Pharmacokinetics of detomidine and its metabolites following intravenous and intramuscular administration in horses

Reasons for performing study: Detomidine is commonly used i.v. for sedation and analgesia in horses, but the pharmacokinetics and metabolism of this drug have not been well described. Objectives: To describe the pharmacokinetics of detomidine and its metabolites, 3‐hydroxy‐detomidine (OH‐detomidine) and detomidine 3‐carboxylic acid (COOH‐detomidine), after i.v. and i.m. administration of a single dose to horses. Methods: Eight horses were used in a balanced crossover design study. In Phase 1, 4 horses received a single dose of i.v. detomidine, administered 30 μg/kg bwt and 4 a single dose i.m. 30 üg/kg bwt. In Phase 2, treatments were reversed. Plasma detomidine, OH‐detomidine and COOH‐detomidine were measured at predetermined time points using liquid chromatography‐mass spectrometry. Results: Following i.v. administration, detomidine was distributed rapidly and eliminated with a half‐life (t_1/2(el)) of approximately 30 min. Following i.m. administration, detomidine was distributed and eliminated with t_1/2(el) of approximately one hour. Following, i.v. administration, detomidine clearance had a mean, median and range of 12.41, 11.66 and 10.10–18.37 ml/min/kg bwt, respectively. Detomidine had a volume of distribution with the mean, median and range for i.v. administration of 470, 478 and 215–687 ml/kg bwt, respectively. OH‐detomidine was detected sooner than COOH‐detomidine; however, COOH‐detomidine had a much greater area under the curve. Conclusions and potential relevance: These pharmacokinetic parameters provide information necessary for determination of peak plasma concentrations and clearance of detomidine in mature horses. The results suggest that, when a longer duration of plasma concentration is warranted, the i.m. route should be considered.     

Evaluation of a romifidine constant rate infusion protocol with or without butorphanol for dentistry and ophthalmologic procedures in standing horses

ObjectiveTo compare the clinical usefulness of constant rate infusion (CRI) protocols of romifidine with or without butorphanol for sedation of horses.Study designProspective ‘blinded’ controlled trial using block randomization.AnimalsForty healthy Freiberger stallions.MethodsThe horses received either intravenous (IV) romifidine (loading dose: 80 μg kg^?1; infusion: 30 μg kg^?1 hour^?1) (treatment R, n = 20) or romifidine combined with butorphanol (romifidine loading: 80 μg kg^?1; infusion: 29 μg kg^?1 hour^?1, and butorphanol loading: 18 μg kg^?1; infusion: 25 μg kg^?1 hour^?1) (treatment RB, n = 20). Twenty-one horses underwent dentistry and ophthalmic procedures, while 19 horses underwent only ophthalmologic procedure and buccal examination. During the procedure, physiologic parameters and occurrence of head/muzzle shaking or twitching and forward movement were recorded. Whenever sedation was insufficient, additional romifidine (20 μg kg^?1) was administered IV. Recovery time was evaluated by assessing head height above ground. At the end of the procedure, overall quality of sedation for the procedure was scored by the dentist and anaesthetist using a visual analogue scale. Statistical analyses used two-way anova or linear mixed models as relevant.ResultsSedation quality scores as assessed by the anaesthetist were R: median 7.55, range: 4.9–9.0 cm, RB: 8.8, 4.7–10.0 cm, and by the dentist R: 6.6, 3.0–8.2 cm, RB: 7.9, 6.6–8.8 cm. Horses receiving RB showed clinically more effective sedation as demonstrated by fewer poor scores and a tendency to reduced additional drug requirements. More horses showed forward movement and head shaking in treatment RB than treatment R. Three horses (two RB, one R) had symptoms of colic following sedation.Conclusions and clinical relevanceThe described protocols provide effective sedation under clinical conditions but for dentistry procedures, the addition of butorphanol is advantageous.     

