Evaluation of sedative and cardiorespiratory effects of romifidine and romifidine-butorphanol in cats

OBJECTIVE: To determine sedative and cardiorespiratory effects of romifidine alone and romifidine in combination with butorphanol and effects of preemptive atropine administration in cats sedated with romifidine-butorphanol. DESIGN: Randomized crossover study. ANIMALS: 6 healthy adult cats. PROCEDURES: Cats were given saline (0.9% NaCl) solution followed by romifidine alone (100 microg/kg [45.4 microg/lb], i.m.), saline solution followed by a combination of romifidine (40 microg/kg [18.1 microg/lb], i.m.) and butorphanol (0.2 mg/kg [0.09 mg/lb], i.m.), or atropine (0.04 mg/kg [0.02 mg/lb], s.c.) followed by romifidine (40 microg/kg, i.m.) and butorphanol (0.2 mg/kg, i.m.). Treatments were administered in random order, with > or = 1 week between treatments. Physiologic variables were determined before and after drug administration. Time to recumbency, duration of recumbency, time to recover from sedation, and subjective evaluation of sedation, muscle relaxation, and analgesia were assessed. RESULTS: Bradycardia developed in all cats that received saline solution and romifidine-butorphanol or romifidine alone. Preemptive administration of atropine prevented bradycardia for 50 minutes in cats given romifidine-butorphanol. Oxyhemoglobin saturation was significantly decreased 10 minutes after romifidine-butorphanol administration in atropine-treated cats. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that administration of romifidine alone or romifidine-butorphanol causes a significant decrease in heart rate and that preemptive administration of atropine in cats sedated with romifidine-butorphanol effectively prevents bradycardia for 50 minutes.     

Investigation of romifidine and detomidine for the clinical sedation of horses

The effects of two intravenous doses of romifidine (80 and 120 microg/kg) and one dose of detomidine (20 microg/kg) were compared in a blinded study in 30 horses requiring to be sedated for routine dental treatment. Several physiological parameters were assessed before and for two hours after the administration of the drugs, and the horses' teeth were rasped 30 minutes after they were administered. Romifidine produced a dose-dependent effect on most parameters. Detomidine at 20 microg/kg was similar to romifidine at 120 microg/kg in the magnitude of its sedative effects, but was similar to romifidine at 80 pg/kg in its duration. There were no significant differences between the three treatments in terms of the clinical procedure score.     

Cardiovascular effects of romifidine in dogs

OBJECTIVE: To characterize the cardiovascular effects of romifidine at doses ranging from 5 to 100 microg/kg of body weight, IV. ANIMALS: 25 clinically normal male Beagles. PROCEDURE: Romifidine was administered IV at a dose of 5, 10, 25, 50, or 100 microg/kg (n = 5/group). Heart rate, arterial pressure, central venous pressure, mean pulmonary arterial pressure, pulmonary capillary wedge pressure, body temperature, cardiac output, and PCV were measured immediately prior to and at selected times after romifidine administration. Cardiac index, stroke index, rate-pressure product, systemic and pulmonary vascular resistance indices, and left and right ventricular stroke work indices were calculated. Degree of sedation was assessed by an observer who was blinded to the dose administered. RESULTS: Romifidine induced a decrease in heart rate, pulmonary arterial pressure, rate-pressure product, cardiac index, and right ventricular stroke work index and an increase in central venous pressure, pulmonary capillary wedge pressure, and systemic vascular resistance index. In dogs given romifidine at a dose of 25, 50, or 100 microg/kg, an initial increase followed by a prolonged decrease in arterial pressure was observed. Arterial pressure immediately decreased in dogs given romifidine at a dose of 5 or 10 microg/kg. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that IV administration of romifidine induces dose-dependent cardiovascular changes in dogs. However, the 2 lowest doses (5 and 10 microg/kg) induced less cardiovascular depression, and doses > or = 25 microg/kg induced similar cardiovascular changes, suggesting that there may be a ceiling on the cardiovascular effects of romifidine.     

