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

Abstract

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.

Introduction

Medetomidine hydrochloride (Domitor; Pfizer Canada Animal Health, London, Ontario) and atipamezole hydrochloride (Antisedan; Pfizer Canada Animal Health) are relatively new products in veterinary practice in Canada, even though they are widely used in small animals in Europe. This survey was made only 6–8 mo after these drugs were licensed for use in veterinary practice in Canada. We were interested in evaluating the early perceptions of veterinary practitioners in Quebec as to the acceptability and perceived value of these new drugs.

Medetomidine is a highly selective alpha-2 agonist, which has sedative, anxiolytic, muscle relaxant, and analgesic properties. It is the most potent alpha-2 agonist available for clinical use in veterinary medicine at this time. It is supplied in a racemic mixture of 2 optical enantiomers (dexmedetomidine and levomedetomidine). Dexmedetomidine, the active enantiomer, has a high affinity for alpha-2 adrenoceptors, where it acts as a full agonist (1–3). Medetomidine has a selectivity ratio of 1620/1 (α2/α1), which is 5–10 times higher than that for detomidine (260/1) and xylazine (160/1) (1,4). Medetomidine has a very low affinity for α-1 adrenoceptors and interacts with central imidazoline receptors, in contrast to xylazine. This makes it potentially superior for use in small animals, particularly by developing an anti-arrhythmic property, mediated by an imidazoline/vagal tone stimulation (3).

Medetomidine can be given intramuscularly (IM), intravenously (IV), or subcutaneously (SC). After IM administration, the drug is rapidly absorbed and peak plasma levels are reached within 30 min. When given, IV, the onset of action is rapid, but the peripheral cardiovascular effects are more pronounced than when given, IM. When given, SC, in dogs, the absorption time of the drug is slow and variable, which makes this route of administration less favorable (5).

In healthy dogs, the recommended dose range of medetomidine in North America is 10–40 μg/kg bodyweight (BW) (6). It is more appropriate to calculate the dosage of medetomidine on the body surface area than the body weight, but the latter is easier and practitioners are more familiar with dosing according to bodyweight. Earlier studies of medetomidine in clinical practice suggested the optimal dose to be 30–40 μg/kg BW for dogs (7). The highest dose of medetomidine recommended for dogs is 80 μg/kg BW (8). However, much smaller doses are adequate for perioperative use when given with other anesthetic/analgesic drugs, since the sedative and analgesic effects of medetomidine are very profound (9) and are additive or synergistic (10). The major adverse effects of the alpha-2 adrenoceptor agonists are on the cardiovascular system: they can produce biphasic blood pressure response (hypertension followed by normo/hypotension), followed by decreased heart rate (profound bradycardia) and cardiac index, increased systemic vascular resistance index and central venous pressure, and decreased myocardial contractility and perfusion (8,11,12). These effects are to a certain extent dose-dependent (13,14).

Atipamezole is an alpha-2 antagonist synthesized to antagonize the behavioral, cardiovascular, gastrointestinal, neurochemical, and hypothermic effects of medetomidine (1,11,15). The arousal time after IM administration of atipamezole (at a dose approximately 5 times that of medetomidine) is approximately 5 min (16). Administration of the antagonist will also reverse analgesia produced by medetomidine (17). Reversal with atipamezole is recommended when significant cardiopulmonary complications (profound bradycardia, myocardial failure, hypoventilation) occur (15). Its main indication is reversal after nonpainful diagnostic or therapeutic procedures; usually it is not given perioperatively.

This paper presents the results of a survey of small animal veterinary practitioners in Quebec made early in 2002, using a mail-in questionnaire about the use of these 2 drugs, with the intent to define the early perceptions related to the use of these products.

Materials and methods

An anonymous questionnaire to investigate utilization of the alpha-2 agonist medetomidine and its reversing agent, the alpha-2 antagonist atipamezole, in private small animal veterinary practice was mailed to 898 members of the College of Veterinary Medicine in Quebec (Ordre des Médecins Vétérinaires du Québec, OMVQ) in December 2001. The answers were received until mid-February 2002. The 1st page of the questionnaire explained that the survey was initiated by the anesthesia unit at the Faculty of Veterinary Medicine (FMV) and that the information it provided would assist the unit in directing the veterinary continuing education program.

