Clinical applicability of dexmedetomidine for sedation, premedication and analgesia in cats 1 / 2007

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1 1 / 2007 Clinical applicability of dexmedetomidine for sedation, premedication and analgesia in cats 1 5 Dexmedetomidine: a new 2-adrenoceptor agonist for modern multimodal anaesthesia in dogs and cats 6 7 Clinical applicability of dexmedetomidine for sedation, premedication and analgesia in cats Dexmedetomidine is an 2 -adrenoceptor agonist ( 2 -agonist) licensed for sedation, analgesia and premedication in cats before induction and maintenance of general anaesthesia with ketamine in the USA and EU. 1

2 Although other 2 -agonists are licensed for sedation and anaesthesia in cats or dogs (such as medetomidine or xylazine), dexmedetomidine is superior in its selectivity for binding to the 2 -adrenoreceptor compared to other agents (Scheinin et al. 1989). It is hypothesized that more severe cardiovascular side effects caused by xylazine, compared to medetomidine, result from the agonist effect of xylazine at 1 - adrenoreceptors. Therefore it appears to be advantageous to choose an 2 -agonist with the greatest selectivity for the 2- adrenoreceptor, such as dexmedetomidine, over older 2 -agonist drugs. Dexmedetomidine has sedative, hypnotic and analgesic properties and can therefore play a pivotal role in the premedication and sedation of cats in clinical practice (Granholm et al. 2006). The sedation caused by dexmedetomidine is more profound than sedation that can be achieved with other drugs such as acepromazine or benzodiazepines. This characteristic of dexmedetomidine makes it particularly useful for the management of fractious cats in the peri-anaesthetic period. Sedation or premedication: what s the difference? Although the aims of sedation and premedication are different, the types of drugs used for these two procedures are similar, and often the same drugs are used at different doses to achieve the desired effect (sedation or premedication). Owners often believe that sedation is safer than general anaesthesia, but it is important to realise that this is frequently not the case. The administration of drugs for sedation usually results in the depression of cardiovascular and respiratory systems, while the possibilities to monitor and support the animal during sedation are more limited, certainly with regard to the placement of an endotracheal tube and the administration of oxygen. Sedated animals are also not provided with the same monitoring and support that is automatically given to anaesthetised animals. Therefore when evaluating whether to opt for sedation or anaesthesia it is important to consider the risks associated with sedation, particularly in high-risk patients. Clinical uses of dexmedetomidine in cats The role of dexmedetomidine in the anaesthesia and sedation of cats can be broadly divided into the four areas listed below: 1. Sedation to allow minor procedures to be carried out 2. Premedication prior to induction of anaesthesia 3. General anaesthesia as part of a total injectable anaesthesia protocol in combination with ketamine 4. Analgesia or sedation in the postoperative period Unlike racemic medetomidine, dexmedetomidine holds a license for premedication in cats, and the characteristics of the drug make it very useful for premedication of healthy cats. In addition, there is significant clinical experience with using medetomidine for premedication of both cats and dogs in the UK and continental Europe. This article will first discuss the clinical considerations of using dexmedetomidine (for the methods listed), followed by a detailed analysis of the criteria required for patient selection for dexmedetomidine administration. Patient selection is an important consideration because although the use of dexmedetomidine has many advantages in veterinary anaesthesia, the drug has potent effects on physiological systems. Therefore understanding patient selection is the key to using dexmedetomidine safely and effectively in clinical practice. Use of dexmedetomidine for sedation and premedication The clinical use of dexmedetomidine for sedation and premedication will be considered together because of the similarity between these applications. Dexmedetomidine has a number of advantages when used as a sedative and premedicant agent compared to other sedative drugs such as acepromazine. Profound sedation that is superior to the sedation that can be obtained from acepromazine and opioid combinations. Dexmedetomidine