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Effects of a prolonged infusion of fentanyl, with or without atropine, on the minimum alveolar concentration of isoflurane in dogs
Veterinary Anaesthesia and Analgesia, 2016, 43, 136–144
doi:10.1111/vaa.12282
RESEARCH PAPER
Effects of a prolonged infusion of fentanyl, with or without atropine, on the minimum alveolar concentration of isoflurane in dogs Clarissa R Sim~oes, Eduardo R Monteiro, Julia PP Rangel, Juarez S Nunes-Junior & Daniela Campagnol School of Veterinary Medicine, University of Vila Velha, Vila Velha, ES, Brazil
Correspondence: Eduardo R Monteiro, Department of Animal Medicine, Faculty of Veterinary Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS 91540-000, Brazil. E-mail: [email protected] Present address: Eduardo R Monteiro, Department of Animal Medicine, Faculty of Veterinary Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
Abstract Objectives To evaluate the effect of a prolonged constant rate infusion (CRI) of fentanyl on the minimum alveolar concentration (MAC) of isoflurane (ISOMAC) and to establish whether concurrent atropine administration influences ISOMAC in dogs. Study design Prospective, crossover study. Animals Six healthy dogs weighing 13.0 4.1 kg. Methods Dogs were anesthetized with isoflurane under conditions of normocapnia and normothermia. Arterial blood pressure was monitored invasively. Each dog was administered two treatments, on different occasions, in a crossover design. The dogs were administered intravenously (IV) an atropine bolus 0.02 mg kg 1 and CRI at 1 0.04 mg kg hour 1 (fentanyl–atropine treatment) or no atropine (fentanyl treatment). For each dog, baseline ISOMAC was measured in duplicate using a tail clamp technique. Subsequently, all dogs were administered a fentanyl bolus (5 lg kg 1) and CRI (9 lg kg 1 hour 1) IV, and ISOMAC was redetermined at 120 and 300 minutes after initiation of the fentanyl CRI. Results Baseline ISOMAC values in the fentanyl and fentanyl–atropine treatments were 1.38 0.16%
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and 1.39 0.14%, respectively. Fentanyl significantly decreased the ISOMAC by 50 9% and 47 13% after 120 minutes and by 51 14% and 50 9% after 300 minutes (p < 0.001) in the fentanyl and fentanyl–atropine treatments, respectively. Compared with baseline, heart rate decreased significantly in the fentanyl treatment by 35% and 43% at 120 and 300 minutes, respectively. In the fentanyl–atropine treatment, heart rate did not change significantly over time. In both treatments, systolic arterial pressure increased from baseline after fentanyl. Conclusions and clinical relevance In this study, fentanyl reduced the ISOMAC by approximately 50%. The ISOMAC remained stable throughout the 300 minute CRI of fentanyl, suggesting no cumulative effect of the opioid. Atropine did not influence ISOMAC in dogs. Keywords anticholinergic, inhalation anesthesia, opioid, phenylpiperidine derivative.
Introduction Opioid analgesic drugs are administered during the intraoperative period with the aim of reducing requirements for inhalation anesthetic agents and blunting neuroendocrine responses to noxious stimulation (Mastrocinque & Fantoni 2003; Allweiler
Fentanyl and isoflurane MAC in dogs CR Sim~oes et al. et al. 2007; Bufalari et al. 2007). Numerous studies have shown that l-opioid agonists decrease the minimum alveolar concentration (MAC) of inhalation anesthetics in a dose-dependent manner in dogs (Murphy & Hug 1982; Hellyer et al. 2001; Ueyama et al. 2009). Fentanyl is a synthetic opioid with high affinity for l-receptors. It has a rapid onset of action after intravenous (IV) administration, which supports its intraoperative use for the provision of surgical analgesia (Pascoe 2000). Fentanyl has a short distribution half-time of approximately 3 minutes in dogs and 99% of a single dose (10 lg kg 1) has been shown to disappear from the plasma within 30 minutes after IV administration in dogs (Murphy et al. 1979). The effects of fentanyl have been found to correlate with plasma concentrations (Murphy & Hug 1982). Consequently, prolongation of analgesia by administration of fentanyl as a constant rate infusion (CRI) has been proposed (Pascoe 2000; Lamont & Mathews 2007). Administration of a fentanyl CRI can reduce the MAC of enflurane by up to 65% (Murphy & Hug 1982). The context-sensitive half-time is defined as the time to a 50% decrease in the plasma concentration of a drug after the infusion is discontinued (B€ urkle et al. 1996). It has been proposed as a more accurate prediction of recovery from IV infusion of an anesthetic agent than the terminal elimination half-life (Kapila et al. 1995). In humans, the context-sensitive half-time of fentanyl was found to depend on the duration of infusion and a rapid rise in plasma concentration was observed during a CRI of > 3 hours (Hughes et al. 1992). Available pharmacokinetic data for fentanyl administered as a CRI in dogs differ from those reported in humans. In one study, the plasma concentration of fentanyl remained relatively stable in conscious dogs during a 4 hour CRI at 10 lg kg 1 hour 1 (Sano et al. 2006). Concurrent administration of an inhalation anesthetic may influence the pharmacokinetics of fentanyl (Sano et al. 2006). In enflurane-anesthetized dogs, IV administration of three successive doses of fentanyl (10 lg kg 1 each) resulted in accumulation as indicated by progressively higher plasma concentrations of the opioid (Murphy et al. 1979). Furthermore, the reduction in MAC of enflurane by fentanyl was found to depend on the plasma concentration of the opioid (Murphy & Hug 1982). Thus it might be speculated that, if accumulation occurs during a prolonged infusion of fentanyl, a rise
in its plasma concentration will result in a greater sparing effect on the MAC over time. To the authors’ knowledge, no study has reported the effects of a prolonged infusion of fentanyl on the MAC of inhalation anesthetic agents in dogs. Bradycardia is the cardiovascular effect of an opioid of most concern (Lamont & Mathews 2007). A reduction of approximately 50% in heart rate (HR) has been reported in enflurane-anesthetized dogs administered a fentanyl CRI (Ilkiw et al. 1994). Anticholinergic agents are used to prevent or to treat opioid-induced bradycardia (Lamont & Mathews 2007). In studies on the determination of MAC, glycopyrrolate has been preferred over atropine for this purpose because it does not cross the blood– brain barrier in dogs (Proakis & Harris 1978) and is less likely to influence MAC. Although intramuscular (IM) administration of atropine (0.045 mg kg 1) did not influence the MAC of halothane in cats (Webb & McMurphy 1987), its effect on the MAC of inhalation anesthetics has not been determined in dogs. The primary objective of the present study was to evaluate the effect of a prolonged CRI of fentanyl on the MAC of isoflurane (ISOMAC) in dogs. We hypothesized that the ISOMAC determined at 300 minutes after initiation of a fentanyl CRI would be decreased to a greater extent than the ISOMAC determined at 120 minutes after the start of the CRI. This study also investigated the effect of a CRI of atropine on the ISOMAC. Materials and methods Animals This study was approved by the Institutional Animal Care Committee of the University of Vila Velha, Vila Velha, ES, Brazil (protocol 178/2011). Six adult spayed female mongrel dogs weighing 13.0 4.1 kg were used. Health status was assessed by means of physical examination, an electrocardiogram (ECG), a complete blood count and serum chemistry measurements. Any dog with clinical signs of systemic disease or abnormal laboratory data was excluded from the study. Instrumentation Food but not water was withheld for 12 hours prior to anesthesia. A 20 gauge catheter (BD Angiocath; Becton, Dickinson & Co., SP, Brazil) was placed in a
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Fentanyl and isoflurane MAC in dogs CR Sim~oes et al.
