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Effects of methadone on the minimum alveolar concentration of isoflurane in dogs
Veterinary Anaesthesia and Analgesia, 2010, 37, 240–249
doi:10.1111/j.1467-2995.2010.00528.x
RESEARCH PAPER
Effects of methadone on the minimum alveolar concentration of isoflurane in dogs Renato G Credie*, Francisco J Teixeira Neto*, Tatiana H Ferreira*, Antoˆnio JA Aguiar*, Fabio C Restitutti & Jose´ E Correnteà *Departamento de Cirurgia e Anestesiologia Veterina´ria, Faculdade de Medicina Veterina´ria e Zootecnia, Universidade Estadual Paulista, Botucatu, SP, Brazil Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland àDepartmento de Bioestatı´stica, Instituto de Biocieˆncias, Universidade Estadual Paulista, Botucatu, SP, Brazil
Correspondence: Francisco J Teixeira Neto, Departamento de Cirurgia e Anestesiologia Veterina´ria, Faculdade de Medicina Veterina´ria e Zootecnia, Universidade Estadual Paulista, Distrito de Rubia˜o Jr S/N, CEP 18618-000, Botucatu, SP, Brazil. E-mail: [email protected]
Abstract Objective To investigate the effects of methadone on the minimum alveolar concentration of isoflurane (ISOMAC) in dogs. Study design Prospective, randomized cross-over experimental study. Animals Six adult mongrel dogs, four males and two females, weighing 22.8 ± 6.6 kg. Methods Animals were anesthetized with isoflurane and mechanically ventilated on three separate days, at least 1 week apart. Core temperature was maintained between 37.5 and 38.5 C during ISOMAC determinations. On each study day, ISOMAC was determined using electrical stimulation of the antebrachium (50 V, 50 Hz, 10 mseconds) at 2.5 and 5 hours after intravenous injection of physiological saline (control) or one of two doses of methadone (0.5 or 1.0 mg kg)1). Results Mean (±SD) ISOMAC in the control treatment was 1.19 ± 0.15% and 1.18 ± 0.15% at 2.5 and 5 hours, respectively. The 1.0 mg kg)1 dose of methadone reduced ISOMAC by 48% (2.5 hours) and by 30% (5 hours), whereas the 0.5 mg kg)1 dose caused smaller reductions in ISOMAC (35% and 15%
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reductions at 2.5 and 5 hours, respectively). Both doses of methadone decreased heart rate (HR), but the 1.0 mg kg)1 dose was associated with greater negative chronotropic actions (HR 37% lower than control) and mild metabolic acidosis at 2.5 hours. Mean arterial pressure increased in the MET1.0 treatment (13% higher than control) at 2.5 hours. Conclusions and clinical relevance Methadone reduces ISOMAC in a dose-related fashion and this effect is lessened over time. Although the isoflurane sparing effect of the 0.5 mg kg)1 dose of methadone was smaller in comparison to the 1.0 mg kg)1 dose, the lower dose is recommended for clinical use because it results in less evidence of cardiovascular impairment. Keywords isoflurane, methadone, minimum alveolar concentration.
Introduction Inhalant anesthetics allow rapid and precise control of anesthetic drug concentration at the effect site (central nervous system, CNS) via monitoring endtidal inhalant anesthetic concentrations. Modern inhalant agents are also devoid of cumulative effects and this characteristic allows fast recoveries that are not substantially influenced by the duration of anes-
Methadone and isoflurane MAC in dogs RG Credie et al.