The questionnaire consisted of 19 questions. Most questions were designed to require a checkmark of 1 or more of the provided answers. A few questions invited written responses or comments. The first 4 questions asked for general information about the use of these drugs in normal daily practice: how often these drugs are used, for which procedures, for which animals, and for animals of what age. Questions 5 through 8 asked about medetomidine: routes of administration, dosage and an opinion about the quality of the sedation and analgesia obtained. Questions 9 and 10 asked about atipamezole: route of administration and quality of reversal effects. Question 11 asked about the use of medetomidine in combination with other agents presenting pure or mixed anesthetic, sedative or analgesic properties, and question 12 asked what monitoring was typically used during anesthesia. Questions 13 through 17 asked about the adverse effects of these drugs and their occurrence in practice. The 2 final questions invited practitioners to write their comments about the advantages and disadvantages of using these drugs in their practice.

Statistical and power analysis software (NCSS 2001 and PASS 2000; Number Cruncher Statistical Systems, Kaysville, Utah, USA) was used to calculate the statistical power of the analysis, analyze the responses to the multiple choice questions, realize graphic descriptions, and provide 95% confidence intervals. The written answers and comments were read and interpreted by veterinarians working in the anesthesia service at the FMV. Due to the descriptive nature of this survey, only descriptive statistical analysis of the results was relevant.

Results

The results are presented as percentages with 95% confidence intervals between brackets. Two hundred and eleven questionnaires were returned (23.5%). Of the practitioners who answered, 71.1% (65–78) did not use either medetomidine or atipamezole in their practice. In 69.3% (58–82) of the answers to multiple choice questions, lack of information was selected as the reason not using these products. In 23.3% (15–38) of the answers, these products were not available at the workplace, and 7.3% (1–14) of the answering practitioners did not use them for various other reasons, including the aspect of insecurity concerning the safety of alpha-2 agonists. Of the practitioners who used these products, 70.4% (59–83) used them only rarely, 22.9% (15–38) occasionally, and 6.5% (1–14) frequently.

Further questions about the circumstances for using these drugs, monitoring, and the advantages and inconveniences with the drug use were answered only by the veterinarians who had used the drugs.

Circumstances for which practitioners used medetomidine were as follows (Figure 1): 73.7% of use was primarily for sedation alone, and secondarily (18.7%) for premedication before general anesthesia; 7.5% (4–21) of use was for profound restraint for minor procedures, analgesia, or euthanasia. Seventy-seven percent (67–90) of responding veterinarians used medetomidine and atipamezole exclusively for dogs; in 48% (37–63) of the cases for dogs aged between 5 and 60 mo. The dosing curves provided by the drug distributing company were used by 70.4% (59–83) of responding practitioners. These dose recommendations were divided into 3 different dosing curves, depending on the depth of sedation and analgesia required; the drug distributor also provided different curves for medetomidine when used in combination with butorphanol. Medetomidine was administered, IM, exclusively by 63.9% (23–48) of responders. With these dose levels and most often with IM injections, the sedation obtained was qualified as good by 44.2% (32–58) of responders, as excellent by 36% (23–48) of responders, and as average, poor, or variable by 19.6% (11–32) of responders. With the dose levels that were used, the analgesia produced by medetomidine was qualified as good by 46.5% (32–58) of responders, average by 32.7% (23–48) of responders, excellent by 13.8% (7–27) of responders, and poor or variable by 6.9% (1–14) of responders. Concerning atipamezole, used by all medetomidine users (29.9% of responders), the preferential route of administration was IM for 81.8% (73–94); 8.2% (4–21) of responders did not have any preference about its route of administration. The rapidity of awakening after atipamezole administration was qualified as good (5–10 min) by 47.5% (37–63) of responders, as excellent (less than 5 min) by 40.9% (28–53) of responders, and average by 11.4% (4–21) of responders.

Figure 1.

Circumstances where medetomidine was used in small animal practice. 1) Sedation 73.7% (64–87); 2) premedication 18.7% (11–32); and 3) anesthesia in minor procedures, analgesia, or euthanasia 7.5% (4–21).

Medetomidine was used as a sole agent by 31.2% (19–43) of responders, in combination with anticholinergics by 28.7% (19–43) of responders, and in combination with an opioid by 25% (15–38) of responders. Some veterinarians also reported other combinations, such as medetomidine with benzodiazepines (diazepam, midazolam), ketamine, acepromazine, and volatile anesthetics.

No monitoring during anesthesia was used by 11.4% (4–21) of veterinarians, but 58.5% (46–71) reported that they used at least a pulse oximeter. Five responders used only manual assessment of clinical signs to monitor depth of anesthesia, 12 used the Doppler system, 7 used electrocardiography (ECG), 3 used respiratory monitoring, and 2 used an esophageal stethoscope. Even though 24.5% (15–38) of users had not observed any severe bradycardia when using medetomidine, 52.4% (37–63) had used atropine or glycopyrrolate to counteract the bradycardic effects, and commented that this was not always effective.

