Reversal of medetomidine sedation by atipamezole in dogs

Atipamezole reversed the sedative effect of medetomidine in twelve laboratory beagles. The dogs were sedated with medetomidine doses of 20, 40 and 80 micrograms/kg body wt i.m. Atipamezole was injected (i.m.) 20 min later at dose rates two, four, six and ten times higher (in micrograms/kg) than the preceding medetomidine dose. Placebo treatment was included in the study. The deeply sedated dogs showed signs of arousal in 3-7 min and took their first steps 4-12 min after atipamezole injection. The dose-related reversal effect of atipamezole proved to be optimal with doses which were four, six or ten times higher than the preceding medetomidine dose. Drowsiness was found 0.5-1 h after atipamezole injection in 41% of the cases. No adverse effects nor cases of over-alertness or excitement were found.     

Antagonism of detomidine sedation with atipamezole in horses

The reversal of detomidine-induced sedation with iv atipamezole was studied in 6 horses. All horses were injected iv with 10 μg and 20 μg/kg bwt detomidine and 15 min later this was followed by 6-, 8- and 10-fold doses of iv atipamezole. Atipamezole caused a quick arousal in all horses with minor side effects. Bradycardia, rhythm disturbances and head ptosis caused by detomidine were not abolished completely at the end of the 15 min observation period, even with the highest atipamezole doses. All horses remained slightly sedated but without ataxia. There were no significant differences in head height, heart rate and sedation score between the different doses of atipamezole for either dose of detomidine. According to the degree of sedation, doses of 100 μg to 160 μg/kg bwt atipamezole are adequate to antagonise detomidine-induced sedation in the horse.     

Effects of atipamezole on xylazine sedation in ponies.

Atipamezole antagonism of xylazine sedation was evaluated in six ponies. Atipamezole (0.15 mg/kg) or saline was injected intravenously 15 minutes after the ponies had been sedated with xylazine (1.0 mg/kg). Arterial blood pressure and gases, pulse and respiratory rates, the electrocardiogram, nose-to-ground distance and a subjective sedation score were recorded. The pretreatment nose-to-ground distance and PaO2 returned to normal sooner after atipamezole than after saline and the ponies' appetite and normal locomotion also recovered sooner. No significant differences were observed between the effects of saline and atipamezole on the other measurements.     

Reversal of medetomidine-induced sedation in reindeer (Rangifer tarandus tarandus) with atipamezole increases the medetomidine concentration in plasma

The pharmacokinetics of two potent α₂-adrenoceptor agents that can be used for immobilization (medetomidine) and reversal (atipamezole) of the sedation in mammals, were studied in three reindeer ( Rangifer tarandus tarandus) in winter and again in summer. Medetomidine (60 μg/kg) was injected intravenously (i.v.), followed by atipamezole (300 μg/kg) intravenously 60 min later. Drug concentrations in plasma were measured by HPLC. The administration of atipamezole resulted in an immediate 2.5–3.5 fold increase in the medetomidine concentration in plasma. Clearance for medetomidine (median 19.3 mL/min·kg) was lower than clearance for atipamezole (median 31.0 mL/min·kg). The median elimination half-lives of medetomidine and atipamezole in plasma were 76.1 and 59.9 min, respectively. The animals became resedated 0.5–1 h after the reversal with atipamezole. Resedation may be explained by the longer elimination half-life of medetomidine compared to atipamezole.     

Sedative effects of medetomidine in pigs.

Sedative effects of medetomidine, a potent selective and specific alpha 2-adrenoceptor agonist, were evaluated in pigs using 5 different doses (30, 50, 80, 100 and 150 micrograms/kg of body weight) and compared with those of xylazine (2 mg/kg). Atropine (25 micrograms/kg) was mixed with both drugs to prevent severe bradycardia. All drugs were administered intramuscularly. Medetomidine at a dosage of 30 micrograms/kg produced more potent sedation than xylazine. The depth of sedation induced by medetomidine was dose dependent within the range from 30 to 80 micrograms/kg. At 100 or 150 micrograms/kg, the depth of sedation was mostly the similar level to that at 80 micrograms/kg but the duration was prolonged. The degree of muscle relaxation produced by medetomidine also seemed to be dose dependent from 30 to 80 micrograms/kg and was stronger than that produced by xylazine. An increase in the duration of muscle relaxation was dose dependent up to 150 micrograms/kg. No analgesic effect was produced by xylazine, however moderate analgesia was obtained by medetomidine. There were no marked changes in heart rate and respiratory rate during the observation period in pigs of any groups, however mild hypothermia after the administration of both drugs was observed. From these results, medetomidine has a significant and dose-dependent sedative effects which are much more potent than that of xylazine, and a combination of 80 micrograms/kg of medetomidine and 25 micrograms/kg of atropine is suitable for sedation with lateral recumbency and moderate muscle relaxation without notable side effects in pigs.     