thesia (Steffey & Mama 2007). Although inhalation anesthetics produce unconsciousness and some degree of muscle relaxation, that is sufficient for performing surgical procedures, many of the more modern drugs do not provide a specific analgesic effect. Surgical procedures carried out under inhalant anesthesia alone may result in hyperalgesia during the postoperative period because of central sensitization of the CNS caused by the surgical trauma (Muir & Woolf 2001). Inhalant anesthetics inhibit autonomic outflow (Yamamura et al. 1983) and cause dose-related cardiorespiratory depression (Steffey & Howland 1978; Mutoh et al. 1997). Relatively, high doses of inhalant anesthetics are necessary to inhibit the cardiovascular responses to nociception (Roizen et al. 1981) and when these drugs are used at concentrations necessary to produce surgical anesthesia, hypotension and substantial decreases in cardiac output/tissue oxygen delivery may follow. The minimum alveolar concentration (MAC), defined as the end-tidal concentration of an inhalant anesthetic required to prevent purposeful movement in response to a supramaximal noxious stimulus in 50% of a population, is useful to assess objectively changes in inhalant anesthetic requirements caused by drugs used during anesthesia (Quasha et al. 1980). In dogs, pure l-opioid agonists decrease the MAC of volatile anesthetics to a maximum of 65–70% (Murphy & Hug 1982; Hall et al. 1987a,b). Methadone is drug that acts as a competitive agonist at l-opioid receptors. The mechanism of methadone-induced analgesia also appears to involve a noncompetitive antagonism of NMDA receptors located in the CNS (Ebert et al. 1995). In human patients, methadone is considered a long-acting opioid because it has a long elimination half-life (22–35 hours) and produces postoperative analgesia that lasts longer than morphine (Gourlay et al. 1982; Chui & Gin 1992; Eap et al. 2002). Dogs differ from humans because methadone is more rapidly eliminated from the body due to a high clearance. In dogs, methadone elimination half-lives recorded after intravenous administration ranged from 1.53 to 4.3 hours (Schmidt et al. 1994; KuKanich et al. 2005a; KuKanich & Borum 2008a). Because methadone is more rapidly eliminated in dogs than in humans, one may expect that this opioid would need to be administered more frequently in this species. Few controlled studies assessing the perioperative use of methadone are available in small animals, yet
this drug has become popular as a premedicant before general anesthesia in some countries (Bauer et al. 1976; Monteiro et al. 2008). In isofluraneanesthetized dogs undergoing cranial cruciate ligament repair, when epidural methadone (0.3 mg kg)1) was compared to the same dose administered intravenously (IV), epidural opioid administration resulted in greater reduction of inhalant anesthetic requirements for maintaining surgical anesthesia than the intravenous route of administration (Leibetseder et al. 2006). The hypothesis of the study reported here was that methadone would induce dose-related reductions in the MAC of isoflurane. Materials and methods Animals This study was carried out after obtaining approval of the University Animal Care and Use Committee (Protocol number 35/2005 CEEA). A total of six adult healthy mongrel dogs (four castrated male and two spayed female) weighing 22.8 ± 6.6 kg (mean ± SD) were selected for this study. Health status was assessed via physical examination, complete blood cell count and serum biochemistry values within reference intervals. Experimental protocol All animals randomly received three treatments administered IV: saline (control), 0.5 mg kg)1 of methadone (MET0.5), and 1.0 mg kg)1 of methadone (MET1.0). Each treatment was administered on a different experimental day, allowing a minimum washout period of 7 days between experiments. Food was withheld for 12 hours, with water ad libitum. Anesthesia was induced and maintained with isoflurane (Isoforine; Crista´lia, Brazil). During induction of anesthesia, a vaporized concentration of 5% of isoflurane diluted in 4–5 L of oxygen was delivered to the animal via a face-mask connected to a circle breathing circuit (Linea C; Intermed, Brazil). After an adequate depth of anesthesia was achieved, a cuffed orotracheal tube was placed in the dog’s trachea, the oxygen flow rate was reduced to values between 1 and 2 L minute)1, and the precision vaporizer was adjusted to maintain a moderate depth of anesthesia, on the basis of clinical assessment. Animals were placed in lateral recumbency