cephalic vein. All animals were administered lactated Ringer’s solution (Fresenius Kabi Ltda, SP, Brazil) at 3 mL kg 1 hour 1 by an infusion pump (Nutrimat II; Laborat orios B. Braun SA, RJ, Brazil). The dogs were administered propofol IV (3 mg kg 1, Propovan; Crist alia Ltda, SP, Brazil) to induce sedation or unconsciousness and isoflurane (Isoforine; Crist alia Ltda) was then delivered by means of a face mask. During the induction phase, the precision vaporizer was adjusted to deliver 4% isoflurane. The trachea was then intubated with a cuffed endotracheal tube and anesthesia was maintained by administration of isoflurane in oxygen delivered via an adult-size circle breathing circuit with an oxygen flow rate of 3 L minute 1. Dogs were positioned in dorsal recumbency on an electrical heating pad throughout anesthesia to maintain esophageal temperature (Lifewindow 6000Vet; Digicare Animal Health, FL, USA) at 37.5–38.5 °C. A catheter was introduced through the lumen of the endotracheal tube so that its tip was positioned at the middle third of the tube. Samples of airway gases were obtained continuously from this catheter into an infrared gas analyzer (ILCA Sensor Module; Dr€ ager Safety AG & Co., Germany) to monitor end-tidal carbon dioxide partial pressure (PE′CO2) and isoflurane (FE′Iso) concentrations. A standard calibration gas mixture (Agent/End-Tidal CO2 Calibration Gas; Smiths Medical PM, Inc., WI, USA) was used to verify the calibration of the gas analyzer before and every 3 hours during each experiment. The dogs were mechanically ventilated to maintain PE′CO2 at 30– 35 mmHg (4.0–4.7 kPa). A 20 gauge catheter was introduced percutaneously into the dorsal pedal artery and connected to a pressure transducer system filled with heparinized physiologic saline solution for displaying systolic (SAP), mean (MAP) and diastolic (DAP) blood pressures (Lifewindow 6000Vet; Digicare Animal Health). The zero reference level of the pressure transducer was set at the manubrium. Needle electrodes were attached to the skin in accordance with a lead II ECG to monitor HR. The FE′Iso was maintained at 1.8% during instrumentation. Study design and treatments Each dog was administered two treatments, on different occasions, in a crossover design with a 1 week washout interval. Treatments were administered in a non-randomized manner. In the first anesthetic procedure, dogs 1, 2 and 3 were assigned 138
to the fentanyl treatment, whereas dogs 4, 5 and 6 were assigned to the fentanyl–atropine treatment. In the second anesthetic procedure, the treatments were reversed so that all dogs underwent both treatments. In the fentanyl treatment, the animals were administered an IV bolus of fentanyl (5 lg kg 1 over 2 minutes) followed immediately by a CRI at 9 lg kg 1 hour 1. In the fentanyl–atropine treatment, an IV bolus of atropine (0.02 mg kg 1 over 1 minute) followed by a CRI at 0.04 mg kg 1 hour 1 was initiated before the start of the fentanyl CRI to maintain HR at 80–150 beats minute 1. Additional bolus doses of atropine were administered if HR decreased to < 80 beats minute 1 and the atropine CRI was decreased to 0.02 mg kg 1 hour 1 if HR increased to > 150 beats minute 1. All CRIs were administered by means of syringe pumps (LF Inject; Lifemed Ltda, SP, Brazil), the accuracy of which was checked prior to the beginning of the study. ISOMAC determination and experimental procedure For each MAC determination, the FE′Iso concentration was kept constant for at least 15 minutes. The first FE′Iso to be tested was 1.6% in all dogs. Heart rate, arterial blood pressure and esophageal temperature were recorded. A 25 cm Foerster sponge forceps was applied to the tail and closed to the third ratchet. The tail was moved continuously for 1 minute or until a positive response was observed (gross purposeful movement of the head, trunk or limbs). Clamping of the tail was performed in a distal to proximal direction, starting approximately 10 cm from the base of the tail. The same observer (CRS) was responsible for evaluating the response to noxious stimuli on all occasions. If no response (gross purposeful movement) was observed, the FE′Iso was decreased by 0.2%, the new concentration was kept constant for at least 15 minutes, and the stimulus was applied again. This procedure was repeated until purposeful movement occurred. The FE′Iso was then increased by 0.1% until purposeful movement was abolished. The ISOMAC was calculated as the arithmetic mean of the FE′Iso values that allowed and abolished purposeful movement. The ISOMAC was determined in duplicate and the average reported. Baseline ISOMAC determinations were initiated 60 minutes after induction of anesthesia. In the fentanyl–atropine treatment, administration of
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 136–144
Fentanyl and isoflurane MAC in dogs CR Sim~oes et al. atropine was initiated 15 minutes before baseline ISOMAC was measured (i.e. 45 minutes after anesthetic induction). After baseline ISOMAC had been determined, the fentanyl CRI was started and 30 minutes were allowed to elapse before ISOMAC determinations were begun. The ISOMAC was redetermined at two target time points of 120 and 300 minutes after the beginning of the fentanyl CRI. The actual time of the baseline ISOMAC determination was considered to be the time that elapsed between the beginning of the equilibration period at the first FE′Iso to be tested (1.6%) and the completion of ISOMAC determination. The actual times for determination of the ISOMAC at 120 minutes and 300 minutes were considered as the times that elapsed between the start of the fentanyl CRI and the completion of ISOMAC determination at the corresponding target time point. Cardiovascular data (HR, SAP, DAP and MAP), PE′CO2 and esophageal temperature were recorded immediately before noxious stimulations. The parametric variables corresponding to each ISOMAC were calculated as the arithmetic mean of the values observed at the FE′Iso concentrations used for determining ISOMAC. After completion of each ISOMAC determination, arterial blood samples were collected from the arterial catheter into heparinized syringes and immediately analyzed using a portable blood gas analyzer (i-STAT 1; Abbott Point of Care, NJ, USA) to display the pH, arterial partial pressures of carbon dioxide (PaCO2) and oxygen (PaO2), and bicarbonate (HCO3 ) values. After the ISOMAC at 300 minutes had been determined, the dogs were administered IV meloxicam (0.2 mg kg 1, Maxicam 0.2%; Ouro Fino Sa ude Animal, SP, Brazil), anesthesia was discontinued and recovery was observed. The times from the discontinuation of anesthesia until extubation (return of the swallowing reflex), sternal recumbency and standing were recorded. The duration of anesthesia (time from intubation until isoflurane administration was stopped) and the duration of the fentanyl CRI (time from the loading dose until discontinuation of the fentanyl CRI) were also recorded. Statistical analysis The sample size was calculated using G*Power for Windows Version 3.1.6 (Heinrich Heine Universit€ at D€ usseldorf, Germany). Based on data from previous studies (Hellyer et al. 2001; Ueyama et al. 2009), a
sample of six animals was considered adequate to detect a reduction of at least 0.15% in the ISOMAC assuming a power of 80% and an alpha error of 5%. Statistical analysis was performed using Prism Version 5.0 for Windows (GraphPad Software, Inc., CA, USA). Data were assessed for normality with the Kolmogorov–Smirnov test. Differences between treatments in cardiopulmonary variables and ISOMAC were compared by two-way repeatedmeasures analyses of variance (ANOVAs) and Bonferroni correction. Differences within each treatment between values recorded at baseline and the targeted time points (120 and 300 minutes) were compared by one-way repeated-measures ANOVA and Tukey’s test for multiple comparisons. Differences between treatments in the actual times for completion of ISOMAC determination, duration of anesthesia, duration of fentanyl CRI and recovery were compared using a paired t-test or Wilcoxon’s signed rank test. Results were interpreted at the 5% level of significance. Results All six dogs completed the study. There were no significant differences between treatments in the actual times for concluding ISOMAC determinations at baseline, 120 and 300 minutes, or in the duration of anesthesia, duration of the fentanyl CRI or recovery time (Tables 1 and 2). The mean ISOMAC did not differ significantly between treatments at any of the time points. Compared with baseline, the ISOMAC was significantly decreased in both treatments at 120 and 300 minutes (p < 0.001). The percentage reductions from baseline in ISOMAC values at 120 and 300 minutes were, respectively, 50% and 51% in the fentanyl treatment, and 47% and 50% in the fentanyl–atropine treatment. The ISOMAC values determined at 300 minutes did not differ significantly from values determined at 120 minutes in either treatment (Table 1). The variability in individual ISOMAC values determined at baseline was small such that the ISOMAC value for each dog did not vary more than 0.1% between the fentanyl and fentanyl–atropine treatments. Conversely, there was substantial variation in individual ISOMAC values determined during the fentanyl CRI such that ISOMAC values in a single dog differed by as much as 0.35% between the fentanyl and fentanyl–atropine treatments. Individual ISOMAC values determined at
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Fentanyl and isoflurane MAC in dogs CR Sim~oes et al.
Table 1 Minimum alveolar concentration (MAC) of isoflurane (ISOMAC) in six dogs administered fentanyl alone [5 lg kg 1 initial bolus, 9 lg kg 1 hour 1 constant rate infusion (CRI)] or in combination with atropine (0.02 mg kg 1 initial bolus, 0.04 mg kg 1 hour 1 CRI) in a crossover study. ISOMAC values were determined before and at 120 and 300 minutes after the start of the fentanyl infusion. Actual times for baseline ISOMAC are after induction of anesthesia and before fentanyl administration; actual times for ISOMAC at 120 and 300 minutes are from the start of the fentanyl CRI. All values are given as the mean standard deviation Treatment
Variable
Fentanyl
Baseline ISOMAC (%) Actual time (minutes) ISOMAC at 120 minutes (%) Actual time (minutes) ISOMAC at 300 minutes (%) Actual time (minutes)
1.38 152 0.69 143 0.68 330
0.16 21 0.14* 9 0.18* 20
Fentanyl– atropine 1.39 160 0.73 143 0.69 324
0.14 10 0.25* 24 0.17* 14
*Significant difference compared with baseline (p < 0.05).
