Clinical evaluation of the efficacy and safety of a constant rate infusion of dexmedetomidine for postoperative pain management in dogs

ObjectiveTo compare postoperative analgesia provided by a constant rate infusion (CRI) of dexmedetomidine (DMED) to that of a well-established positive control [morphine (MOR)] in critically ill dogs. The sedative, cardiorespiratory effects and clinical safety of a 24-hour DMED CRI were also evaluated.Study designProspective, randomised, blinded, positive-controlled parallel-group clinical study.AnimalsForty hospitalised, client-owned dogs requiring post-operative pain management after invasive surgery.MethodsAfter surgery, a loading dose of either DMED (25 μg m^?2) or MOR (2500 μg m^?2) followed by a 24-hour CRI of DMED (25 μg m^?2 hour^?1) or MOR (2500 μg m^?2 hour^?1) was administered. Pain was measured using the Short Form of the Glasgow Composite Measure Pain Scale, sedation and physiological variables were scored at regular intervals. Animals considered to be painful received rescue analgesia and were allocated to a post-rescue protocol; animals which were unresponsive to rescue analgesia were removed from the study. Data were analysed with anova, two-sample t-tests or Chi-square tests. Time to intervention was analysed with Kaplan–Meier methodology.ResultsForty dogs were enrolled. Twenty dogs (9 DMED and 11 MOR) did not require rescue analgesia. Eleven DMED and eight MOR dogs were allocated to the post-rescue protocol and seven of these removed from the study. Significant differences in pain scores between groups were not observed during the first 12 hours, however, DMED dogs were less (p = 0.009) painful during the last 12 hours. Sedation score over the entire 24-hour study was not significantly different between groups.Conclusion / Clinical RelevanceDexmedetomidine CRI was equally effective as MOR CRI at providing postoperative analgesia and no clinically significant adverse reactions were noted. This study shows the potential of DMED to contribute to a balanced postoperative analgesia regimen in dogs.     

Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs

OBJECTIVE: To determine the plasma concentration and define the pharmacokinetic characteristics of fentanyl (10 microg kg(-1)) administered as a single intravenous (IV) injection followed by: (a) no further drug; or (b) a constant rate infusion (CRI) of fentanyl 10 microg kg(-1) hour(-1) lasting 1, 3 or 4 hours in dogs. Animals Fourteen healthy adult beagles (seven males and seven females). EXPERIMENTAL DESIGN: Randomized cross-over design. MATERIALS AND METHODS: Dogs were randomly assigned to four treatment groups. Drugs were administered to each dog in a randomized cross-over design with at least a 14-day washout interval between experiments. All dogs received an IV loading dose of fentanyl (10 microg kg(-1)). One group received no further fentanyl. In others, the loading dose was followed by a CRI of fentanyl (10 microg kg(-1) hour(-1)) for 1, 3 or 4 hours. Blood samples were collected and plasma fentanyl concentrations determined using high-performance liquid chromatography-mass spectrometry. Plasma pharmacokinetic estimates were obtained by plotting plasma concentrations versus time data and by fitting the change in concentration to a pharmacokinetic model, using a purpose-built program written by the Graduate School of Pharmaceutical Sciences (Kyoto University) in Visual Basic (VBA) on Excel (Microsoft Corporation). RESULTS: Plasma fentanyl concentration decreased rapidly after single IV injection: the plasma concentration-time curve best fitted a two-compartment model. Pharmacokinetic variables for IV injection were characterized by a short distribution half-time (t1/2alpha was 4.5 minutes), a relatively long elimination half time (t1/2beta was 45.7 minutes), a large volume of distribution (approximately 5 L kg(-1)) and high total body clearance (77.9 mL minute(-1) kg(-1)). Stable plasma fentanyl levels were obtained in all CRI groups although pharmacokinetic variables were influenced by the duration of administration. CONCLUSIONS AND CLINICAL RELEVANCE: While this study clarified the pharmacokinetic features of rapid IV fentanyl injection and CRI in dogs, the plasma concentration achieving analgesia was not and so further research is needed. Further studies on the effects of other sedatives and/or anaesthetics on fentanyl's disposition are also required as the drug is commonly used with other agents.     