Behavioural and cardiovascular effects of medetomidine constant rate infusion compared with detomidine for standing sedation in horses

ObjectiveTo compare the efficacy of a medetomidine constant rate infusion (CRI) with a detomidine CRI for standing sedation in horses undergoing high dose rate brachytherapy.Study designRandomized, controlled, crossover, blinded clinical trial.AnimalsA total of 50 horses with owner consent, excluding stallions.MethodsEach horse was sedated with intravenous acepromazine (0.02 mg kg^–1), followed by an α₂-adrenoceptor agonist 30 minutes later and then by butorphanol (0.1 mg kg^–1) 5 minutes later. A CRI of the same α₂-adrenoceptor agonist was started 10 minutes after butorphanol administration and maintained for the treatment duration. Treatments were given 1 week apart. Each horse was sedated with detomidine (bolus dose, 10 μg kg^–1; CRI, 6 μg kg^–1 hour^–1) or medetomidine (bolus dose, 5 μg kg^–1; CRI, 3.5 μg kg^–1 hour^–1). If sedation was inadequate, a quarter of the initial bolus of the α₂-adrenoceptor agonist was administered. Heart rate (HR) was measured via electrocardiography, and sedation and behaviour evaluated using a previously published scale. Between treatments, behaviour scores were compared using a Wilcoxon signed-rank test, frequencies of arrhythmias with chi-square tests, and HR with two-tailed paired t tests. A p value <0.05 indicated statistical significance.ResultsTotal treatment time for medetomidine was longer than that for detomidine (p = 0.04), and ear movements during medetomidine sedation were more numerous than those during detomidine sedation (p = 0.03), suggesting there may be a subtle difference in the depth of sedation. No significant differences in HR were found between treatments (p ≥ 0.09). Several horses had arrhythmias, with no difference in their frequency between the two infusions.Conclusions and clinical relevanceMedetomidine at this dose rate may produce less sedation than detomidine. Further studies are required to evaluate any clinical advantages to either drug, or whether a different CRI may be more appropriate.     

The use of sedatives,analgesic and anaesthetic drugs in the horse: An electronic survey of members of the American Association of Equine Practitioners (AAEP)

Reasons for performing study: To determine the sedative, analgesic and anaesthetic drugs and techniques that are used by equine veterinarians. Hypothesis or objectives: To provide equine veterinarians with information concerning veterinary use of anaesthetic techniques, a reflection of the collective experiences of the profession. Methods: A survey was conducted of those members of the American Association of Equine Practitioners (AAEP) with an electronic mail address on file with the organisation using proprietary, web‐based software. The survey was comprised of 30 questions divided into 8 sections: nonsteroidal anti‐inflammatory drugs; local anaesthesia; alternative techniques; standing chemical restraint; epidural anaesthesia; short‐term anaesthesia; long‐term anaesthesia; and a place for the respondent to make comments. Results: The response rate was 13.8% (952/6911) AAEP member veterinarians primarily use phenylbutazone and flunixin as anti‐inflammatory drugs, and lidocaine and mepivacaine for local anaesthesia. Combinations of drugs are preferred for standing chemical restraint. While many veterinarians frequently utilise short‐term anaesthesia, longer anaesthesia is less frequently performed. Conclusions: Most AAEP member veterinarians use sedatives in combination to provide standing chemical restraint. Extra‐label use of drugs is a core component of current equine sedation and anaesthetic practice. Potential relevance: Equine veterinarians can compare their choices of anaesthetic drugs with others practising equine medicine and surgery and may be stimulated to investigate alternative methods of providing comfort to horses.     