Clinical effectiveness of atipamezole as a medetomidine antagonist in cats

The efficacy of atipamezole to reverse medetomidine induced effects in cats was investigated in a clinical study (n=160) including placebo. The atipamezole doses (intramuscularly) were two, four and six times (2X, 4X and 6X) the preceding medetomidine dose, which was 100 ug/kg body weight intramuscularly. Medetomidine was shown to produce moderate to deep sedation, recumbency and bradycardia in cat. Atipamezole was clearly able to reverse these effects of medetomidine. The median arousal time in the atipamezole dose groups was five minutes and walking time, 10 minutes, compared with more than 30 minutes in the placebo group. Heart rate was increased towards normal by atipamezole in a dose related manner. The clinical evaluation of the ability of atipamezole to reverse the effects of medetomidine was found to be ‘good’ in 82-5, 75 or 65 per cent of cases in dose groups 2X, 4X and 6X, respectively. The effect of atipamezole was evaluated as being ‘too potent’ in 2–5, 5 or 25 per cent of the cases in these respective groups. The incidence of side effects was negligible. In conclusion, atipamezole at the dose of two to four times the preceding dose of medetomidine seems to be an effective medetomidine antagonist for clinical use in cats.     

Antagonism of xylazine induced sedation by idazoxan in calves.

Idazoxan was studied at three dose rates to assess its potential as an antagonist to xylazine. Calves in the study group were initially given xylazine at a dose rate of 0.2 mg/kg intravenously followed 12 minutes later by idazoxan at a dose rate of either 0.05, 0.075 or 0.10 mg/kg intravenously. A control group received a saline injection instead of idazoxan. All three dose levels of idazoxan successfully reversed the xylazine induced central nervous depression and all animals stood within two minutes of injection. No residual signs of sedation were noticed and relapse did not occur. In addition idazoxan was successful in reversing respiratory and cardiovascular depression produced by xylazine. The results indicated that idazoxan may be used for rapid reversal of xylazine induced sedation in calves.     

Clinical observations on medetomidine/ketamine anaesthesia in sheep and its reversal by atipamezole

Medetomidine (25 μg/kg) and ketamine (1mg/kg) were administered intramuscularly to anaesthetise 13 sheep for experimental oral surgery. Anaesthesia was characterised by good muscle relaxation and tachypnoea. Heart rates were not significantly different from those recorded before administration of the anaesthetic agents. Spontaneous recovery from anaesthesia was allowed in five sheep. In eight sheep atipamezole, at a total dose of 125 μg/kg, divided and administered both intravenously and intramuscularly, hastened return to full awareness.     

The clinical effectiveness of atipamezole as a medetomidine antagonist in the dog

The efficacy of atipamezole, a recently introduced alpha 2-adrenoceptor antagonist, in reversing medetomidine-induced effects in dogs was investigated in a clinical study. Dogs from eight Finnish small-animal hospitals were sedated with a 40-microgram/kg dose of the alpha 2-agonist medetomidine i.m. In the first part of the study (n = 319), a randomized, double-blind design with respect to the dose of atipamezole (0, 80, 160 and 240 micrograms/kg i.m.) was used. In a separate study (n = 358), which was an open trial, the selected dose of atipamezole was 200 micrograms/kg i.m. Atipamezole at dose rates of 80-240 micrograms/kg rapidly and effectively reversed medetomidine-induced deep sedation-analgesia, recumbency and bradycardia. The median arousal time after atipamezole was 3-5 min, and walking time was 6-10 min compared to greater than 30 min for both effects after placebo. Heart rate also increased in a dose-related manner after atipamezole administration. The investigators' overall evaluation of the ability of atipamezole to reverse the effects of medetomidine was 'good' in 90%, and 'moderate' in 9% of cases. Relapse into sedation was reported in three individual cases. Side-effects were minimal. It is concluded that at doses four- to sixfold the medetomidine dose, atipamezole is a highly effective and safe agent in reversing medetomidine-induced sedation-analgesia, recumbency and bradycardia in dogs in veterinary practice.     