Pharmacokinetics of hydromorphone hydrochloride in healthy dogs

ObjectiveTo assess the pharmacokinetics of hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs.Study designRandomized experimental trial.AnimalsSeven healthy male neutered Beagles aged 12.13 ± 1.2 months and weighing 11.72 ± 1.10 kg.MethodsThe study was a randomized Latin square block design. Dogs were randomly assigned to receive hydromorphone hydrochloride 0.1 mg kg⁻¹ or 0.5 mg kg⁻¹ IV (n = 4 dogs) or 0.1 mg kg⁻¹ (n = 6) or 0.5 mg kg⁻¹ (n = 5) SC on separate occasions with a minimum 14-day washout between experiments. Blood was sampled via a vascular access port at serial intervals after drug administration. Serum was analyzed by mass spectrometry. Pharmacokinetic parameters were determined with computer software.ResultsSerum concentrations of hydromorphone decreased quickly after both routes of administration of either dose. The serum half-life, clearance, and volume of distribution after IV hydromorphone at 0.1 mg kg⁻¹ were 0.57 hours (geometric mean), 106.28 mL minute⁻¹ kg⁻¹, and 5.35 L kg⁻¹, and at 0.5 mg kg⁻¹ were 1.00 hour, 60.30 mL minute⁻¹ kg⁻¹, and 5.23 L kg⁻¹, respectively. The serum half-life after SC hydromorphone at 0.1 mg kg⁻¹ and 0.5 mg kg⁻¹ was 0.66 hours and 1.11 hours, respectively.Conclusions and clinical relevanceHydromorphone has a short half-life, suggesting that frequent dosing intervals are needed. Based on pharmacokinetic parameters calculated in this study, 0.1 mg kg⁻¹ IV or SC q 2 hours or a constant rate infusion of hydromorphone at 0.03 mg kg⁻¹ hour⁻¹ are suggested for future studies to assess the analgesic effect of hydromorphone.     

Effects of two fentanyl constant rate infusions on thermal thresholds and plasma fentanyl concentrations in awake cats

Objective

To determine the pharmacokinetics and effects on thermal thresholds (TT) of two fentanyl constant rate infusions in awake cats.

Postoperative analgesic effects of either a constant rate infusion of fentanyl,lidocaine, ketamine,dexmedetomidine, or the combination lidocaine‐ketamine‐dexmedetomidine after ovariohysterectomy in dogs

ObjectiveTo evaluate the postoperative analgesic effects of a constant rate infusion (CRI) of either fentanyl (FENT), lidocaine (LIDO), ketamine (KET), dexmedetomidine (DEX), or the combination lidocaine-ketamine-dexmedetomidine (LKD) in dogs.Study designRandomized, prospective, blinded, clinical study.AnimalsFifty-four dogs.MethodsAnesthesia was induced with propofol and maintained with isoflurane. Treatments were intravenous (IV) administration of a bolus at start of anesthesia, followed by an IV CRI until the end of anesthesia, then a CRI at a decreased dose for a further 4 hours: CONTROL/BUT (butorphanol 0.4 mg kg⁻¹, infusion rate of saline 0.9% 2 mLkg⁻¹ hour⁻¹); FENT (5 μg kg⁻¹, 10 μg kg⁻¹hour⁻¹, then 2.5 μg kg⁻¹ hour⁻¹); KET (1 mgkg⁻¹, 40 μg kg⁻¹ minute⁻¹, then 10 μg kg⁻¹minute⁻¹); LIDO (2 mg kg⁻¹, 100 μg kg⁻¹ minute⁻¹, then 25 μg kg⁻¹ minute⁻¹); DEX (1 μgkg⁻¹, 3 μg kg⁻¹ hour⁻¹, then 1 μg kg⁻¹ hour⁻¹); or a combination of LKD at the aforementioned doses. Postoperative analgesia was evaluated using the Glasgow composite pain scale, University of Melbourne pain scale, and numerical rating scale. Rescue analgesia was morphine and carprofen. Data were analyzed using Friedman or Kruskal–Wallis test with appropriate post-hoc testing (p < 0.05).ResultsAnimals requiring rescue analgesia included CONTROL/BUT (n = 8), KET (n = 3), DEX (n = 2), and LIDO (n = 2); significantly higher in CONTROL/BUT than other groups. No dogs in LKD and FENT groups received rescue analgesia. CONTROL/BUT pain scores were significantly higher at 1 hour than FENT, DEX and LKD, but not than KET or LIDO. Fentanyl and LKD sedation scores were higher than CONTROL/BUT at 1 hour.Conclusions and clinical relevanceLKD and FENT resulted in adequate postoperative analgesia. LIDO, CONTROL/BUT, KET and DEX may not be effective for treatment of postoperative pain in dogs undergoing ovariohysterectomy.     

Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs

OBJECTIVE: To evaluate cardiovascular and respiratory effects and pharmacokinetics of a 24-hour intravenous constant rate infusion (CRI) of dexmedetomidine (DMED) during and after propofol (PRO) or isoflurane (ISO) anaesthesia in dogs. STUDY DESIGN: Prospective, randomized, cross-over study. ANIMALS: Ten healthy adult Beagles. METHODS: Instrumented dogs received a DMED-loading bolus (25 microg m(-2)) at time 0 followed by a 24-hour CRI (25 microg m(-2) hour(-1)), with PRO or ISO induction/maintenance of anaesthesia during the first 2 hours (PRO and ISO treatment groups, respectively). Cardiovascular, respiratory, blood gas, airway gas, serum chemistry variables and DMED plasma concentration data were collected at -15, 5, 15, 30, 45, 60, 90 and 120 minutes. A number of cardiorespiratory and tissue oxygenation variables were calculated from the above data. After the 2-hours of anaesthesia, heart and respiratory rates and electrocardiograms were recorded and DMED plasma concentrations were determined for up to 26 hours. RESULTS: Vasopressor effects and the decrease in heart rate (HR) and cardiac index induced by DMED were greater for PRO than ISO, but were within clinically acceptable ranges. Adequate oxygenation was maintained above the critical O(2) delivery level. The overall incidence of unfavourable arrhythmias was low and tended to vary inversely with HR. Mean DMED plasma concentration ranged from 0.23 to 0.47 ng mL(-1) for both groups during the 24-hour CRI with a mean elimination half-life of approximately 0.46 hour. CONCLUSION AND/CLINICAL RELEVANCE: DMED CRI resulted in typical alpha(2)-agonist induced haemodynamic changes with minimal respiratory effects, and appeared to be an efficacious adjunct during and after PRO or ISO anaesthesia in healthy dogs.     

Propofol and fentanyl infusions in dogs of various breeds undergoing surgery

ObjectiveTo report the cardiovascular variables, anaesthetic effects and recovery quality of an anaesthesia technique using variable rate infusion propofol combined with constant rate infusion fentanyl in dogs undergoing elective surgery.Study designProspective clinical trial.AnimalsA total of 27 dogs, aged 2.7 ± 2.65 years and weighing 24 ± 11 kg.MethodsFollowing intramuscular acepromazine (0.03 or 0.05 mg kg^?1) and subcutaneous carprofen (4 mg kg^?1) pre-medication, anaesthesia was induced with propofol (4.0 ± 0.5 mg kg^?1) intravenously (IV). All dogs were ventilated with 100% oxygen to maintain normocapnia. Propofol was infused at 0.4 mg kg^?1 minute^?1 for 20 minutes and then at 0.3 mg kg^?1minute^?1. If mean arterial blood pressure (MAP) decreased below 70 mmHg, propofol infusion was reduced by 0.1 mg kg^?1 minute^?1. Five minutes after induction of anaesthesia, fentanyl was administered (2 μg kg^?1) IV followed by the infusion at 0.5 μg kg^?1 minute^?1 and atropine (40 μg kg^?1) IV. Heart rate, MAP, respiratory rate, tidal volume, end-tidal carbon dioxide, presence of reflexes, movements and recovery times and quality were recorded.ResultsMean anaesthetic duration was 131 ± 38.5 minutes. Mean heart rate peaked 10 minutes after atropine injection and gradually declined, reaching pre-anaesthetic values at 55 minutes. MAP easily was maintained above 70 mmHg. Mean times to return of spontaneous ventilation, extubation, head lift and sternal recumbency were 21 ± 10.1, 33 ± 14.6, 43 ± 19.7 and 65 ± 23.4 minutes, respectively. Recovery was smooth and quiet. The time to sternal recumbency was significantly correlated with the duration of anaesthesia and total dose of propofol; time to extubation was correlated to total dose of propofol.Conclusion and clinical relevancePropofol and fentanyl infusions provided stable cardiovascular function and satisfactory conditions for surgery. Some modifications of infusion rates are required to improve the long-recovery times.     