A preliminary trial of the sedation induced by intranasal administration of midazolam alone or in combination with dexmedetomidine and reversal by atipamezole for a short‐term immobilization in pigeons

ObjectiveTo assess the sedative and immobilization effect of intranasal administration (INS) of midazolam (MID) without or with INS dexmedetomidine (DXM), and some physiological changes induced by the drugs. The ability of INS atipamezole to reverse the DXM component was also assessed.Study designProspective ‘blinded’ experimental study.AnimalsIn total, 15 pigeons.MethodsPigeons were sedated by INS MID alone at a dose of 5 mg kg⁻¹ (group MID, n = 6) or in combination with INS DXM at a dose 80 μg kg⁻¹ (group MID-DXM, n = 6). Measurements were made of heart rate (HR), respiratory rate (f_R) and cloacal temperature (CT). The degree of sedation was assessed at 15 minutes prior to, immediately after, and at intervals until 100 minutes after drug administrations. Following MID-DXM, INS atipamezole (250 μg kg⁻¹) was administered and the same indices measured 5 and 10 minutes later.ResultsMID had no effect on HR and f_R, and although CT decreased, it remained within physiological range. MID-DXM caused significant falls in HR, f_R and CT that persisted until the end of sedation. Atipamezole antagonized sedation and cardiorespiratory side effects of MID-DXM within 10 minutes of application. In addition, for MID compared to MID-DXM, the lowest sedation scores [10 (7–14) and 10.5 (5–14) versus 2 (1–4) and 2 (1–5)] were achieved in the 10th and 20th minute versus the 20th and 30th minute of the sedation, respectively.Conclusions and clinical relevanceMID alone, given INS had minimal side effects on vital functions but caused inadequate immobilization of pigeons for restraint in dorsal recumbency. MID-DXM caused an effective degree of immobilization from 20 to 30 minutes after administration, at which time birds tolerated postural changes without resistance. Atipamezole antagonized both side effects and sedation, but complete recovery had not occurred within 10 minutes after its application.     

Serum concentrations and effects of detomidine delivered orally to horses in three different mediums

Objective To compare the effect of orally delivered detomidine on head posture when administered alone or in combination with two different food items, and to determine the serum concentrations of detomidine after oral delivery. Study Design Prospective randomized experimental study. Animals Fifteen adult grade mares weighing 328–537 kg. Methods The horses were randomly assigned to one of the three treatment groups (five horses each). The groups were given detomidine (0.06 mg kg^?1): alone; mixed with 3 mL of an apple sauce and gum mixture; or mixed with 3 mL molasses. Head droop, measured before treatment and at 15, 30, 45, 60, 75, 90, and 105 minutes after treatment, was used to evaluate sedation. Yohimbine (0.1 mg kg^?1 IV) was administered after the 90‐minute evaluation. Blood samples were collected from the detomidine‐alone group before treatment and at 15, 30, 45, 60, 75, and 90 minutes after treatment. Sera were analyzed for detomidine equivalent concentrations by an ELISA. Head droop percentages were compared using a repeated measures analysis of variance. Results Significant mean head droop developed in each treatment group by 30 minutes and persisted until reversal with yohimbine. After yohimbine administration, head positions returned to 87–91% of pre‐treatment levels. There were no significant differences among the oral treatment groups at any time. Mean serum detomidine equivalents increased slowly until 45‐minute post‐administration, but never exceeded 30 ng mL^?1. Conclusions Orally administered detomidine results in measurable serum drug concentrations using any of the delivery mediums investigated, and can be expected to produce profound head droop in horses approximately 45 minutes after administration.     

Thermal and mechanical nociceptive threshold testing in horses: a review

OBJECTIVE: This review evaluates the thermal and mechanical nociceptive threshold testing techniques that have been used in horses and discusses them with reference to their applications, limitations and the factors which can influence both the testing procedure itself and the animal's responses. Methods to optimise the reliability and repeatability of the testing procedures are suggested and the potential clinical applications discussed. DATABASES USED: Web of Science and Medline. CONCLUSIONS: Thermal and mechanical nociceptive threshold testing techniques have valuable roles in both the identification of altered nociceptive function and the pre-clinical evaluation of analgesics in horses.     

A review of the general pharmacology of ketamine and its clinical use for injectable anaesthesia in horses

Ketamine is the most commonly used injectable anaesthetic in horses. Combinations of ketamine have been used to produce short durations of anaesthesia or as total intravenous anaesthesia (TIVA) for longer diagnostic or surgical procedures. In recent years, ketamine has been used for pain management due to its effectiveness in producing analgesia at subanaesthetic doses. This paper provides a review of the pharmacological effects of ketamine in general and its clinical use for injectable anaesthesia and pain management in horses.     