Comparison of romifidine and medetomidine pre-medication in propofol-isoflurane anaesthetised dogs

The objective of this paper was to evaluate romifidine as a pre-medicant in dogs prior to propofol-isoflurane anaesthesia, and to compare it with medetomidine. For this, eight healthy dogs were anaesthetised. Each dog received three pre-anaesthetic protocols: R40 (romifidine, 40 microg/kg, IV), R80 (romifidine, 80 microg/kg, IV) or MED (medetomidine, 10 microg/kg, IV). Induction of anaesthesia was delivered with propofol and maintained with isoflurane. The following variables were studied before sedative administration and 10 min after sedative administration: heart rate (HR), mean arterial pressure (MAP), systolic arterial pressure (SAP) and diastolic arterial pressure (DAP) and respiratory rate (RR). During maintenance, the following variables were recorded at 5-min intervals: HR, MAP, SAD, DAP, arterial oxygen saturation (SpO(2)), end-tidal CO(2)(EtCO(2)), end-tidal concentration of isoflurane (EtISO) required for maintenance of anaesthesia and tidal volume (TV). Time to extubation, time to sternal recumbency and time to standing were also registered. HR and RR experimented a significantly decreased during sedation in all protocols respect to baseline values. Mean HR, MAP, SAP, DAP, SpO(2), EtCO(2), and TV during anaesthesia were similar for the three protocols. End tidal of isoflurane concentration was statistically similar for all protocols. Recovery time for R40 was significantly shorter than in R80 and MED. The studied combination of romifidine, propofol and isoflurane appears to be an effective drug combination for inducing and maintaining general anaesthesia in healthy dogs.     

Pharmacokinetics and pharmacodynamics of intravenous romifidine and propranolol administered alone or in combination for equine sedation

Objective

Propranolol has been suggested for anxiolysis in horses, but its sedation efficacy and side effects, both when administered alone and in combination with α₂-adrenoceptor agonists, remain undetermined. This study aimed to document the pharmacokinetics and pharmacodynamics of propranolol, romifidine and their combination.

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.     

Effects of medetomidine and buprenorphine administered for sedation in dogs

Medetomidine at doses of 10, 20 or 30 microg/kg was administered along with 10 microg/kg buprenorphine intramuscularly to 48 dogs requiring sedation for various diagnostic or therapeutic procedures. The heart rate, respiratory rate and degree of sedation were recorded before and 30 minutes after administration of the drugs. Heart rate fell by a mean of 55 per cent and respiratory rate by a mean of 62 per cent. Mean sedation scores were increased in all groups. Administration of atipamezole at the end of the period of sedation produced rapid recoveries, with a mean time to standing of 12 minutes. Animals that were anaesthetised required much less thiopentone than the 10 mg/kg recommended after premedication with acepromazine maleate.     

Development of a romifidine constant rate infusion with or without butorphanol for standing sedation of horses

ObjectiveTo determine constant rate infusion (CRI) protocols for romifidine (R) and romifidine combined with butorphanol (RB) resulting in constant sedation and romifidine plasma concentrations.Study designBlinded randomized crossover study.AnimalsTen adult research horses.MethodsPart I: After determining normal height of head above ground (HHAG = 100%), loading doses of romifidine (80 μg kg^?1) with butorphanol (RB: 18 μg kg^?1) or saline (R) were given intravenously (IV). Immediately afterwards, a butorphanol (RB: 25 μg kg^?1 hour^?1) or saline (R) CRI was administered for 2 hours. The HHAG was used as marker of sedation depth. Sedation was maintained for 2 hours by additional romifidine (20 μg kg^?1) whenever HHAG > 50%. The dose rate of romifidine (μg kg^?1 hour^?1) required to maintain sedation was calculated for both treatments. Part II: After loading doses, the romifidine CRIs derived from part I were administered in parallel to butorphanol (RB) or saline (R). Sedation and ataxia were evaluated periodically. Romifidine plasma concentrations were measured by HPLC-MS-MS at 0, 5, 10, 15, 30, 45, 60, 90, 105, and 120 minutes. Data were analyzed using paired t-test, Fisher's exact test, Wilcoxon signed rank test, and two-way anova for repeated measures (p < 0.05).ResultsThere was no significant difference in romifidine requirements (R: 30; RB: 29 μg kg^?1 hour^?1). CRI protocols leading to constant sedation were developed. Time to first additional romifidine bolus was significantly longer in RB (mean ± SD, R: 38.5 ± 13.6; RB: 50.5 ± 11.7 minutes). Constant plasma concentrations of romifidine were achieved during the second hour of CRI. Ataxia was greater when butorphanol was added.ConclusionRomifidine bolus, followed by CRI, provided constant sedation assessed by HHAG. Butorphanol was ineffective in reducing romifidine requirements in unstimulated horses, but prolonged the sedation caused by the initial romifidine bolus.Clinical relevanceBoth protocols need to be tested under clinical conditions.     

