Materials and Methods

Animals—The study was approved by the Institutional Animal Care Committee under protocol number 84/2005. Twenty-four client-owned female dogs scheduled for unilateral mastectomy because of mammary neoplasia were enrolled in the study after written owner consent was obtained. Dogs were randomly and equally assigned to 3 groups (control, lidocaine, and fentanyl). Preoperative screening included cytologic examination of fine-needle aspirates of the affected mammary glands, thoracic radiography, CBC, and serum biochemical analyses. Cardiac evaluation (electrocardiography) was requested if cardiac enlargement or abnormal results of cardiac auscultation were detected on physical examination. Dogs with abnormal laboratory data, clinical signs of systemic disease, or evidence of lung metastasis were not included in the study.

Anesthetic procedure—Dogs were premedicated with acepromazine^b (0.05 mg/kg [0.023 mg/lb]) and morphine sulphate^c (0.3 mg/kg [0.14 mg/lb]) administered IM. A cephalic vein was aseptically catheterized with a 20-gauge catheter,^d and approximately 20 minutes after premedication, anesthesia was induced via IV administration of 5 mg of ketamine^e/kg (2.27 mg/lb) and 0.25 mg of diazepam^f/kg (0.11 mg/lb). After endotracheal intubation, anesthesia was maintained with isoflurane^g in oxygen administered through a circular breathing circuit. Oxygen flow rates were set at approximately 100 mL/kg/min (45.4 mL/lb/min) immediately after induction. After a stable anesthetic depth was achieved, O₂ flow rates were reduced to approximately 50 mL/kg/min (22.7 mL/lb/min) for the remaining period. A balanced electrolyte solution (lactated Ringer's solution) was administered IV at a rate of 10 mL/kg/min (4.54 mL/lb/min) throughout anesthesia by use of a peristaltic infusion pump.^h Dogs were positioned in dorsal recumbency and maintained on a circulating warm water blanket throughout anesthesia. Body temperature was monitored by use of an esophageal temperature probe.

Cardiopulmonary measurements and adjustment of anesthetic depth—After induction of anesthesia, adhesive electrodes were placed to obtain a continuous lead II ECG. Heart rate and rhythm were obtained from the ECG tracings. By use of an aseptic technique, a dorsal pedal artery was catheterized with a 20gauge catheter connected to a blood pressure transducer system to measure SAP, DAP, and MAP.ⁱ The zero reference point of the pressure transducer was set at the level of the heart.

Arterial blood samples were anaerobically collected in heparinized syringes and analyzed immediately with an automated blood gas analyzer.^j Blood gas values were corrected according to esophageal temperature.

Airway gas samples were continuously obtained (200 mL/min) from the proximal end of the endotracheal tube and analyzed with an infrared gas analyzerⁱ to monitor ETco₂ and ETiso concentrations. The gas analyzer was calibrated before starting each experiment with a standard gas mixture provided by the manufacturer.^k

Ventilator adjustment—By use of a volume-limited time-cycled ventilator,^l intermittent positive-pressure ventilation was instituted to maintain eucapnia (Paco₂ values from 35 to 45 mm Hg) during anesthesia. Peak inspiratory pressure was adjusted to 10 to 15 cm H₂O, and inspiration-to-expiration ratio was maintained constant at 1:2. A preliminary arterial blood gas analysis was performed, and the arterial-to-ETco₂ gradient was determined. After the first data sampling, respiratory rate was adjusted on the basis of ETco₂ readings to maintain Paco₂ within the expected range.

Experimental protocol—Immediately after induction of anesthesia, a CRI of either saline (0.9% NaCl) solution (control), lidocaine,^m or fentanyl citrateⁿ was started. A loading dose (1.5 mg/kg) of lidocaine was administered IV over 1 minute, followed by a CRI of 250 μg/kg/min. In the fentanyl group, after a loading dose of 5 μg/kg given over 1 minute, a CRI of 0.5 μg/kg/min was started. Drug concentrations were adjusted to obtain the same volume on an milliliter per kilogram basis.