Table 2 Variables associated with anesthesia recorded in six isoflurane-anesthetized dogs. The dogs were administered fentanyl alone [5 lg kg 1 initial bolus, 9 lg kg 1 hour 1 constant rate infusion (CRI)] or in combination with atropine (0.02 mg kg 1 initial bolus, 0.04 mg kg 1 hour 1 CRI) in a crossover study
Duration of anesthesia (minutes), mean SD Duration of fentanyl CRI (minutes), mean SD Time to extubation (minutes), median (IQR) Time to sternal recumbency (minutes), median (IQR) Time to standing (minutes), median (IQR)
Fentanyl
Fentanyl– atropine
504 16
509 22
340 21
334 18
13 (4–20)
7 (6–19)
17 (8–30)
11 (8–28)
24 (15–36)
23 (15–37)
IQR, interquartile range; SD, standard deviation.
300 minutes either increased, decreased or did not change compared with values at 120 minutes (Fig. 1). 140
Compared with baseline, HR in the fentanyl treatment was significantly decreased by 35% and 43% at 120 and 300 minutes, respectively (p < 0.001). In the fentanyl–atropine treatment, HR did not change over time and values were higher than in the fentanyl treatment at baseline and at 120 and 300 minutes (p < 0.001) (Table 3). In the fentanyl–atropine treatment, additional bolus doses of atropine were not administered to any dog, but a reduction in the CRI of atropine was necessary in three of the six dogs because HR increased to > 150 beats minute 1. There was no significant difference between treatments in SAP, MAP or DAP. Compared with baseline, SAP increased significantly at 120 minutes in the fentanyl (p < 0.01) and fentanyl–atropine (p < 0.05) treatments; at 300 minutes, SAP increased significantly in the fentanyl treatment (p < 0.001) only (Table 3). Esophageal temperature was maintained at 37.6– 38.3 °C during ISOMAC determinations (Table 3). Arterial blood gas variables did not differ significantly between treatments or over time and mean values were maintained within reference ranges for mechanically ventilated dogs breathing an inspired oxygen fraction of > 90%. Discussion A CRI of fentanyl at 9 lg kg 1 hour 1 in dogs reduced the ISOMAC by approximately 50%. The sparing effect of fentanyl on ISOMAC was not influenced by the duration of infusion and thus the percentage reduction after 120 minutes of infusion did not differ from that observed after 300 minutes of infusion. This study also revealed that the administration of a CRI of atropine to prevent bradycardia induced by fentanyl did not influence the ISOMAC. The propofol dose for induction of anesthesia in unpremedicated dogs has been reported as 6.5 0.9 mg kg 1 (Kojima et al. 2002). The propofol dose (3 mg kg 1) used in the present study did not allow endotracheal intubation and induction was completed by isoflurane delivered by mask. This low dose of propofol was chosen to reduce a possible influence of propofol on the ISOMAC because in a previous study in humans, propofol was found to reduce the sevoflurane MAC in a concentrationdependent manner (Luo et al. 2010). The baseline ISOMAC of 1.38–1.39% is similar to MAC values reported in some studies in which anesthesia was
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 136–144
Fentanyl and isoflurane MAC in dogs CR Sim~oes et al.
Figure 1 Individual values for minimum alveolar concentration (MAC) of isoflurane (ISOMAC) in six dogs administered fentanyl alone [5 lg kg 1 initial bolus, 9 lg kg 1 hour 1 constant rate infusion (CRI)] or in combination with atropine (0.02 mg kg 1 initial bolus, 0.04 mg kg 1 hour 1 CRI) in a crossover study. For each dog, the first and second columns represent baseline ISOMAC values, the third and fourth columns represent ISOMAC values at 120 minutes after the start of fentanyl infusion, and the fifth and sixth columns represent ISOMAC values at 300 minutes after the start of fentanyl infusion. Table 3 Heart rate (HR), systolic, diastolic and mean arterial blood pressures (SAP, DAP and MAP) and esophageal temperature in six isoflurane-anesthetized dogs administered fentanyl alone [5 lg kg 1 initial bolus, 9 lg kg 1 hour 1 constant rate infusion (CRI); FEN] or in combination with atropine (0.02 mg kg 1 initial bolus, 0.04 mg kg 1 hour 1 CRI; FEN-AT) in a crossover study. Baseline values are before fentanyl administration. Times of 120 and 300 minutes are from the start of the fentanyl CRI. All values are given as the mean standard deviation
HR (beats minute 1) SAP (mmHg) DAP (mmHg) MAP (mmHg) Temperature (°C)
Treatment
Baseline
FEN FEN-AT FEN FEN-AT FEN FEN-AT FEN FEN-AT FEN FEN-AT
95 138 116 112 59 67 75 81 38.0 38.0
16† 12 21 10 9 9 13 8 0.2 0.1
120 minutes 62 143 136 130 58 71 80 90 38.0 37.8
13*† 11 9* 19* 6 11 4 13 0.2 0.1*
300 minutes 54 131 143 123 56 67 78 84 38.0 37.9
10*† 8 11* 22 6 12 6 14 0.2 0.1
*Significant difference compared with baseline. †Significant difference between treatments at a given time point (p < 0.05).
induced with isoflurane alone in dogs (Valverde et al. 2004; Pypendop et al. 2007). Therefore, the authors consider it unlikely that propofol influenced the ISOMAC values determined in this study. In a previous study, Ueyama et al. (2009) reported a 35% reduction in the ISOMAC approximately 1.7 hours after starting a fentanyl CRI at the same infusion regimen used in the present study. The difference between the MAC reduction in the
previous study and the 50% MAC reduction in the present study may be explained by individual variation. Values for ISOMAC reported in dogs ranged from 1.22 0.06% to 1.80 0.21% (Hellyer et al. 2001; Valverde et al. 2003; Ueyama et al. 2009; Queiroz-Williams et al. 2014). This represents intraspecies variation of 48%. Despite this large reported intraspecies variation in ISOMAC, the baseline value reported by Ueyama et al.
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Fentanyl and isoflurane MAC in dogs CR Sim~oes et al.
(2009) was similar to the baseline ISOMAC determined in the present study (1.42 0.08% versus 1.38 0.16%). Intraspecies and intraindividual variations in MAC during fentanyl CRI are unknown. In the present study, the reduction in ISOMAC observed during a single regimen of fentanyl infusion was extremely variable. The comparison of individual ISOMAC values determined at 120 and 300 minutes revealed that the ISOMAC increased, decreased or did not change over time. A similar pattern was observed when the ISOMAC values determined in the fentanyl treatment at 120 and 300 minutes were compared with values determined in the fentanyl– atropine treatment at the same time points. The finding that ISOMAC values were more variable at 120 and 300 minutes in the present study suggests that individual variation in MAC values may be greater during fentanyl CRI than when the inhalation anesthetic is administered alone. Previously, the reduction in enflurane MAC induced by fentanyl in dogs was found to be doserelated such that greater percentage reductions in MAC were observed with increasing plasma concentrations of fentanyl (Murphy & Hug 1982). The large individual variation in the effectiveness of fentanyl in decreasing the ISOMAC in this study is difficult to explain, but it may relate to pharmacokinetic differences between dogs. In enflurane-anesthetized dogs, IV administration of a single dose of fentanyl resulted in plasma concentrations ranging from 4.6–15.9 ng mL 1 after 10 lg kg 1 fentanyl and from 16–116 ng mL 1 after 100 lg kg 1 fentanyl (Murphy et al. 1979). In awake dogs administered a loading dose of fentanyl (10 lg kg 1) followed by a CRI at 10 lg kg 1 hour 1, plasma concentrations of fentanyl remained between 0.2 and 1.8 ng mL 1 for 80–240 minutes of infusion (Sano et al. 2006). However, data on the pharmacokinetics of fentanyl during CRI in dogs under general anesthesia are limited. Therefore, the same infusion regimen administered to different dogs anesthetized with isoflurane may lead to dissimilar plasma concentrations as a result of individual differences in the pharmacokinetics of the opioid. It is unknown if this explains the findings in the present study because fentanyl plasma concentrations were not measured. Further consideration involves the fentanyl pharmacokinetic–pharmacodynamic relationship. The same plasma concentration of a drug may result in different MAC reductions in different dogs. In previous studies, the maximum reduction in ISOMAC 142
