Effects of acepromazine or dexmedetomidine on fentanyl disposition in dogs during recovery from isoflurane anesthesia

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1 Veterinary Anaesthesia and Analgesia, 2016, 43, doi: /vaa RESEARCH PAPER Effects of acepromazine or dexmedetomidine on fentanyl disposition in dogs during recovery from isoflurane anesthesia Stephanie Keating*, Carolyn Kerr*, Wayne McDonell*, Alexander Valverde*, Ron Johnson, Heather Knych & Andrea Edginton *Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada Department of Veterinary Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA School of Pharmacy, University of Waterloo, Waterloo, ON, Canada Correspondence: Stephanie Keating, Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario N1G 4S7, Canada. Abstract Objective To describe fentanyl pharmacokinetics during isoflurane anesthesia and on recovery from anesthesia with concurrent administration of acepromazine, dexmedetomidine or saline in dogs. Study design Experimental blinded, randomized, crossover study. Animals Seven adult hound dogs. Methods Dogs were administered intravenous (IV) fentanyl as a bolus (5 lg kg 1 ) followed by an infusion (5 lg kg 1 hour 1 ) for 120 minutes during isoflurane anesthesia and emergence from anesthesia, and for 60 minutes after extubation during recovery from anesthesia. At the time of extubation, dexmedetomidine (2.5 lg kg 1 ), acepromazine (0.05 mg kg 1 ) or saline were administered IV. Venous blood was sampled during the maintenance and recovery periods. Fentanyl plasma concentrations were measured using high-performance liquid chromatography mass spectrometry and population pharmacokinetic analyses were performed. Results Mean fentanyl plasma concentrations were ng ml 1 during isoflurane anesthesia and ng ml 1 during recovery from anesthesia. Recovery from isoflurane anesthesia without sedation was associated with an increase in the volume of the central compartment from 0.80 to 1.02 L kg 1. After administration of acepromazine, systemic clearance of fentanyl increased from 31.5 to 40.3 ml minute 1 kg 1 and the volume of the central compartment increased from 0.70 to 0.94 L kg 1. Administration of dexmedetomidine did not significantly change fentanyl pharmacokinetics. Inter-individual variability for fentanyl parameter estimates in all treatments ranged from 2.2% to 54.5%, and residual error ranged from 6.3% to 13.4%. Conclusions and clinical relevance The dose rates of fentanyl used in this study achieved previously established analgesic plasma concentrations for the duration of the infusion. Despite alterations in fentanyl pharmacokinetics, differences in fentanyl plasma concentrations among treatments during recovery from anesthesia were small and were unlikely to be of clinical significance. 35

2 Keywords acepromazine, anesthesia, dexmedetomidine, dog, fentanyl, recovery. Introduction Opioids are routinely administered to dogs to provide analgesia during the intraoperative and postoperative periods (Steagall et al. 2006; Egger et al. 2007). Short-acting opioids are frequently delivered as intravenous (IV) infusions, following a loading dose, to minimize fluctuations in plasma drug concentrations that would occur with repeated bolus administration, and to provide consistent and titratable analgesia (Sano et al. 2006; Anderson & Day 2008). Fentanyl is a synthetic l-opioid receptor agonist with a rapid onset and short duration of action. It is often used as an IV infusion in dogs intraoperatively to reduce requirements for other anesthetic agents and to improve analgesia, and administration is continued into the period of recovery from anesthesia in order to manage postoperative pain (Ilkiw et al. 1994; Steagall et al. 2006; Anderson & Day 2008). Dogs may also be administered a sedative with an opioid during recovery from anesthesia with the aim of preventing or minimizing dysphoria caused by opioid administration, emergence delirium or general anxiety (Dyson et al. 1998). Acepromazine and dexmedetomidine have been recommended for this purpose (Pascoe 2000). Although both drugs provide sedation in dogs during recovery from anesthesia, their combination with an opioid can result in additive or synergistic cardiopulmonary depression (Jacobson et al. 1994; Grimm et al. 2005; Monteiro