There were 44.2% (32–58) of veterinarians that reported having encountered problems when using medetomidine or atipamezole. Principal problems with their use included the following: bradycardia, insufficient (sedative or analgesic) effects, pale mucous membranes, and abnormal respiratory patterns. Rare problems were aggression (n = 2), polyuria (n = 1), hypotension (n = 1), excessive sedation (n = 1), an episode of convulsions (n = 1), and death (n = 1). Problems in peripheral venous catheterization after administration of medetomidine were reported by 18% (11–32) of responders. The color of the mucous membranes after medetomidine administration was reported to be pale by 43.3% (32–58) of responders and of normal color by 32.7% (23–48). Relapse into sedation at some time after atipamezole administration was rarely seen, reported by only 4.9% of the user veterinarians. Other secondary effects of medetomidine mentioned were vomiting (n = 2) and cyanotic mucous membranes (n = 12).

Principal advantages reported for the use of medetomidine and atipamezole were rapid reversibility of sedative and other effects (n = 53), thereby, decreasing hospitalization time; good relaxation and sedation (n = 6); security (n = 3); and ease of administration (n = 4). Among other comments about the advantages of using these products were anxiolysis of nervous and aggressive dogs, and client satisfaction related to the fast recovery of the animal. Some veterinarians commented that the use of medetomidine and atipamezole was safe and reliable; others used the words “fast and effective.” Principal inconveniences reported by 31 veterinarians were a certain discomfort in their use and, thereby, the need for constant monitoring because of the adverse effects (bradycardia, respiratory depression, and cyanosis). Other principal inconveniences were reported to be the inadequate, variable, or inconsistent sedative and analgesic effects (n = 19) and the high cost of these products (n = 9). Other comments included long waiting time after injection before the animal could be manipulated, excessive urination at the time of awakening, and vasoconstriction, which made catheterization difficult. Veterinarians also mentioned difficulties in evaluating whether patients were normal when under the influence of medetomidine and the limitation of their use for only healthy and young patients. Some veterinarians called their use unreliable and dangerous. Also, some mentioned that the use of these products would be much easier, if they had been available during their veterinary education.

Discussion

Our results provide important information on the early perceptions of the practitioners in regard to these drugs. The response rate, and the fact that these products were fairly new, with only a few of the responding practitioners using them in their daily practice, could indicate that our results were biased toward a more negative point of view about the use of these products.

The low utilization rate, however, may be related to the original experiences in using xylazine, another alpha-2 agonist. When xylazine was introduced to the veterinary market, its potency was not always respected. This drug was used indiscriminately on all types of patients at relatively high doses and, in some circumstances, without consideration of the potent dose-sparing benefits on other drug use (18). Despite their widespread clinical use, at least in Europe, concerns about the cardiovascular effects of alpha-2 agonists have prevented their full adoption into veterinary practice in Canada (3). In fact, in morbidity and mortality studies from the UK and Canada, xylazine premedication was considered to have a higher complication and mortality risk than that associated with other preanesthetic regimes (19,20). It has been suggested that the arrhythmogenic potential of xylazine may have contributed to the relatively high occurrence of deaths associated with xylazine in the UK study (19). However, the total number of dogs that received xylazine in that survey was low (only 152). We are missing equivalent information for medetomidine, but surveys are in progress. We think that these former studies and experiences with xylazine may have caused the low interest in using medetomidine determined from this survey. Also, these former studies have presumably affected the instruction on and use of alpha-2 agonists in general in veterinary teaching hospitals, which, in turn, influences their use by private practitioners.

Xylazine increased the likelihood of dysrhythmias in halothane and isoflurane-anesthetized dogs (21,22). Subsequent studies in dogs showed that lower levels of more specific alpha-2 agonists do not facilitate the development of reentrant ventricular arrhythmias in halothane or isoflurane-anesthetized dogs (21,23–25). The difference in affinity to alpha-2 receptors of xylazine and medetomidine could explain the difference in dysrhythmogenic potential between them. Further, the decrease in sympathetic tone and increase in parasympathetic tone induced by medetomidine may actually attenuate the development of epinephrine-induced arrhythmias in healthy dogs (26). The vagal activity plays a significant role in this potential anti-arrhythmic action (27), which is mediated more by imidazoline I-1 receptors in the central nervous system than by alpha-2 adrenoceptors, and unlike xylazine, medetomidine has an imidazole ring in its structure that may interact with the imidazoline receptor (3,27,28). There is no evidence of a protective effect in dogs with preexisting arrhythmia, but concerns for precipitating a fatal arrhythmia in a healthy dog should not exist, based on this evidence.