Desmectomy of a septic accessory ligament of the deep digital flexor tendon in the hindlimb of a horse under standing sedation

A horse presented with a discharging wound over the proximal aspect of the right metatarsal region. Examination, radiography and ultrasonography diagnosed a septic process within the accessory ligament of the deep digital flexor tendon (ALDDFT). Due to previous unsuccessful treatment with systemic antibiotics as well as financial restrictions, an ALDDFT desmectomy was performed with the patient under standing sedation and local analgesia. Histopathology confirmed the septic process within the affected structure. The patient made a rapid recovery and was discharged from the hospital 7 days post operatively and 2 years later was still in full work. This report describes the first case of infective hindlimb ALDDFT and the first desmectomy of this structure performed under standing sedation.     

The effects of a loading dose followed by constant rate infusion of xylazine compared with romifidine on sedation,ataxia and response to stimuli in horses

ObjectiveTo compare xylazine and romifidine constant rate infusion (CRI) protocols regarding degree of sedation, and effects on postural instability (PI), ataxia during motion (A) and reaction to different stimuli.Study designBlinded randomized experimental cross-over study.AnimalsTen adult horses.MethodsDegree of sedation was assessed by head height above ground (HHAG). Effects on PI, A and reaction to visual, tactile and acoustic stimulation were assessed by numerical rating scale (NRS) and by visual analogue scale (VAS). After baseline measurements, horses were sedated by intravenous loading doses of xylazine (1 mg kg^?1) or romifidine (80 μg kg^?1) administered over 3 minutes, immediately followed by a CRI of xylazine (0.69 mg kg^?1 hour^?1) or romifidine (30 μg kg^?1 hour^?1) which was administered for 120 minutes. Degree of sedation, PI, A and reaction to the different stimuli were measured at different time points before, during and for one hour after discontinuing drug administration. Data were analysed using two-way repeated measures anova, a Generalized Linear Model and a Wilcoxon Signed Rank Test (p < 0.05).ResultsSignificant changes over time were seen for all variables. With xylazine HHAG was significantly lower 10 minutes after the loading dose, and higher at 150 and 180 minutes (i.e. after CRI cessation) compared to romifidine. Reaction to acoustic stimulation was significantly more pronounced with xylazine. Reaction to visual stimulation was greater with xylazine at 145 and 175 minutes. PI was consistently but not significantly greater with xylazine during the first 30 minutes. Reaction to touch and A did not differ between treatments. Compared to romifidine, horses were more responsive to metallic noise with xylazine.ConclusionsTime to maximal sedation and to recovery were longer with romifidine than with xylazine.Clinical relevanceWith romifidine sufficient time should be allowed for complete sedation before manipulation.     

Exercising arrhythmias and sudden cardiac death in horses: Review of the literature and comparative aspects

Arrhythmias are common in equine athletes during and immediately after exercise. Many of these rhythm variations are not clinically relevant. In horses, a link between different exercising arrhythmias and poor performance or between exercising arrhythmias and sudden cardiac death (SCD) is strongly suspected but not fully understood or proven. SCD during races or competitions is rare, but has catastrophic consequences for the safety of the human partner and public perceptions of welfare during equestrian sports. This review summarises current knowledge of equine exercise arrhythmias and their implications in SCD and compares existing principles and recommendations for equine subjects with those for human athletes.     