Sedative effects of intramuscular administration of a low dose of romifidine in dogs

OBJECTIVE: To evaluate sedative effects of IM administration of a low dose of romifidine in dogs. ANIMALS: 13 healthy adult Beagles. PROCEDURE: Physiologic saline solution (0.2 ml), 0.1 % romifidine (10, 20, or 40 microg/kg), or 10% xylazine (1 mg/kg) was given IM in a crossover study design. Heart rate, respiratory rate, rectal temperature, hemoglobin saturation, and scores for sedation, muscle relaxation, posture, auditory response, and positioning response were recorded before and at regular intervals for up to 240 minutes after drug administration. RESULTS: Scores for sedation, muscle relaxation, posture, auditory response, and positioning response increased in a dose-dependent manner after romifidine administration. Sedation induced by the highest dose of romifidine (40 microg/kg) was comparable to that induced by xylazine (1 mg/kg). Heart rate, respiratory rate, and rectal temperature decreased in a dose-dependent manner after romifidine administration, but hemoglobin saturation did not change. CONCLUSIONS AND CLINICAL IMPLICATIONS: Romifidine (10, 20, or 40 microg/kg, IM) is an effective sedative in dogs, but causes a decrease in heart rate, respiratory rate, and rectal temperature.     

Electrocardiographic and cardiopulmonary effects of intramuscular administration of glycopyrrolate and romifidine in conscious beagle dogs

Objective To determine the electrocardiographic and cardiopulmonary effects of IM administration of romifidine with and without prior administration of glycopyrrolate in conscious dogs. Study design Prospective randomized study. Animals Twelve healthy, adult beagles. Materials and methods Dogs were assigned at random to each of three treatments with glycopyrrolate (six dogs), and to each of three treatments without glycopyrrolate (six dogs). Baseline data were recorded, and saline solution or glycopyrrolate (10 µg kg^–1) was given IM. After 15 minutes, saline solution (control) or romifidine (20 or 40 µg kg^–1) was given IM. An ECG, heart rate (HR), systemic blood pressures, and respiratory rate (RR) were recorded before and 2.5, 5, 10, 15, 30, 45, 60, 75, 90, 105 and 120 minutes after romifidine administration. Rectal temperature (RT), pH, PaCO₂, PaO₂, hematocrit and plasma protein were determined before and 15, 30, 60 and 120 minutes after romifidine administration. Data were analyzed using analysis of variance for repeated measures and Tukey multiple comparison tests. Results Without glycopyrrolate, HR (beats minute^–1) decreased to minimum values (mean ± SD) of 52 ± 7 and 49 ± 12 (control 89 ± 20) 45 minutes after administration of romifidine at doses of 20 and 40 µg kg^–1, respectively. Sinus bradycardia (HR < 60 beats minute^–1), which persisted for up to 120 minutes, was observed in five of six and six of six dogs given romifidine at doses of 20 and 40 µg kg^–1, respectively. With glycopyrrolate, decreases in HR were prevented and mean arterial pressure (mm Hg) increased to maximum values of 139 ± 25 and 173 ± 17 (control 113 ± 11) 30 minutes after administration of romifidine at doses of 20 and 40 µg kg^–1, respectively. With and without glycopyrrolate, RR did not change appreciably, RT decreased, and pH, PaCO₂, PaO₂, hematocrit and plasma protein did not change after administration of romifidine. Conclusions and clinical relevance In healthy conscious beagles, IM administration of romifidine at doses of 20 and 40 µg kg^–1 causes sinus bradycardia which persists for up to 120 minutes. Administration of glycopyrrolate 15 minutes before administration of romifidine, prevents sinus bradycardia and induces moderate increases in arterial pressure.     

