Chronotropic effect of propofol or alfaxalone following fentanyl administration in healthy dogs

ObjectiveTo compare the effect of alfaxalone and propofol on heart rate (HR) and blood pressure (BP) after fentanyl administration in healthy dogs.Study designProspective, randomised clinical study.AnimalsFifty healthy client owned dogs (ASA I/II) requiring general anaesthesia for elective magnetic resonance imaging for neurological conditions.MethodsAll dogs received fentanyl 7 μg kg⁻¹ IV and were allocated randomly to receive either alfaxalone (n = 25) or propofol (n = 25) to effect until endotracheal (ET) intubation was possible. Heart rate and oscillometric BP were measured before fentanyl (baseline), after fentanyl (Time F) and after ET intubation (Time GA). Post-induction apnoea were recorded. Data were analysed using Fisher’s exact test, Mann Whitney U test and one-way anova for repeated measures as appropriate; p value <0.05 was considered significant.ResultsDogs receiving propofol showed a greater decrease in HR (-14 beat minute⁻¹, range -47 to 10) compared to alfaxalone (1 beat minute⁻¹, range -33 to 26) (p = 0.0116). Blood pressure decreased over the three time periods with no difference between groups. Incidence of post-induction apnoea was not different between groups.ConclusionFollowing fentanyl administration, anaesthetic induction with propofol resulted in a greater negative chronotropic effect while alfaxalone preserved or increased HR.Clinical relevanceFollowing fentanyl administration, HR decreases more frequently when propofol rather than alfaxalone is used as induction agent. However, given the high individual variability and the small change in predicted HR (-7.7 beats per minute after propofol), the clinical impact arising from choosing propofol or alfaxalone is likely to be small in healthy animals. Further studies in dogs with myocardial disease and altered haemodynamics are warranted.     

Reduction of isoflurane MAC by fentanyl or remifentanil in rats

Objective The main objective of the study was to determine the effects of three different infusion rates of fentanyl and remifentanil on the minimum alveolar concentration (MAC) of isoflurane in the rat. A secondary objective was to assess the cardiovascular and respiratory effects of the two opioid drugs. Animal population Thirty‐seven male Wistar rats were randomly allocated to one of six treatment groups. Material and methods For all treatment groups anaesthesia was induced with 5% isoflurane in oxygen using an induction chamber. A 14‐gauge catheter was used for endotracheal intubation, and anaesthesia was maintained with isoflurane delivered in oxygen via a T‐piece breathing system. A baseline determination of the minimum alveolar concentration of isoflurane (MAC_ISO) was made for each animal. Fentanyl (15, 30, 60 µg kg^?1 hour^?1) or remifentanil (60, 120, 240 µg kg^?1 hour^?1) were infused intravenously into a previously cannulated tail vein. Thirty minutes after the infusion started, a second MAC_ISO (MAC_ISO+drug) was determined. The carotid artery was cannulated to monitor the arterial pressure and to take samples for arterial gas measurements. Cardiovascular (heart rate and arterial pressure) and respiratory (respiratory rate and presence/absence of apnoea) effects after opioid infusion were also recorded. Results Fentanyl (15, 30, 60 µg kg^?1 hour^?1) and remifentanil (60, 120, 240 µg kg^?1 hour^?1) similarly reduced isoflurane MAC in a dose‐dependent fashion: by 10% at lower doses, 25% at medium doses and by 60% at higher doses of both the drugs. Both opioids reduced the respiratory rate in a similar way for all doses tested. No episodes of apnoea were recorded in the remifentanil groups, while administration of fentanyl resulted in apnoea in three animals (one at each dose level). The effects on the cardiovascular system were similar with both drugs. Conclusions We conclude that the intraoperative use of remifentanil in the rat reduces the MAC of isoflurane, and that this anaesthetic sparing effect is dose‐dependent and similar to that produced by fentanyl at the doses tested. Clinical relevance The use of remifentanil during inhalant anaesthesia in the rat can be considered an intravenous alternative to fentanyl, providing similar reduction in isoflurane requirements. Due to its rapid offset, it is recommended that alternative pain relief be instituted before it is discontinued.     