Pharmacokinetics of ammonium sulfate gradient loaded liposome‐encapsulated oxymorphone and hydromorphone in healthy dogs

ObjectiveTo evaluate the pharmacokinetics, in dogs, of liposome–encapsulated oxymorphone and hydromorphone made by the ammonium sulfate gradient loading technique (ASG).AnimalsFour healthy purpose–bred Beagles aged 9.5 ± 3.2 months and weighing 13.4 ± 2.3 kg.Study designRandomized cross–over design.MethodsEach dog was given either 4.0 mg kg^?1 of ASG–oxymorphone or 8.0 mg kg^?1 of ASG–hydromorphone SC on separate occasions with a 3–month washout period. Blood was collected at baseline and at serial time points up to 1032 hours (43 days) after injection for determination of serum opioid concentrations. Serum opioid concentrations were measured with HPLC–MS and pharmacokinetic parameters were calculated using commercial software and non–compartmental methods.ResultsSerum concentrations of oxymorphone remained above the limit of quantification for 21 days, while those for hydromorphone remained above the limit of quantification for 29 days. C_max for ASG–oxymorphone was 7.5 ng mL^?1; C_max for ASG–hydromorphone was 5.7 ng mL^?1.Conclusions and clinical relevanceOxymorphone and hydromorphone, when encapsulated into liposomes using the ammonium sulfate gradient loading technique, result in measureable serum concentrations for between 3 to 4 weeks. This formulation may have promise in the convenient use of opioids for clinical treatment of chronically painful conditions in dogs.     

Effect of fentanyl on the induction dose and minimum infusion rate of propofol preventing movement in dogs

Objective

To determine the effect of fentanyl on the induction dose of propofol and minimum infusion rate required to prevent movement in response to noxious stimulation (MIR_NM) in dogs.

Effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone preventing movement in dogs

Objective

To determine the effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone required to prevent movement in response to a noxious stimulus (MIR_NM) in dogs.

Comparison between continuous rate infusion and target-controlled infusion of propofol in dogs: a randomized clinical trial

