell in all groups, with lowest values after 30 minutes (7.23 +/- 0.03 with M-K, 7.28 +/- 0.05 with M-F-Mz, and 7.36 +/- 0.04 with X-K). The X-K animals showed significantly (p < 0.001) higher pH values than medetomidine recipients. During 1 hour of anaesthesia pH values in the medetomidine groups remained below those of the X-K group. CONCLUSIONS: Surgical anaesthesia was induced in most animals receiving medetomidine-based combinations. Arterial blood pressure was maintained at baseline values for about 1 hour after M-K. Transient apnoea occurred with M-F-Mz and mandates respiratory function monitoring. Oxygen enrichment of inspired gases is necessary with all three combinations. Endotracheal intubation is essential in rabbits receiving M-F-Mz. CLINICAL RELEVANCE: The quality of surgical anaesthesia was greatest with M-K. All combinations allowed recoveries of similar duration. It is theoretically possible to antagonize each component of the M-F-Mz combination.     

Evaluation of butorphanol, medetomidine and midazolam as a reversible narcotic combination in free-ranging African lions (Panthera leo)

ObjectiveTo evaluate the effects of the combination butorphanol, medetomidine and midazolam (BMM) and its reversibility in lions.Study designProspective clinical trial.AnimalsThirty free-ranging lions, 10 male and 20 female, weighing 81-210 kg.MethodsLions were immobilised with butorphanol mean 0.31 ± SD 0.034 mg kg^?1, medetomidine 0.052 ± 0.006 mg kg^?1, midazolam 0.21 ± 0.024 mg kg^?1 and hyaluronidase 1250 IU administered intramuscularly with a dart gun. Upon recumbency, physiological parameters and anaesthetic depth were monitored 10-15 minutes after darting (T1) and repeated every 10 minutes for a further 30 minutes (T2, T3, T4). Arterial blood gas analyses were performed at T1 and T4. At the end of the procedure, 45-60 minutes after initial darting, immobilisation was reversed with naltrexone 0.68 ± 0.082 mg kg^?1, atipamezole 0.26 ± 0.031 mg kg^?1, and flumazenil 0.0032 ± 0.0007 mg kg^?1 administered intravenously and subcutaneously.ResultsThe BMM combination rapidly induced immobilisation and lateral recumbency was reached within 7.25 ± 2.3 minutes. Median induction score [scored 1 (excellent) to 4 (poor)] was 1.4 (range 1-2). Cardio-respiratory parameters were stable. Heart rate varied from 32 to 72 beats per minute, respiratory rate from 14 to 32 breaths minute^?1 and rectal temperature from 36.6 to 40.3 °C. No sudden arousals were observed. Arterial blood gas analyses revealed a mean pH of 7.33, PaCO₂ of 33 mmHg and PaO₂ of 87 mmHg. Mild to moderate hypoxemia was seen in four lions. Recovery was smooth and lions were walking within 4.4 ± 4.25 minutes. Median recovery score [scored 1 (excellent) to 4 (poor)] was 1.3 (range 1-2).Conclusion and clinical relevanceThe drug combination proved to be effective in immobilising free-ranging healthy lions of both sexes with minimal cardio-respiratory changes.     

Chemical restraint by medetomidine and medetomidine–midazolam and its reversal by atipamezole in Japanese macaques (Macaca fuscata)