The effect of inhalant anesthetic and body temperature on peri-anesthetic serum concentrations of transdermally administered fentanyl in dogs

Objectives To determine whether moderate hypothermia during anesthesia significantly affects the serum concentration of transdermally delivered fentanyl and whether halothane or isoflurane affect these concentrations. Study Design Randomized cross‐over experimental trial. Animals Six mature, healthy Beagles (three males, three females) weighing 10.6 ± 0.43 kg. Methods A 50‐µg hour^?1 fentanyl patch was applied 36 hours prior to anesthesia. Anesthesia was induced at time 0 (t = 0). Each dog received four treatments: isoflurane + normothermia (ISO‐NORM), isoflurane + hypothermia (ISO‐HYPO), halothane + normothermia (HAL‐NORM), and halothane + hypothermia (HAL‐HYPO). Dogs were intubated and maintained at 1.5 times MAC. Animals in the hypothermia treatments were cooled to 35 °C during anesthesia. Serum fentanyl analysis was performed at ?36, ?24, ?12, 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 18, and 26 hours. Direct arterial blood pressures and arterial blood gases were monitored. Results The mean body temperatures (±SEM) during the anesthetic period for the four treatments were: ISO‐NORM = 37.7 ± 0.07 °C, ISO‐HYPO = 35.8 ± 0.1 °C, HAL‐NORM = 37.7 ± 0.06 °C, and HAL‐HYPO = 35.8 ± 0.13 °C. The mean (±SEM) serum fentanyl concentrations (SFC) for both hypothermia treatments were significantly lower than baseline concentrations at t = 1 hour and persisted for the duration of anesthesia for the ISO‐HYPO treatment but only from t = 1 to 2 hours for the HAL‐HYPO treatment. Serum fentanyl concentrations returned to baseline within one hour of the end of anesthesia, regardless of body temperature. There were no significant differences between treatments for systolic or diastolic blood pressure but mean blood pressures were higher during normothermia versus hypothermia during the last hour of anesthesia. Conclusions and clinical relevance Hypothermia during inhalation anesthesia produced a significant reduction in SFC using transdermal administration and was more protracted with isoflurane than halothane anesthesia. While significant reductions in SFC occurred, the SFC were still within the range believed to confer analgesia.     

The anti-nociceptive and cardiopulmonary effects of extradural fentanyl–xylazine in sheep

Objective To compare the anti‐nociceptive effects of extradural xylazine, fentanyl and a xylazine–fentanyl combination in sheep, and to measure the cardiopulmonary effects of the xylazine–fentanyl combination. Study design Prospective, randomized study. Animals Twenty‐five half‐merino ewes 2–4 years of age and body mass 54.2 ± 1.1 kg. Methods Six sheep in group 1 received 0.2 mg kg^?1 xylazine by extradural injection, six in group 2 received fentanyl 1.5 µg kg^?1 and 13 in group 3 received the combination of both treatments. In all groups, drugs were mixed with saline (0.15 mL kg^?1 before injection). Pulmonary and carotid arterial catheters were placed in seven sheep of group 3 which were used to evaluate cardiopulmonary effects. Anti‐nociception was determined by the response to electrical stimulation (40 V for 1.5 milliseconds) of the left flank and by superficial and deep muscular ‘pinpricking’ stimulation of the pelvic and thoracic limbs and thoracolumbar region. Results Lack of response to electrical stimulation at the left flank was present in 10 ± 1.1 minutes (mean ± SEM) (group 1) and in 4.5 ± 0.5 minutes in group 3. The duration of lack of response to electrical stimulation at the left flank was 96 ± 6 minutes in group 1 and 315 ± 6 minutes in group 3. Responses persisted in group 3. Significant decreases (p < 0.05) in cardiac output 30, 45, 60 and 90 minutes after injection, and in cardiac work at 30 and 45 minutes were observed in the seven animals of group 3. Arterial blood pH was lowest at 90 minutes, arterial bicarbonate was lowest at 60 minutes and values for both arterial and mixed venous base excess increased significantly at 60 and 90 minutes. There was no significant change from baseline values in heart rate, mean arterial blood pressure, respiratory rate, body temperature, systemic vascular resistance, arterial and mixed venous PO₂, PCO₂, oxygen saturation, blood oxygen content, haemoglobin concentration, mixed venous blood bicarbonate and pH. Conclusions Fentanyl decreases the onset time and prolongs the duration of anti‐nociception produced by xylazine. The combination decreases cardiac output but is without significant respiratory effects. Clinical relevance Further studies are required to show that surgery is possible in sheep after extradural xylazine–fentanyl injection.     