Reasons for not using these products, as answered in this questionnaire, were primarily, the lack of information about the products and a lack of availability in the veterinary clinic. With these answers, we could presume that education about and increased knowledge and marketing of these drugs may result in an increase in their use among practitioners in Quebec. The infrequent use of medetomidine, noticed in this survey, may reflect a lack of perceived need for or discomfort with its use, thereby restricting its use to situations with extreme need for restraint. It may also reflect a lack of education on the safe use of these drugs, which could indicate that there is a place for more education in veterinary colleges and also continuing education for practitioners about anesthesia and, specifically, about new drugs either on the market now or coming in future.

The responses indicated that practitioners have a good understanding related to patient selection for the use of these drugs. In accordance with the licenses of these drugs in Canada, these products were used mainly for dogs and mostly for healthy animals, rather than for older or cardiovascular compromised patients. In Europe these products are also licensed for cats.

Most responders used these drugs according to the dosing curves provided by the drug distributing company (at the time of the survey, this was Novartis santé animale) in Canada. Based on these curves, the dose level for a 16–20 kg dog is 20 μg/kg BW for light, 40 μg/kg BW for moderate, and 60 μg/kg BW for profound sedation and analgesia. Compared with the recommended dose range of medetomidine in North America, which is 10–40 μg/kg BW (6), the dosing curves for profound and even moderate sedation appear excessive. Much lower doses than those shown in the lowest dosing curve are currently considered adequate for premedication or perioperative analgesia (1–10 μg/kg BW) (4,29).

The administration of medetomidine in this survey was IM exclusively for 63.9% of responders, but some considered that the effectiveness of medetomidine was better when administered IV, because after IM administration the delay before sedation was too long. This contrasts with the results of other studies where the absorption after IM injection is rapid and complete (5,30). If the IM administration inadvertently deposits the drug between fascias or within connective tissue or fat, absorption may be delayed, resulting in poor sedation. Other factors influencing efficacy and interfering with smooth sedation are high endogenous catecholamine levels in the patient due to stress, excitement, or pain. When possible, a calm, gentle handling of the animal during administration of the drug is desirable. Sedation is more effective in quiet areas without environmental stimulation (17), and sedation is of superior quality when combined with an opioid (31).

Cardiac or respiratory disorders (among other disorders), obesity, or cachexia may influence levels of sedation. Very young and very old animals usually need lower doses of medetomidine to achieve sedation than would be predicted from their body weight alone. Also small dogs seem to need higher doses of medetomidine per kilogram, compared with large dogs, to get an equivalent effect (32), which agrees with the principle of dosing on surface area.

The answers in this survey were in accordance with research studies where medetomidine was found to produce profound sedation and good analgesia (33,34). Furthermore, the use of atipamezole in this survey is in agreement with previous publications (11,15,16), where preferential route of administration was IM. However, the IV route may be used in emergency situations to allow an even more rapid antagonist effect or partial reversal by using slow titration to effect.

Only a few responders used medetomidine with any other sedatives or general anesthetics, but about 30% used them with anticholinergics. In veterinary practice, the use of anticholinergics with alpha-2 agonists is controversial and has been summarized well in a previously published review (18). The concomitant use of medetomidine and an anticholinergic is associated with a high risk of detrimental hemodynamic effects, where the increase in afterload induced by medetomidine is worsened by the partial counteractive effect of the anticholinergic on the reflex bradycardia, leading to increased myocardial workload and oxygen demand (18). Moreover, with regard to the recent discovery of the imidazoline/vagally mediated anti-arrhythmic property of medetomidine, it could be hypothesized that concomitant use of an anticholinergic may abolish this beneficial effect of medetomidine. For these reasons, it has been suggested that the safest remedy for life-threatening bradyarrhythmias is reversal by an alpha-2 antagonist (14,35).

The use of combinations of opioids and alpha-2 agonists is encouraged and supported by the authors of this survey. The combination can result in profound sedation and analgesia in dogs (17). Evidence of synergistic effects of alpha-2 agonists with opioids has been defined in studies with mice (36), rats (10), and cats (37). Also, when used in combination, the adverse actions of both drugs may be diminished due to the lower doses required. The use of medetomidine (5–10 μg/kg BW) and butorphanol (0.1–0.2 mg/kg BW), morphine (0.1–0.3 mg/kg BW) or hydromorphone (0.1 mg/kg BW) is highly promising for sedation for diagnostic procedures and premedication for routine elective surgery in small animals, providing excellent sedation, muscle relaxation, and analgesia (4,18,29,31). The potential reversal of medetomidine by using atipamezole hastens recovery of the patient, while the maintenance of analgesia is retained due to the opioid. Care must be taken to avoid complete medetomidine reversal when some mild sedative effects could be beneficial (excitable dogs).