Metabolism,pharmacokinetics and selected pharmacodynamic effects of codeine following a single oral administration to horses

ObjectiveTo describe the pharmacokinetics and selected pharmacodynamic variables of codeine and its metabolites in Thoroughbred horses following a single oral administration.Study designProspective experimental study.AnimalsA total of 12 Thoroughbred horses, nine geldings and three mares, aged 4–8 years.MethodsHorses were administered codeine (0.6 mg kg^–1) orally and blood was collected before administration and at various times until 120 hours post administration. Plasma and urine samples were collected and analyzed for codeine and its metabolites by liquid chromatography–mass spectrometry, and plasma pharmacokinetics were determined. Heart rate and rhythm, step counts, packed cell volume and total plasma protein were measured before and 4 hours after administration.ResultsCodeine was rapidly converted to the metabolites norcodeine, codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Plasma codeine concentrations were best represented using a two-compartment model. The C_max, t_max and elimination t_½ were 270.7 ± 136.0 ng mL^–1, 0.438 ± 0.156 hours and 2.00 ± 0.534 hours, respectively. M3G was the main metabolite detected (C_max 492.7 ± 35.5 ng mL^–1), followed by C6G (C_max 96.1 ± 33.8 ng mL^–1) and M6G (C_max 22.3 ± 4.96 ng mL^–1). Morphine and norcodeine were the least abundant metabolites with C_max of 3.17 ± 0.95 and 1.42 ± 0.79 ng mL^–1, respectively. No significant adverse or excitatory effects were observed.Conclusions and clinical relevanceFollowing oral administration, codeine is rapidly metabolized to morphine, M3G, M6G, C6G and norcodeine in horses. Plasma concentrations of M6G, a presumed active metabolite of morphine, were comparable to concentrations reported previously following administration of an analgesic dose of morphine to horses. Codeine was well tolerated based on pharmacodynamic variables and behavioral observations.     

Paecilomycosis in dogs and horses and a review of the literature

We reviewed 14 cases of paecilomycosis in a tertiary care veterinary hospital and all reports of the disease in the veterinary literature. Paecilomycosis is a rare disease primarily of dogs, horses, reptiles, and humans. Clinical manifestations in veterinary patients vary but include disseminated disease and diskospondylitis, particularly in dogs: pneumonia in dogs, horses, and reptiles; keratitis in horses; and miscellaneous local infections. It is important to have an appropriate index of suspicion because the diagnosis can be difficult, particularly in localized disease where it is difficult to determine whether a positive culture represents an etiology or a contamination with an environmental saprophyte. Spinal radiographs, transtracheal washes, histopathology, and fungal culture have proven to be valuable diagnostic tools. The prognosis for paecilomycosis is poor, although some treatment success has been reported, and success rates could improve if additional information were available regarding fungal species occurring in veterinary patients and drugs to which these fungi are susceptible.     

Lyme borreliosis in cattle and horses: a review of the literature.

A complete search of the literature concerning Lyme borreliosis as it relates to horses and cattle was done. The epidemiology, pathogenesis, immunological response to the disease, diagnosis and treatment are discussed. A review of clinical cases in horses and cattle is presented. Clinical signs of Lyme borreliosis in horses include: chronic weight loss, sporadic lameness, laminitis, low grade fever, swollen joints, muscle tenderness, and anterior uveitis. In addition to those clinical signs, neurological signs such as depression, behavioral changes, dysphagia, head tilt and encephalitis can be seen in chronic cases. Borreliosis occurs in cattle, usually as a herd problem. In acute Lyme borreliosis, cattle often will show a fever, stiffness, swollen joints, and decreased milk production. Chronic weight loss, laminitis and abortion are also possible outcomes of borreliosis in cattle. Diagnosis of clinical Lyme borreliosis is difficult and depends upon recognition of clinical signs, a history of possible exposure, and identification of the spirochete in the affected animal. Since the spirochete is very difficult to culture, confirmation of B. burgdorferi infection often relies on serologic testing. Subclinical seropositive animals do occur, thus confusing the diagnosis. An approach to treatment of cattle and horses with Lyme borreliosis is outlined.     

Recognition and quantification of pain in horses: A tutorial review

Pain management is dependent on the quality of the pain evaluation. Ideally, pain evaluation is objective, pain‐specific and easily incorporated into a busy equine clinic. This paper reviews the existing knowledge base regarding the identification and quantification of pain in horses. Behavioural indicators of pain in horses in the context of normal equine behaviour, as well as various physiological parameters potentially useful for pain evaluation, are discussed. Areas where knowledge is sparse are identified and a new equine pain scale based on results from all reviewed papers is proposed. Finally, the most important considerations in relation to the implementation of a pain scale in a hospital setting are discussed.     