The influence of route of administration upon the sedative effect of romifidine in dogs

The sedative and some physiological effects of iv romifídine at 120 μg/kg bwt were compared with the same dose administered subcutaneously (sc) and an iv placebo in 12 clinically normal adult beagle dogs in a blinded randomised change-over study. Following iv romifídine, the dogs became recumbent and there was an increase in a subjective score awarded to the degree of sedation. Heart rate and respiratory rate decreased and minor bradyarrhythmias were noted. When romifídine was given sc the onset of sedation was slower, and the magnitude of the sedative effect was less until 30 min after administration, after which time sedation was no different between the 2 routes of administration. Recovery from sedation was similar following either route. Heart rate and respiratory rate changes were similar with either route although respiratory rate decreased more quickly following iv romifídine. It appears therefore that, in dogs, romifídine is equally efficacious by either iv or sc routes.     

Reversal of xylazine sedation in dogs.

Intramuscular injections of atipamezole (200 micrograms/kg), doxapram (2.5 mg/kg) and saline (0.1 ml/kg) were compared for their ability to reverse xylazine sedation in dogs. Atipamezole effectively reversed the sedative effects and partially reversed the cardiopulmonary effects of xylazine. Doxapram did not arouse the dogs as much as atipamezole, but it shortened the time taken for them to stand although the dogs were still ataxic.     

Cardiovascular effects following epidural injection of romifidine in isoflurane‐anaesthetized dogs

ObjectiveTo investigate the cardiovascular effects of epidural romifidine in isoflurane-anaesthetized dogs.Study designProspective, randomized, blinded experiment.AnimalsA total of six healthy adult female Beagles aged 1.25 ± 0.08 years and weighing 12.46 ± 1.48 (10.25–14.50) kg.MethodsAnaesthesia was induced with propofol (6–9 mg kg^?1) and maintained with 1.8–1.9% end-tidal isoflurane in oxygen. End-tidal CO₂ was kept between 35 and 45 mmHg (4.7–6.0 kPa) using intermittent positive pressure ventilation. Heart rate (HR), arterial blood pressure and cardiac output (CO) were monitored. Cardiac output was determined using a LiDCO monitor and the derived parameters were calculated. After baseline measurements, either 10 μg kg^?1 romifidine or saline (total volume 1 mL 4.5 kg^?1) was injected into the lumbosacral epidural space. Data were recorded for 1 hour after epidural injection. A minimum of 1 week elapsed between treatments.ResultsAfter epidural injection, the overall means (± standard deviation, SD) of HR (95 ± 20 bpm), mean arterial blood pressure (MAP) (81 ± 19 mmHg), CO (1.63 ± 0.66 L minute^?1), cardiac index (CI) (2.97 ± 1.1 L minute^?1 m^?2) and stroke volume index (SI) (1.38 ± 0.21 mL beat^?1 kg^?1) were significantly lower in the romifidine treatment compared with the overall means in the saline treatment [HR (129 ± 24 bpm), MAP (89 ± 17 mmHg), CO (3.35 ± 0.86 L minute^?1), CI (6.17 ± 1.4 L minute^?1 m^?2) and SI (2.21 ± 0.21 mL beat^?1 kg^?1)]. The overall mean of systemic vascular resistance index (SVRI) (7202 ± 2656 dynes seconds cm^?5 m^?2) after epidural romifidine injection was significantly higher than the overall mean of SVRI (3315 ± 1167 dynes seconds cm^?5 m^?2) after epidural saline injection.ConclusionEpidural romifidine in isoflurane-anaesthetized dogs caused significant cardiovascular effects similar to those reportedly produced by systemic romifidine administration.Clinical relevanceSimilar cardiovascular monitoring is required after epidural and systemically administered romifidine. Further studies are required to evaluate the analgesic effects of epidural romifidine.     