An experienced anesthetist (DC) adjusted vaporizer settings to maintain surgical depth of anesthesia. Determination of surgical depth of anesthesia was based on clinical signs, including absence of palpebral reflexes, absence of jaw tonus, and MAP from 60 to 90 mm Hg. To avoid bias in the adjustment of vaporizer settings, a nonprecision out-of-circuit vaporizer° was used and the anesthetist in charge of controlling anesthetic depth was kept unaware of the treatment being administered and the ETiso measurements provided by the gas analyzer. Dogs with low HR (< 60 beats/min) associated with persistent hypotension (MAP < 60 mm Hg) for > 10 minutes were treated with atropine (0.02 mg/kg [0.01 mg/lb], IV).

Baseline data were collected 30 minutes after starting the infusions, and surgery commenced immediately after baseline data collection. Arterial blood gas samples were collected at baseline and 30 and 60 minutes after surgery was started. Cardiovascular variables (HR, SAP, DAP, and MAP), ETiso, ETco₂, and esophageal temperature values were obtained at baseline and at 15-minute intervals for 60 minutes after initiation of surgery.

At the end of surgery, ketoprofen^p (2.2 mg/kg [1 mg/lb], IM) and morphine^c (0.5 mg/kg [0.23 mg/lb], IM) were administered for pain control. The ventilator's respiratory rate was adjusted to 3 breaths/min and anesthetic administration was interrupted until the dog started breathing spontaneously.

Surgery time (time elapsed from the first incision until placement of the last suture), anesthesia time (time elapsed from induction time until the end of infusion of drugs), and extubation time (time elapsed from the end of the infusion until the dog started swallowing) were recorded for each dog.

Data analysis—Data are reported as mean ± SD values. Statistical analysis was performed by use of a statistical software package.^q To study temporal changes during anesthesia, a 1-way ANOVA for repeated measures was performed for each treatment group. When a significant effect of time was detected, values for each time point were compared with baseline values (before surgery) by use of the Dunnet test. For comparisons between groups, 1-way ANOVA was performed at each time point. When a significant treatment effect was detected, post hoc comparisons were performed by means of a Tukey test. Differences were considered significant at P < 0.05.

Results

Breeds included in this study were crossbred (n = 6), Cocker Spaniel (2), Doberman Pinscher (2), Akita (3), Border Collie (1), Boxer (1), Pit Bull Terrier (1), German Shepherd Dog (4), Rottweiller (1), Fila Brasileiro (2), and Dalmatian (1). There were no significant differences among groups for demographic data, weight, age, surgery time, anesthesia time, or time to extubation (Table 1).

Cardiopulmonary data were tabulated (Table 2). In the fentanyl group, 3 dogs received atropine (0.02 mg/kg, IV) because of bradycardia (HR < 60 beats/min) associated with MAP < 60 mm Hg. Because atropine may be a confounding factor when interpreting cardiovascular data (HR, SAP, DAP, and MAP), dogs that received atropine were removed from statistical analysis for these variables. Except at baseline, HR values were significantly lower in the fentanyl group, compared with the control and lidocaine groups. Systolic arterial pressure did not differ among groups throughout the experiment. Although no differences among groups for DAP and MAP were observed for most time points, in the lidocaine group, DAP and MAP was transiently higher at baseline, compared with the control and fentanyl groups. Administration of lidocaine also resulted in significantly higher DAP, compared with the fentanyl group, 15 minutes after initiation of surgery. Compared with baseline values, DAP was significantly increased from 15 to 60 minutes, whereas MAP significantly increased from 15 to 45 minutes after initiation of surgery in the control group.

Respiratory rate and arterial blood gas values did not differ within or among groups (Table 2). Esophageal temperature did not differ among groups, except at baseline, when this variable was lower in the control group. Significant decreases from baseline values were observed from 30 to 60 minutes and from 15 to 60 minutes in the control and fentanyl groups, respectively.