Objective To evaluate the sedative effects of medetomidine, and a medetomidine–midazolam combination, in Japanese macaques and the antagonism of medetomidine–midazolam with atipamezole. Study design Prospective randomized study. Animals Thirteen healthy Japanese macaques between 3 and 21 years old and weighing between 4.3 and 15.1 kg. Methods Medetomidine (120 µg kg^?1) alone or a medetomidine (30 µg kg^?1) plus midazolam (0.3 mg kg^?1) mixture were injected intramuscularly in the hind limb of 12 animals (n = 6 for each group) and their effects, particularly behavioural changes, response to external stimuli, sedative onset time, time to lateral recumbency and time in lateral recumbency, were monitored for 120 minutes. Another group (n = 7) were given medetomidine–midazolam and injected 30 minutes later with atipamezole (120 µg kg^?1). Behavioural changes and responses to external stimuli were assessed as before. Results Animals given medetomidine became sedated but could be aroused by external stimuli. Despite the lower (25%) dose of medetomidine involved, the effects of medetomidine–midazolam were more marked. Macaques given this combination became sedated in 4 ± 2 minutes (mean ± SD) and remained unresponsive to external stimuli for at least 60 minutes. Five out of six macaques became laterally recumbent for 74 ± 37 minutes. Intramuscular atipamezole effectively reversed sedation, shortening the arousal and total recovery time. The recovery from sedation was rapid and smooth, being completed 19 ± 11 minutes after antagonism. Conclusions The medetomidine–midazolam combination described provided useful chemical restraint and may prove useful in macaques undergoing some experimental, diagnostic or therapeutic procedures. The use of atipamezole as an antagonist increases the value of this technique in macaques.     

Evaluation of medetomidine-ketamine and dexmedetomidine-ketamine in Chinese water deer (Hydropotes inermis)

ObjectiveTo investigate physiological and sedative/immobilization effects of medetomidine or dexmedetomidine combined with ketamine in free-ranging Chinese water deer (CWD).Study designProspective clinical trial.Animals10 free-ranging adult Chinese water deer (11.0 ± 2.6 kg).MethodsAnimals were darted intramuscularly with 0.08 ± 0.004 mg kg^?1 medetomidine and 3.2 ± 0.2 mg kg^?1 ketamine (MK) or 0.04 ± 0.01 mg kg^?1 dexmedetomidine and 2.9 ± 0.1 mg kg^?1 ketamine (DMK) If the animal was still laterally recumbent after 60 minutes of immobilization, atipamezole was administered intravenously (MK: 0.4 ± 0.02 mg kg^?1, DMK: 0.2 ± 0.03 mg kg^?1). Heart rate (HR) respiratory rate (f_R) and temperature were recorded at 5-minute intervals. Arterial blood was taken 15 and 45 minutes after initial injection. Statistical analysis was performed using Student’s t-test or anova. p < 0.05 was considered significant.ResultsAnimals became recumbent rapidly in both groups. Most had involuntary ear twitches, but there was no response to external stimuli. There were no statistical differences in mean HR (MK: 75 ± 14 beats minute^?1; DMK: 85 ± 21 beats minute^?1), f_R (MK: 51 ± 35 breaths minute^?1; DMK; 36 ± 9 breaths minute^?1), temperature (MK: 38.1 ± 0.7 °C; DMK: 38.4 ± 0.5 °C), blood gas values (MK: PaO₂ 63 ± 6 mmHg, PaCO₂ 49.6 ± 2.6 mmHg, HCO₃^? 30.8 ± 4.5 mmol L^?1; DMK: PaO₂ 77 ± 35 mmHg, PaCO₂ 45.9 ± 11.5 mmHg, HCO₃^? 31.0 ± 4.5 mmol L^?1) and biochemical values between groups but temperature decreased in both groups. All animals needed antagonism of immobilization after 60 minutes. Recovery was quick and uneventful. There were no adverse effects after recovery.Conclusion and clinical relevanceBoth anaesthetic protocols provided satisfactory immobilisation. There was no clear preference for either protocol and both appear suitable for CWD.     

Atipamezole changes the antinociceptive effects of butorphanol after medetomidine–ketamine anaesthesia in rats

Objective  To investigate the effects of atipamezole administered before butorphanol, on tail-flick latency (TFL) and also following medetomidine–ketamine anaesthesia in rats.
Study design  Prospective, randomized experimental study.
Animals  Thirty-four adult male Sprague–Dawley rats weighing 260–390 g.
Methods  TFL in 50 °C water was used to measure antinociception. In the first experiment, rats received saline ( n  = 5) or atipamezole ( n  = 5) followed by butorphanol treatments. In the second experiment, three groups of rats received saline ( n  = 8), atipamezole ( n  = 8) or atimpamezole ( n  = 8) followed by butorphanol 60 minutes after medetomidine–ketamine administration.
Results  In the first experiment, butorphanol significantly increased TFL compared to baseline. Atipamezole significantly decreased this effect. In the second experiment, TFL was significantly increased after recovery from medetomidine–ketamine anaesthesia compared to baseline. This was almost completely blocked by atipamezole. Atipamezole with butorphanol after recovery from the anaesthesia significantly reduced TFL compared to saline but still significantly increased TFL compared to the baseline.
Conclusion and clinical relevance  Atipamezole attenuated the analgesic effects of butorphanol. When postoperative atipamezole is used to hasten recovery from anaesthesia in rats, it may interfere with the postoperative analgesic effect of butorphanol.     