achieved by ketamine varied among different animals and the percentage reduction in ISOMAC at similar concentrations of ketamine also varied between dogs (Solano et al. 2006; Pypendop et al. 2007). To the authors’ knowledge, a pharmacokinetic–pharmacodynamic relationship for fentanyl has not been established in isoflurane-anesthetized dogs and individual differences may have contributed to the discrepancy between the percentage reductions in ISOMAC observed in the present study and those found in the study by Ueyama et al. (2009). In humans, administration of a prolonged infusion of fentanyl resulted in accumulation of the opioid as expressed by its long context-sensitive half-time (Hughes et al. 1992). The results of the present study showed no evidence of accumulation after a 5 hour CRI of fentanyl when infused at 9 lg kg 1 hour 1 to isoflurane-anesthetized dogs. Progressively increasing plasma concentrations of fentanyl would be expected to enhance the sparing effect of fentanyl on ISOMAC over time. However, in the present study, mean ISOMAC values determined at 120 and 300 minutes did not differ. In addition, recovery to standing was fast after more than 330 minutes of fentanyl CRI; times were similar to those in dogs anesthetized with isoflurane alone or isoflurane–remifentanil for 8.9 hours (Monteiro et al. 2010). This finding further supports the absence of accumulation of fentanyl in isofluraneanesthetized dogs after a prolonged CRI at the infusion regimen used in the present study. Atropine has been reported to be able to cross the blood–brain barrier and to induce central behavioral effects in humans (Ellinwood et al. 1990). In dogs, atropine was also found to cross the blood–brain barrier (Proakis & Harris 1978). Nevertheless, IM administration of atropine did not influence the MAC of halothane in cats (Webb & McMurphy 1987). The present results suggest that atropine does not influence MAC in dogs as ISOMAC values did not differ between the fentanyl and fentanyl–atropine treatments. These results support the use of atropine as a substitute for glycopyrrolate to prevent or treat bradycardia in MAC studies performed in dogs and cats. Opioid-induced bradycardia originates in central vagal control centers (Reitan et al. 1978). Anticholinergic agents can prevent opioid-induced slowing of HR by blockade of M2 muscarinic receptors in the sinoatrial and atrioventricular nodes (Lemke 2007). In the present study, atropine was administered to dogs in the fentanyl–atropine treatment to prevent
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 136–144
Fentanyl and isoflurane MAC in dogs CR Sim~oes et al. fentanyl-induced bradycardia. The current results indicate that this infusion regimen was effective in preventing the decrease in HR during administration of a CRI of fentanyl. Tachycardia (HR > 150 beats minute 1) developed in three of six dogs and was treated satisfactorily by reducing the infusion rate to 0.02 mg kg 1 hour 1. Blood pressure was improved during the fentanyl CRI in the fentanyl and fentanyl–atropine treatments. Significant increases in SAP ranging from 10% to 23% were observed during the fentanyl CRI. In conscious dogs administered progressively increasing doses of fentanyl (2.5, 5.0 and 20.0 lg kg 1), MAP did not change, despite an approximate 30% decrease in cardiac output (Arndt et al. 1984). By contrast, isoflurane decreased MAP in a dose-dependent manner compared with values measured in the conscious state (Pagel et al. 1991). At 1.25 MAC, this effect was the result of decreased systemic vascular resistance. Increasing the depth of anesthesia to 1.75 MAC further reduced MAP as a result of a decrease in cardiac output (Pagel et al. 1991). In the present study, the reduction of approximately 50% in ISOMAC induced by fentanyl may have attenuated the effect of isoflurane on systemic vascular resistance, which, in turn, resulted in increased SAP. Therefore, the increase in SAP after initiation of the CRI of fentanyl was most probably associated with the decrease in FE′Iso in the fentanyl and fentanyl– atropine treatments. Under the conditions of this study, fentanyl reduced the ISOMAC by approximately 50%. The ISOMAC remained stable throughout the 5 hour period of CRI of fentanyl in dogs, suggesting no cumulative effect of the opioid at the infusion regimen employed. The present study also revealed that the administration of a CRI of atropine did not influence ISOMAC. Acknowledgements Funding for this research was provided by the ~o de Amparo a Pesquisa do Espırito Santo Fundacßa (FAPES), ES, Brazil. References Allweiler S, Brodbelt DC, Borer K et al. (2007) The isoflurane-sparing and clinical effects of a constant rate infusion of remifentanil in dogs. Vet Anaesth Analg 34, 388–393.
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, 355–361. Bufalari A, Di Meo A, Nannarone S et al. (2007) Fentanyl or sufentanil continuous infusion during isoflurane anaesthesia in dogs: clinical experiences. Vet Res Commun 31(Suppl 1), 277–280. B€ urkle H, Dunbar S, Van Aken H (1996) Remifentanil: a novel, short-acting, l-opioid. Anesth Analg 83, 646–651. Ellinwood EH Jr, Nikaido AM, Gupta SK et al. (1990) Comparison of central nervous system and peripheral pharmacodynamics to atropine pharmacokinetics. J Pharmacol Exp Ther 255, 1133–1139. Hellyer PW, Mama KR, Shafford HL et al. (2001) Effects of diazepam and flumazenil on minimum alveolar concentrations for dogs anesthetized with isoflurane or a combination of isoflurane and fentanyl. Am J Vet Res 62, 555–560. Hughes MA, Glass PS, Jacobs JR (1992) Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 76, 334–341. Ilkiw JE, Pascoe PJ, Haskins SC et al. (1994) The cardiovascular sparing effect of fentanyl and atropine, administered to enflurane anesthetized dogs. Can J Vet Res 58, 248–253. Kapila A, Glass PS, Jacobs JR et al. (1995) Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 83, 968–975. Kojima K, Nishimura R, Mutoh T et al. (2002) Effects of medetomidine–midazolam, acepromazine–butorphanol, and midazolam–butorphanol on induction dose of thiopental and propofol and on cardiopulmonary changes in dogs. Am J Vet Res 63, 1671–1679. Lamont LA, Mathews KA (2007) Opioids, nonsteroidal anti-inflammatories, and analgesic adjuvants. In: Lumb & Jones’ Veterinary Anesthesia and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA (eds). Blackwell Publishing, USA. pp. 241–272. Lemke KA (2007) Anticholinergics and sedatives. In: Lumb & Jones’ Veterinary Anesthesia and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA (eds). Blackwell Publishing, USA. pp. 203–239. Luo LL, Zhou LX, Wang J et al. (2010) Effects of propofol on the minimum alveolar concentration of sevoflurane for immobility at skin incision in adult patients. J Clin Anesth 22, 527–532. Mastrocinque S, Fantoni DT (2003) A comparison of preoperative tramadol and morphine for the control of early postoperative pain in canine ovariohysterectomy. Vet Anaesth Analg 30, 220–228. Monteiro ER, Teixeira Neto FJ, Campagnol D et al. (2010) Hemodynamic effects in dogs anesthetized with isoflurane and remifentanil–isoflurane. Am J Vet Res 71, 1133–1141.
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Murphy MR, Hug CC (1982) The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC. Anesthesiology 57, 485–488. Murphy MR, Olson WA, Hug CC Jr (1979) Pharmacokinetics of 3H-fentanyl in the dog anesthetized with enflurane. Anesthesiology 50, 13–19. Pagel PS, Kampine JP, Schmeling WT et al. (1991) Comparison of the systemic and coronary hemodynamic actions of desflurane, isoflurane, halothane, and enflurane in the chronically instrumented dog. Anesthesiology 74, 539–551. Pascoe PJ (2000) Opioid analgesics. Vet Clin North Am Small Anim Pract 30, 757–772. Proakis AG, Harris GB (1978) Comparative penetration of glycopyrrolate and atropine across the blood–brain and placental barriers in anesthetized dogs. Anesthesiology 48, 339–344. Pypendop BH, Solano A, Boscan P et al. (2007) Characteristics of the relationship between plasma ketamine concentration and its effect on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 34, 209–212. Queiroz-Williams P, Egger CM, Qu W et al. (2014) The effect of buprenorphine on isoflurane minimum alveolar concentration in dogs. Vet Anaesth Analg 41, 312–318. Reitan J, Stengert K, Wymore M et al. (1978) Central vagal control of fentanyl-induced bradycardia during halothane anesthesia. Anesth Analg 57, 31–36.
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Sano T, Nishimura R, Kanazawa H et al. (2006) Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs. Vet Anaesth Analg 33, 266–273. Solano AM, Pypendop BH, Boscan PL et al. (2006) Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs. Am J Vet Res 67, 21–25. Ueyama Y, Lerche P, Eppler CM et al. (2009) Effects of intravenous administration of perzinfotel, fentanyl, and a combination of both drugs on the minimum alveolar concentration of isoflurane in dogs. Am J Vet Res 70, 1459–1464. Valverde A, Morey TE, Hernandez J et al. (2003) Validation of several types of noxious stimuli for use in determining the minimum alveolar concentration for inhalation anesthetics in dogs and rabbits. Am J Vet Res 64, 957– 962. Valverde A, Doherty TJ, Hern andez J et al. (2004) Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 31, 264–271. Webb AI, McMurphy RM (1987) Effect of anticholinergic preanesthetic medicaments on the requirements of halothane for anesthesia in the cat. Am J Vet Res 48, 1733–1735. Received 19 November 2014; accepted 7 March 2015.