End-tidal isoflurane concentrations were determined (Figure 1). Because atropine may change inhalant uptake into the lungs because of changes in cardiac output, dogs that received atropine in the fentanyl group (n = 3) were not included in the ETiso analysis. Prior to initiation of surgery (baseline), there were no significant differences in ETiso concentration among groups. At this time, mean ± SD ETiso values were 1.27 ± 0.46%, 0.73 ± 0.47%, and 0.68 ± 0.35% in the control, lidocaine, and fentanyl groups, respectively. After surgery began, mean ± SD ETiso values ranged from 1.16 ± 0.35% to 1.94 ± 0.96% in the control group. Although not significantly different, inhalant requirements for maintaining a surgical level of anesthesia were lower in the lidocaine group, with mean ETiso values approximately 34% to 44% lower than in the control group after surgery was begun (mean ± SD ETiso values ranged from 0.73 ± 0.36% to 1.1 ± 0.66%). After initiation of surgery, fentanyl administration was associated with a significant decrease in isoflurane requirements, with mean ETiso values 54% to 66% lower than in the control dogs (mean ETiso values ranged from 0.53 ± 0.38% to 0.69 ± 0.36%). Recovery from anesthesia was smooth and quiet in all dogs, without vocalization, vomition, or signs of nausea.

View Full Size

Mean ± SD ETiso concentrations in dogs undergoing unilateral mastectomy. A CRI of saline (0.9% NaCl) solution (controls; open circles; n = 8), lidocaine (solid triangles; 8), or fentanyl (open squares; 5) was administered concurrently with isoflurane. Baseline data were collected prior to surgery. *Significant (P < 0.05) difference between fentanyl and control groups.

Citation: Journal of the American Veterinary Medical Association 229, 4; 10.2460/javma.229.4.522

• Download Figure
• Download figure as PowerPoint slide

Discussion

The present study revealed that the inhalant-sparing effect of fentanyl and lidocaine, as judged on the basis of clinical evaluation, was qualitatively similar to the reduction in the MAC observed in previous laboratory studies.^3,6 The MAC is the end-tidal concentration of a volatile anesthetic that prevents gross purposeful movement to a supramaximal noxious stimulus in 50% of the population.¹⁷ In dogs, mean isoflurane MAC values are reported to range from 1.2% to 1.8%.^1,5,6,12 To maintain a surgical plane of anesthesia in 95% of the population, end-tidal inhalant concentrations equivalent to 1.2 to 1.4 times the MAC are usually necessary.¹⁸ In healthy young dogs, isoflurane is generally used to maintain anesthesia after premedication with acepromazine and an opioid and induction with an injectable anesthetic, which are drugs known for reducing the MAC of volatile anesthetics.¹⁸ Therefore, the premedication and induction agents used in the present study probably reduced the concentration of isoflurane required to maintain a surgical plane of anesthesia. Even though isoflurane concentrations were influenced by these drugs, premedication and induction were the same for control and experimental groups. Therefore, this factor did not influence the comparison between treated (fentanyl or lidocaine) and control groups.

A decrease in core temperature reduces the MAC of volatile anesthetics.¹⁹ Hypothermia also decreases the inhalant concentration required to cause apnea, but the apneic index (end-tidal concentration that causes apnea/MAC) is not modified for most inhalant drugs.²⁰ In dogs, the MAC of halothane is decreased by 50% in a rectilinear fashion when temperature is decreased from 38° to 28° C, which permits the estimate that the MAC for halothane decreases by approximately 0.5% for each 1° C of decrease in core temperature < 38° C.¹⁹ Although a significant decrease from baseline was recorded only in the control and fentanyl-treated dogs in the present study, mean temperatures recorded at the end of the experiment were 0.7° to 0.8° C lower than mean temperatures recorded at baseline for all groups. In the present study, given the relatively small decrease in temperature over time, the magnitude of the decrease in inhalant requirements was likely small.