Clinical efficacy and cardiorespiratory effects of alfaxalone, or diazepam/fentanyl for induction of anaesthesia in dogs that are a poor anaesthetic risk

ObjectiveTo evaluate the clinical efficacy and cardiorespiratory effects of alfaxalone as an anaesthetic induction agent in dogs with moderate to severe systemic disease.Study designRandomized prospective clinical study.AnimalsForty dogs of physical status ASA III-V referred for various surgical procedures.MethodsDogs were pre-medicated with intramuscular methadone (0.2 mg kg^?1) and allocated randomly to one of two treatment groups for induction of anaesthesia: alfaxalone (ALF) 1–2 mg kg^?1 administered intravenously (IV) over 60 seconds or fentanyl 5 μg kg^?1 with diazepam 0.2 mg kg^?1± propofol 1–2 mg kg^?1 (FDP) IV to allow endotracheal intubation. Anaesthesia was maintained with isoflurane in oxygen and fentanyl infusion following both treatments. All dogs were mechanically ventilated to maintain normocapnia. Systolic blood pressure (SAP) was measured by Doppler ultrasound before and immediately after anaesthetic induction, but before isoflurane administration. Parameters recorded every 5 minutes throughout subsequent anaesthesia were heart and respiratory rates, end-tidal partial pressure of carbon dioxide and isoflurane, oxygen saturation of haemoglobin and invasive systolic, diastolic and mean arterial blood pressure. Quality of anaesthetic induction and recovery were recorded. Continuous variables were assessed for normality and analyzed with the Mann Whitney U test. Repeated measures were log transformed and analyzed with repeated measures anova (p < 0.05).ResultsTreatment groups were similar for continuous and categorical data. Anaesthetic induction quality was good following both treatments. Pre-induction and post-induction systolic blood pressure did not differ between treatments and there was no significant change after induction. The parameters measured throughout the subsequent anaesthetic procedures did not differ between treatments. Quality of recovery was very, quite or moderately smooth.Conclusions and clinical relevanceInduction of anaesthesia with alfaxalone resulted in similar cardiorespiratory effects when compared to the fentanyl-diazepam-propofol combination and is a clinically acceptable induction agent in sick dogs.     

Dexmedetomidine or fentanyl? Cardiovascular stability and analgesia during propofol-ketamine total intravenous anaesthesia in experimental pigs

Objective

To compare cardiovascular function and response to nociception during total intravenous anaesthesia in pigs with propofol, ketamine and either dexmedetomidine or fentanyl administered as a continuous infusion.

Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation

This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 ± 2.2 kg), aged 3–4 weeks, were administered fentanyl citrate at a single dose of 5.0 μg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half‐life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr^?1 kg^?1, volume of distribution at steady‐state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half‐life, volume of distribution at steady‐state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg^?1 hr^?1. Fentanyl citrate administered i.v. at 5.0 μg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ , as lower limits can influence estimated parameters, such as elimination half‐life or systemic clearance and have significant impact on dosage regimen selection in clinical practice.     