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doi:10.1111/vaa.12282
RESEARCH PAPER
Effects of a prolonged infusion of fentanyl, with or without atropine, on the minimum alveolar concentration of isoflurane in dogs Clarissa R Sim~oes, Eduardo R Monteiro, Julia PP Rangel, Juarez S Nunes-Junior & Daniela Campagnol School of Veterinary Medicine, University of Vila Velha, Vila Velha, ES, Brazil
Correspondence: Eduardo R Monteiro, Department of Animal Medicine, Faculty of Veterinary Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS 91540-000, Brazil. E-mail: [email protected] Present address: Eduardo R Monteiro, Department of Animal Medicine, Faculty of Veterinary Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
Abstract Objectives To evaluate the effect of a prolonged constant rate infusion (CRI) of fentanyl on the minimum alveolar concentration (MAC) of isoflurane (ISOMAC) and to establish whether concurrent atropine administration influences ISOMAC in dogs. Study design Prospective, crossover study. Animals Six healthy dogs weighing 13.0 4.1 kg. Methods Dogs were anesthetized with isoflurane under conditions of normocapnia and normothermia. Arterial blood pressure was monitored invasively. Each dog was administered two treatments, on different occasions, in a crossover design. The dogs were administered intravenously (IV) an atropine bolus 0.02 mg kg 1 and CRI at 1 0.04 mg kg hour 1 (fentanyl–atropine treatment) or no atropine (fentanyl treatment). For each dog, baseline ISOMAC was measured in duplicate using a tail clamp technique. Subsequently, all dogs were administered a fentanyl bolus (5 lg kg 1) and CRI (9 lg kg 1 hour 1) IV, and ISOMAC was redetermined at 120 and 300 minutes after initiation of the fentanyl CRI. Results Baseline ISOMAC values in the fentanyl and fentanyl–atropine treatments were 1.38 0.16%
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and 1.39 0.14%, respectively. Fentanyl significantly decreased the ISOMAC by 50 9% and 47 13% after 120 minutes and by 51 14% and 50 9% after 300 minutes (p < 0.001) in the fentanyl and fentanyl–atropine treatments, respectively. Compared with baseline, heart rate decreased significantly in the fentanyl treatment by 35% and 43% at 120 and 300 minutes, respectively. In the fentanyl–atropine treatment, heart rate did not change significantly over time. In both treatments, systolic arterial pressure increased from baseline after fentanyl. Conclusions and clinical relevance In this study, fentanyl reduced the ISOMAC by approximately 50%. The ISOMAC remained stable throughout the 300 minute CRI of fentanyl, suggesting no cumulative effect of the opioid. Atropine did not influence ISOMAC in dogs. Keywords anticholinergic, inhalation anesthesia, opioid, phenylpiperidine derivative.
Introduction Opioid analgesic drugs are administered during the intraoperative period with the aim of reducing requirements for inhalation anesthetic agents and blunting neuroendocrine responses to noxious stimulation (Mastrocinque & Fantoni 2003; Allweiler
Fentanyl and isoflurane MAC in dogs CR Sim~oes et al. et al. 2007; Bufalari et al. 2007). Numerous studies have shown that l-opioid agonists decrease the minimum alveolar concentration (MAC) of inhalation anesthetics in a dose-dependent manner in dogs (Murphy & Hug 1982; Hellyer et al. 2001; Ueyama et al. 2009). Fentanyl is a synthetic opioid with high affinity for l-receptors. It has a rapid onset of action after intravenous (IV) administration, which supports its intraoperative use for the provision of surgical analgesia (Pascoe 2000). Fentanyl has a short distribution half-time of approximately 3 minutes in dogs and 99% of a single dose (10 lg kg 1) has been shown to disappear from the plasma within 30 minutes after IV administration in dogs (Murphy et al. 1979). The effects of fentanyl have been found to correlate with plasma concentrations (Murphy & Hug 1982). Consequently, prolongation of analgesia by administration of fentanyl as a constant rate infusion (CRI) has been proposed (Pascoe 2000; Lamont & Mathews 2007). Administration of a fentanyl CRI can reduce the MAC of enflurane by up to 65% (Murphy & Hug 1982). The context-sensitive half-time is defined as the time to a 50% decrease in the plasma concentration of a drug after the infusion is discontinued (B€ urkle et al. 1996). It has been proposed as a more accurate prediction of recovery from IV infusion of an anesthetic agent than the terminal elimination half-life (Kapila et al. 1995). In humans, the context-sensitive half-time of fentanyl was found to depend on the duration of infusion and a rapid rise in plasma concentration was observed during a CRI of > 3 hours (Hughes et al. 1992). Available pharmacokinetic data for fentanyl administered as a CRI in dogs differ from those reported in humans. In one study, the plasma concentration of fentanyl remained relatively stable in conscious dogs during a 4 hour CRI at 10 lg kg 1 hour 1 (Sano et al. 2006). Concurrent administration of an inhalation anesthetic may influence the pharmacokinetics of fentanyl (Sano et al. 2006). In enflurane-anesthetized dogs, IV administration of three successive doses of fentanyl (10 lg kg 1 each) resulted in accumulation as indicated by progressively higher plasma concentrations of the opioid (Murphy et al. 1979). Furthermore, the reduction in MAC of enflurane by fentanyl was found to depend on the plasma concentration of the opioid (Murphy & Hug 1982). Thus it might be speculated that, if accumulation occurs during a prolonged infusion of fentanyl, a rise
in its plasma concentration will result in a greater sparing effect on the MAC over time. To the authors’ knowledge, no study has reported the effects of a prolonged infusion of fentanyl on the MAC of inhalation anesthetic agents in dogs. Bradycardia is the cardiovascular effect of an opioid of most concern (Lamont & Mathews 2007). A reduction of approximately 50% in heart rate (HR) has been reported in enflurane-anesthetized dogs administered a fentanyl CRI (Ilkiw et al. 1994). Anticholinergic agents are used to prevent or to treat opioid-induced bradycardia (Lamont & Mathews 2007). In studies on the determination of MAC, glycopyrrolate has been preferred over atropine for this purpose because it does not cross the blood– brain barrier in dogs (Proakis & Harris 1978) and is less likely to influence MAC. Although intramuscular (IM) administration of atropine (0.045 mg kg 1) did not influence the MAC of halothane in cats (Webb & McMurphy 1987), its effect on the MAC of inhalation anesthetics has not been determined in dogs. The primary objective of the present study was to evaluate the effect of a prolonged CRI of fentanyl on the MAC of isoflurane (ISOMAC) in dogs. We hypothesized that the ISOMAC determined at 300 minutes after initiation of a fentanyl CRI would be decreased to a greater extent than the ISOMAC determined at 120 minutes after the start of the CRI. This study also investigated the effect of a CRI of atropine on the ISOMAC. Materials and methods Animals This study was approved by the Institutional Animal Care Committee of the University of Vila Velha, Vila Velha, ES, Brazil (protocol 178/2011). Six adult spayed female mongrel dogs weighing 13.0 4.1 kg were used. Health status was assessed by means of physical examination, an electrocardiogram (ECG), a complete blood count and serum chemistry measurements. Any dog with clinical signs of systemic disease or abnormal laboratory data was excluded from the study. Instrumentation Food but not water was withheld for 12 hours prior to anesthesia. A 20 gauge catheter (BD Angiocath; Becton, Dickinson & Co., SP, Brazil) was placed in a
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cephalic vein. All animals were administered lactated Ringer’s solution (Fresenius Kabi Ltda, SP, Brazil) at 3 mL kg 1 hour 1 by an infusion pump (Nutrimat II; Laborat orios B. Braun SA, RJ, Brazil). The dogs were administered propofol IV (3 mg kg 1, Propovan; Crist alia Ltda, SP, Brazil) to induce sedation or unconsciousness and isoflurane (Isoforine; Crist alia Ltda) was then delivered by means of a face mask. During the induction phase, the precision vaporizer was adjusted to deliver 4% isoflurane. The trachea was then intubated with a cuffed endotracheal tube and anesthesia was maintained by administration of isoflurane in oxygen delivered via an adult-size circle breathing circuit with an oxygen flow rate of 3 L minute 1. Dogs were positioned in dorsal recumbency on an electrical heating pad throughout anesthesia to maintain esophageal temperature (Lifewindow 6000Vet; Digicare Animal Health, FL, USA) at 37.5–38.5 °C. A catheter was introduced through the lumen of the endotracheal tube so that its tip was positioned at the middle third of the tube. Samples of airway gases were obtained continuously from this catheter into an infrared gas analyzer (ILCA Sensor Module; Dr€ ager Safety AG & Co., Germany) to monitor end-tidal carbon dioxide partial pressure (PE′CO2) and isoflurane (FE′Iso) concentrations. A standard calibration gas mixture (Agent/End-Tidal CO2 Calibration Gas; Smiths Medical PM, Inc., WI, USA) was used to verify the calibration of the gas analyzer before and every 3 hours during each experiment. The dogs were mechanically ventilated to maintain PE′CO2 at 30– 35 mmHg (4.0–4.7 kPa). A 20 gauge catheter was introduced percutaneously into the dorsal pedal artery and connected to a pressure transducer system filled with heparinized physiologic saline solution for displaying systolic (SAP), mean (MAP) and diastolic (DAP) blood pressures (Lifewindow 6000Vet; Digicare Animal Health). The zero reference level of the pressure transducer was set at the manubrium. Needle electrodes were attached to the skin in accordance with a lead II ECG to monitor HR. The FE′Iso was maintained at 1.8% during instrumentation. Study design and treatments Each dog was administered two treatments, on different occasions, in a crossover design with a 1 week washout interval. Treatments were administered in a non-randomized manner. In the first anesthetic procedure, dogs 1, 2 and 3 were assigned 138
