Fentanyl In Dogs Research Articles

Effect of heart rate on the pharmacokinetics of fentanyl in dogs anesthetized with isoflurane and hydromorphone

ObjectiveTo compare the pharmacokinetics of fentanyl at lower (LHR) or higher heart rate (HHR) in dogs anesthetized with isoflurane. Study designProspective, randomized, crossover controlled trial. AnimalsA group of six healthy 13-month-old male Beagle dogs weighing 9.9 ± 0.7 kg (mean ± standard deviation). MethodsDogs were allocated to two treatments: LHR (HR: 45–75 beats minute−1) and HHR (HR: 100–130 beats minute−1). Anesthesia was maintained with isoflurane and hydromorphone (0.1 mg kg−1 followed by 0.02–0.10 mg kg−1 hour−1) for both treatments. Glycopyrrolate was administered in HHR to maintain HR within the desired range. Afterwards, fentanyl (20 μg kg−1) was intravenously administered over 5 minutes. Arterial blood samples were collected for plasma fentanyl concentration measurement by liquid chromatography/mass spectrometry. The pharmacokinetics of fentanyl were compared between treatments and the differences were considered significant at p < 0.05. ResultsA three-compartment model best fitted the changes in plasma fentanyl concentration. Clearance (CL; mL minute−1 kg−1) was 33.2 (24.0–48.0) and 61.3 (44.5–72.7), maximum concentration (ng mL−1) 33.6 (23.4–36.6) and 20.0 (16.7–28.0), apparent volume of the rapid peripheral compartment (mL kg−1) 436 (352–723) and 925 (499–1887), apparent volume at steady state (mL kg−1) 4064 (3453–6546) and 7195 (5077–8601), cardiac index (CI; mL minute−1 m−2) 2.83 (1.98–3.67) and 4.91 (3.22–6.09) and HR (beats minute−1) 68 (49–72) and 120 (102–129) for LHR and HHR, respectively, with significant differences between treatments. Significant correlations (0.92 and 0.90) were found between CI and CL, and between HR and CL, respectively. Conclusions and clinical relevanceThe increase in HR and the resultant improvement in cardiac output increased fentanyl CL and volume of distribution, which resulted in a decrease in plasma fentanyl concentration in isoflurane-anesthetized dogs.

Comparison of fentanyl and hydromorphone constant rate infusions for pain management in dogs in an intensive care unit

ObjectiveTo compare the efficacy and quality of analgesia provided by constant rate infusions (CRIs) of hydromorphone and fentanyl in dogs in the intensive care unit (ICU). Study designProspective, randomized, blinded, clinical trial. AnimalsA total of 29 client-owned dogs. MethodsDogs prescribed a μ-opioid agonist infusion for postsurgical or medical pain were randomized to be administered either hydromorphone (0.025 or 0.05 mg kg−1 bolus, followed by a 0.03 mg kg−1 hour−1 infusion) or fentanyl (2.5 or 5 μg kg−1 bolus, followed by a 3 μg kg−1 hour−1 infusion). The technical staff and clinicians were blinded as to which drug was administered. Pain scores, using the Colorado State University Canine Acute Pain Scale, sedation scores and nausea scores were assigned at regular intervals and compared between groups. Dose escalation and de-escalation of the study drug were performed according to set protocols. Adverse clinical signs and all other medications administered were recorded and compared between groups. The study drug was discontinued if the animal remained painful despite dose escalations, or if adverse effects were noted. ResultsThe pain scores were of low magnitude and were not significantly different between groups. The use of concurrent analgesia, sedation/anxiolytic medications and antacid/antiemetic medications was not different between groups. Sedation and nausea scores were not statistically different between groups. Conclusions and clinical relevanceHydromorphone and fentanyl CRIs appear to be equally effective for adequate pain relief in dogs, with no significant differences in adverse effects. Therefore, either drug may be chosen for control of postsurgical or medical pain in an ICU setting.