sedation is dose dependent, however similar to acepromazine a plateau is reached and beyond this point further increases in dose prolong the duration of effect rather than increase the intensity of sedation. Synergism between 2 -agonists and opioids or benzodiazepines means that combining dexmedetomidine with either of these agents will lead to more profound sedation, allowing the dose of dexmedetomidine to be reduced. Good sedation after premedication facilitates intravenous induction of anaesthesia in fractious or nervous cats, while reliable sedation increases the success of carrying out minor procedures under a sedative protocol. Provision of analgesia: 2 -agonists have marked analgesic properties (Smith and Elliott 2001), therefore inclusion of dexmedetomidine in a sedation or premedication protocol provides 2

3 analgesia. This contributes to provision of a multi-modal analgesia technique when given in combination with other analgesic drugs (such as opioids or ketamine). Stable plane of anaesthesia: When dexmedetomidine is used for premedication it is usually easier to achieve a stable plane of anaesthesia and avoid large intra-operative swings in depth of anaesthesia as a result of changing surgical stimulation. This stability in anaesthetic depth results from the profound hypnotic and analgesic properties of the drug. Dose sparing effect of other anaesthetic drugs: When dexmedetomidine is given for premedication it will significantly reduce the dose of other drugs required for induction and maintenance of anaesthesia. This results from the sedative / hypnotic properties of dexmedetomidine combined with a reduction in the rate of metabolism of other intravenous drugs such as propofol. It is important to remember the dose sparing effect and give the induction drug slowly and to effect to avoid anaesthetic overdose. (The dose of thiopental or propofol required for induction of anaesthesia may be reduced to 1-3 mg/kg after premedication with 10 µg/kg of dexmedetomidine combined with buprenorphine (20 µg/kg) IM. The concentration of inhalant agent should be adjusted based on clinical assessment of anaesthetic depth). Reversibility: The effects of dexmedetomidine are reversed by the administration of atipamezole. The recovery period has been identified as a high risk period after anaesthesia, probably because animals are poorly monitored and supported even though they are not fully recovered from the effects of the anaesthesia drugs. Shortening the recovery period by the administration of an antagonist may contribute to improved patient safety in the peri-operative period. Practically, reducing the duration of the recovery period after sedation or anaesthesia means that the animal can be returned more quickly to the owner, which is beneficial for both the owner and veterinary surgeon. It is important to be aware that atipamezole also reverses analgesia caused by dexmedetomidine, therefore adequate analgesia from other drugs (such as opioids or NSAIDs) must be given before reversal of dexmedetomidine. These are some tips to improve the quality and safety of sedation after administration of dexmedetomidine to cats: 1. Use dexmedetomidine in combination with an opioid (see table 1 for doses). 2. After administration of dexmedetomidine ensure the cat is placed in a quiet environment for minutes to allow maximum sedation to be achieved. 3. Onset of sedation can be fairly rapid (5 minutes) in some cats. Check the animal to ensure that it does not become recumbent in a position that compromises the airway (e.g. lying with a flexed neck). Vomiting frequently occurs after intramuscular dexmedetomidine. If this occurs ensure the cat does not lie face down in the vomit, which could potentially compromise the airway. 4. If the sedation provided by dexmedetomidine and opioid is inadequate to allow a procedure to be carried out it is usually more successful to proceed to a short duration of anaesthesia with intravenous propofol rather than give top up doses of dexmedetomidine. 5. It is advisable (as with any sedative drug protocol) to provide supplementary oxygen by face-mask to the sedated animal. 