Anaesthesia of a Sumatran tiger on eight occasions with ketamine, medetomidine and isoflurane

CASE: An 18-month-old male Sumatran tiger was referred for endoscopy and dilatation of an oesophageal stricture. Anaesthesia and bouginage was undertaken on eight occasions 2-3 weeks apart to dilate the oesophageal stricture. CLINICAL FINDINGS: On the first occasion, sedation was induced with a combination of medetomidine (30 microg/kg) and ketamine (2.35 mg/kg) given intramuscularly. Cardiopulmonary depression (characterised by bradycardia, ventricular arrhythmias, hypoventilation and cyanosis) was severe and in subsequent anaesthesias the medetomidine dose was decreased to about 18 microg/kg and the ketamine dose increased to about 3 microg/kg given intramuscularly. Immobilisation was adequate and the severity of the cardiopulmonary depression was reduced at the revised drug dosages. Atipamezole was effective in reversing both the cardiopulmonary and central nervous system depression. CONCLUSION: The dosage of medetomidine and ketamine recommended in the literature for immobilising tigers produced severe cardiopulmonary depression in this animal. A reduced dosage of medetomidine and higher dosage of ketamine provided adequate restraint with decreased cardiopulmonary depression.     

Preliminary studies of chemical immobilization of captive juvenile estuarine (Crocodylus porosus) and Australian freshwater (C. johnstoni) crocodiles with medetomidine and reversal with atipamezole

ObjectiveTo establish a safe, reliable and reversible immobilization protocol for captive juvenile crocodiles.Study designProspective, randomized, clinical study.AnimalsThirty male estuarine crocodiles (body mass 1–12.1 kg) and 10 male Australian freshwater crocodiles (body mass 4.1–12.8 kg).MethodsAn optimized dose of medetomidine (0.5 mg kg^?1) was administered intramuscularly (IM) into the tail (Group 1; n = 5), pelvic limb (Group 2; n = 5) and thoracic limb (Groups 3 and 4; n = 5 in each group) of estuarine crocodiles weighing 3–12.1 kg. Their heart and respiratory rates and degree of immobilization were monitored every 15 minutes until recovery and daily thereafter for 3 subsequent days. In Group 4 (n = 5), medetomidine was antagonized with an optimized dose of atipamezole (2.5 mg kg^?1) given IM into the thoracic limb and time to recovery recorded. The effects of increasing doses of medetomidine given IM in the thoracic limb (n = 4) and intravenously (n = 6) were determined in 1–2 kg estuarine crocodiles. Australian freshwater crocodiles (4.1–12.8 kg) were administered medetomidine IM into the thoracic limb in divided doses at 0.5 mg kg^?1 (n = 5) and 0.75 mg kg^?1 (n = 5) and similarly monitored.ResultsImmobilization was achieved only in the estuarine crocodiles >3 kg and when medetomidine was administered into the thoracic limb. Immobilization was achieved within 30 minutes and the duration of immobilization lasted approximately 90 minutes. Immobilization in estuarine crocodiles was readily reversed with atipamezole. A dose of 0.75 mg kg^?1 was required to immobilize Australian freshwater crocodiles and the onset of immobilization was longer and the duration shorter than seen in the estuarine crocodiles. The heart and respiratory rates of all immobilized animals decreased significantly and arterial blood pressure became undetectable in the animals in which it was measured.Conclusions and clinical relevanceMedetomidine administered in the thoracic limb of captive estuarine and Australian freshwater crocodiles, ranging from 3 to 12.8 kg, provides a predictable onset and duration of immobilization sufficient for physical examination, sample collection, short minor procedures and translocation of the animals. Atipamezole administered in the thoracic limb results in complete reversal of the effects of medetomidine in the estuarine crocodile and a rapid return to normal behaviour.     