Isoflurane minimum alveolar concentration sparing effects of fentanyl in the dog

ObjectiveTo characterize the isoflurane-sparing effects of a high and a low dose of fentanyl in dogs, and its effects on mean arterial pressure (MAP) and heart rate (HR). Study designProspective, randomized crossover trial. AnimalsEight healthy male Beagle dogs weighing 12.1 ± 1.6 kg [mean ± standard deviation (SD)] and approximate age 1 year. MethodsDogs were anesthetized using isoflurane and minimum alveolar concentration (MAC) was determined in duplicate by the bracketing method using an electrical stimulus on the tarsus. Animals were administered fentanyl: low dose (33 μg kg−1 loading dose, 0.2 μg kg−1 minute−1) or high dose (102 μg kg−1 loading dose, 0.8 μg kg−1 minute−1) and MAC was re-determined (MACISO-F). Blood was collected for analysis of plasma fentanyl concentrations before administration and after MACISO-F determination. All values are presented as mean ± SD. ResultsIsoflurane MAC (MACISO) was 1.30 ± 0.23% in the low dose treatment, which significantly decreased to 0.75 ± 0.22% (average MAC reduction 42.3 ± 9.4%). MACISO was 1.30 ± 0.18% in the high dose treatment, which significantly decreased to 0.30 ± 0.11% (average MAC reduction 76.9 ± 7.4%). Mean fentanyl plasma concentrations were 6.2 and 29.5 ng mL−1 for low and high dose treatments, respectively. MAP increased significantly only in the high dose treatment (from 81 ± 8 to 92 ± 9 mmHg). HR decreased significantly in both treatments from 108 ± 25 to 61 ± 14 beats minute−1 with the low dose and from 95 ± 14 to 42 ± 4 beats minute−1 with the high dose. Conclusions and clinical relevanceFentanyl administration resulted in a dose-dependent isoflurane MAC-sparing effect with bradycardia at both doses and an increase in MAP only at high dose. Further evaluation is needed to determine the effects of fentanyl on the overall cardiovascular function.

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.

Comparison of anaesthetic and analgesic effects of emulsified isoflurane used alone or combined with lidocaine and fentanyl in dogs

AIM: The objective of this study was to investigate the effects of a combination of emulsified isoflurane, lidocaine, and fentanyl (EI-L-F) compared with the efficacy of emulsified isoflurane alone (EI), a combination of emulsified isoflurane and lidocaine (EI-L) or emulsified isoflurane and fentanyl (EI-F) for anaesthetising dogs.METHODS: Eight mongrel dogs were anesthetised with EI (8 mL/kg/hour), EI-L (3 mg/kg/hour lidocaine and 6 mL/kg/hour of emulsified isoflurane), EI-F (1.5 μg/kg/hour fentanyl and 6 mL/kg/hour of emulsified isoflurane), and EI-L-F (5 mL/kg/hour of emulsified isoflurane, 1 μg/kg/hour of fentanyl and 2.4 mg/kg/hour of lidocaine). Each dog received all four treatments and there was a 15-day washout period between the treatments. The dogs' anaesthesia and analgesia scores and physiological parameters were determined before and 5, 10, 20, 30, 40, 50, 60, 70 and 80 minutes after the administration of anaesthetic agents.RESULTS: The dogs in each of the four groups became laterally recumbent within 1 minute. Respiration rate and heart rate increased (p<0.05) during the first 5 minutes of anaesthesia in all groups. Respiration rate in the EI-F-L group was higher (p=0.037) than other groups from 30 to 50 minutes. Heart rate was higher in the EI than EI-F-L group (p=0.018) from 10 to 20 minutes, then returned to near baseline. Arterial oxygen saturation decreased during the period of anaesthesia but was higher (p=0.032) from 10 to 50 minutes in EI-F-L group than in other groups. The total anaesthesia scores in the EI-L-F group were higher than the EI and EI-L groups (p<0.05). The mean time to body movement was 5 (SD 2), 5 (SD 2), 7 (SD 2) and 8 (SD 2) minutes for the EI, EI-L, EI-F and EI-F-L groups, respectively. The mean time to standing was 8 (SD 2), 9 (SD 2), 10 (SD 2) and 13 (SD 3) minutes for the EI, EI-L, EI-F and EI-F-L groups, respectively. No excitement was observed during recovery after anaesthesia.CONCLUSIONS: The EI-F-L combination that was used in this study provided an adequate anaesthesia effect in dogs, which was characterised by adequate analgesia and muscle relaxation without any complications.

The Effect of Four Anaesthetic Protocols for Maintenance of Anaesthesia on Trans-Diaphragmatic Pressure in Dogs