to the fentanyl treatment, whereas dogs 4, 5 and 6 were assigned to the fentanyl–atropine treatment. In the second anesthetic procedure, the treatments were reversed so that all dogs underwent both treatments. In the fentanyl treatment, the animals were administered an IV bolus of fentanyl (5 lg kg 1 over 2 minutes) followed immediately by a CRI at 9 lg kg 1 hour 1. In the fentanyl–atropine treatment, an IV bolus of atropine (0.02 mg kg 1 over 1 minute) followed by a CRI at 0.04 mg kg 1 hour 1 was initiated before the start of the fentanyl CRI to maintain HR at 80–150 beats minute 1. Additional bolus doses of atropine were administered if HR decreased to < 80 beats minute 1 and the atropine CRI was decreased to 0.02 mg kg 1 hour 1 if HR increased to > 150 beats minute 1. All CRIs were administered by means of syringe pumps (LF Inject; Lifemed Ltda, SP, Brazil), the accuracy of which was checked prior to the beginning of the study. ISOMAC determination and experimental procedure For each MAC determination, the FE′Iso concentration was kept constant for at least 15 minutes. The first FE′Iso to be tested was 1.6% in all dogs. Heart rate, arterial blood pressure and esophageal temperature were recorded. A 25 cm Foerster sponge forceps was applied to the tail and closed to the third ratchet. The tail was moved continuously for 1 minute or until a positive response was observed (gross purposeful movement of the head, trunk or limbs). Clamping of the tail was performed in a distal to proximal direction, starting approximately 10 cm from the base of the tail. The same observer (CRS) was responsible for evaluating the response to noxious stimuli on all occasions. If no response (gross purposeful movement) was observed, the FE′Iso was decreased by 0.2%, the new concentration was kept constant for at least 15 minutes, and the stimulus was applied again. This procedure was repeated until purposeful movement occurred. The FE′Iso was then increased by 0.1% until purposeful movement was abolished. The ISOMAC was calculated as the arithmetic mean of the FE′Iso values that allowed and abolished purposeful movement. The ISOMAC was determined in duplicate and the average reported. Baseline ISOMAC determinations were initiated 60 minutes after induction of anesthesia. In the fentanyl–atropine treatment, administration of
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Fentanyl and isoflurane MAC in dogs CR Sim~oes et al. atropine was initiated 15 minutes before baseline ISOMAC was measured (i.e. 45 minutes after anesthetic induction). After baseline ISOMAC had been determined, the fentanyl CRI was started and 30 minutes were allowed to elapse before ISOMAC determinations were begun. The ISOMAC was redetermined at two target time points of 120 and 300 minutes after the beginning of the fentanyl CRI. The actual time of the baseline ISOMAC determination was considered to be the time that elapsed between the beginning of the equilibration period at the first FE′Iso to be tested (1.6%) and the completion of ISOMAC determination. The actual times for determination of the ISOMAC at 120 minutes and 300 minutes were considered as the times that elapsed between the start of the fentanyl CRI and the completion of ISOMAC determination at the corresponding target time point. Cardiovascular data (HR, SAP, DAP and MAP), PE′CO2 and esophageal temperature were recorded immediately before noxious stimulations. The parametric variables corresponding to each ISOMAC were calculated as the arithmetic mean of the values observed at the FE′Iso concentrations used for determining ISOMAC. After completion of each ISOMAC determination, arterial blood samples were collected from the arterial catheter into heparinized syringes and immediately analyzed using a portable blood gas analyzer (i-STAT 1; Abbott Point of Care, NJ, USA) to display the pH, arterial partial pressures of carbon dioxide (PaCO2) and oxygen (PaO2), and bicarbonate (HCO3 ) values. After the ISOMAC at 300 minutes had been determined, the dogs were administered IV meloxicam (0.2 mg kg 1, Maxicam 0.2%; Ouro Fino Sa ude Animal, SP, Brazil), anesthesia was discontinued and recovery was observed. The times from the discontinuation of anesthesia until extubation (return of the swallowing reflex), sternal recumbency and standing were recorded. The duration of anesthesia (time from intubation until isoflurane administration was stopped) and the duration of the fentanyl CRI (time from the loading dose until discontinuation of the fentanyl CRI) were also recorded. Statistical analysis The sample size was calculated using G*Power for Windows Version 3.1.6 (Heinrich Heine Universit€ at D€ usseldorf, Germany). Based on data from previous studies (Hellyer et al. 2001; Ueyama et al. 2009), a
sample of six animals was considered adequate to detect a reduction of at least 0.15% in the ISOMAC assuming a power of 80% and an alpha error of 5%. Statistical analysis was performed using Prism Version 5.0 for Windows (GraphPad Software, Inc., CA, USA). Data were assessed for normality with the Kolmogorov–Smirnov test. Differences between treatments in cardiopulmonary variables and ISOMAC were compared by two-way repeatedmeasures analyses of variance (ANOVAs) and Bonferroni correction. Differences within each treatment between values recorded at baseline and the targeted time points (120 and 300 minutes) were compared by one-way repeated-measures ANOVA and Tukey’s test for multiple comparisons. Differences between treatments in the actual times for completion of ISOMAC determination, duration of anesthesia, duration of fentanyl CRI and recovery were compared using a paired t-test or Wilcoxon’s signed rank test. Results were interpreted at the 5% level of significance. Results All six dogs completed the study. There were no significant differences between treatments in the actual times for concluding ISOMAC determinations at baseline, 120 and 300 minutes, or in the duration of anesthesia, duration of the fentanyl CRI or recovery time (Tables 1 and 2). The mean ISOMAC did not differ significantly between treatments at any of the time points. Compared with baseline, the ISOMAC was significantly decreased in both treatments at 120 and 300 minutes (p < 0.001). The percentage reductions from baseline in ISOMAC values at 120 and 300 minutes were, respectively, 50% and 51% in the fentanyl treatment, and 47% and 50% in the fentanyl–atropine treatment. The ISOMAC values determined at 300 minutes did not differ significantly from values determined at 120 minutes in either treatment (Table 1). The variability in individual ISOMAC values determined at baseline was small such that the ISOMAC value for each dog did not vary more than 0.1% between the fentanyl and fentanyl–atropine treatments. Conversely, there was substantial variation in individual ISOMAC values determined during the fentanyl CRI such that ISOMAC values in a single dog differed by as much as 0.35% between the fentanyl and fentanyl–atropine treatments. Individual ISOMAC values determined at
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Table 1 Minimum alveolar concentration (MAC) of isoflurane (ISOMAC) in six dogs administered fentanyl alone [5 lg kg 1 initial bolus, 9 lg kg 1 hour 1 constant rate infusion (CRI)] or in combination with atropine (0.02 mg kg 1 initial bolus, 0.04 mg kg 1 hour 1 CRI) in a crossover study. ISOMAC values were determined before and at 120 and 300 minutes after the start of the fentanyl infusion. Actual times for baseline ISOMAC are after induction of anesthesia and before fentanyl administration; actual times for ISOMAC at 120 and 300 minutes are from the start of the fentanyl CRI. All values are given as the mean standard deviation Treatment
Variable
Fentanyl
Baseline ISOMAC (%) Actual time (minutes) ISOMAC at 120 minutes (%) Actual time (minutes) ISOMAC at 300 minutes (%) Actual time (minutes)
1.38 152 0.69 143 0.68 330
0.16 21 0.14* 9 0.18* 20
Fentanyl– atropine 1.39 160 0.73 143 0.69 324
0.14 10 0.25* 24 0.17* 14
*Significant difference compared with baseline (p < 0.05).