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and a cephalic vein and a dorsal pedal artery were catheterized (Insyte; Becton Dickinson, Brazil). Intravenous fluid therapy with lactated Ringer’s solution (5 mL kg)1 hour)1) was maintained throughout anesthesia using a peristaltic infusion pump (LF2001; Lifemed). For recording systolic, diastolic, and mean arterial blood pressures (SAP, DAP, and MAP), the catheter placed in the dorsal pedal artery was connected to a multiparametric monitor (AS3 Monitor; Datex-E¨ngstrom, Finland) via a pressure transducer filled with heparinized saline (TruWave; Edwards Lifesciences, CA, USA) that was previously zeroed at the level of the manubrium. Accuracy of the pressure transducer was checked with a mercury manometer before each experiment. Blood samples were drawn from the arterial catheter into heparinized syringes and analyzed immediately by an automated blood-gas analyzer (Model 348; Chiron Diagnostics, UK). Displayed blood-gas values were corrected on the basis of core temperature, which was recorded by a probe placed in the thoracic portion of the esophagus. Adhesive electrodes were placed according to a Lead II orientation and the ECG tracing was stored on a PC computer using an interface (ECGPC; Tecnologia Eletroˆnica Brasileira, Brazil). A sampling line was attached between the orotracheal tube and the anesthetic breathing circuit for continuous aspiration of airway gases (200 mL minute)1) into an infrared gas analyzer (M-Caio; Datex-E¨ngstrom) for recording end-tidal isoflurane (E¢ISO) and end-tidal CO2 (PE¢CO2) concentrations. The infrared gas analyzer was calibrated with a reference gas mixture containing 3% anesthetic agent (CHF3 as enflurane substitute), 55% O2, 33% N2O, 5% CO2 and N2 balance (Quick Cal 755582; Datex-E¨ngstrom). With the anesthetic agent monitor used, calibration for all halogenated anesthetics (e.g. isoflurane) is automatically adjusted when the calibration procedure is performed with the enflurane substitute. Gas calibration was performed prior and during each experiment; the percent volume of inhalant anesthetic was found not to drift by more than 0.03% (absolute values) from the reference value (3%) on the same experimental day. Core temperature was maintained between 37.5 and 38.5 C throughout the experimental procedure by means of a warm air blanket (Warmtouch; Mallinkrodt, CA, USA) and an electrically heated pad. Eucapnia (PaCO2 between 35 and 45 mmHg, 4.7 and 6 kPa) was maintained throughout anesthesia by positive pressure ventila242
tion. To maintain PaCO2 levels within the desired range, the ventilator (Linea C) was adjusted to deliver a peak inspiratory pressure ranging between 9 and 16 cmH2O and a respiratory rate between 8 and 18 breaths minute)1, while the inspiration to expiration ratio was held constant (1:2). To facilitate ventilator adjustments, PE¢CO2 values were used as estimates of PaCO2 values. Because the difference between arterial and PE¢CO2 may vary substantially among individuals, the arterial to PE¢CO2 gradient [P(a-E¢)CO2] was determined for each animal during anesthesia and PE¢CO2s were considered acceptable estimates of PaCO2 when an alveolar plateau could be identified on the capnographic waveform. During the procedure for determining isoflurane MAC (ISOMAC), spontaneous respiratory efforts are commonly observed during supramaximal noxious stimulation or during substantial reduction in E¢ISO values. During the noxious stimulation, the inspiratory flow sensitivity of the ventilator was adjusted to trigger-assisted ventilatory cycles between the controlled breaths. After the end of the instrumentation, E¢ISO values were stabilized at 1.8% for 15 minutes and each animal randomly received one of three intravenous treatments. In the control treatment, 0.9% saline solution (0.2 mL kg)1) was administered as a placebo; whereas in the MET0.5 and in the MET1.0 treatment groups, methadone (Metadon; Crista´lia, SP, Brazil) was administered as an IV bolus over 1 minute at 0.5 and 1.0 mg kg)1, respectively. Determination of isoflurane minimum alveolar concentration Two 22-gauge stainless steel hypodermic needles transfixing skin on the lateral aspect of the middle third of the antebrachium at a distance of 5 cm from each other were used for electrical stimulation during ISOMAC determinations. The needles were connected to an electrical stimulator (Grass S48 Stimulator; Astromed Inc, RI, USA) that was adjusted to deliver a 50 V stimulus, at 50 Hz with a 10 msecond pulse duration. The noxious stimulation consisted of four stimuli administered at 5 second intervals (two simple stimuli and two continuous stimuli lasting 3 seconds each). In a previous study, this electrical stimulation pattern was characterized as supramaximal, yielding ISOMAC values that did not differ from those obtained with a tail clamp in dogs (Valverde et al. 2003). The electrical stimulation was interrupted if the animal had