Clinical observations on medetomidine/ ketamine anaesthesia and its antagonism by atipamezole in the cat

A combination of medetomidine and ketamine was administered intramuscularly to produce anaesthesia in 34 cats undergoing elective surgery or diagnostic procedures. Vomiting before the onset of sedation was observed in six cats. Surgical anaesthesia was rapid in onset and of consistently high quality. In order to hasten return to full awareness at the termination of surgery, atipamezole was administered, intramuscularly, in 33 cats. Recovery was smooth in all cases, with return to full consciousness occurring within a short time of the injection of atipamezole.     

Effect of medetomidine and its antagonism with atipamezole on stress-related hormones, metabolites, physiologic responses, sedation, and mechanical threshold in goats

OBJECTIVE: To evaluate the effects of medetomidine and its antagonism with atipamezole in goats. STUDY DESIGN: Prospective randomized crossover study with 1 week between treatments. ANIMALS: Six healthy 3-year-old neutered goats (three male and three female) weighing 39.1-90.9 kg (60.0 +/- 18 kg, mean +/- SD). METHODS: Goats were given medetomidine (20 microg kg(-1), IV) followed, 25 minutes later, by either atipamezole (100 microg kg(-1), IV) or saline. Heart and respiratory rate, rectal temperature, indirect blood pressure, and mechanical threshold were measured, and sedation and posture were scored and blood samples obtained to measure epinephrine, norepinephrine, free fatty acids, glucose, and cortisol concentrations at baseline (immediately before medetomidine), 5 and 25 minutes after medetomidine administration, and at 5, 30, 60, and 120 minutes after the administration of antagonist or saline. Parametric and nonparametric tests were used to evaluate data; p < 0.05 was considered significant. RESULTS: Medetomidine decreased body temperature, heart rate, and respiratory rate and increased mean arterial blood pressure, cortisol, and glucose. Recumbency occurred 89 +/- 50 seconds after medetomidine administration. All goats were standing 86 +/- 24 seconds after atipamezole administration whereas all goats administered saline were sedate and recumbent at 2 hours. Tolerance to compression of the withers and metacarpus increased with medetomidine. From 5 to 120 minutes after saline or atipamezole administration, there were differences in body temperature, glucose, and cortisol but none in heart rate or blood pressure. Three of the six goats receiving saline developed bloat; five of six urinated. After atipamezole, four of six goats developed piloerection and all goats were agitated and vocalized. CONCLUSION: At the doses used, atipamezole antagonized the effects of medetomidine on recumbency, sedation, mechanical threshold, and the increase in glucose. Atipamezole increased the rate of return of cortisol toward baseline, and prevented further decline in rectal body temperature. CLINICAL RELEVANCE: Atipamezole may be used to antagonize some, but not all effects of medetomidine.     

The effect of medetomidine and its antagonism with atipamezole on stress-related hormones, metabolites, physiologic responses, sedation, and analgesia in goats