Table 2 Variables associated with anesthesia recorded in six isoflurane-anesthetized dogs. The dogs were administered fentanyl alone [5 lg kg 1 initial bolus, 9 lg kg 1 hour 1 constant rate infusion (CRI)] or in combination with atropine (0.02 mg kg 1 initial bolus, 0.04 mg kg 1 hour 1 CRI) in a crossover study
Duration of anesthesia (minutes), mean SD Duration of fentanyl CRI (minutes), mean SD Time to extubation (minutes), median (IQR) Time to sternal recumbency (minutes), median (IQR) Time to standing (minutes), median (IQR)
Fentanyl
Fentanyl– atropine
504 16
509 22
340 21
334 18
13 (4–20)
7 (6–19)
17 (8–30)
11 (8–28)
24 (15–36)
23 (15–37)
IQR, interquartile range; SD, standard deviation.
300 minutes either increased, decreased or did not change compared with values at 120 minutes (Fig. 1). 140
Compared with baseline, HR in the fentanyl treatment was significantly decreased by 35% and 43% at 120 and 300 minutes, respectively (p < 0.001). In the fentanyl–atropine treatment, HR did not change over time and values were higher than in the fentanyl treatment at baseline and at 120 and 300 minutes (p < 0.001) (Table 3). In the fentanyl–atropine treatment, additional bolus doses of atropine were not administered to any dog, but a reduction in the CRI of atropine was necessary in three of the six dogs because HR increased to > 150 beats minute 1. There was no significant difference between treatments in SAP, MAP or DAP. Compared with baseline, SAP increased significantly at 120 minutes in the fentanyl (p < 0.01) and fentanyl–atropine (p < 0.05) treatments; at 300 minutes, SAP increased significantly in the fentanyl treatment (p < 0.001) only (Table 3). Esophageal temperature was maintained at 37.6– 38.3 °C during ISOMAC determinations (Table 3). Arterial blood gas variables did not differ significantly between treatments or over time and mean values were maintained within reference ranges for mechanically ventilated dogs breathing an inspired oxygen fraction of > 90%. Discussion A CRI of fentanyl at 9 lg kg 1 hour 1 in dogs reduced the ISOMAC by approximately 50%. The sparing effect of fentanyl on ISOMAC was not influenced by the duration of infusion and thus the percentage reduction after 120 minutes of infusion did not differ from that observed after 300 minutes of infusion. This study also revealed that the administration of a CRI of atropine to prevent bradycardia induced by fentanyl did not influence the ISOMAC. The propofol dose for induction of anesthesia in unpremedicated dogs has been reported as 6.5 0.9 mg kg 1 (Kojima et al. 2002). The propofol dose (3 mg kg 1) used in the present study did not allow endotracheal intubation and induction was completed by isoflurane delivered by mask. This low dose of propofol was chosen to reduce a possible influence of propofol on the ISOMAC because in a previous study in humans, propofol was found to reduce the sevoflurane MAC in a concentrationdependent manner (Luo et al. 2010). The baseline ISOMAC of 1.38–1.39% is similar to MAC values reported in some studies in which anesthesia was
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Fentanyl and isoflurane MAC in dogs CR Sim~oes et al.
Figure 1 Individual values for minimum alveolar concentration (MAC) of isoflurane (ISOMAC) in six dogs administered fentanyl alone [5 lg kg 1 initial bolus, 9 lg kg 1 hour 1 constant rate infusion (CRI)] or in combination with atropine (0.02 mg kg 1 initial bolus, 0.04 mg kg 1 hour 1 CRI) in a crossover study. For each dog, the first and second columns represent baseline ISOMAC values, the third and fourth columns represent ISOMAC values at 120 minutes after the start of fentanyl infusion, and the fifth and sixth columns represent ISOMAC values at 300 minutes after the start of fentanyl infusion. Table 3 Heart rate (HR), systolic, diastolic and mean arterial blood pressures (SAP, DAP and MAP) and esophageal temperature in six isoflurane-anesthetized dogs administered fentanyl alone [5 lg kg 1 initial bolus, 9 lg kg 1 hour 1 constant rate infusion (CRI); FEN] or in combination with atropine (0.02 mg kg 1 initial bolus, 0.04 mg kg 1 hour 1 CRI; FEN-AT) in a crossover study. Baseline values are before fentanyl administration. Times of 120 and 300 minutes are from the start of the fentanyl CRI. All values are given as the mean standard deviation
HR (beats minute 1) SAP (mmHg) DAP (mmHg) MAP (mmHg) Temperature (°C)
Treatment
Baseline
FEN FEN-AT FEN FEN-AT FEN FEN-AT FEN FEN-AT FEN FEN-AT
95 138 116 112 59 67 75 81 38.0 38.0
16† 12 21 10 9 9 13 8 0.2 0.1
120 minutes 62 143 136 130 58 71 80 90 38.0 37.8
13*† 11 9* 19* 6 11 4 13 0.2 0.1*
300 minutes 54 131 143 123 56 67 78 84 38.0 37.9
10*† 8 11* 22 6 12 6 14 0.2 0.1
*Significant difference compared with baseline. †Significant difference between treatments at a given time point (p < 0.05).
induced with isoflurane alone in dogs (Valverde et al. 2004; Pypendop et al. 2007). Therefore, the authors consider it unlikely that propofol influenced the ISOMAC values determined in this study. In a previous study, Ueyama et al. (2009) reported a 35% reduction in the ISOMAC approximately 1.7 hours after starting a fentanyl CRI at the same infusion regimen used in the present study. The difference between the MAC reduction in the
previous study and the 50% MAC reduction in the present study may be explained by individual variation. Values for ISOMAC reported in dogs ranged from 1.22 0.06% to 1.80 0.21% (Hellyer et al. 2001; Valverde et al. 2003; Ueyama et al. 2009; Queiroz-Williams et al. 2014). This represents intraspecies variation of 48%. Despite this large reported intraspecies variation in ISOMAC, the baseline value reported by Ueyama et al.
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(2009) was similar to the baseline ISOMAC determined in the present study (1.42 0.08% versus 1.38 0.16%). Intraspecies and intraindividual variations in MAC during fentanyl CRI are unknown. In the present study, the reduction in ISOMAC observed during a single regimen of fentanyl infusion was extremely variable. The comparison of individual ISOMAC values determined at 120 and 300 minutes revealed that the ISOMAC increased, decreased or did not change over time. A similar pattern was observed when the ISOMAC values determined in the fentanyl treatment at 120 and 300 minutes were compared with values determined in the fentanyl– atropine treatment at the same time points. The finding that ISOMAC values were more variable at 120 and 300 minutes in the present study suggests that individual variation in MAC values may be greater during fentanyl CRI than when the inhalation anesthetic is administered alone. Previously, the reduction in enflurane MAC induced by fentanyl in dogs was found to be doserelated such that greater percentage reductions in MAC were observed with increasing plasma concentrations of fentanyl (Murphy & Hug 1982). The large individual variation in the effectiveness of fentanyl in decreasing the ISOMAC in this study is difficult to explain, but it may relate to pharmacokinetic differences between dogs. In enflurane-anesthetized dogs, IV administration of a single dose of fentanyl resulted in plasma concentrations ranging from 4.6–15.9 ng mL 1 after 10 lg kg 1 fentanyl and from 16–116 ng mL 1 after 100 lg kg 1 fentanyl (Murphy et al. 1979). In awake dogs administered a loading dose of fentanyl (10 lg kg 1) followed by a CRI at 10 lg kg 1 hour 1, plasma concentrations of fentanyl remained between 0.2 and 1.8 ng mL 1 for 80–240 minutes of infusion (Sano et al. 2006). However, data on the pharmacokinetics of fentanyl during CRI in dogs under general anesthesia are limited. Therefore, the same infusion regimen administered to different dogs anesthetized with isoflurane may lead to dissimilar plasma concentrations as a result of individual differences in the pharmacokinetics of the opioid. It is unknown if this explains the findings in the present study because fentanyl plasma concentrations were not measured. Further consideration involves the fentanyl pharmacokinetic–pharmacodynamic relationship. The same plasma concentration of a drug may result in different MAC reductions in different dogs. In previous studies, the maximum reduction in ISOMAC 142