et al. 2008). It is currently unknown whether the physiologic effects resulting from these drug interactions are caused by pharmacodynamic alterations alone, or whether pharmacokinetic interactions also play a role. The pharmacokinetics of fentanyl following an IV loading dose and constant rate infusion (CRI) have been previously evaluated in conscious dogs (Sano et al. 2006); however, pharmacokinetic analysis of a fentanyl CRI has not been performed in dogs anesthetized with isoflurane. Inhalation anesthetics have been shown to significantly alter the pharmacokinetic profiles of fentanyl, lidocaine and remifentanil in other species (Feary et al. 2005; Thomasy et al. 2005, 2007; Pypendop et al. 2008). Dexmedetomidine may also be associated with significant drug interactions (Kharasch et al. 1991, 1992) and has been shown to increase alfentanil plasma concentrations in human patients (Karol & Maze 2000). Despite the potential for significant drug interactions, there are currently no published studies evaluating the effects of different sedatives on fentanyl pharmacokinetics. The objectives of the current study were: 1) to describe fentanyl pharmacokinetics in dogs under isoflurane anesthesia; 2) to characterize changes in fentanyl disposition resulting from the elimination of isoflurane and recovery from anesthesia; and 3) to determine the pharmacokinetic influences of concurrently administered acepromazine or dexmedetomidine. Materials and methods Animals Seven intact, purpose-bred, male hounds were used in the study. Dogs were aged months and had a mean standard deviation (SD) body weight of kg. They were considered to be healthy based on their history, physical examination, complete blood count and serum biochemistry analyses. All dogs were allowed free access to water, but food was withdrawn for 12 hours prior to induction of anesthesia. The study was approved by the Institutional Animal Care Committee at the University of Guelph (ON, Canada). Experimental design A randomized, blinded, crossover design was used to evaluate fentanyl pharmacokinetics in three treatments. The treatment order was randomized manually for each dog by the blind drawing of a series of papers containing the treatment codes. Each dog was submitted to the same protocol for the induction and maintenance of anesthesia before the administration of the treatment drug at the time of recovery from anesthesia. Dogs underwent a washout period of at least 7 days between treatments. Study protocol The study protocol has been described previously in detail (Keating 2013; Keating et al. 2013). Anesthesia was induced with propofol (Diprivan 1%; AstraZeneca Canada, Inc., ON, Canada) IV to effect ( mg kg 1 ) and, after endotracheal intubation, was maintained with isoflurane (IsoFlo; Abbott Laboratories Ltd, QC, Canada) delivered in 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43,

3 oxygen using an F-circuit and a vaporizer setting of %. Dogs were then placed in lateral recumbency and instrumented to monitor cardiopulmonary function, which involved the aseptic placement of a pulmonary artery catheter. An 8.5 Fr introducer (Intro-Flex-Percutaneous Sheath Introducer Kit; Edwards Lifescience LLC, CA, USA) was inserted in a jugular vein to allow the placement of a 7 Fr thermodilution catheter (Edwards Swan-Ganz; Edwards Lifescience LLC) into the pulmonary artery. Catheter placement was performed using fluoroscopic guidance to ensure correct location within the pulmonary artery and further assessed by verifying appropriate pressure tracings. The central venous port of the pulmonary artery catheter was used to obtain blood samples for fentanyl analysis, and a 20 gauge, 4.78 cm catheter (Insyte-W; Becton Dickinson Infusion Therapy Systems, Inc., UT, USA) was placed in a cephalic vein for the IV administration of fentanyl and crystalloid solution. A second cephalic vein catheter was placed in the opposite limb for treatment administration during recovery from anesthesia. Following instrumentation, the dogs remained in lateral recumbency and were allowed to breathe spontaneously. A multi-parameter anesthetic monitor (S/5 Anesthesia Monitor; Datex-Ohmeda Division, Instrumentarium Corp., Finland) was used to record cardiovascular variables and expired gas composition. Gas calibration