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gross purposeful movement before the entire stimulation sequence was completed. Obvious lifting of the head and neck, twisting movements of the trunk, and gross repetitive limb movements (paddling) observed during noxious stimulation or up to 1 minute after the end of the stimulation sequence were considered positive motor responses. Negative responses included: retraction/movement of the limb undergoing electrical stimulation, arching of the back, discrete and repetitive movements of the limbs (flexion of the metacarpal and/or metatarsal joints only), slight flexion of the neck and/or head, and spontaneous respiratory efforts (Quasha et al. 1980; Valverde et al. 2003). Two experienced individuals who were unaware of the treatment administered to the animal were responsible for assessing the presence or absence of gross movement in response to noxious stimulation. If there was disagreement between them with regard to the classification of the motor response, the electrical stimulation was repeated 1 minute after the first stimulation for redefining motor response. Fifteen minutes after drug administration, E¢ISO was adjusted to maintain moderate depth of anesthesia on the basis of clinical judgment (relaxation of the mandible, absence of palpebral reflexes, absence of spontaneous respiratory efforts during mechanical ventilation). Noxious stimulation was applied after the E¢ISO was stable for 15 minutes. If a negative motor response was initially observed, the E¢ISO concentration was reduced by 0.2% decrements and the noxious stimulation was repeated after an additional 15 minute re-equilibration period at the new E¢ISO level. When a positive motor response was observed, the E¢ISO was then increased in 0.1% increments and noxious stimulation was repeated after 15 minute equilibration periods at each new E¢ISO until the motor response was inhibited. If the motor response to the first noxious stimulation was positive, the changes in E¢ISO were performed in the opposite direction using the same steps until a negative response was obtained. The ISOMAC was calculated as the arithmetic mean of the highest E¢ISO concentration that allowed a gross purposeful movement in response to noxious stimulation and the lowest E¢ISO that prevented such response, with a difference of 0.1% in the E¢ISO values that resulted in this alternating pattern of response to stimulation (Quasha et al. 1980). The altitude of our laboratory is 785 m above sea level, with an average barometric pressure of
680 mmHg. Isoflurane MAC was corrected to values at sea level (barometric pressure: 760 mmHg) according to the formula: Altitude corrected ISOMAC ðvol%Þ ¼ measured ISOMAC ðvol%Þ 680=760:
Times of ISOMAC determination The ISOMAC measurements were made at 2.5 ± 0.5 and 5 ± 0.5 hours. If ISOMAC could not be determined within these pre-defined time intervals, the experiment was aborted and the same treatment was repeated after a minimum interval of 1 week until ISOMAC determinations could be concluded within the pre-defined time intervals. If an additional experiment was necessary to fulfill these time criteria, the E¢ISO first used during ISOMAC determinations was modified to values that were thought to be closer to the ISOMAC during each targeted time. Cardiorespiratory evaluation Cardiovascular data (HR, SAP, DAP, and MAP), arterial blood-gases (pH, PaCO2, PaO2, HCO3)) and core body temperature were recorded for each ISOMAC determination (2.5 and 5.0 hours). The physiological data corresponding to each time were calculated as the arithmetic mean of the two sets of values recorded immediately before the noxious stimulation that gave origin to the ISOMAC. Characteristics of recovery from anesthesia After the last MAC determination was concluded, isoflurane administration was discontinued and the times for endotracheal tube removal (performed upon the return of the swallowing reflex) and to standing were recorded. These variables were measured as the time elapsed from turning off the isoflurane vaporizer. Statistical analysis Normal distribution of data was verified by using the Kolgomorov–Smirnov test. Using a computer software program (SAS for Windows v. 8.02; SAS Institute Inc, NC, USA), a split-plot design was used for the analysis of the effects of treatments (control, MET0.5 or MET1.0) on ISOMAC and on physiologic variables, considering time as plot and treatment as
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Methadone and isoflurane MAC in dogs RG Credie et al.