ObjectiveTo compare a propofol continuous rate infusion (CRI) with a target-controlled infusion (TCI) in dogs.Study designRandomized prospective double-blinded clinical study.AnimalsA total of 38 healthy client-owned dogs.MethodsDogs premedicated intramuscularly with acepromazine (0.03 mg kg^–1) and an opioid (pethidine 3 mg kg^–1, morphine 0.2 mg kg^–1 or methadone 0.2 mg kg^–1) were allocated to P-CRI group (propofol 4 mg kg^–1 intravenously followed by CRI at 0.2 mg kg^–1 minute^–1), or P-TCI group [propofol predicted plasma concentration (Cp) of 3.5 μg mL^–1 for induction and maintenance of anaesthesia via TCI]. Plane of anaesthesia, heart rate, respiratory rate, invasive blood pressure, oxygen haemoglobin saturation, end-tidal carbon dioxide and body temperature were monitored by an anaesthetist blinded to the group. Numerical data were analysed by unpaired t test or Mann–Whitney U test, one-way analysis of variance and Dunnett’s post hoc test. Categorical data were analysed with Fisher’s exact test. Significance was set for p < 0.005.ResultsOverall, propofol induced a significant incidence of relative hypotension (mean arterial pressure 20% below baseline, 45%), apnoea (71%) and haemoglobin desaturation (65%) at induction of anaesthesia, with a higher incidence of hypotension and apnoea in the P-CRI than P-TCI group (68% versus 21%, p = 0.008; 84% versus 58%, p = 0.0151, respectively). Propofol Cp was significantly higher at intubation in the P-CRI than P-TCI group (4.83 versus 3.5 μg mL^–1, p < 0.0001), but decreased during infusion, while Cp remained steady in the P-TCI group. Total propofol administered was similar between groups.Conclusions and clinical relevanceBoth techniques provided a smooth induction of anaesthesia but caused a high incidence of side effects. Titration of anaesthesia with TCI caused fewer fluctuations in Cp and lower risk of hypotension compared with CRI.     

Context-sensitive half-time of fentanyl in dogs

Context-sensitive half-times (CSHTs) of fentanyl in dogs were determined using pharmacokinetic models reported by Murphy et al. and Sano et al., and compared with a human model. The CSHT was defined as the time required for a 50% decrease in drug concentration in the central compartment after the termination of infusion. Although CSHTs increased gradually as the infusion time increased, the CSHTs in dogs were shorter than those in humans. The CSHTs at steady-state were 31.3 and 69.2 min in dogs, and 306.5 min in humans. The CSHTs of fentanyl in dogs are apparently shorter than those in humans; therefore, a continuous infusion of fentanyl may be a rational regimen in dogs, even if duration of infusion is extended.     

Pharmacokinetics of buprenorphine following constant rate infusion for postoperative analgesia in dogs undergoing ovariectomy

Objective

To investigate the pharmacokinetics of buprenorphine and its main active metabolite, norbuprenorphine, after administration of an intravenous loading dose followed by constant rate infusion (CRI) in dogs.

Comparison of transdermal fentanyl and oral tramadol for lateral thoracotomy in dogs: cardiovascular and behavioural data

Objective

To compare the analgesic efficacy and suitability of an existing oral tramadol-based protocol with a transdermal fentanyl-based protocol following lateral thoracotomy in dogs.

Effects of oxymorphone and hydromorphone on the minimum alveolar concentration of isoflurane in dogs

OBJECTIVES: To quantify the change in the minimum alveolar concentration (MAC) of isoflurane (ISO) associated with oxymorphone (OXY) or hydromorphone (HYDRO) in dogs. DESIGN: Randomized crossover study with at least 1 week between assessments. ANIMALS: Six young, healthy, mixed-breed dogs (1-3 years old), weighing 24.7 +/- 4.70 kg. METHODS: Following mask induction, anesthesia was maintained with ISO in 100% O(2) using mechanical ventilation. The dogs received 0.05 mg kg(-1) OXY, 0.1 mg kg(-1) HYDRO, or 1 mL saline (control) IV. Following equilibration (15 minutes) at each percentage ISO tested, a supramaximal electrical stimulus was applied to the toe web and the response was assessed. Two separate MAC determinations were carried out during 4.5 hours of anesthesia, with completion of the evaluations at 1.5-2 and 4-4.5 hours after drug administration. A two-factor anova was used to determine whether there was a time or treatment effect on MAC and a Tukey test compared the drug effects at each time. Significance is reported at p < 0.05. RESULTS: The mean MAC values (+/-SD) were 1.2 +/- 0.18 and 1.2 +/- 0.16% for control, 0.7 +/-0.15 and 1.0 +/- 0.15% for OXY, and 0.6 +/- 0.14 and 0.8 +/- 0.17% for HYDRO. The initial MAC with OXY and the MAC determined at both times with HYDRO were significantly different from the control MAC values. CONCLUSIONS: Both OXY and HYDRO significantly reduced the MAC of ISO in dogs at 2 hours. At approximately 4.5 hours, HYDRO had a significant MAC-sparing effect, whereas OXY did not. CLINICAL RELEVANCE: Although both OXY and HYDRO resulted in a significant reduction in the MAC of ISO at approximately 2 hours, HYDRO may be preferred for procedures of long duration and rarely needs repeated dosing before 4.5 hours.     

