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

Objective To compare the pharmacokinetics of fentanyl at lower (LHR) or higher heart rate (HHR) in dogs anesthetized with isoflurane. Study design Prospective, randomized, crossover controlled trial. Animals A group of six healthy 13-month-old male Beagle dogs weighing 9.9 +/- 0.7 kg (mean +/- standard deviation). Methods Dogs 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 mu g 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. Results A 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 relevance The 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.