subplot. The F-value of the ANOVA table was used for analyzing the effect of time, treatment, and treatment · time interaction. Using the PDIFF option of the PROC GLM, a multiple comparison test was used for comparing the effects of treatment drug and time on the continuous variables. An ANOVA followed by a Tukey’s test compared the times until orotracheal tube removal and until standing. The null hypothesis (no effect of methadone on ISOMAC, on physiologic variables, and on times to recover from anesthesia) was rejected when p < 0.05. Results Isoflurane MAC values were not determined within the pre-defined time intervals (2.5 ± 0.5 and 5.0 ± 0.5 hours) in three animals treated with 1 mg kg)1 of methadone. In one of these animals, the determination of ISOMAC was also obtained outside the time intervals after the administration of 0.5 mg kg)1 of methadone. After treatment was repeated in these same animals on a second occasion, ISOMAC was successfully determined within the targeted time periods. A small but statistically significant difference in the real times of ISOMAC determination was observed when the control and the MET0.5 treatment groups were compared at 5.0 hours (Table 1). The ISOMAC values did not change over time in the control treatment. Both doses of methadone significantly reduced ISOMAC values in comparison to the control treatment at 2.5 and 5 hours. The reduction in ISOMAC induced by methadone was directly related to the dose administered, with the
1.0 mg kg)1 dose resulting in significantly greater reductions in ISOMAC than the 0.5 mg kg)1 dose at 2.5 hours (decreased by 35 ± 15% and 48 ± 18% for MET0.5 and MET1.0, respectively) and at 5.0 hours (decreased by 15 ± 11% and 30 ± 12% for MET0.5 and MET1.0, respectively). The reduction in ISOMAC caused by methadone was also inversely related to time; the ISOMAC reduction induced by both doses of methadone was significantly less at 5.0 hours than at 2.5 hours. With the exception of one animal that had episodes of bradycardia (HR < 60 beats minute)1) with heart rates (HRs) between 49 and 55 beats minute)1 during the experimental period, there were no changes in HR or rhythm in the control treatment. Bradycardia was recorded in all animals after receiving methadone. Minimum HRs for individual animals recorded throughout the experimental procedure ranged from 34 to 42 beats minute)1 in the MET0.5 treatment group and from 31 to 42 beats minute)1 in the MET1.0 treatment group. Two animals that received methadone (0.5 and 1.0 mg kg)1) had bradycardia and episodes of sinus arrest. In these two animals, the episodes of sinus arrest were still present immediately prior to noxious stimulations used for ISOMAC determinations at 2.5 and 5 hours. Another animal had a ventricular escape rhythm associated with third degree atrioventricular block and isolated ventricular escape beats after receiving 0.5 and 1.0 mg kg)1 of methadone. During the first ISOMAC determination (2.5 hours), these arrhythmias persisted in the MET1.0 treatment, but were not observed during
Table 1 Changes in isoflurane minimum alveolar concentration (ISOMAC, mean ± SD) recorded approximately 2.5 and 5 hours after intravenous administration of 0.9% NaCl solution (Control) or two doses of methadone [0.5 mg kg)1 (MET0.5) or 1.0 mg kg)1 (MET1.0)] to six dogs. Actual times for ISOMAC determination are shown within parenthesis (mean ± SD)
Treatment
Variable
Control
ISOMAC at 2.5 hours (%) Actual time (hours) ISOMAC at 5 hours (%) Actual time (hours)
1.19 (2.61 1.18 (4.82
± ± ± ±
0.15A 0.16) 0.15A 0.11B)
MET0.5
0.78 (2.48 1.01 (5.08
± ± ± ±
MET1.0 0.21B 0.19) 0.18*B 0.17A)
0.61 (2.44 0.82 (4.99
± ± ± ±
0.17C 0.23) 0.14*C 0.34AB)
For a given variable (rows), treatment mean values followed by different superscript letters are significantly different from each other (p < 0.05) (A > B > C). *For a given treatment (columns), mean ISOMAC at 5 hours is significantly higher than at 2.5 hours (p < 0.05).