Effects of morphine and fentanyl constant rate infusion on urine output in healthy and traumatized dogs

ObjectiveTo determine whether healthy and traumatized dogs receiving a constant rate infusion (CRI) of either morphine or fentanyl have decreased urine production.Study designProspective randomized controlled study.Animal populationEighteen privately owned previously healthy dogs that had undergone trauma were included. Twenty-three privately owned healthy dogs were used as the controls.MethodsTraumatized dogs were randomized into one of two groups. Group Tmorphine received a CRI of morphine (0.12 mg kg⁻¹ hour⁻¹) and group Tfentanyl received a CRI of fentanyl (3 μg kg⁻¹ hour⁻¹) both administered in lactated Ringer’s solution (LRS) at a rate of 60 mL kg⁻¹ day⁻¹. Control healthy dogs were randomized into one of three groups. The LRS control group (CLRS) (n = 8) received LRS at a rate of 60 mL kg⁻¹ day⁻¹. Group Cmorphine (n = 8) and group Cfentanyl (n = 7) received the same infusions as Tmorphine and Tfentanyl, respectively. Collected data were identical for all groups and consisted of measuring total fluid administered, urine output, and urine specific gravity (USG) for a 24-hour period. An analysis of variance (anova) was used for statistical analysis and a p < 0.05 was considered statistically significant.ResultsUrine output was significantly decreased (p < 0.05) in all groups compared with the LRS control group. The end mean USG was significantly lower (p = 0.003) in the LRS control group compared with all other groups.ConclusionsThere was a decrease in urine output with a CRI of morphine or fentanyl in both healthy and traumatized dogs.Clinical relevanceDecreased urine output caused by an opioid effect might lead to improper assessments of renal function and urine production.     

Opioid-sparing effect of a medetomidine constant rate infusion during thoraco-lumbar hemilaminectomy in dogs administered a ketamine infusion

ObjectiveTo evaluate the perioperative opioid-sparing effect of a medetomidine (MED) infusion compared to a saline (SAL) infusion in otherwise healthy dogs undergoing thoraco-lumbar hemilaminectomy surgery.Study designRandomized, partially blinded, clinical study.AnimalsA total of 44 client-owned adult dogs.MethodsAll dogs were administered a 1 μg kg^–1 MED loading dose, followed by a 1.7 μg kg^–1 hour^–1 constant rate infusion (CRI) intravenously or equivalent volumes of SAL. Infusions were started 10–15 minutes before surgical incision and continued throughout the surgical procedure. All dogs were administered a standardized anaesthetic and analgesic protocol (including a ketamine CRI). Multiparametric monitoring, including invasive arterial blood pressure, was performed. A trained investigator, unaware of the treatment, performed pain scores for 4 hours postoperatively. Rescue analgesia consisted of fentanyl administered intraoperatively and methadone postoperatively. Data were tested for normality and analysed with Fisher’s exact test, Mann–Whitney U-test, analysis of variance and Kaplan–Meier survival analysis. Data are shown as median (interquartile range) and p-value was set at < 0.05.ResultsThe total dose of fentanyl was significantly lower with MED 0 (0–0.8) μg kg^–1 hour^–1 compared to SAL 3 (1.8–5.3) μg kg^–1 hour^–1 (p = 0.004). In the MED group, one dog compared to 12 dogs in the SAL group required a fentanyl CRI (p = 0.001). There were no statistically significant differences between groups regarding the total dose of methadone administered.Conclusions and clinical relevanceThe addition of a low-dose medetomidine CRI to the anaesthetic protocol decreased the need for a fentanyl CRI in otherwise healthy dogs undergoing thoraco-lumbar hemilaminectomy surgery during administration of a ketamine CRI.