6. When dexmedetomidine is used for sedation or premedication the cardiovascular effects of dexmedetomidine will have a profound influence on the characteristics of the ensuing sedation or anaesthesia, particularly with respect to monitored parameters (for example pale mucous membranes and a relatively low heart rate). It is important to understand why these effects occur in order to feel comfortable using dexmedetomidine in clinical practice (Murrell & Hellebrekers 2005). Table 1: Dose rates and drug combinations for premedication and sedation with dexmedetomidine in cats. Dose of dex- Dose of Route of Sedation or medetomidine adjunctive drug administration premedication Dex 5 µg/kg Buprenorphine 20 µg/kg or IV Premedication or Morphine 0.1 mg/kg or mild sedation Butorphanol 0.1 mg/kg Dex 10 µg/kg Buprenorphine 20 µg/kg IM Premedication Morphine 0.2 mg/kg Butorphanol 0.4 mg/kg Dex µg/kg Buprenorphine 20 µg/kg IM Profound Morphine 0.2 mg/kg sedation Butorphanol 0.4 mg/kg TIPS Conservation of body temperature: A clinical spin-off from the peripheral vasoconstriction induced by dexmedetomidine is that it can be easier to maintain normothermia in anaesthetised and sedated cats. 3

4 Dexmedetomidine for general anaesthesia as part of a total injectable anaesthesia protocol in combination with ketamine The combination of dexmedetomidine and ketamine can be used to provide a short duration of anaesthesia (approximately minutes, dependent on dose) in cats. The sedative and muscle relaxant properties of dexmedetomidine offset the muscle rigidity and CNS excitation that occur when ketamine is used alone, while the analgesic properties of dexmedetomidine contribute to a multi-modal analgesia technique. Dexmedetomidine and ketamine can be combined in the same syringe allowing a single, low-volume, intramuscular injection for induction and maintenance of anaesthesia. This protocol can be very useful for the anaesthesia of very fractious, aggressive cats, when intravenous injection is problematic. The speed of onset of anaesthesia combined with the predictable medium duration of anaesthesia also make it a useful protocol when a high surgical throughput is essential (for example in neutering clinics for feral cats). Addition of an opioid to the combination (either butorphanol or buprenorphine) provides additional analgesia and allows similar anaesthetic conditions to be achieved, but with a lower dose of dexmedetomidine. It also ensures that a balanced, multi-modal anaesthesia and analgesia technique is administered. The reversibility and temperature conservation properties of dexmedetomidine are also advantageous for the total injectable combination. Dexmedetomidine for analgesia or sedation in the post-operative period Sedation: The profound sedative properties of dexmedetomidine mean that it can be useful to ameliorate excitement during the recovery period when given as a single IV bolus (1 µg/kg). Cats showing excitatory behaviour during recovery after any anaesthesia protocol can be difficult to manage and can injure themselves unless the behaviour is controlled. Onset of sedation after intravenous dexmedetomidine is almost immediate allowing rapid control over the excitation to be achieved. Duration of sedation can be up to 60 minutes, when recovery from the sedation / analgesia is usually uneventful. It is important to exclude pain as the cause of the poor recovery before a low, sedative dose of dexmedetomidine is given to manage the behaviour. Analgesia should be given as well as, or instead of, dexmedetomidine if post-operative pain is likely to be a contributing factor. Analgesia: The role of dexmedetomidine solely as a post-operative analgesic agent has not yet been evaluated in cats in a clinical environment. 2 adrenoreceptor agonist drugs have analgesic properties (Ansah et al. 2000) but it is likely that the dose of dexmedetomidine required to provide analgesia is higher than the dose required to cause sedation, therefore further work is required to establish whether dexmedetomidine is a useful adjunct to postoperative pain management in cats and to establish the optimal dose. In order to provide continued analgesia a continuous rate infusion of dexmedetomidine is necessary rather than intermittent bolus dosing. Although dexmedetomidine is unlikely to become a first line analgesic drug, it may be a useful adjunct, particularly in combination with opioids, when effective pain management is proving difficult in individual patients. Dexmedetomidine: patient selection Use of dexmedetomidine is only suitable for use in healthy animals that are undergoing procedures that are unlikely to be associated with a deterioration in cardiovascular function. As a result of the physiological effects of dexmedetomidine the following patient groups should not be given dexmedetomidine: Cats with cardiovascular disease (e.g. mitral regurgitation): The cardiovascular effects of dexmedetomidine are usually well tolerated. However in animals with reduced cardiovascular reserve, dexmedetomidine may result in a marked deterioration of cardiovascular function due to an inability to maintain cardiac output in the presence of a peripheral vasoconstriction and bradycardia. 4