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ISOMAC determination at 5 hours. With 0.5 mg kg)1 of methadone in this animal, these arrhythmias were of shorter duration and were not seen during the ISOMAC determinations at 2.5 and 5 hours. During the noxious stimulation that was applied at the E¢ISO values that gave origin to the ISOMAC, there was an increase in HR from pre-stimulation values and the arrhythmias could no longer be detected in all animals, regardless of the treatment group. In the control treatment, mean values of HR, SAP, DAP, and MAP did not change over the time between the two time points measured (2.5 and 5 hours) (Table 2). Both doses of methadone decreased HR in comparison to control values. During the first ISOMAC determination (2.5 hours), the decrease in HR induced by methadone was directly related to the dose administered (mean HR values after 1.0 mg kg)1 were significantly lower than mean HR values after 0.5 mg kg)1). Mean SAP values 2.5 hours after administering 0.5 mg kg)1 of methadone were significantly high-
er than mean SAP values recorded in the control treatment. There were no significant differences for DAP. During the first ISOMAC determination (2.5 hours), animals that received 1.0 mg kg)1 of methadone showed that MAPs were significantly higher than the control treatment. Five hours after drug administration, MAPs were significantly lower than values recorded at 2.5 hours for both doses of methadone. During the ISOMAC determination at 2.5 hours, methadone was associated with a significant decrease in arterial pH values in comparison to the control group (differences in mean pH values ranging from 0.05 to 0.09). At 2.5 hours, concomitantly to a dose-dependent decrease in pH induced by methadone, there was also a dose-dependent decrease in HCO3) levels; while PaCO2 tensions did not differ among treatment groups. During the second ISOMAC determination (5 hours), pH values were also lower in methadone-treated animals than in the control treatment but HCO3) values were not significantly altered. At 5 hours, PaCO2 was higher in methadone-treated animals in comparison to the
Table 2 Physiological variables (mean ± SD) recorded 2.5 and 5.0 hours after intravenous administration of 0.9% NaCl (Control) or one of two doses of methadone (0.5 and 1.0 mg kg)1 in the MET0.5 and MET1.0 treatment groups, respectively) at equipotent concentrations of isoflurane (1 · ISOMAC) in six dogs Treatment
Variable
Time (hours)
Control
MET0.5
HR (beats minute)1)
2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0
75 ± 8A 73 ± 13A 126 ± 17B 128 ± 20 52 ± 9 51 ± 7 69 ± 9B 67 ± 9 7.40 ± 0.02A 7.41 ± 0.02A 37 ± 1 (4.9 ± 0.1) 36 ± 1A (4.8 ± 0.1) 486 ± 38 (64.6 ± 5.1) 476 ± 39 (63.3 ± 5.2) 22.2 ± 1.3A 22.1 ± 1.2 37.7 ± 0.2AB 37.7 ± 0.2B
54 60 145 138 55 50 74 67 7.35 7.38 39 39 474 474 20.5 21.8 38.0 38.1
SAP (mmHg) DAP (mmHg) MAP (mmHg) pH PaCO2 mmHg (kPa) PaO2 mmHg (kPa) HCO3) (mmol L)1) Temperature (oC)
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
7B 8B 24A 29 4 3 4AB 5* 0.02B 0.03*B 2 (5.2 ± 0.3) 2B (5.2 ± 0.3) 46 (63.0 ± 6.1) 42 (63.0 ± 5.6) 1.4B 0.9 0.4A 0.2A
MET1.0
47 55 135 126 58 51 78 70 7.31 7.36 39 39 476 463 18.9 21.4 37.7 37.9
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
9C 12B 13AB 15 8 6 8A 6* 0.03C 0.01*B 3 (5.2 ± 0.4) 2B (5.2 ± 0.3) 46 (63.3 ± 6.1) 32 (61.6 ± 4.3) 0.8C 1.2* 0.3B 0.4AB
HR, heart rate; SAP, systolic arterial blood pressure; DAP, diastolic arterial blood pressure; MAP, mean arterial blood pressure. Mean values (rows) followed by different superscript letters differ significantly from each other (A > B > C) (p < 0.05). *Mean values (columns) at 5.0 hours are significantly different from mean values recorded at 2.5 hours (p < 0.05).
