Anaesthetic, clinical and physiological effects of medetomodine, midazolam and ketamine combinations in dogs

The quality, duration and cardiorespiratory effects of 3 anaesthetic drugs were determined in 15 healthy adult male dogs. Dogs were divided into 3 equal groups, each group was intravenously administered a combination of 2 of the following drugs: midazolam (0.3 mg/kg), medetomidine (20 μg/kg) and ketamine (10 mg/kg). Induction, anaesthetic and recovery times were recorded. Heart rate, systolic and diastolic blood pressures, respiratory rate, percent saturation of haemoglobin with oxygen (SpO2%), rectal body temperature and blood glucose were traced before and at 5, 10, 15, 30, 45, 60, 90 and 120 minutes after drugs administration. The results revealed that, medetomidine + midazolam combination showed the longest anaesthetic time (43.4±3.5 min), while midazolam + ketamine combination revealed the shortest anaesthetic time (22.8±3.6 min). Medetomidine + ketamine combination caused the least alteration of the heart rate, while midazolam + ketamine combination produced the least changes in the haemoglobin oxygen saturation. Slight dyspnoea and vomiting were observed in some dogs administered medetomidine + ketamine, while dropped eye ball was seen after medetomidine + midazolam injection. The 2 combinations those had medetomidine showed slight elevations in blood glucose. The results concluded that combining ketamine with medetomidine or midazolam decreases their suppressive effect on cardiovascular system and improves the quality of anaesthesia. Introduction Injectable anaesthetics are used to produce short-term anaesthesia in dogs. While inhalant anaesthesia provides controlled anaesthetic depth at relatively low cost, it requires special equipment and pre-anaesthetic medications. Alternatively, injectable anaesthetic drugs are relatively easy to administer and require minimal resources. However, once administered, the drug effect cannot be stopped and respiratory support might be required. Many drugs have been employed alone or in combinations to achieve adequate and temporary anaesthesia in dogs. The ideal injectable short-term anaesthetic drugs should produce adequate hypnosis, muscle relaxation and analgesia, act rapidly, produce 170 Khalil and Hassan predictable and minimal cardiorespiratory effects, be reversible and maintain analgesia after recovery from anaesthesia (Wiese and Muir, 2007). Injectable anaesthetic drugs include hypnotics such as chloralhydrate, opiates such as morphine and fentanyl, α2 agonist such as medetomidine and detomidine, and benzodiazepines such as midazolam (Muir et al, 2007). Medetomidine is a potent and highly selective α2-adrenoceptor agonist and when given to dogs produces dosedependent sedation, analgesia and marked changes to the cardiovascular system, mostly through stimulation of central receptors. Its α2/ α1 selectivity ratio is 1620, which is 5-10 times higher than that for detomidine, clonidine and xylazine (Virtanen et al, 1988). The pharmacological actions of midazolam are identical to those of other benzodiazepines including hypnosis, sedation, and anxiolysis (Kupietzky and Houpt, 1993). Midazolam differs from other agents by virtue of its more rapid onset of clinical effects and shorter duration of action. Midazolam belongs to a newer class of benzodiazepines called imidazobenzodiazepines (Greenblatt and Abemethy, 1985). Ketamine, a dissociative anesthetic, is an N-methyl-D-aspartate (NMDA) antagonist that acts by blocking preand post-synaptic NMDA receptors (Pozzi et al, 2006). Ketamine anesthesia is characterized by a relatively short duration of action and comparatively mild cardiorespiratory effects when used as the sole anesthetic; lower doses (5–10 mg/kg) preserve cardiac function but do not provide surgically acceptable muscle relaxation, analgesia or unconsciousness and may cause hypersalivation (Haskins et al, 1985). The poor muscle relaxation, violent recovery and convulsions has limited the use of ketamine as a sole anaesthetic in dogs (Wright, 1982), therefore, ketamine was usually used as a combination with a variety of tranquilizers and sedatives to achieve adequate analgesia with acceptable muscle relaxation (Haskins et al, 1985; Muir et al, 2007). The purpose of this study was to determine the quality of anaesthesia and cardio-respiratory effects of medetomidine hydrochloride, midazolam and ketamine hydrochloride combination on healthy dogs, therefore to reveal the best combinations. Materials and methods Animals and animal grouping This study was approved by Scientific Ethical Committee, Faculty of Veterinary Medicine, Suez Canal University. 