Six 3‐year‐old goats (three males and three females) weighing 60.0 ± 18 kg (mean ± SD) were used to investigate the effect of medetomidine (MED; 20 µg kg^?1 IV) and its antagonism with atipamezole (ATI; 100 µg kg^?1 IV) on physiologic responses (heart rate (HR; beats minute^?1), respiratory rate (RR; breaths minute^?1), electrocardiogram (ECG), rectal temperature (T; °C), blood pressure (oscillometric; mm Hg), sedation (SED), posture (REC), analgesia (ALG), and stress‐related hormonal and metabolic responses (epinephrine and norepinephrine (high performance liquid chromatography with electrochemical detection), cortisol (COR; µg dL^?1; radioimmunoassay), glucose (GLU; mg mL^?1; enzymatic colorimetric assay), and free fatty acids (modified enzymatic colorimetric assay)); each goat received ATI or SAL in random order separated by 1 week. Jugular catheters were placed for drug administration and blood sampling (10–12 mL sample^?1) using a lidocaine skin block (20 mg) 2 hours prior to beginning of each trial; during this trial, goats breathed room air. Physiologic parameters were measured, SED, REC, and ALG were scored, and blood samples were collected from jugular catheters at baseline (time = ?30 minutes), 5 minutes post‐MED administration (time = ?25 minutes), 25 minute post‐MED administration and immediately prior to antagonism (time = 0 minute), and at 5, 30, 60, and 120 minutes after administering ATI or SAL. ALG was tested by clamping the withers and metacarpus with hoof testers fitted with a force transducer to measure applied isometric force (lb) (a technique used previously in goats to evaluate analgesia). Continuous variables were analyzed by Repeated Measures analysis of variance (anova ); categorical data were analyzed using a Friedman Repeated Measures anova on ranks. A p‐value of <0.05 was considered significant. If a significant difference was found, a Dunnett's pair‐wise comparison of means was conducted. Differences between ATI and SAL were examined at 5, 30, 60, and 120 minutes using a paired t‐test with a Bonferroni correction. Administration of MED resulted in a decrease in T (38.7 ± 0.3 to 34.5 ± 0.4 °C), HR (78 ± 19 to 55 ± 9), and RR (31 ± 12 to 14 ± 5) over time; an increase in mean arterial blood pressure (90 ± 19 to 132 ± 23), COR (0.254 ± 0.125 to 4.327 ± 1.233), and GLU (82.0 ± 13.2 to 255.9 ± 38.9); and changes in SED (alert to marked sedation), REC (standing to recumbent), and ALG (metacarpus = 5 ± 2 to 14 ± 0; withers = 3 ± 2 to 14 ± 0). GLU was 62–70% higher at 60 and 120 minutes and COR was 336% higher after SAL than after ATI at 120 minutes; at 30, 60, and 120 minutes, T was 4–10% higher after ATI than SAL. There were no other significant differences. REC, SED, and ALG were antagonized after ATI. ATI did not antagonize the effect of MED on HR, RR, or MAP, but stabilized T and antagonized the increase in GLU and COR.     

Use of medetomidine and butorphanol for sedation in dogs

Medetomidine 10 μg/kg, was combined with butorphanol 0.1 mg/kg and administered intramuscularly to 27 dogs requiring sedation for various diagnostic or therapeutic procedures. All the dogs became deeply sedated. Heart rate fell by a mean of 55 per cent. Eighteen dogs showed signs of pain as the combination was injected. Sedation was sufficient for the intended procedure to be carried out in 25 of the dogs. General anaesthesia was induced in four dogs — the mean dose of thiopentone required for induction of anaesthesia was 2 mg/kg. Administration of atipamezole at the end of the procedure produced rapid and sudden recoveries in all the dogs, with a mean time to standing of nine minutes.     

Cardiopulmonary effects of a two hour medetomidine infusion and its antagonism by atipamezole in horses and ponies

The cardiopulmonary effects of an intravenous (iv) medetomidine injection (5 μg/kg) followed 5 min later by its infusion at 3.5 μg/kg/h for 115 rnin were studied in 9 horses and ponies. Five minutes after the end of infusion 60 μg/kg atipamezole were given. Physiological data during infusion were compared with pre-sedation values. Stroke volume was reduced significantly 5 min after initial medetomidine injection. Cardiac index was reduced significantly and systemic vascular resistance increased significantly for the first 20 min, but returned towards pre-sedation values after this time. Arterial blood pressures were reduced significantly from 30 min until the end of the procedure (minimum MAP was 102.4 ± 9.61 mmHg). Mixed venous oxygen tension was reduced significantly during the infusion. Respiratory rate fell and PaCO₂- rose significantly from 40 min onward. Other variables showed no significant changes. The horses recovered rapidly after atipamezole was injected. Arterial blood pressures remained significantly lowered, but other cardiovascular variables returned towards pre-sedation values. It is concluded that the infusion of medetomidine at 3.5 μg/kg/h causes minimum cardiopulmonary depression once the effects of an initial 5 μg/kg injection have waned, and so could prove suitable as part of an anaesthetic technique in equidae.     

Pharmacokinetics of medetomidine in ponies and elaboration of a medetomidine infusion regime which provides a constant level of sedation.

The pharmacokinetics of intravenous (i.v.) medetomidine (7 mcg kg(-1)) were best described by a two-compartment model in five ponies. Total body clearance was 4 (SD 0.60) 1 kg h,(-1)t(1/2alpha)7. 6 (0.91) minutes and t(1/2beta)51.3 (13.09) minutes. In one pony the one-compartmental model was best fit, and total body clearance was 4. 2 l kg h(-1)and t(1/2)was 11 minutes. Medetomidine plasma levels had fallen below the limits of quantification (0.05 ng ml(-1)) within 4 hours. Medetomidine 5 mcg kg(-1)i.v. followed by an infusion of 3.5 mcg kg h(-1)for two hours provided a constant level of sedation reaching steady state plasma medetomidine levels of 1-1.5 ng ml(-1)within 30 minutes. Sedation was reversed effectively by atipamezole (60 mcg kg(-1)) i.v. The pharmacokinetics of medetomidine make it suitable for prolonged use by infusion, such as is required as part of a total intravenous anaesthetic technique in horses.     