was performed prior to the study using a manufacturer-recommended gas mixture (Scott Medical Products Division, Air Liquide Healthcare America Corp., PA, USA). Isoflurane administration was adjusted to achieve an end-tidal isoflurane concentration (FE ISO) of 1.2%. Once FE ISO had been stable for 10 minutes, a bolus of fentanyl (5 lg kg 1 ; fentanyl citrate, 50 lg ml 1 ; Sandoz Canada, Inc., QC, Canada) was delivered IV by hand over 15 seconds, followed immediately by a CRI of fentanyl at 5 lg kg 1 hour 1 administered using a syringe pump that was calibrated before the experiment (Medfusion 3500 syringe pump; Smiths Medical ASD, Inc., MN, USA). The fentanyl CRI was delivered in balanced electrolyte solution (Plasma-Lyte A; Baxter Corp., ON, Canada) infused at 3 ml kg 1 hour 1. Dogs were administered fentanyl isoflurane anesthesia for 120 minutes from the start of the fentanyl infusion, after which only the isoflurane was discontinued. Extubation was performed when FE ISO was 0.8% and the assigned treatment was administered at this time. Treatments were acepromazine (0.05 mg kg 1 ; Atravet; Wyeth Animal Health, Inc., ON, Canada), dexmedetomidine (2.5 lg kg 1 ; Dexdomitor; Pfizer Animal Health Canada, Inc., QC, Canada) or a saline control, each prepared to a final volume of 1 ml with physiologic saline and administered IV. The fentanyl infusion was continued for an additional 60 minutes from the time of treatment administration before being discontinued. The collection of blood for fentanyl analysis continued for 30 minutes after the fentanyl infusion was stopped. Blood samples were collected after instrumentation before fentanyl administration (baseline), at 5, 10, 15, 30, 60, 90 and 120 minutes from the start of fentanyl administration during isoflurane anesthesia, and at 5, 10, 15, 30, 60, 75 and 90 minutes after extubation and treatment administration. At each sampling time, 4 ml of venous blood was collected into a heparinized tube (BD Vacutainer; Becton Dickinson & Co., NJ, USA) for fentanyl analysis and 8 ml of physiologic saline was delivered to partially replace the sampled blood volume. Plasma fentanyl analysis Blood samples were centrifuged at 2236 g for 10 minutes and plasma was isolated and stored at 80 C until analysis. Fentanyl concentrations were quantitated by liquid chromatography mass spectrometry analysis of protein precipitated samples, using a modification of a previously published method (Thomasy et al. 2007). Fentanyl-d 5 was used as the internal standard. The technique was optimized to provide a minimum limit of quantification of 0.03 ng ml 1 and a limit of detection of 0.01 ng ml 1 for fentanyl. Levels of accuracy (percentage of nominal concentration) and precision (percentage-relative SD) were 99.5% and 101.0%, and 2.5% and 4.0% at 0.04 and 1.5 ng ml 1, respectively. Pharmacokinetic analysis A na ıve pooled approach was used for each treatment to determine the base structural pharmacokinetic model. One-, two- and three-compartment IV bolus + infusion (180 minute infusion) models were fitted to observed fentanyl plasma concentrations and the most appropriate model was selected using the Akaike information criterion value and goodness-of-fit plots. Population pharmacokinetic analysis of observed fentanyl plasma concentrations was conducted using nonlinear mixed-effects modeling Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 35 43

4 (Phoenix NLME Version 1.2; Pharsight Corp., MO, USA). Estimation used the first order conditional estimation extended least squares (FOCE ELS) method with interaction between the between-subject (g) and random (e) effects. Inter-individual variability for each structural parameter was modeled using an exponential error model, such that: P i = P TV 9 exp(g i ), where P i is the parameter value of the ith subject, and g i is a random deviation describing the difference between P i and P TV. P TV is the typical value of the parameter in the population with no covariates considered. The values of g i are normally distributed with a mean of 0 and a variance of x 2. Inter-individual variability was calculated as the square root of the variance multiplied by 100%. Residual variability was described using a proportional error model, such that: C ij = C pred,ij (1 + e pro,ij ), where C ij is the jth