The diaphragm is the main inspiratory muscle and the main indicator of diaphragmatic contractility is the trans-diaphragmatic pressure (Pdi). The aim of this clinical study was to determine the effect of four different anaesthetic protocols on Pdi in anaesthetized healthy dogs. Eighty client-owned dogs were recruited in this clinical study. All the animals received dexmedetomidine and morphine as premedication and propofol for induction. Anaesthesia was maintained with one of four protocols: isoflurane (I), isoflurane with CRI of propofol (IP), isoflurane with CRI of fentanyl (IF), and isoflurane with CRI of ketamine (IK). When the surgical plane of anaesthesia was achieved, two balloon catheters were inserted, one into the stomach and one into the mid-third of the oesophagus for Pdi measurement. Pdi value was the highest in groups I (14.9±4.7 mmHg) and IK (15.2±3.5 mmHg) and the lowest in groups IP (12.2±3.2 mmHg) and IF (12.0±5.9 mmHg). There was a statistically significant difference (p = 0.029) between groups IK and IF. PE’CO2 was statistically significantly higher (p<0.0005) in group IF (7.7±0.8 kPa) than in group IK (6.5±0.7 kPa). Isoflurane alone or isoflurane with ketamine for the maintenance of anaesthesia seem to better preserve the respiratory function and the diaphragmatic contractility than isoflurane with either propofol or fentanyl in dogs. Therefore, the use of isoflurane or isoflurane with ketamine may be of benefit when animals with respiratory problems have to be anaesthetized.

Prevalence of Dysphoria after Fentanyl in Dogs Undergoing Stifle Surgery

To describe the prevalence of dysphoria after intraoperative administration of fentanyl by infusion and identify other risk factors influencing this in dogs undergoing stifle surgery. Prospective, randomized clinical study. Dogs (n = 92) that had tibial plateau leveling osteotomy (TPLO) or tibial tuberosity advancement (TTA). Dogs were anesthetized using a standardized anesthetic protocol, and randomly assigned to receive a loading dose followed by 1 of 3 infusions of fentanyl perioperatively: 2 μg/kg/h, 10 μg/kg/h, or 20 μg/kg/h. Dog characteristics and all additional medications were recorded and included as part of the statistical analysis. Dog behavior was scored before anesthesia and during recovery using a scale of 1-4 (Appendices A and B). If no improvement in behavior was seen in 3-5 minutes postextubation, dogs with a score of 3 or 4 during recovery were administered fentanyl (2 μg/kg intravenously [IV]) in the event that the behaviors associated with the higher scores were related to pain. If they did not respond favorably to the administration of additional fentanyl and wound palpation did not elicit a response, but the untoward behaviors continued, dogs were administered either a tranquilizer, sedative, or opioid antagonist, and were considered dysphoric. Of 92 dogs, 22 (23.9%) were considered dysphoric using aforementioned criteria. About one-fourth of dogs enrolled in this study were dysphoric based on study criteria.

Clinical Evaluation of Peri-Operative Pain Control Using Constant Rate Infusions of Remifintanil Combined with Low Dose Fentanyl in Dogs

Clinical Evaluation of Peri-Operative Pain Control Using Constant Rate Infusions of Remifintanil Combined with Low Dose Fentanyl in Dogs

Comparison of Behavioral Effects of Morphine and Fentanyl in Dogs and Cats

Behavioral effects induced by intravenous administration of morphine at 0.3, 0.6, 1.2, and 2.4 µg/kg and fentanyl at 5, 10, 20, and 40 µg/kg were evaluated in dogs and cats. In dogs, fentanyl and morphine depressed activity and level of consciousness in a dose- dependant manner. In cats, higher doses of fentanyl stimulated activity temporarily, but excitement, so-called "opioid mania," was not observed. Morphine induced distinctive behavioral changes characterized by sitting with fixed staring, and "opioid mania" was not observed in cats.

Comparison between tow techniques for induction of general anesthesia : popofol –fentanyl and ketamine fentanyl in dogs

This study was conducted to evaluate the anesthetic quality between propofol-fentanyl mixture (P-F)(2 mg/kg+0.004 mg/kg, i.v., respectively)and ketamine-fentanyl mixture (K-F)(10 mg/kg+0.004 mg/kg, i.v., respectively) in six adult dogs premedicated with atropine (0.05 mg/kg, i.m.) and xylazine (2 mg/kg, i.m.).The results revealed the presence of significant difference (p&lt; 0.05) only in the induction of anesthesia, recovery and standing period between both protocols.P-F mixture produced rapid, smooth and free of excitement induction (9.50 ± 0.76 sec) with transit apnea (19.16±2.4 sec). The duration of anesthesia was (23.33 ± 2.10 min), narcosis (32.50± 1.70 min) and anesthesia characterized by good muscle relaxation and abolishment of all reflexes with decrease in R.R. and increase in H R. Recovery was calm and rapid (46.6±2.25 min) and standing time was short (14.16±1.40 min),While anesthesia with K-F mixture characterized by slow and rough induction (29.16±1.53 sec), poor to moderate muscle relaxation and relatively shorter duration of anesthesia (18.83 ± 3.11 min)with narcosis for about(30.83 ± 5.23 min). The reflexes did not abolish completely especially eye reflexes (corneal and palpebral) and the eyes remained open. H.R. was increased but R.R. was decreased. Recovery was long and rough (78.33 ± 4.77 min) and stand time for (47.50±3.09 min).In conclusion, (P-F) mixtures produce excellent induction of general anesthesia rather than (K-F) in dogs and up to know this is the first report on the uses of these mixtures for induction of anesthesia in 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.