5 Systemic disease causing deterioration in cardiovascular function (e.g. toxaemia). Liver disease: Dexmedetomidine will reduce liver blood flow. Although this is not of clinical significance in healthy animals it may compromise liver function in animals with liver disease. Geriatric animals do not have the normal functional organ reserve of adult animals, therefore it is advisable to avoid dexmedetomidine in this patient group. Very young animals: The physiological effects of dexmedetomidine in kittens are unknown. Therefore dexmedetomidine is not the premedicant or sedative agent of choice in animals less than 12 weeks of age. Diabetes Mellitus: This group of patients often have multiple organ disease. This factor, in combination with the effect of dexmedetomidine on blood glucose concentration, means that dexmedetomidine is not the ideal premedicant or sedative drug for cats with diabetes mellitus. Cats with a foreign body where vomiting before induction of anaesthesia is contraindicated (e.g. a cat with a linear foreign body). Conclusions The excellent sedation and analgesia afforded by dexmedetomidine offers tremendous advantages when used for sedation, premedication or as part of a total injectable anaesthesia technique. Dexmedetomidine causes unique changes in the cardiovascular system, with a reduction in heart rate being the most obvious clinical effect. These changes are well tolerated in healthy animals and numerous studies demonstrate that blood flow to vital organs such as the heart, brain, liver and kidneys are well maintained following administration of dexmedetomidine at clinical doses. However it is not a suitable agent to use in animals with reduced cardiovascular reserve or systemic disease. Appropriate case selection and a good understanding of the physiological effects of dexmedetomidine ensure that it can be used safely and very effectively in clinical practice. Some tips to improve the quality and safety of total injectable anaesthesia using dexmedetomidine and ketamine in cats: TIPS 1. Addition of an opioid to the protocol that will provide improved anaesthesia conditions is advisable (see Table 2 for dose combinations). 2. Onset of anaesthesia can be very rapid and it is important to check animals frequently to ensure that they do not become recumbent in a position that compromises the airway (e.g. with a flexed neck). 3. The combination is only suitable to perform surgeries that are of short duration (30-40 minutes or shorter) and predictable in length. Although top-up ketamine and dexmedetomidine can be given to prolong anaesthesia, if a longer duration of anaesthesia is required it is preferable to use an inhalant agent for maintenance of anaesthesia to avoid a prolonged recovery. 4. As with any protocol, administration of supplemental oxygen during anaesthesia is advisable. 5. The cardiovascular effects of ketamine (increase in heart rate and blood pressure) tend to offset the reduction in heart rate that occurs when dexmedetomidine is given alone. This should be considered when monitoring patients anaesthetised with this combination. 6. The eyes will remain open as a result of the central nervous system effects of ketamine. Ensure that a topical lubricant is applied to the surface of the eyes to prevent drying and damage to the corneal surface. 7. The effects of dexmedetomidine can be reversed at the end of anaesthesia by administration of atipamezole. It is advisable to wait 45 minutes after the administration of ketamine before giving atipamezole in order to avoid signs of ketamine excitation during recovery. Table 2: Dose rates for total injectable anaesthesia combinations with ketamine. Dose of dex- Dose of Dose of opioid Route of Duration of medetomidine ketamine administration anaesthesia Dex 15 µg/kg Ket 2.5 mg/kg None IV minutes Dex 15 µg/kg Ket 2.5 mg/kg Buprenorphine IV > 40 minutes 20 µg/kg Butorphanol 0.1 mg/kg Dex 20 µg/kg Ket 5 mg/kg None IM minutes Dex 15 µg/kg Ket 5 mg/kg Buprenorphine 20 µg/kg IM > 40 minutes Butorphanol 0.4 mg/kg Dr. Jo Murrell, BVSc. (hons), PhD, DipECVAA University of Bristol, UK References Ansah OB, Raekallio M, Vainio O. Correlation between serum concentrations following