observed concentration value in the ith subject, C pred,ij is the jth predicted concentration value in the ith subject and the proportional error value is e pro,ij. e pro,ij values are assumed to have a mean of 0 and a variance of r 2 pro. Residual error was calculated by multiplying the SD by 100%. The pharmacokinetic parameters selected for estimation were systemic clearance (CL), intercompartmental clearance (Q), volume of the central compartment (V 1 ), and volume of the peripheral compartment (V 2 ). Covariate analysis was performed to determine whether the value of the pharmacokinetic parameter for the period of recovery from anesthesia was equivalent to that for the period of anesthesia maintenance. A treatment covariate (TRT) was defined categorically as either 0 (no treatment effect) or 1 (treatment effect). Specifically, TRT was set to 0 on all plasma concentrations from t = 0 to 120 minutes (anesthesia maintenance period). Treatment covariate was assessed for significance by setting all concentrations after t = 120 minutes (recovery from anesthesia period) to either 0 or 1. The TRT covariate influenced the value of the fentanyl pharmacokinetics parameter (h) according to the following: h = h 1 * (1 + TRT * h 2 ), where h 1 is the typical value of the parameter with fentanyl alone and h 2 is the fractional change in the value attributable to the effect of the treatment. Covariate model building used a forward stepwise addition and a reverse deletion approach. The effects of the covariate were assessed based on the change in the objective function value (OFV; 2 log likelihood), visual diagnostics and increased precision of parameter estimates. A covariate effect on the parameter was considered significant (p < 0.05, df = 1) when the change in the OFV was >3.84 for each added parameter in the forward addition step. A stricter significance level (p < 0.01) (DOFV > 6.64, df = 1) was used for the backward deletion step. For each final model, a visual predictive check was performed using Monte-Carlo simulation. A dataset of 1000 subjects was generated and model-predicted concentrations falling between the 2.5th and 97.5th percentiles from the simulated data were overlaid on the observed data. It is expected that when 95% of observed data are within the 95th percentile, the model is well specified. The final models were also subject to nonparametric bootstrap analysis to assess the precision and stability of the parameter estimates. Results Fentanyl plasma concentrations obtained during the anesthesia maintenance phase were similar for each treatment (Fig. 1). Fentanyl concentrations in both saline- and acepromazine-treated dogs initially declined at the onset of recovery from anesthesia, whereas there was minimal change following dexmedetomidine administration (Fig. 2). A two-compartment model best fit the fentanyl plasma concentration data and was accepted as the base model for all treatments. Selected pharmacokinetic parameters in the saline and acepromazine treatments differed in the maintenance and recovery phases, whereas parameters in the dexmedetomidine group remained unchanged (Table 1). Inter-individual variability for parameter estimates in all treatments ranged from 2.2% to 54.5%, and residual error ranged from 6.3% to 13.4% (Table 2). Each final treatment model was considered robust as estimates derived from these models were within the 95% confidence intervals obtained through bootstrap analysis (Tables S1 & S2). Visual predictive checks demonstrated that the model was well specified (Fig. 3). Diagnostic plots of population predicted plasma concentrations and individual predicted plasma concentrations versus observed plasma concentrations distributed around the line of identity demonstrate the goodness of fit for each treatment model (Figs S1 S3). The final pharmacokinetic model for the saline control treatment revealed a treatment effect for V 1, with values increasing from 0.80 L kg 1 during the maintenance phase to 1.02 L kg 1 during recovery Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43,