The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs

Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 microg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 microg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time (MRT) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.

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

ObjectivesTo determine whether moderate hypothermia during anesthesia significantly affects the serum concentration of transdermally delivered fentanyl and whether halothane or isoflurane affect these concentrations. Study DesignRandomized cross-over experimental trial. AnimalsSix mature, healthy Beagles (three males, three females) weighing 10.6 ± 0.43 kg. MethodsA 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. ResultsThe 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 relevanceHypothermia 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.

Cardiorespiratory effects of epidural administration of morphine and fentanyl in dogs anesthetized with sevoflurane.

To determine the cardiorespiratory effects of epidural administration of morphine alone and in combination with fentanyl in dogs anesthetized with sevoflurane. Prospective study. 6 dogs. Dogs were anesthetized with sevoflurane and allowed to breathe spontaneously. After a stable plane of anesthesia was achieved, morphine (0.1 mg/kg [0.045 mg/lb]) or a combination of morphine and fentanyl (10 microg/kg [4.5 microg/lb]) was administered through an epidural catheter, the tip of which was positioned at the level of L6 or L7. Cardiorespiratory variables were measured for 90 minutes. Epidural administration of morphine alone did not cause any significant changes in cardiorespiratory measurements. However, epidural administration of morphine and fentanyl induced significant decreases in diastolic and mean arterial blood pressures and total peripheral resistance. Stroke volume was unchanged, PaCO2 was significantly increased, and arterial pH and base excess were significantly decreased. Heart rate was significantly lower after epidural administration of morphine and fentanyl than after administration of morphine alone. None of the dogs had any evidence of urine retention, vomiting, or pruritus after recovery from anesthesia. Results suggest that epidural administration of morphine at a dose of 0.1 mg/kg in combination with fentanyl at a dose of 10 microg/kg can cause cardiorespiratory depression in dogs anesthetized with sevoflurane.

Evaluation of postoperative respiratory function by serial blood gas analysis in dogs treated with transdermal fentanyl

AbstractObjective: To perform blood gas analysis of the respiratory response to transdermal fentanyl in dogs which have experienced an open‐chest surgical procedure.Design: Prospective trial.Setting: Veterinary Teaching Hospital Surgical Research and Student Laboratory.Intervention: Dogs were purchased for a surgical laboratory. Students performed a cranial abdominal exploratory and diaphragmatic hernia repair. Sixteen dogs were divided into 2 groups. Dogs received transdermal fentanyl (group F), using an average dose of 4.8 µg/kg/hr, applied to the caudal‐lateral abdomen 22 hours before surgery, or intravenous buprenorphine (group B; 0.02 mg/kg) given 1 hour prior to anesthetic induction and every 6 hours postoperatively. All dogs received intravenous acepromazine (0.05 mg/kg) preoperatively and every 6 hours postoperatively. Dogs were instrumented with carotid artery catheters.Measurements and main results: Arterial blood gas values were analyzed every 2 hours postoperatively. Plasma fentanyl levels were analyzed every 4 hours postoperatively. The mean carbon dioxide tension (PCO2) did not exceed 45 mmHg in either group. The range in mean PCO2 levels was 32.9 (± 3.4)−38.1 (± 3.9) in group B and 34.7 (± 3.25)−43.6 (± 5.5) in group F. At 2 time points, the mean PCO2 was significantly lower in group B compared with normal levels in group F. Hypoxemia occurred in both the groups. The range in mean oxygen tension (PO2) was 76.5 (± 18.3)−91.1 (± 16.3) in group B and 76.0 (± 10.8)−96.6 (± 7.6) in group F. There was no significant difference in PO2 between groups. Levels of fentanyl considered to be analgesic were maintained for the postoperative period.Conclusions: The use of a relatively high dose of transdermal fentanyl did not induce postoperative hypoventilation as evidenced by serial arterial blood gas analysis in this model.

The influence of inhaled anesthetic and body temperature on serum fentanyl concentrations with transdermally administered fentanyl in anesthetized dogs

This investigation was designed to determine if: (a) hypothermia during 4 hours of anesthesia significantly influences the peri-anesthetic serum concentration of transdermally administered fentanyl, and (b) there is a significant difference between the peri-anesthetic serum concentrations of transdermally administered fentanyl in dogs anesthetized with halothane compared to dogs anesthetized with isoflurane.