The suitability of medetomidine sedation for intradermal skin testing in dogs

The objective of this study was to determine the suitability of medetomidine sedation for facilitating intradermal skin testing in dogs. Quality of sedation and immobilization, and effects of sedation on responses to intradermally injected histamine were evaluated. Ten clinically normal dogs were injected intradermally before and after medetomidine sedation (10 μg kg^?1 intravenously) with diminishing concentrations of histamine (100–10^?5μg mL^?1) and a negative control. Mean wheal responses at injection sites were compared before and during sedation, and no significant suppression of responses occurred during sedation. Medetomidine produced sedation that notably increased the ease of performing multiple intradermal injections in all dogs and sedative effects were rapidly reversed by the antagonist atipamezole. It was concluded that medetomidine may be an excellent sedative for facilitating intradermal skin testing in dogs provided further studies similarly reveal no inhibition of responses to intradermally injected allergens in atopic dogs.     

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.     

The echocardiographic effects of romifidine in dogs with and without prior or concurrent administration of glycopyrrolate

Objective To determine the cardiopulmonary response to romifidine (RO) in the dog with or without prior or concurrent administration of glycopyrrolate. Study Design Randomized, cross‐over experimental study. Animals Six (three male, three female) cross‐bred dogs weighing 23 ± 2.4 kg. Methods Two‐dimensional guided M‐mode echocardiography was performed in conscious dogs simultaneously with measurement of systolic arterial blood pressure (SBP) and heart rate (HR). Dimensions of the left ventricle (LVID), interventricular septum (IVS), and left ventricular free wall (LVFW) were obtained in systole (S) and diastole (D). Amplitude of motion (Amp) of the IVS and LVFW were also measured. From these, measures of wall stress (WS) and fractional shortening (FS) of the left ventricle were derived. Baseline echocardiographic measurements were recorded, following which one of the five treatments was administered. Glycopyrrolate (G) 0.01 mg kg^?1, or saline (S) 0.5 mL, was administered IM as pre‐medication (Gp or Sp), or G was administered concurrently (Gc) with romifidine (RO). Treatments were: T₁, Sp + RO (40 μg kg^?1); T₂, Gp + RO (40 μg kg^?1); T₃, Sp + RO (120 μg kg^?1); T₄, Gp + RO (120 μg kg^?1); and T₅, Sp + Gc +RO (120 μg kg^?1). Romifidine or RO + Gc was administered SC 20 minutes after pre‐medication (time 0), and further measurements were taken 10, 20, 30, 60, and 90 minutes after RO. Results Echocardiographic indices of cardiac systolic function (LVID‐S, FS, Amp‐LVFW) and HR were decreased in RO‐sedated dogs (p < 0.0001) . The magnitude of change in cardiac indices was least with low‐dose RO. At most sampling times, high‐dose RO produced significantly more alteration in cardiac indices. Systolic blood pressure increased in all treatment groups, with the greatest increases in those groups receiving G. Glycopyrrolate significantly increased HR; however, cardiac indices were further reduced. Wall stress significantly increased, with a more dramatic increase in groups receiving G. Conclusions Indices of LV systolic function were reduced in RO‐sedated dogs in a dose‐related manner. Glycopyrrolate further reduced these indices and dramatically increased measurements of wall stress in dogs sedated with RO. Clinical relevance Use of low‐dose RO minimizes cardiac dysfunction; however, it should still be used cautiously in dogs with cardiomyopathy or heart failure. The routine use of G is not recommended to alleviate the bradycardia associated with RO in conscious dogs.     