Development and optimization of a fentanyl pharmacokinetic model for target-controlled infusion in anaesthetized dogs

ObjectiveTo investigate pharmacokinetics (PK) of fentanyl administered by target-controlled infusion (TCI), and to develop a PK model optimized by covariates for TCI in anaesthetized dogs.Study designProspective clinical study.AnimalsA group of 20 client-owned dogs with spinal pain undergoing anaesthesia for magnetic resonance imaging.MethodsFentanyl was administered as an infusion to 20 anaesthetized dogs using a TCI system incorporating a previously described fentanyl two-compartment PK. Arterial blood samples were collected at specific time points during the infusion and over 60 minutes post-infusion for measurement of fentanyl plasma concentrations. The predictive performance of the Sano PK model was assessed by comparing predicted and measured plasma concentrations. A population PK analysis was then performed using a nonlinear mixed-effect modelling approach, allowing inter- and intra-individual variability estimation. Finally, a quantitative stepwise evaluation of the influence of various covariates such as weight, body condition score, size, size-related age, sex and type of premedication on the PK model was considered.ResultsOverall predictive performance of the Sano PK set of variables was not clinically acceptable in anaesthetized dogs. Fentanyl PK was best described by a three-compartment model. Weight and sex were found to affect the volume of distribution of the central compartment. Addition of these two covariate/variable associations resulted in a reduction of the objective function value (OFV) from –340.18 to –448.34, and of the median population weighted residual and the median population absolute weighted residual from 16.1% and 38.6% to 3.9% and 20.3%, respectively. Fentanyl infusions at measured concentrations up to 5.4 ng mL^–1 in sevoflurane-anaesthetized dogs resulted in stable anaesthesia and smooth recoveries without complications.Conclusions and clinical relevanceA population three-compartment PK model for fentanyl TCI in anaesthetized dogs was developed. Weight and sex have been detected and incorporated as significant covariates.     

Effect of intravenous fentanyl on cough reflex and quality of endotracheal intubation in cats

ObjectiveTo assess the effects of intravenous (IV) fentanyl on cough reflex and quality of endotracheal intubation (ETI) in cats.Study designRandomized, blinded, negative controlled clinical trial.AnimalsA total of 30 client-owned cats undergoing general anaesthesia for diagnostic or surgical procedures.MethodsCats were sedated with dexmedetomidine (2 μg kg^–1 IV), and 5 minutes later either fentanyl (3 μg kg^–1, group F) or saline (group C) was administered IV. After alfaxalone (1.5 mg kg^–1 IV) administration and 2% lidocaine application to the larynx, ETI was attempted. If unsuccessful, alfaxalone (1 mg kg^–1 IV) was administered and ETI re-attempted. This process was repeated until successful ETI. Sedation scores, total number of ETI attempts, cough reflex, laryngeal response and quality of ETI were scored. Postinduction apnoea was recorded. Heart rate (HR) was continuously recorded and oscillometric arterial blood pressure (ABP) was measured every minute. Changes (Δ) in HR and ABP between pre-intubation and intubation were calculated. Groups were compared using univariate analysis. Statistical significance was set as p < 0.05.ResultsThe median and 95% confidence interval of alfaxalone dose was 1.5 (1.5–1.5) and 2.5 (1.5–2.5) mg kg^–1 in groups F and C, respectively (p = 0.001). The cough reflex was 2.10 (1.10–4.41) times more likely to occur in group C. The overall quality of ETI was superior in group F (p = 0.001), with lower laryngeal response to ETI (p < 0.0001) and ETI attempts (p = 0.045). No differences in HR, ABP and postinduction apnoea were found.Conclusions and clinical relevanceIn cats sedated with dexmedetomidine, fentanyl could be considered to reduce the alfaxalone induction dose, cough reflex and laryngeal response to ETI and to improve the overall quality of ETI.