Survey of utilization of medetomidine and atipamezole in private veterinary practice in Quebec in 2002

This survey evaluates early perceptions about the use of medetomidine and atipamezole among veterinary practitioners in Quebec in 2002. Response rate was 23.5%; 71.1% of the practitioners did not use these products because of lack of information (69.3%), unavailability of the drugs in the practice (23.3%), or other reasons (7.3%), including concerns about the safety of alpha-2 agonists. Most veterinarians who used these products (70.4%) used them only rarely. Sedation by medetomidine was qualified as good (44.2%) or excellent (36%), and analgesia as good (46.5%) or average (32.7%). Waking up after atipamezole was qualified as good (47.5%) or excellent (40.9%). These perceptions indicate an opportunity for wider use of the products in veterinary practice. With more education and experience, practitioners could find medetomidine hydrochloride alone or in combination with an opioid useful for sedation, analgesia, and premedication for healthy animals. Reversal with atipamezole hydrochloride is considered effective, when residual sedation is undesirable.     

Some factors influencing the level of clinical sedation induced by medetomidine in rabbits

Rabbits (n=23) received intravenous bolus medetomidine at 100 mug/kg. Prior to medetomidine administration, heart and respiratory rates were measured, arterial blood was collected and analysed for plasma cortisol, glucose and albumin concentrations. Fifteen minutes after medetomidine administration, heart and respiratory rates were measured again and sedation was scored. The rabbit was afterwards anaesthetized with 20 mg/kg ketamine administered intravenously to enable spinal tap and heart puncture. Cerebrospinal fluid (CSF) was collected (this occurred 20 min post medetomidine administration) and analysed for medetomidine concentration. Blood was collected by heart puncture immediately after the spinal tap and analysed for serum medetomidine concentration. Cerebrospinal fluid medetomidine concentration correlated negatively with sedation. Serum medetomidine correlated positively with CSF medetomidine concentration. Cerebro-spinal fluid medetomidine was 17 +/- 13% of serum medetomidine concentration. Plasma cortisol and glucose concentrations correlated negatively with serum medetomidine. We conclude that after an intravenous bolus administration of a low sedative dose of medetomidine to rabbits; CSF concentration of the drug correlate negatively with sedation and that this may be because of the fact that only the free and unbound medetomidine may be available for detection in the CSF, the concentration of medetomidine detected in the CSF was much lower than that in blood and a positive correlation exists between CSF and serum medetomidine concentrations. Stress may have some effect on the distribution or metabolism of medetomidine in rabbits.     

The impact of MK‐467 on plasma drug concentrations,sedation and cardiopulmonary changes in sheep treated with intramuscular medetomidine and atipamezole for reversal

The effect of MK‐467, a peripheral α₂‐adrenoceptor antagonist, on plasma drug concentrations, sedation and cardiopulmonary changes induced by intramuscular (IM) medetomidine was investigated in eight sheep. Additionally, the interactions with atipamezole (ATI) used for reversal were also evaluated. Each animal was treated four times in a randomized prospective crossover design with 2‐week washout periods. Medetomidine (MED) 30 μg/kg alone or combined in the same syringe with MK‐467 300 μg/kg (MMK) was injected intramuscular, followed by ATI 150 μg/kg (MED + ATI and MMK + ATI) or saline intramuscular 30 min later. Plasma was analysed for drug concentrations, and sedation was subjectively assessed with a visual analogue scale. Systemic haemodynamics and blood gases were measured before treatments and at intervals thereafter. With MK‐467, medetomidine plasma concentrations were threefold higher prior to ATI, which was associated with more profound sedation and shorter onset. No significant differences were observed in early cardiopulmonary changes between treatments. Atipamezole reversed the medetomidine‐related cardiopulmonary changes after both treatments. Sedation scores decreased more rapidly when MK‐467 was included. In this study, MK‐467 appeared to have a pronounced effect on the plasma concentration and central effects of medetomidine, with minor cardiopulmonary improvement.