Cytology of the lower respiratory tract in horses: An updated review

The diagnosis of respiratory diseases in horses can be difficult due to the nonspecific nature of the clinical signs, which overlap between the different diseases. Cytological examination of the respiratory secretions is a helpful diagnostic tool that, when combined with clinical features and other diagnostic techniques, has the potential to improve diagnostic accuracy significantly. This review article should help readers to become familiar with the cytology of the normal respiratory tract and with the cytopathological abnormalities associated with common respiratory disorders in horses.     

Comparison of the effects of the alpha-2 agonists detomidine, romifidine and xylazine on nociceptive withdrawal reflex and temporal summation in horses

ObjectiveTo evaluate and compare the antinociceptive effects of the three alpha-2 agonists, detomidine, romifidine and xylazine at doses considered equipotent for sedation, using the nociceptive withdrawal reflex (NWR) and temporal summation model in standing horses.Study designProspective, blinded, randomized cross-over study.AnimalsTen healthy adult horses weighing 527–645 kg and aged 11–21 years old.MethodsElectrical stimulation was applied to the digital nerves to evoke NWR and temporal summation in the left thoracic limb and pelvic limb of each horse. Electromyographic reflex activity was recorded from the common digital extensor and the cranial tibial muscles. After baseline measurements a single bolus dose of detomidine, 0.02 mg kg^?1, romifidine 0.08 mg kg^?1, or xylazine, 1 mg kg^?1, was administered intravenously (IV). Determinations of NWR and temporal summation thresholds were repeated at 10, 20, 30, 40, 60, 70, 90, 100, 120 and 130 minutes after test-drug administration alternating the thoracic limb and the pelvic limb. Depth of sedation was assessed before measurements at each time point. Behavioural reaction was observed and recorded following each stimulation.ResultsThe administration of detomidine, romifidine and xylazine significantly increased the current intensities necessary to evoke NWR and temporal summation in thoracic limbs and pelvic limbs of all horses compared with baseline. Xylazine increased NWR thresholds over baseline values for 60 minutes, while detomidine and romifidine increased NWR thresholds over baseline for 100 and 120 minutes, respectively. Temporal summation thresholds were significantly increased for 40, 70 and 130 minutes after xylazine, detomidine and romifidine, respectively.Conclusions and clinical relevanceDetomidine, romifidine and xylazine, administered IV at doses considered equipotent for sedation, significantly increased NWR and temporal summation thresholds, used as a measure of antinociceptive activity. The extent of maximal increase of NWR and temporal summation thresholds was comparable, while the duration of action was drug-specific.     

Non-strangulating intestinal infarction in horses in the UK: A review of 15 cases

The clinicopathological features of 15 horses diagnosed with non-strangulating intestinal infarction (NSII) based on identification of focal areas of intestinal necrosis without mesenteric strangulation were reviewed. The mean age at presentation was 16.3 years, median 13 years, and there was no age, sex, or breed predilection. The major presenting clinical signs included: acute colic ≤ 24 h duration in nine horses; diarrhoea, depression, and inappetence in four horses; and low-grade chronic or recurrent colic, depression, and inappetence in two horses. One horse presented with both acute colic and diarrhoea. Predisposing diseases included colitis or typhlocolitis in five horses and an initial strangulating small intestinal obstruction in three horses, but in seven horses no underlying or predisposing disease was identified. Four cases were managed medically and 11/15 were managed surgically. The most useful diagnostic test was exploratory celiotomy and the only successful treatment was complete resection of the necrotic intestine. Prognosis for survival was poor with a survival rate of only 1/15 (7%). Among the 15 horses, both single and multiple NSII lesions were seen, and they occurred in both the small intestine and large intestines. There was no evidence of Strongylus vulgaris infestation in any of the affected horses.