This clinical study used standard nociceptive stimuli (unilateral mastectomy), surgeries were performed by the same surgeon (BWM), and depth of anesthesia was controlled by the same anesthetist (DC), which reduced variability, especially regarding intraoperative isoflurane requirements. When surgical conditions vary among dogs, such as with different surgical procedures and surgeons, the degree of intraoperative pain and trauma may also vary and this may influence control of anesthetic depth. Additionally, different anesthetists may also represent a source of bias because of different criteria for judging depth of anesthesia.²¹ Signs of surgical plane of anesthesia were based on the absence of palpebral reflexes, absence of jaw tonus, and maintenance of MAP from 60 to 90 mm Hg. Clinical assessment of inhalant requirements was based on a study by Torske et al,²¹ in which the vaporizer concentration was adjusted according to the response to surgical manipulation and to clinical variables.²¹ In the present study, to avoid any bias in the adjustment of vaporizer settings, a nonprecision outof-circuit vaporizer was used, which does not have temperature or flow compensation or a dial that allows precise determination of vaporizer output.²² By use of clinical evaluation of anesthetic depth by an anesthetist unaware of treatment groups, it was possible to determine the isoflurane-sparing effect of the drugs.

Results of the present study indicated that a high infusion rate of fentanyl resulted in a major inhalantsparing effect in dogs undergoing surgery. In laboratory studies^3,4 that used classical MAC determinations in dogs, fentanyl decreased MAC in a dose-dependent fashion. However, in dogs and humans, fentanyl has a ceiling effect regarding its ability to reduce anesthetic requirements.^3,10 In dogs, the peak inhalant-sparing effect (65% reduction of MAC) is observed at plasma fentanyl concentrations of approximately 30 ng/mL.³ Plasma concentrations of 70 ng/mL cause a similar decrease in enflurane MAC (65%), which supports the hypothesis of a ceiling effect when plasma concentration exceeds 30 ng/mL.⁴ On the basis of the pharmacokinetic profile, a loading dose of 10 μg/kg followed by an infusion rate of 0.7 μg/kg/min has been recommended to achieve a plasma concentration of approximately 28 ng/mL, which leads to a maximal reduction in the volatile anesthetic requirement.^3,8,16 In the present study, fentanyl administered at a loading dose of 5 μg/kg followed by a CRI of 0.5 μg/kg/min was associated with up to 66% reduction in mean ETiso concentrations, which is similar to the reported maximal MAC reduction that can be achieved with this opioid agent. Also, fentanyl is a potent respiratory depressant when used concomitantly with inhalant anesthetics, and positive-pressure ventilation should be instituted if respiratory depression or apnea occur.⁸ In the present study, all dogs received positive-pressure ventilation to maintain eucapnia and because of the use of mechanical ventilation, arterial blood gases did not differ within or among groups.

During inhalant anesthesia, antagonism of opioidinduced bradycardia may be necessary to achieve an improvement in cardiovascular variables.^4,23 In 1 study,⁴ although reduction in enflurane concentrations achieved by use of fentanyl resulted in improvement in some cardiovascular variables, an increase in cardiac output and oxygen delivery was evident only after fentanyl-induced bradycardia was reversed by use of an anticholinergic agent (atropine). During clinical anesthesia, treatment of bradycardia (HR < 65 beats/min) with an anticholinergic agent (glycopyrrolate) consistently improves arterial blood pressure.²³ Heart rate values were lower in the fentanyl group than in the control and lidocaine groups throughout the present study. This result was expected because fentanyl increases parasympathetic tone and leads to vagally mediated bradycardia, with minimal effects on myocardial contractility.^4,24 In the present study, one might expect that the significant reduction in inhalant requirements associated with the use of fentanyl would have resulted in improvement in arterial blood pressure because isoflurane causes dose-dependent hypotension.¹ However, arterial blood pressure in the fentanyl group was not different from that of control dogs. Therefore, it is possible that fentanyl-induced bradycardia blunted the improvement in blood pressure expected with lower isoflurane concentrations.^4,23

There was an increase in MAP from baseline for most time points in the control group. This phenomenon may have been caused by surgical stimulation, which causes cardiovascular stimulation. Conversely, an increase in MAP from baseline was not observed in the lidocaine and fentanyl groups.