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control treatment. Mean PaCO2 remained within reference intervals (35–45 mmHg, 4.7–6 kPa) in all treatment groups throughout the study. Significant differences in core temperature were observed between treatment groups at 2.5 and 5 hours (maximum differences in mean temperature values: 0.4 C). There was no significant difference among treatments for the variables recorded during recovery from anesthesia (Table 3). Complications such as emesis or excitation during recovery were not observed. Discussion The present study showed that methadone decreases ISOMAC in a dose-related manner and that the magnitude of the inhalant sparing effect induced by a single bolus administration of this opioid is reduced over time. The ISOMAC reduction was more intense and prolonged with the use of a higher dose of the opioid (1 mg kg)1), as the ISOMAC was still reduced by 30 ± 12% 5 hours after administration of 1 mg kg)1 of methadone. The inhalant anesthetic sparing effect induced by methadone in the study reported here appeared to be more intense and prolonged than the ISOMAC reduction reported with the use of morphine in dogs. In a previous study, Steffey et al. (1993) observed that, 30 minutes after intravenous morphine administration (1 mg kg)1), ISOMAC was reduced by 39% (Steffey et al. 1993). In that same study, authors reported that the isoflurane sparing effect was no longer significant (<10%) 4 hours
Table 3 Time until orotracheal tube removal (time to extubation) and time until regaining standing position (mean ± SD) recorded in six isoflurane-anesthetized dogs that received intravenous administration of 0.9% NaCl (Control) or one of two doses of methadone (0.5 and 1.0 mg kg)1 in the MET0.5 and MET1.0 treatment groups, respectively) for minimum alveolar concentration of isoflurane determinations at 2.5 and 5 hours after treatment administration
Treatments
Variable
Control
MET0.5
MET1.0
Time to extubation (minutes) Time until standing (minutes)
12 ± 6 16 ± 7
14 ± 8 26 ± 12
18 ± 10 24 ± 14
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after opioid administration (Steffey et al. 1993). A difference in the pharmacokinetic profile of methadone and morphine could explain the longer duration of ISOMAC reduction provided by methadone in the study reported here. The mean elimination halflives reported after the intravenous administration of 0.5 mg kg)1 of methadone (1.5–4.3 hours) are longer than the mean elimination half-lives reported after the administration of the same dose of intravenous morphine (0.87–1.28 hours) (Schmidt et al. 1994; KuKanich et al. 2005a,b,c; KuKanich & Borum 2008a,b). The magnitude and duration of ISOMAC reduction induced by the higher dose of methadone (1 mg kg)1) seemed not to differ substantially from the magnitude and duration of ISOMAC reduction reported after the use of hydromorphone in dogs (Machado et al. 2006). In the study presented here, ISOMAC was reduced by 48 ± 18% and 30 ± 12% at 2.5 and 5 hours after administration of 1 mg kg)1 of methadone, respectively; while Machado et al. (2006) reported that intravenous hydromorphone (0.1 mg kg)1) reduced ISOMAC by 48 ± 6% and by 34 ± 7% 2 and 4 hours after opioid administration, respectively (Machado et al. 2006). The magnitude of ISOMAC reduction induced by the 0.5 mg kg)1 dose of methadone was significantly less than at the 1 mg kg)1 dose. Despite a statistically significant reduction in ISOMAC at 2.5 (35 ± 15%) and at 5 hours (15 ± 11%) recorded after administration of 0.5 mg kg)1 of methadone, the inhalant sparing effect recorded at 5 hours may not be considered of clinical relevance (<20% reduction in ISOMAC in 4/6 animals). On the basis of these findings, during prolonged anesthetic procedures in dogs given 0.5 mg kg)1 of methadone, there would be a need for re-administering the same dose of methadone, 2.5 hours after the first dose, to maintain a 30% reduction in inhalant anesthetic requirements. In the control treatment, ISOMAC was constant over a 2.5-hour interval between measurements (1.19 ± 0.15% and 1.18 ± 0.15% after 2.5 and 5 hours of 0.9% NaCl administration). This repeatability over time is expected and is in agreement with previous studies (Eger et al. 1965a). In the present study, some factors that are known to influence the MAC of inhalant anesthetics were controlled (temperature, PaCO2, PaO2). In dogs, as temperature is reduced from 38 to 28 C, halothane MAC decreases in a rectilinear fashion by 5% for