Effect of tiletamine/zolazepam sedation on intradermal allergy testing in atopic dogs.

Seven atopic dogs underwent intradermal allergy testing with 46 inhalant antigens before and after administration of a tiletamine/zolazepam solution (4 mg/kg of body weight, IV). This anesthetic protocol had no significant effect on the intradermal response caused by histamine, whole flea extract, or various inhalant allergens. Short-acting chemical restraint induced by the drug combination facilitated the intradermal testing procedure.     

The cardiopulmonary effects of romifidine in dogs with and without prior or concurrent administration of glycopyrrolate

Objective To determine the electrocardiographic and cardiopulmonary effects of romifidine with and without prior or concurrent administration of glycopyrrolate. Study design Randomized crossover experimental study. Animals Six (three male, three female) cross‐bred dogs weighing 23 ± 2.4 kg. Methods Baseline cardiopulmonary measurements were obtained in conscious dogs and one of five treatments was administered. Glycopyrrolate (G) 0.01 mg kg^?1, or saline (S) 0.5 mL, were administered IM as premedication (Gp or Sp), or G was administered concurrently (Gc) with romifidine (RO). Treatments were as follows T1, Sp + RO 40 µg kg^?1; T2, Gp + RO (40 µg kg^?1); T3, Sp + RO 120 µg kg^?1; T4, Gp + RO (120 µg kg^?1); T5, Sp + Gc + RO (120 µg kg^?1). Romifidine or RO + Gc was administered subcutaneously 20 minutes after premedication (time 0), and further measurements were taken 10, 20, 30, 60 and 90 minutes after RO. The main treatment effect was evaluated using two‐way anova for repeated measures, followed by one‐way anova and a post‐hoc least squares difference test with a modified Bonferroni correction (p < 0.02). A Student's t‐test was used to compare the effect of romifidine at 20 and 60 minutes versus baseline values (p < 0.05). Results Both low‐ and high‐dose RO (T1, T3) significantly decreased heart rate (HR), respiratory rate (RR), cardiac index (CI) and stroke volume index, and increased arterial blood pressure (SAP), systemic vascular resistance (SVR), pulmonary arterial occlusion pressure (PAOP) and central venous pressure. High‐dose RO produced greater increases in SVR and SAP measurements. Neither dose of RO produced an alteration in blood gas values or the alveolar to arterial oxygen gradient. Glycopyrrolate significantly increased HR and CI from 10 to 90 minutes between T1/T2 and T3/T4. Increases in SAP were dose related with significant differences between T1/T3 and T2/T4 at 90 and 10 minutes, respectively, and were highest in animals receiving Gp or Gc. High‐dose RO groups (T3, T4) had higher values for SVR than low‐dose RO groups (T1, T2), unrelated to G administration. There was an increase in PAOP in all treatments. The oxygen extraction ratio was increased with all treatments: larger increases were observed in T1, T3 and T4 compared with only minimal changes in T2. Concurrent G administration was associated with an increased frequency of high‐grade second‐degree atrioventricular heart block with variable conduction at 10 and 20 minutes. Conclusions Romifidine produced effects consistent with other selective α₂‐adrenoreceptor agonists. Glycopyrrolate offset the decrease in HR and partially offset the decrease in CI associated with RO administration. Glycopyrrolate premedication produced an initial tachycardia and added to the increase in SAP associated with RO. Concurrent G administration was associated with a higher frequency of dysrhythmias and is not recommended. Despite the decrease in RR, RO sedation did not alter blood gas values. Clinical relevance It appears likely that G administration prior to or concurrent with RO produces an increase in myocardial workload and oxygen demand suggesting that this combination should not be used in dogs with cardiomyopathy or heart failure. The improvement in oxygen extraction ratio with T2 suggests that G may be beneficial with lower doses of RO, nevertheless, the use of G and RO in cardiovascularly compromised patients is not advised.