15 adult male dogs weighing between 12.2 and 14.7 kg were included in this study. The dogs were housed in cages separately and fed balanced diet with free access to water. Dogs were randomly divided into 3 equal groups; group (1) was administered medetomidine + midazolam, group (2) administered medetomidine + ketamine, while group (3) was administered with midazolam + ketamine combinations. Before the start of experiment, each dog was SCVMJ, XVI (2) 2011 169 judged to be in good health based on a physical examination and serum chemistry. Experimental procedures and drug doses The anaesthetic doses were decided according to pilot and published studies to achieve duration of nonresponsiveness to a noxious stimulus (toe and tail pinch) of approximately 30 minutes (Muir et al, 2003). Food but not water was withheld from each dog for 6 hours before anaesthesia. According to animal grouping, dogs were intravenously administered a combination of two of the following drugs: 0.3 mg/kg midazolam (Astellas ® ), 20 μg/kg medetomidine hydrochloride (Domitor ® ; Pfizer) and 10 mg/kg ketamine hydrochloride (Ketalar ® 50; Parke-Davis). Data were recorded during stable conditions once the dogs were acclimatized to the laboratory environment before anaesthetics administration and 5, 10, 15, 30, 45, 60, 90 and 120 minutes after drugs administration. Heart rate (beats/min), systolic and diastolic blood pressures (mmHg), respiratory rate (breaths/min), percent saturation of haemoglobin with oxygen (SpO2%), rectal body temperature (oC) and blood glucose (mg/dL) were recorded. The pulse oximeter sensing probe was placed on the ear in conscious dogs and on tongue in anaesthetised ones. Times to lateral recumbency, duration of anaesthesia, and recovery to sternal recumbency were recorded. Dogs were observed for adverse events defined as apnoea for greater than 1 min, SpO2 less than 75% or a systolic arterial blood pressure less than 90 mmHg. Analgesic scoring A noxious stimulus was applied, in the same location, to a rear limb metatarsus and the base of the tail. The noxious stimulus was applied after recording cardiac and respiratory data. A 22 cm Pean intestinal clamp was used to produce a mechanical noxious stimulus by closing it to the first ratchet on the metatarsus or base of the tail for 10 or 60 seconds, respectively, or until the dog responded with a purposeful movement (Vaha-Vahe, 1989). Response to the noxious stimulus was categorized as no response (score of excellent), minimal movement (good), limb/tail withdrawal (fair), or limb/tail withdrawal and lifting of the head (poor). Anaesthesia was considered adequate if the score was excellent. Statistical analysis Results are expressed as mean±SD for the 5 dogs used in each group. Statistical analysis was performed using the One-Way Analysis Of Variance (ANOVA) to compare among the groups for overall differences. A paired Student’s t-test was used to compare between the test groups and control. A level of significance of p<0.05 was accepted. Results After intravenous administration of a combination of two anaesthetic drugs in dogs, medetomidine + midazolam combination showed the longest anaesthetic time (43.4±3.5 min), while midazolam + ketamine combination revealed the shortest anaesthetic time 170 Khalil and Hassan Time (minutes) 0 5 10 15 30 45 60 90 120 Heart rate 88.8±11.4 47.8±7.4* 44.6±7.4* 39.4±8.7* 47.6±9.0* 45.2±9.7* 51.4±9.7* 67±11.1* 76.8±10.1 Systolic b. pressure 124.4±4.2 129.2±5.9 134.6±10.7 128.0±7.3 125.6±5.1 120.6±2.3 123.8±3.4 125.2±4.2 125.0±4.7 Diastolic b. pressure 81.6±3.5 87.2±5.3* 92.8±4.6* 79.8±3.6 79.2±3.8 79.6±3.5* 80.2±5.1 81.8±6.6 79.8±4.9 Respiratory rate 26.8±4.9 19.4±1.7* 16.8±2.6* 15.4±2.1* 17.4±1.1* 18.0±2.2* 21.2±3.8 26.6±2.5 27.2±2.8 SpO2 98.2±2.5 88.4±4.7* 75.8±8.6* 68.6±10.0* 76.8±8.6* 85.2±5.4* 90.2±6.1 96.6±2.5 97.0±2.5 Body temperature 38.40±0.31 39.14±0.28 39.12±0.34 39.22±0.30 39.36±0.33 39.2±0.25 39.06±0.32 39.06±0.25 38.86±0.29 Blood glucose 97.2±7.2 93.4±8.4 98.6±7.8 96.6±7.4 105.2±9.5 106.6±11.3 108.6±12.3 106.8±11.3 107.2±10.3 (22.8±3.6 min). On the other hand, medetomidine + ketamine showed the shortest induction time (6.6±1.1 sec) with moderate anaesthetic time (28.2±2.7 min), (table 1).