The need for monitoring of the patient during anesthesia must be emphasized. Use of the pulse oximeter, ECG, and esophageal stethoscope was noted in this survey, but these techniques are not considered early predictors of cardiovascular insufficiency (38). These monitors do not reliably indicate the state of perfusion or blood pressure (39). Hypotension is the most common complication during anesthesia (40) and can lead to other problems, such as renal hypoperfusion or cardiac complications. Even though the monitoring during anesthesia reported in this survey was sometimes limited and, therefore, would reduce complication identification, there were many veterinarians (44.2%) that reported having encountered complications when using medetomidine or atipamezole. Principal problems were cardiorespiratory and insufficient sedative/analgesic effects. Some less frequently encountered complications were mentioned, but in most of the cases the unwanted effects were successfully reversed with atipamezole. Almost all the mentioned complications are known secondary effects of medetomidine (polyuria, hypotension, vomiting, pale mucous membranes, etc.) that should be kept in mind when using it as a sedative/analgesic drug for any patient.

Although most of the users in this survey did not perceive peripheral vasoconstriction and subsequent difficulties in peripheral venous catheterization as a problem, practitioners should keep these factors in mind when using medetomidine for premedication. The use of much lower doses of medetomidine for premedication is considered appropriate and also decreases the peripheral vasoconstriction detected by smaller increases of systemic vascular resistance (13). The vasoconstriction effect of medetomidine causes the mucous membranes to be paler than veterinarians are familiar with when using other sedatives. In spite of the pale or cyanotic color of mucous membranes, the arterial oxygen tensions are only insignificantly changed and oxygen saturation is usually over 95% (5,6). It has been suggested that the cyanosis occurs due to venous desaturation because of the bradycardia and slower flow through tissues, leading to increased oxygen extraction. The color of mucous membranes is not a reliable indicator of blood pressure or perfusion problems during anesthesia, which should encourage veterinarians to use specific blood pressure monitoring during anesthesia.

Relapse sedation after atipamezole administration was rarely reported in this survey. This is in accordance with research studies (1,4,6,11,15,16,41). Atipamezole has been shown to have a great affinity to alpha-2 receptors (α2/α1 ratio of 8500) and when used at 4–6 times the dose of medetomidine, anytime between 15–60 min after the injection of medetomidine, it has an effect which lasts sufficiently long to prevent return to sedation (16).

It is not surprising that the principal advantages of medetomidine reported by private practitioners in this survey were reversibility and decreased hospitalization time, resulting in efficiency and, of course, greater client satisfaction. The reversal property is also useful to hasten recovery after anesthesia, without interrupting the analgesia, if an opioid is also used.

Concern for safety was reported in this survey as a reason for limited or lack of use. Veterinarians felt that there was the need for more monitoring than done with the more commonly used sedatives/analgesics because of the adverse effects (bradycardia, respiratory depression, cyanosis). However, all clinically used sedatives and general anesthetics have potential adverse effects. Opioids produce extensive respiratory depression and are also candidates for inducing dysphoria and hyperalgesia. Sedatives, such as acepromazine, produce inconsistent sedation, of possibly undesirable long duration, and vasodilatation, which is associated with hypotension. All general anesthetics (thiopental, propofol, halothane, isoflurane, etc.) have dramatic effects on myocardial and respiratory functions and a very narrow therapeutic range (29). This shows that the question of selecting 1 drug rather than another in healthy animals is purely a question of experience with the drugs, previous knowledge about adverse effects, and individual patient tolerance for such secondary effects. Other principal inconveniences were reported to be the inadequate, variable, and inconsistent effects. Several reasons for this have been discussed previously. The high cost of these products was also regarded as a major inconvenience. It might be argued that when used at adequately low doses and in combinations with other drugs, medetomidine has a great anesthetic drug-sparing effect, that in turn decreases the cost of these other anesthetics. When using medetomidine as premedication, there is a major reduction in any subsequent anesthetic requirements (41–43).

In conclusion, with further education and greater experience in use, more practitioners in Quebec might find these drugs a useful addition in their daily practice. Also, the lack of education, both in veterinary college clinics for veterinary students and continuing education for practitioners, suggests that there is room for improvement in these areas. Such continuing education programs are exactly the way to promote, enhance, and advance anesthesia quality and pain management in animals.