Anaesthesia of gemsbok (Oryx gazella) with a combination of A3080, medetomidine and ketamine

An effective anaesthesia protocol was developed for adult free-ranging gemsbok (Oryx gazella) using a combination of A3080, medetomidine and ketamine. A short induction time; good muscle relaxation, adequate oxygenation and stable heart rate and respiration rate characterised this anaesthetic regime. Equal doses of A3080 and medetomidine (22-45 microg/kg) plus 200 mg of ketamine were administered to each animal. The anaesthesia was rapidly and completely reversed by intramuscular naltrexone at a dose of X = 0.9 +/- 0.2 mg/kg and atipamezole at a dose X +/- 90 +/- 20 microg/kg. No mortality or morbidity occurred with this protocol.     

Antagonistic effects of atipamezole, flumazenil and 4-aminopyridine against anaesthesia with medetomidine, midazolam and ketamine combination in cats

Antagonistic effects of atipamezole (ATI), flumazenil (FLU) and 4-aminopyridine (4AP) alone and in various combinations after administration of medetomidine-midazolam-ketamine (MED-MID-KET) were evaluated in cats. Animals were anaesthetised with MED (50 microg/kg), MID (0.5 mg/kg) and KET (10 mg/kg) given intramuscularly. Twenty minutes later, physiological saline, ATI (200 microg/kg), FLU (0.1 mg/kg), 4AP (0.5 mg/kg), ATI-FLU, FLU-4AP, ATI-4AP or ATI-FLU-4AP was administered intravenously. FLU, 4AP alone, or FLU-4AP did not effectively antagonise the anaesthesia, hypothermia, bradycardia, and bradypnoea induced by MED-MID-KET. ATI alone was effective. ATI-FLU, ATI-4AP and ATI-FLU-4AP combinations produced an immediate and effective recovery from anaesthesia. The combination of ATI-FLU-4AP was the most effective in antagonising the anaesthetic effects, but was associated with tachycardia, tachypnoea, excitement, and muscle tremors. Combinations with ATI are more effective for antagonising anaesthesia, but ATI-FLU-4AP is not suitable.     

Clinicophysiological Effects of Spinally Administered Ketamine and Its Combination with Xylazine and Medetomidine in Healthy Goats

The study was conducted in 9 healthy adult goats of either sex, weighing 15–20 kg, to evaluate and compare the clinicophysiological effects of spinally administered ketamine alone and in combination with xylazine and medetomidine. Nine trials each of the three treatments were conducted randomly by injecting ketamine (2.5 mg/kg) (n = 9), ketamine and xylazine (2.5 mg/kg and 0.05 mg/kg) (n = 9) and ketamine and medetomidine (2.5 mg/kg and 10 μg/kg) (n = 9). The drugs were administered at the lumbosacral subarachnoid space under strict aseptic conditions. The treatments were evaluated on the basis of clinicophysiological, haematological, biochemical and haemodynamic observations. Ketamine produced mild to moderate analgesia of the hindquarters. Its combination with either xylazine or medetomidine produced complete analgesia of the hindquarters for 45–60 min. Ataxia was moderate in the ketamine group, whereas animals attained sternal recumbency in the combination groups. A moderate degree of sedation was recorded in the combination groups. Heart rate and respiratory rate depression in the combination groups and heart rate and respiratory rate stimulation in ketamine group were recorded. Haematological parameters decreased in all the groups. Increase in serum glucose, creatinine and urea nitrogen was recorded in all the groups. Serum electrolytes did not show any significant change. The results showed that the combination of ketamine with xylazine or medetomidine at these dose rates produced a comparable degrees of analgesia of hindquarters with transient and minimal cardiopulmonary side effects.     