5 Figure 1 Mean standard deviation plasma concentrations of fentanyl during isoflurane anesthesia in dogs before (baseline) and for 120 minutes of fentanyl administration using a loading dose (5 lg kg 1 ) and a constant rate infusion (5 lg kg 1 hour 1 ). Dogs were administered saline (n = 6), acepromazine (n = 7) or dexmedetomidine (n = 7) after anesthesia ended. BL, baseline. Figure 2 Mean standard deviation plasma concentrations of fentanyl in dogs at the termination of isoflurane anesthesia (Iso) and at 120 minutes of a constant rate infusion of intravenous (IV) fentanyl (5 lg kg 1 hour 1 ) and during recovery from anesthesia. Treatments (T) were administered IV at extubation [dexmedetomidine (2.5 lg kg 1 ; n = 7), acepromazine (0.05 mg kg 1 ; n = 7), 0.9% saline (n = 6)] and the fentanyl infusion was continued for a further 60 minutes. No other parameters demonstrated a treatment effect in the final saline pharmacokinetic model and thus remained unchanged from the maintenance phase to the recovery phase. In the final acepromazine model, a treatment effect was observed for both CL and V 1 of fentanyl. Specifically, CL increased significantly from 31.5 ml minute 1 kg 1 during the anesthesia maintenance phase to 40.3 ml minute 1 kg 1 during the recovery phase with acepromazine administration, and V 1 increased from 0.70 to 0.94 L kg 1. There were no differences in Q or V 2 on recovery with acepromazine compared with values during isoflurane anesthesia. Covariate analysis did not detect a treatment effect in the final dexmedetomidine model, indicating there were no differences in fentanyl pharmacokinetics between anesthesia and after the administration of dexmedetomidine on recovery from anesthesia. Discussion Fentanyl administered in a loading dose and a CRI in dogs during isoflurane anesthesia demonstrated moderate volumes of distribution and CL, and best fit a two-compartment model. Recovery from anesthesia without sedation (saline control) or with concurrent acepromazine administration altered fentanyl disposition, whereas recovery with dexmedetomidine administration did not significantly change fentanyl pharmacokinetics Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 35 43

6 Table 1 Estimates of volume of the central compartment (V 1 ), volume of the peripheral compartment (V 2 ), systemic clearance (CL) and intercompartmental clearance (Q) of fentanyl for each treatment during the anesthesia (isoflurane) maintenance and recovery phases in dogs. Treatments were saline (n = 6), acepromazine (0.05 mg kg 1 ; n = 7), and dexmedetomidine (2.5 lg kg 1 ; n = 7) administered at the time of extubation Saline Acepromazine Dexmedetomidine Parameter Isoflurane Recovery Isoflurane Recovery Isoflurane Recovery V 1 (L kg 1 ) * * V 2 (L kg 1 ) CL (ml minute 1 kg 1 ) * Q (ml minute 1 kg 1 ) *Significantly different from parameter estimate during isoflurane within a treatment. Table 2 Inter-individual and residual variability in volume of the central compartment (V 1 ), volume of the peripheral compartment (V 2 ), systemic clearance (CL) and intercompartmental clearance (Q) of fentanyl in dogs. Dogs were administered fentanyl as an intravenous loading dose (5 lg kg 1 ) and infusion (5 lg kg 1 hour 1 ) for 120 minutes during isoflurane anesthesia (FE ISO 1.2%), and for an additional 60 minutes after the discontinuation of isoflurane. Dogs were administered saline (n = 6), acepromazine (n = 7) or dexmedetomidine (n = 7) at the time of extubation Parameter Saline Acepromazine Dexmedetomidine Inter-individual variability x 2 V 1 (% variability) (26.7) (24.6) (13.9) x 2 V 2 (% variability) (25.1) (30.2) (2.2) x 2 CL (% variability) (21.5) (11.6) (12.2) x 2 Q (% variability) (54.5) (36.2) (41.6) Residual variability r 2 pro (% residual error) (13.4) (6.8) (6.3) x 2, variance for the parameter; r 2 pro, standard deviation of the proportional error. In this study, the administration of 5 lg kg 1 fentanyl as a loading dose and an infusion of 5 lg kg 1 hour 1 in dogs under isoflurane anesthesia resulted in fentanyl plasma concentrations that declined from peak values for approximately 30 minutes before reaching more stable concentrations. Despite this, plasma concentrations were within the minimum effective analgesic range of ng ml 1 reported in humans and dogs (Sear 1998; Robinson et al. 1999). These plasma concentrations would also be expected to provide significant isoflurane-sparing effects as fentanyl plasma concentrations of around 1 ng ml 1 reduce the minimum alveolar concentration (MAC) of