achieved by ketamine varied among different animals and the percentage reduction in ISOMAC at similar concentrations of ketamine also varied between dogs (Solano et al. 2006; Pypendop et al. 2007). To the authors’ knowledge, a pharmacokinetic–pharmacodynamic relationship for fentanyl has not been established in isoflurane-anesthetized dogs and individual differences may have contributed to the discrepancy between the percentage reductions in ISOMAC observed in the present study and those found in the study by Ueyama et al. (2009). In humans, administration of a prolonged infusion of fentanyl resulted in accumulation of the opioid as expressed by its long context-sensitive half-time (Hughes et al. 1992). The results of the present study showed no evidence of accumulation after a 5 hour CRI of fentanyl when infused at 9 lg kg 1 hour 1 to isoflurane-anesthetized dogs. Progressively increasing plasma concentrations of fentanyl would be expected to enhance the sparing effect of fentanyl on ISOMAC over time. However, in the present study, mean ISOMAC values determined at 120 and 300 minutes did not differ. In addition, recovery to standing was fast after more than 330 minutes of fentanyl CRI; times were similar to those in dogs anesthetized with isoflurane alone or isoflurane–remifentanil for 8.9 hours (Monteiro et al. 2010). This finding further supports the absence of accumulation of fentanyl in isofluraneanesthetized dogs after a prolonged CRI at the infusion regimen used in the present study. Atropine has been reported to be able to cross the blood–brain barrier and to induce central behavioral effects in humans (Ellinwood et al. 1990). In dogs, atropine was also found to cross the blood–brain barrier (Proakis & Harris 1978). Nevertheless, IM administration of atropine did not influence the MAC of halothane in cats (Webb & McMurphy 1987). The present results suggest that atropine does not influence MAC in dogs as ISOMAC values did not differ between the fentanyl and fentanyl–atropine treatments. These results support the use of atropine as a substitute for glycopyrrolate to prevent or treat bradycardia in MAC studies performed in dogs and cats. Opioid-induced bradycardia originates in central vagal control centers (Reitan et al. 1978). Anticholinergic agents can prevent opioid-induced slowing of HR by blockade of M2 muscarinic receptors in the sinoatrial and atrioventricular nodes (Lemke 2007). In the present study, atropine was administered to dogs in the fentanyl–atropine treatment to prevent
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 136–144
Fentanyl and isoflurane MAC in dogs CR Sim~oes et al. fentanyl-induced bradycardia. The current results indicate that this infusion regimen was effective in preventing the decrease in HR during administration of a CRI of fentanyl. Tachycardia (HR > 150 beats minute 1) developed in three of six dogs and was treated satisfactorily by reducing the infusion rate to 0.02 mg kg 1 hour 1. Blood pressure was improved during the fentanyl CRI in the fentanyl and fentanyl–atropine treatments. Significant increases in SAP ranging from 10% to 23% were observed during the fentanyl CRI. In conscious dogs administered progressively increasing doses of fentanyl (2.5, 5.0 and 20.0 lg kg 1), MAP did not change, despite an approximate 30% decrease in cardiac output (Arndt et al. 1984). By contrast, isoflurane decreased MAP in a dose-dependent manner compared with values measured in the conscious state (Pagel et al. 1991). At 1.25 MAC, this effect was the result of decreased systemic vascular resistance. Increasing the depth of anesthesia to 1.75 MAC further reduced MAP as a result of a decrease in cardiac output (Pagel et al. 1991). In the present study, the reduction of approximately 50% in ISOMAC induced by fentanyl may have attenuated the effect of isoflurane on systemic vascular resistance, which, in turn, resulted in increased SAP. Therefore, the increase in SAP after initiation of the CRI of fentanyl was most probably associated with the decrease in FE′Iso in the fentanyl and fentanyl– atropine treatments. Under the conditions of this study, fentanyl reduced the ISOMAC by approximately 50%. The ISOMAC remained stable throughout the 5 hour period of CRI of fentanyl in dogs, suggesting no cumulative effect of the opioid at the infusion regimen employed. The present study also revealed that the administration of a CRI of atropine did not influence ISOMAC. Acknowledgements Funding for this research was provided by the ~o de Amparo a Pesquisa do Espırito Santo Fundacßa (FAPES), ES, Brazil. References Allweiler S, Brodbelt DC, Borer K et al. (2007) The isoflurane-sparing and clinical effects of a constant rate infusion of remifentanil in dogs. Vet Anaesth Analg 34, 388–393.
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, 355–361. Bufalari A, Di Meo A, Nannarone S et al. (2007) Fentanyl or sufentanil continuous infusion during isoflurane anaesthesia in dogs: clinical experiences. Vet Res Commun 31(Suppl 1), 277–280. B€ urkle H, Dunbar S, Van Aken H (1996) Remifentanil: a novel, short-acting, l-opioid. Anesth Analg 83, 646–651. Ellinwood EH Jr, Nikaido AM, Gupta SK et al. (1990) Comparison of central nervous system and peripheral pharmacodynamics to atropine pharmacokinetics. J Pharmacol Exp Ther 255, 1133–1139. Hellyer PW, Mama KR, Shafford HL et al. (2001) Effects of diazepam and flumazenil on minimum alveolar concentrations for dogs anesthetized with isoflurane or a combination of isoflurane and fentanyl. Am J Vet Res 62, 555–560. Hughes MA, Glass PS, Jacobs JR (1992) Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 76, 334–341. Ilkiw JE, Pascoe PJ, Haskins SC et al. (1994) The cardiovascular sparing effect of fentanyl and atropine, administered to enflurane anesthetized dogs. Can J Vet Res 58, 248–253. Kapila A, Glass PS, Jacobs JR et al. (1995) Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 83, 968–975. Kojima K, Nishimura R, Mutoh T et al. (2002) Effects of medetomidine–midazolam, acepromazine–butorphanol, and midazolam–butorphanol on induction dose of thiopental and propofol and on cardiopulmonary changes in dogs. Am J Vet Res 63, 1671–1679. Lamont LA, Mathews KA (2007) Opioids, nonsteroidal anti-inflammatories, and analgesic adjuvants. In: Lumb & Jones’ Veterinary Anesthesia and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA (eds). Blackwell Publishing, USA. pp. 241–272. Lemke KA (2007) Anticholinergics and sedatives. In: Lumb & Jones’ Veterinary Anesthesia and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA (eds). Blackwell Publishing, USA. pp. 203–239. Luo LL, Zhou LX, Wang J et al. (2010) Effects of propofol on the minimum alveolar concentration of sevoflurane for immobility at skin incision in adult patients. J Clin Anesth 22, 527–532. Mastrocinque S, Fantoni DT (2003) A comparison of preoperative tramadol and morphine for the control of early postoperative pain in canine ovariohysterectomy. Vet Anaesth Analg 30, 220–228. Monteiro ER, Teixeira Neto FJ, Campagnol D et al. (2010) Hemodynamic effects in dogs anesthetized with isoflurane and remifentanil–isoflurane. Am J Vet Res 71, 1133–1141.
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Fentanyl and isoflurane MAC in dogs CR Sim~oes et al.
Murphy MR, Hug CC (1982) The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC. Anesthesiology 57, 485–488. Murphy MR, Olson WA, Hug CC Jr (1979) Pharmacokinetics of 3H-fentanyl in the dog anesthetized with enflurane. Anesthesiology 50, 13–19. Pagel PS, Kampine JP, Schmeling WT et al. (1991) Comparison of the systemic and coronary hemodynamic actions of desflurane, isoflurane, halothane, and enflurane in the chronically instrumented dog. Anesthesiology 74, 539–551. Pascoe PJ (2000) Opioid analgesics. Vet Clin North Am Small Anim Pract 30, 757–772. Proakis AG, Harris GB (1978) Comparative penetration of glycopyrrolate and atropine across the blood–brain and placental barriers in anesthetized dogs. Anesthesiology 48, 339–344. Pypendop BH, Solano A, Boscan P et al. (2007) Characteristics of the relationship between plasma ketamine concentration and its effect on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 34, 209–212. Queiroz-Williams P, Egger CM, Qu W et al. (2014) The effect of buprenorphine on isoflurane minimum alveolar concentration in dogs. Vet Anaesth Analg 41, 312–318. Reitan J, Stengert K, Wymore M et al. (1978) Central vagal control of fentanyl-induced bradycardia during halothane anesthesia. Anesth Analg 57, 31–36.
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Sano T, Nishimura R, Kanazawa H et al. (2006) Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs. Vet Anaesth Analg 33, 266–273. Solano AM, Pypendop BH, Boscan PL et al. (2006) Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs. Am J Vet Res 67, 21–25. Ueyama Y, Lerche P, Eppler CM et al. (2009) Effects of intravenous administration of perzinfotel, fentanyl, and a combination of both drugs on the minimum alveolar concentration of isoflurane in dogs. Am J Vet Res 70, 1459–1464. Valverde A, Morey TE, Hernandez J et al. (2003) Validation of several types of noxious stimuli for use in determining the minimum alveolar concentration for inhalation anesthetics in dogs and rabbits. Am J Vet Res 64, 957– 962. Valverde A, Doherty TJ, Hern andez J et al. (2004) Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 31, 264–271. Webb AI, McMurphy RM (1987) Effect of anticholinergic preanesthetic medicaments on the requirements of halothane for anesthesia in the cat. Am J Vet Res 48, 1733–1735. Received 19 November 2014; accepted 7 March 2015.
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