continuous intravenous infusion of dexmedetomidine or medetomidine in cats and their sedative and analgesic effects. J Vet Pharmacol Ther 2000; 23:1 8. Granholm M, McKusick BC, Westerholm FC et al. Evaluation of the clinical efficacy and safety of dexmedetomidine or medetomidine in cats and their reversal with atipamezole. Vet Anaesth Analg 2006;33: Murrell JC and Hellebrekers LJ. Medetomdine and dexmedetomidine: a review of cardiovascular and antinociceptive properties in the dog. Vet Anaesth Analg 2005; 32: Scheinin H, Virtanen R, MacDonald E et al. Medetomidine a novel alpha 2 adrenoreceptor agonist: a review of its pharmacodynamic effects. Prog Neuropsychopharmacol Biol Psychiatry 1989;13: Smith H and Eliott J. Alpha(2) receptors and agonists in pain management. Curr Opin Anaesthesiol 2001;14:

6 Dexmedetomidine: a new 2 -adrenoceptor agonist for modern multimodal anaesthesia in dogs and cats Medetomidine (DOMITOR ), a well-known 2 - adrenoceptor agonist sedative for small animals, was introduced two decades ago, and has since gained a firm position in small animal anesthesiology. It is also known for its good analgesic properties (Sanders and Maze, 2007). Recently, dexmedeto-midine, a new highly selective and specific 2 -adrenoceptor agonist (Savola and Virtanen, 1991), has been approved in the European Union and USA for clinical use in dogs and cats. Pharmacologically, medetomidine is a 1:1 mixture of two enantiomers: dexmedetomidine and levomedetomidine. Dexmedetomidine is the d-enantiomer in medetomidine and is the only enantiomer which possesses pharmacological activity at clinically relevant doses (Kuusela et al. 2000). When compared with the racemate, the selectivity of the active isomer dexmedetomidine is greater for the 2 -receptor than the 1 -receptor (Aantaa et al. 1989). Dexmedetomidine 2 -adrenoceptor agonist of choice for balanced anaesthesia Multimodal pre-emptive, or balanced, anesthesia reduces patient risks and stress, and increases patient safety and comfort. It aims at calming the patient, minimizing pain, and diminishing potential pharmaceutical-related adverse effects. 6 Balanced anesthesia includes the use of different pharmacological substances in order to control the physiological effects caused by anesthesia, together with pain and surgery (or other procedure) related stimuli. In addition to sedatives, anesthetics and analgesics the animal will often receive perioperative antibiotics. This may easily end up to 6-7 different pharmaceuticals used concomitantly (Shih et al. 2007). The removal of inactive enantiomers (such as

7 Total sedative score Time (min) Figure 1. Subjective total sedation score after Dexdomitor or Domitor, administration with or without Antisedan reversal in cats. indicates a significant difference compared to 0 minutes. indicates the time of atipamezole administration. Domitor Dexdomitor Domitor + Antisedan Dexdomitor + Antisedan Minna Rinkinen, DVM, PhD Veterinary Medical Adviser Medical Marketing minna.rinkinen@orionpharma.com Toni Korpivaara, DVM Veterinary Adviser, Clinical R&D Brett C. McKusick, DVM, MS, PhD Clinical Program Leader, Clinical R&D All the writers are from Orion Corporation Orion Pharma the l-enantiomer in medetomidine, levomedetomidine, resulting in pure dexmedetomidine in DEXDOMITOR ) has the advantage of reduced metabolic load and being less likely to cause drug interactions. This may imply a reduced risk for untoward side effects (Kharasch et al. 1992; Ansah et al. 1998). Kuusela et al. suggested that levomedetomidine may actually have some negative cardiovascular effects on dogs. Higher doses of levomedetomidine lowered the heart rate and increased arterial blood pressure (Kuusela et al. 2001). Although bradycardia is common in dogs medicated with 2 -adrenoceptor agonist, dexmedetomidine is not arrhytmogenic. Being a very selective 2 - agonist it does not, unlike xylazine, decrease the arrythomogenic dose of epinephrine (ADE) but instead may even increase the ADE thus acting as an antiarrhytmogenic (Sinclair, 2003). Moreover, a drug formulation containing only the biologically active enantiomer may have some therapeutic advantages over administration of its racemate in that the effects of the active enantiomer could be more predictable, more consistent and easier to control. Unlike medetomidine, DEXDOMITOR has a specific low dosing for premedication. The dosing for premedication is based on body surface area (BSA), making it more accurate in all size dogs and producing less pronounced