enflurane in dogs by 13% and higher concentrations provide further MAC reductions, reaching 65% at a concentration of 30 ng ml 1 (Murphy & Hug 1982; Salmenper a et al. 1994). A similar trend in MAC reduction with fentanyl is reported in dogs under isoflurane anesthesia (Hellyer et al. 2001; Steagall et al. 2006; Ueyama et al. 2009). Several studies have investigated the effects of inhalation anesthesia on the pharmacokinetics of various agents and have consistently demonstrated smaller volumes of distribution and lower clearance in the anesthetized versus the conscious state (Feary et al. 2005; Thomasy et al. 2005; Pypendop et al. 2008). Fentanyl pharmacokinetics have been evaluated in horses during isoflurane anesthesia and also found to demonstrate this trend, but only reductions in clearance were statistically significant (Thomasy et al. 2007). The current study was not designed to directly compare fentanyl pharmacokinetics in awake and anesthetized dogs; however, a comparison of values obtained in anesthetized dogs in this study with values measured in conscious dogs 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43,

7 (a) Figure 3 Visual predictive checks for the final treatment models for dogs administered a loading dose of fentanyl (5 lg kg 1 ) followed by an infusion (5 lg kg 1 hour 1 ) for 120 minutes while under isoflurane anesthesia (FE ISO 1.2%) and for 60 minutes during recovery from anesthesia. Dogs were administered IV (a) 0.9% saline (n = 6), (b) 0.05 mg kg 1 acepromazine (n = 7), or (c) 2.5 lg kg 1 dexmedetomidine (n = 7) at extubation. (b) (c) (Sano et al. 2006) shows that volumes of distribution and CL were lower during anesthesia. Values for V 1 and CL were greater in conscious dogs, at 1.5 L kg 1 and ml minute 1 kg 1, respectively (Sano et al. 2006), than in the anesthetized dogs in the current study ( L kg 1 and ml minute 1 kg 1, respectively). Additionally, the elimination of isoflurane during recovery from anesthesia in our saline control group increased V 1, indicating values were lower during anesthesia, which is consistent with other findings. To evaluate the relationship between pharmacokinetic data and cardiopulmonary function, cardiopulmonary measurements were also recorded during the study and have been previously reported (Keating et al. 2013). Given the high hepatic extraction ratio of fentanyl (Bj orkman & Redke 2000), the marked differences in cardiopulmonary function observed among treatments during recovery from anesthesia would be expected to significantly influence fentanyl pharmacokinetics. Although hepatic blood flow was not specifically measured, cardiac index (CI) was determined and correlates with the observed differences in fentanyl disposition among treatments. Recovery from isoflurane without sedation (saline control) resulted in an initial decline in fentanyl plasma concentrations corresponding to an increase in V 1. The CI also significantly increased during recovery in saline-treated dogs (Keating et al. 2013) and is likely to have contributed to this finding. Increases in CI can be attributed to the elimination of isoflurane, which causes dose-dependent cardiopulmonary depression during anesthesia, as well as disorientation and increased sympathetic activity during emergence from general anesthesia. The increase in CI is likely to have contributed to the increase in V 1 seen during recovery by causing an increase in the perfusion of peripheral tissues, such as skeletal muscle (Hartman et al. 1992). Changes in cardiac function, vascular tone and subsequent fluid shifts in the saline control group may have resulted in the increase in fentanyl plasma concentrations at the 60 minute time point during the Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 35 43