Lidocaine also reduces MAC in a dose-dependent manner.^2,6 A decrease in the MAC of halothane has been coincident with an increase in plasma lidocaine concentrations in dogs,² followed by a plateau where a maximum decrease of 45% in halothane MAC was observed when a lidocaine plasma concentration of 11.6 μg/mL was achieved. In a more recent study,⁶ when lidocaine was administered at 200 μg/kg/min (90.9 mg/lb/min) and 50 μg/kg/min (22.7 mg/lb/min), after a loading dose of 2 mg/kg (0.9 mg/lb), isoflurane MAC was reduced by 43.3% and 18.7%, respectively. Muir et al⁵ reported a 29% reduction in isoflurane MAC in dogs after a CRI of 50 μg/kg/min. In the present study, although not significantly different from the other groups, inhalant requirements for maintaining a surgical level of anesthesia were lower in the lidocaine group, with mean ETiso values approximately 34% to 44% lower than that of the control group. In our study, the loading dose (1.5 mg/kg) was slightly lower, whereas the infusion rate (250 μg/kg/min) was slightly higher than the infusion regimen reported by Valverde et al,⁶ but our results were similar in terms of percentage reduction in isoflurane concentrations.

Although the use of a nonprecision vaporizer represented an advantage in terms of ensuring that the individual controlling depth of anesthesia was completely unaware of isoflurane concentrations, the use of this type of vaporizer results in larger variations in vaporized concentrations.²² Therefore, one may hypothesize that the lack of significant difference observed for ETiso between the control and lidocaine groups in the present study could be, in part, attributed to greater variability in isoflurane concentrations associated with the use of a nonprecision vaporizer. Indeed, the SD values for ETiso concentrations observed in our study⁶ were higher than those reported in a previous study where lidocaine significantly reduced isoflurane MAC. It appears that because of the greater variability in ETiso concentrations, the power of the present study was small to reveal a statistical difference between the animals treated with lidocaine and the control animals.

Lidocaine overdose may result in adverse effects on the CNS such as salivation, tremors, and convulsions.²⁵ The dose that may cause convulsions is reported to range from 11 to 20 mg/kg [5 to 9.1 mg/lb], IV.²⁶ In 1 study,²⁵ cumulative IV administration of boluses totaling (mean ± SD) 22 ± 6.7 mg/kg [10 ± 3.04 mg/lb] caused convulsions in dogs. In the present study, lidocaine infusion was maintained throughout the anesthetic procedure, which lasted 116 ± 17 minutes, resulting in a total cumulative dose of 30.6 ± 4.2 mg/kg (13.9 ± 1.9 mg/lb), a value that exceeded the toxic dose reported to cause convulsions in conscious dogs reported by Liu et al.²⁵ However, it should be emphasized that this cumulative dose was administered as a CRI during approximately 2 hours in anesthetized dogs. It is unlikely that the infusion regimen used in the present study resulted in toxic plasma lidocaine concentrations because elimination half-life in dogs is short (approx 47 minutes) and no adverse effects related to lidocaine toxicosis were observed during the postoperative period.²⁷

The doses of lidocaine and fentanyl used in the present study were not equipotent regarding reduction of isoflurane requirements. Although the infusion rate of fentanyl was similar to the infusion rate estimated to cause maximal MAC reduction (approx 65%), the infusion rate of lidocaine was slightly higher than the infusion rate that resulted in 43% reduction in MAC for isoflurane. At the infusion rates used in the present study, fentanyl resulted in greater isoflurane-sparing effects than did lidocaine. However, it appears that the low HR induced by fentanyl may partially blunt the improvement in arterial blood pressure that would be expected with reduced isoflurane requirements.