preoperative sedation. Dexmedetomidine can be combined with butorphanol (Selmi et al. 2003; Leppänen et al. 2006) as the combination of an 2 - adrenoceptor agonist and an opioid results in better sedation, muscle relaxation and analgesia than 2-agonist alone (Pypendop and Verstegen, 1999; Kuo and Keegan, 2004). Similarly to medetomidine, antagonism of the clinical effects of dexmedetomidine is successfully achieved with specific reversal agent atipamezole (Figure 1), that offers controlled, high quality recoveries providing confidence and convenience in busy practice environment. Similar clinical effects as medetomidine Several studies have been conducted in dogs and cats and have concluded that dexmedetomidine (at half the dose of medetomidine) produces the same reliable sedation, analgesia, and muscle relaxation as medetomidine (Figure 1). Dexmedetomidine has been shown to be as effective as medetomidine when used as premedication prior to general anesthesia as well as in combination with butorphanol for deep sedation and analgesia. Limited information suggests that despite similar clinical effects during early sedation recovery may be shorter for dexmedetomidine compared to medetomidine. Dexmedetomidine is also used in human anesthesiology The active molecule dexmedetominide is also approved by FDA in USA for human use as a sedative for intensive care patients. It has the advantage of well-controlled and reversible sedation up to 24 hours (Szumita et al. 2007). In addition, dexmedetomidine has become a widely used sedative and premedicant for pediatric anaesthesiology as it causes no or only minor respiratory depression, and is has been used on children as young as 5 weeks of age (Tobias, 2007). 2 -agonists, dexmedetomidine amongst them, are also acknowledged for their neuro-, nefro- and cardioprotective properties (Sanders and Maze, 2007; Tobias 2007). Whether dexmedetomidine provides such tissue protection also in cats and dogs remains yet to be examined. References Aantaa R, Kallio A, Virtanen R. Dexmedetomidine, a novel 2 -adrenergic agonist. A review of its pharmacodynamic characteristics. Drugs Future 1989:18, Ansah OB, Raekallio M, Vainio O. Comparison of three doses of dexmedetomidine with medetomidine in cats following intramuscular administration. J Vet Pharmacol Ther 1998;21: Kharasch ED, Herrmann S, Labroo R. Ketamine as a probe for medetomidine stereoisomer inhibition of human liver microsomal drug metabolism. Anesthesiol 1992;77: Kuo WC, Keegan RD. Comparative cardiovascular, analgesic, and sedative effects of medetomidine, medetomidinehydromorphone, and medetomidine-butorphanol in dogs. Am J Vet Res. 2004;65: Kuusela E, Raekallio M, Vainio O. Comparison of three doses of dexmedetomidine and its enantiomers in dogs. J Vet Pharmacol Ther 2000;23: Leppänen MK, McKusick BC, Granholm MM, Westerholm FC, Tulamo R, Short CE. Clinical efficacy and safety of dexmedetomidine and buprenorphine, butorphanol or diazepam for canine hip radiography. J Small Anim Pract. 2006;47: Pypendop B, Verstegen J. Cardiorespiratory effects of a combination of medetomidine, midazolam, and butorphanol in dogs. Am J Vet Res 1999:60: Sanders RD, Maze M. 2 -Adrenoceptor agonists. Curr Opin Investig Drugs 2007:8; Savola JM, Virtanen R. Central 2 -adrenoceptors are highly stereoselective for dexmedetomidine, the dextroenantiomer of medetomidine. Eur J Pharmacol 1991;195; Selmi AL, Mendes GM, Lins BT, Figueiredo JP, Barbudo-Selmi GR. Evaluation of the sedative and cardiorespiratory effects of dexmedetomidine, dexmedetomidine-butorphanol,and dexmedetomidine-ketamine in cats. JAVMA 2003;222: Shih AC, Robertson S, Isaza N, Pablo L, Davies W. Comparison between analgesic effects of buprenorphine, carprofen, and buprenorphine with carprofen for canine ovariohysterectomy. Vet Anaesth Analg 2007 (Online Early Article ahead of print). Sinclair MD. A review of the physiological effects of 2 -agonists related to the clinical use of medetomidine in small animal practice. Can Vet J 2003;44: Szumita PM, Baroletti SA, Anger KE, Wechsler ME. Sedation and analgesia in the intensive care unit: Evaluating the role of dexmedetomidine. Am J Health Syst Pharm. 2007;64: Tobias JD. Dexmedetomidine: Applications in pediatric critical care and pediatric anesthesiology Pediatr Crit Care Med 2007;8:

8 Meet us: Contact us: Orion Pharma Animal Health, P.O. Box 425, FIN TURKU, Finland. Tel , fax DOMOSEDAN /DORMOSEDAN, DOMITOR, DEXDOMITOR and ANTISEDAN are also distributed by Pfizer Animal Health and Zenoaq.