8 recovery period, although the reason for this elevation is not clear. Cardiac index increased in dogs administered acepromazine on recovery similarly to the saline control group, with higher values in acepromazinetreated dogs (Keating et al. 2013). Although fentanyl plasma concentrations declined in both saline- and acepromazine-treated dogs on recovery, the greater increase in CI with acepromazine administration may have resulted in greater hepatic perfusion and increased CL. Additionally, increased blood flow to peripheral vascular beds associated with increases in CI would increase fentanyl distribution and V 1. In contrast to the decline in fentanyl plasma concentrations following acepromazine and saline administration during recovery, dexmedetomidine administration resulted in stable fentanyl plasma concentrations and fentanyl pharmacokinetic parameters did not differ between the maintenance and recovery phases. This stability occurred despite a significant reduction in CI following dexmedetomidine administration (Keating et al. 2013). Although reductions in CI may be expected to reduce total hepatic blood flow and fentanyl clearance, the dramatic decrease in CI from dexmedetomidine is accompanied by the redistribution of blood flow: hepatic perfusion has been found to be maintained or even increased in dogs under halothane fentanyl anesthesia and in conscious sheep (Lawrence et al. 1996; Talke et al. 2000). The pharmacokinetic results in the dexmedetomidine-treated dogs in this study may be explained by an absence of change in hepatic blood flow despite a decrease in CI. The current study refers to clinical protocols commonly used in our hospital for the maintenance of and recovery from anesthesia in dogs. There are some limitations to the study design. A longer sampling period after the discontinuation of fentanyl administration would have strengthened the pharmacokinetic analyses and increased the precision of parameter estimates. The fentanyl loading dose of 5 lg kg 1 was also higher than necessary to achieve steady-state plasma concentrations for the infusion rate delivered; however, the loading dose was selected to reflect dosing that may occur in a clinical scenario and was not selected to obtain a targeted plasma concentration. Despite significant differences in the cardiopulmonary effects of administration of acepromazine and dexmedetomidine during recovery from anesthesia, and the resulting differences in fentanyl pharmacokinetics, the changes in fentanyl plasma concentrations measured after fentanyl and sedative administration were small. Although it is possible that small changes may have greater than expected physiologic effects as a result of the synergistic nature of drug interactions, differences of this magnitude within the observed plasma concentrations do not significantly influence cardiopulmonary performance in dogs administered fentanyl alone (Arndt et al. 1984). Based on these findings, it is likely that the degree of cardiopulmonary change observed when fentanyl is co-administered with sedatives during recovery from anesthesia is primarily attributable to pharmacodynamic mechanisms rather than changes in plasma concentrations and fentanyl pharmacokinetics. Acknowledgements This study was funded by the Ontario Veterinary College Pet Trust Fund, and has been published online in part as a copyrighted DVSc thesis ( dspace.lib.uoguelph.ca/xmlui/bitstream/handle/ 10214/6548/Keating_Stephanie_201304_DVSc. pdf). References Anderson MK, Day TK (2008) Effects of morphine and fentanyl constant rate infusion on urine output in healthy and traumatized dogs. Vet Anaesth Analg 35, Arndt JO, Mikat M, Parasher C (1984) Fentanyl s analgesic, respiratory, and cardiovascular actions in relation to dose and plasma concentration in unanesthetized dogs. Anesthesiology 61, Bj orkman S, Redke F (2000) Clearance of fentanyl, alfentanil, methohexitone, thiopentone and ketamine in relation to estimated hepatic blood flow in several animal species: application to prediction of clearance in man. J Pharm Pharmacol 52, Dyson DH, Maxie MG, Schnurr D (1998) Morbidity and mortality associated with anesthetic management in small animal veterinary practice in Ontario. J Am Anim Hosp Assoc 34, Egger CM, Glerum L, Haag KM et al. (2007) Efficacy and cost-effectiveness of transdermal fentanyl patches for the relief of post-operative pain in dogs after anterior cruciate ligament and pelvic limb repair. Vet Anaesth Analg 34, Feary DJ, Mama KR, Wagner AE et al. (2005) Influence of general anesthesia on pharmacokinetics of intravenous lidocaine infusion in horses. Am J Vet Res 66, Grimm KA, Tranquilli WJ, Gross DR et al. (2005) Cardiopulmonary effects of fentanyl in conscious dogs 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43,

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