Anesthetic and cardiopulmonary effects of total intravenous anesthesia using a midazolam, ketamine and medetomidine drug combination in horses

The anesthetic and cardiopulmonary effects of midazolam, ketamine and medetomidine for total intravenous anesthesia (MKM-TIVA) were evaluated in 14 horses. Horses were administered medetomidine 5 microg/kg intravenously as pre-anesthetic medication and anesthetized with an intravenous injection of ketamine 2.5 mg/kg and midazolam 0.04 mg/kg followed by the infusion of MKM-drug combination (midazolam 0.8 mg/ml-ketamine 40 mg/ml-medetomidine 0.1 mg/ml). Nine stallions (3 thoroughbred and 6 draft horses) were castrated during infusion of MKM-drug combination. The average duration of anesthesia was 38 +/- 8 min and infusion rate of MKM-drug combination was 0.091 +/- 0.021 ml/kg/hr. Time to standing after discontinuing MKM-TIVA was 33 +/- 13 min. The quality of recovery from anesthesia was satisfactory in 3 horses and good in 6 horses. An additional 5 healthy thoroughbred horses were anesthetized with MKM- TIVA in order to assess cardiopulmonary effects. These 5 horses were anesthetized for 60 min and administered MKM-drug combination at 0.1 ml/kg/hr. Cardiac output and cardiac index decreased to 70-80%, stroke volume increased to 110% and systemic vascular resistance increased to 130% of baseline value. The partial pressure of arterial blood carbon dioxide was maintained at approximately 50 mmHg while the arterial partial pressure of oxygen pressure decreased to 50-60 mmHg. MKM-TIVA provides clinically acceptable general anesthesia with mild cardiopulmonary depression in horses. Inspired air should be supplemented with oxygen to prevent hypoxemia during MKM-TIVA.     

Plasma concentration and cardiovascular effects of intramuscular medetomidine combined with three doses of the peripheral alpha2-antagonist MK-467 in dogs

Objective

We investigated the plasma concentrations and cardiovascular effects of intramuscularly (IM) administered medetomidine, administered alone or with three different doses of MK-467.

The effects of medetomidine on the action of vecuronium in dogs anaesthetized with halothane and nitrous oxide

ObjectiveTo quantify the effects of medetomidine on the onset and duration of vecuronium-induced neuromuscular blockade in dogs.Study designRandomized, prospective clinical study.AnimalsTwenty-four, healthy, client-owned dogs of different breeds, aged between 6 months and 10 years and weighing between 5.0 and 40.0 kg undergoing elective surgery.MethodsDogs were randomly allocated to two groups. Pre-anaesthetic medication in group M+ was intramuscular acepromazine (ACP) 25 μg kg⁻¹, morphine 0.5 mg kg⁻¹ and medetomidine 5 μg kg⁻¹. Group M− received ACP and morphine only, at the same dose rate. After induction with thiopental, anaesthesia was maintained with halothane in oxygen and nitrous oxide. End-tidal halothane concentration was maintained at 1.1%. Neuromuscular blockade was produced with intravenous vecuronium (50 μg kg⁻¹) and monitored using a train of four stimulus applied at the ulnar nerve. The times taken for loss and reappearance of the four evoked responses (twitches [T]) were recorded. Normal and nonparametric data were analysed with an independent t-test and Mann-Whitney's U-test, respectively.ResultsThe fourth twitch (T4) disappeared at similar times in each group: 107 ± 19; [72–132] (mean ± SD; [range]) seconds in M+ and 98 ± 17 [72–120] seconds in M− dogs. The first twitch (T1) was lost at 116 ± 15; [96–132] seconds in group M+ and 109 ± 19; [72–132] seconds in M−. The fourth twitch returned significantly earlier in M+ dogs: 20.8 ± 3.8 [14–28] minutes compared with 23.8 ± 2.7 [20–27] minutes (p = 0.032). The duration of drug effect (T4 absent) was significantly shorter (p = 0.027) in M+ (18.9 ± 3.7 minutes) compared with M− dogs (22.2 ± 2.9 minutes). The recovery rate (interval between reappearance of T1 and T4) was significantly more rapid (p = 0.0003) in medetomidine recipients (3.0 ± 1.2 versus 5.2 ± 1.3 minutes).Conclusion and clinical relevance Medetomidine 5 μg kg⁻¹ as pre-anaesthetic medication shortened the duration of effect of vecuronium in halothane-anaesthetized dogs and accelerated recovery, but did not affect the onset time. These changes are of limited clinical significance.