Synergistic antinociceptive interaction between sevoflurane and intrathecal fentanyl in dogs

This study determined the nature of the antinociceptive interaction between sevoflurane and intrathecal fentanyl on somatosympathetic reflexes in anaesthetized dogs. Afferent A delta- and C-fibre-mediated somatosympathetic reflexes, evoked by supramaximal electrical stimulation of tibial nerves, were recorded from renal sympathetic nerves. The effect of fentanyl alone, administered intrathecally (i.t.) in incremental doses from 2 to 64 micrograms, was compared with the effect of the same doses during the administration of 1.5% sevoflurane. The mean ED50s for the depressant effect of fentanyl (i.t.) on A delta and C reflexes were 35.6 micrograms and 14.2 micrograms while 1.5% sevoflurane, when administered alone, depressed them by 15.5% (P < 0.05) and 27.5% (P < 0.01) respectively. During the administration of 1.5% sevoflurane, the mean ED50s of fentanyl (i.t.) for the depression of A delta and C reflexes were reduced by 76% and 75%, to 8.5 micrograms and 3.5 micrograms respectively. The combined antinociceptive effects of sevoflurane and intrathecal fentanyl were not additive but exhibited a high degree of synergistic interaction.

Cerebral Effects of Fentanyl in Dogs

We have studied the cerebral haemodynamic and metabolic effects of fentanyl 50 μg kg−1 and 100 μg kg−1 in dogs undergoing ventilation with oxygen and nitrogen at normocapnia. Cerebral blood flow was measured continuously by direct measurement of the outflow of the posterior sagittal sinus. Arterial and sagittal sinus bloodgas tensions were measured intermittently for calculation of cerebral metabolism. Systemic pressures were measured continuously with intermittent measurements of cardiac output. These doses of fentanyl had minimal effect on cerebral blood flow, cerebral oxygen consumption and the energy state of the brain reflected by the normal concentration of cerebral metabolites at the end of the study. There was also little effect on systemic haemodynamics. It is concluded that, in the absence of other anaesthetic agents which might influence cerebral haemodynamics and metabolism, large doses of fentanyl have little effect on the cerebral circulation.

Relationship Between Cerebral Blood Volume and CSF Pressure During Anesthesia with Isoflurane or Fentanyl in Dogs

Cerebral blood volume (CBV) and intracranial (ICP) were examined in dogs during 3.5 h anesthesia with isoflurane (1.4% expired) or fentanyl (continuous intravenous infusion), and after decreasing the concentration of isoflurane to less than 0.15% expired or discontinuing administration of fentanyl. Isoflurane (1.4%) increased CBV 9-11% for greater than 3 h but increased ICP for only the first 21.7 +/- 1.4 min (mean +/- SEM). Fentanyl decreased CBV 7-10% for greater than 3 h but decreased ICP for only the first 20.3 +/- 2.7 min. Because both halothane or enflurane increase ICP for greater than 3 h in this model, both isoflurane or fentanyl may be preferred to halothane or enflurane for patients at risk for increased ICP.

Dose-Independent Pharmacokinetics of Fentanyl

Fentanyl is used as an analgesic in small doses (1-2 micrograms X kg-1) and as an anesthetic in very large doses (greater than 150 micrograms X kg-1). It has been demonstrated that the effects of fentanyl correlate with its concentrations in plasma. It is important, therefore, to know whether or not the pharmacokinetics of fentanyl vary with dose size in order to predict the plasma concentrations and effects produced by various dosage regiments. The authors studied the pharmacokinetics of fentanyl in dogs. 3H-fentanyl (2.5-640 micrograms X kg-1) was injected intravenously in dogs anesthetized at a stable level with enflurane-O2. Arterial plasma and urine were analyzed for unchanged 3H-fentanyl. Kinetic indices were derived by nonlinear least-squares analysis of log concentration of fentanyl in plasma (ng X ml-1) versus time after a bolus injection. The terminal elimination half-time (t 1/2 beta = 211 min), the apparent volume of distribution (9.5 l X kg-1), the volume of the central compartment (1.14 l X kg-1), and the clearance (37 ml X kg-1 X min-1) of fentanyl were independent of dose over the 6.4-640 micrograms X kg-1 dose range. The distribution volume and distribution half-times were lower for the 2.5 micrograms X kg-1 than for some of the larger doses; this was attributed to differences in experimental conditions. The authors conclude that the pharmacokinetics of fentanyl are dose independent certainly over the 6.4-640 micrograms X kg-1 dose range. There is no evidence of saturation of biotransformation or tissue uptake mechanisms for doses in the range of 2.5 to 640 micrograms X kg-1.