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each 1 C decrease in core temperature (Eger et al. 1965b). In the present study, mean temperatures were maintained within a narrow range (37.7– 38.1 C) and such small variation probably did not bear a significant influence on ISOMAC values. A statistically significant but clinically unimportant difference was also observed in PaCO2 values (mean PaCO2s ranged from 36 to 39 mmHg, 4.8– 5.2 kPa). It was unlikely that this variation in PaCO2 could have biased ISOMAC as only extreme changes in PaCO2 (<10 mmHg or >95 mmHg) reduced the MAC of inhalant anesthetics (Eisele et al. 1967; Quasha et al. 1980). As the temporal factor may influence the magnitude of MAC reduction induced by a drug administered as a single bolus due to decreasing plasma concentrations (Steffey et al. 1993; Machado et al. 2006), comparison of the effect of different doses of one drug on MAC should to be performed at similar time periods. In the study reported here, this confounder was controlled by determining ISOMAC values within pre-established times (2.5 and 5 hours after treatment drug administration). It was not possible to conclude ISOMAC determinations within the limits of tolerance for each targeted time (± 0.5 hours) during the first anesthetic in three animals treated with 1.0 mg kg)1 of methadone and in one animal treated with 0.5 mg kg)1 of methadone. The initial difficulty in fulfilling the time criteria in some animals that received methadone was attributed to the fact that in those animals the E¢ISO concentrations at baseline were very different from those concentrations used for calculating ISOMAC. On the second occasion, ISOMAC determinations were concluded within the pre-defined time intervals because the E¢ISO concentrations were adjusted to values that were closer to those used for determining ISOMAC. Despite the efforts to conclude ISOMAC measurements at constant time periods, the actual time for concluding ISOMAC at 5 hours in the MET0.5 treatment (5.08 ± 0.17 hours) was significantly longer than the actual time recorded in the control treatment (4.82 ± 0.11 hours). However, it is unlikely that this difference had a substantial influence in the ISOMAC values because the absolute difference in mean times for ISOMAC measurements was relatively small (0.26 hours or 16 minutes). The bradycardia, conduction disturbances (sinus arrest and third degree atrioventricular blockade) and ventricular escape beats induced by methadone
are explained by the central vagotonic action typically induced by l-opioid agonists. The higher dose of methadone (1 mg kg)1) was associated with more intense negative chronotropic effects than the 0.5 mg kg)1 dose at 2.5 hours after opioid administration. Studies performed in conscious dogs have shown that 1.0 mg kg)1 of methadone may result in more significant hemodynamic changes than the changes induced by the administration of 0.5 mg kg)1 of methadone (27% and 52% reduction in cardiac index from baseline values for the 0.5 and 1.0 mg kg)1 doses of methadone, respectively) (Maiante et al. 2009). One of the beneficial effects of combining opioids and inhalant anesthetics is to lessen the cardiovascular depression induced by inhalant anesthetics by reducing the amount of inhalant anesthetic required for maintaining anesthesia (Ilkiw et al. 1993). The increases in arterial blood pressure values recorded after methadone could be caused primarily by the reduction in isoflurane requirements induced by the opioid, or to an increase in systemic vascular resistance associated with methadone (Maiante et al. 2009). The negative chronotropic effects induced by opioids may mask or attenuate an overall improvement in hemodynamic function (increased cardiac output, oxygen delivery, and arterial pressure) (Ilkiw et al. 1993). The administration of high doses of fentanyl (15.9 lg kg)1 minute)1 for 20 minutes, followed by 1.065 lg kg)1 minute)1), despite reducing enflurane requirements by 65%, did not result in increases in cardiac output and tissue oxygen delivery because of opioid-induced bradycardia; improvements in these variables were evident after reversal of opioid-induced bradycardia with atropine (Ilkiw et al. 1993). Although no detailed hemodynamic monitoring was used in the study reported here, it is likely that methadone-induced bradycardia also resulted in significant decreases in cardiac output. At 2.5 hours after administering the 1.0 mg kg)1 dose of methadone, mean values for pH (7.31 ± 0.03) and HCO3) (18.9 ± 0.8 mmol L)1) were not only significantly lower than values recorded in the control treatment group and in the MET0.5 treatment group, but were also lower than reference intervals (7.35–7.45 for pH; and 20–26 mmol L)1 for bicarbonate). As PaCO2 did not change significantly at this time (mean PaCO2 values ranged from 37 to 39 mmHg at 2.5 hours), these blood-gas changes suggest that a mild metabolic acidosis was in progress after 2.5 hours of administration of the
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higher dose of the opioid. In another study performed in conscious dogs, administration of 1 mg kg)1 of methadone resulted in a discrete increase in PaCO2 (Hellebrekers et al. 1989). In that study, reductions in HCO3) concentrations were also associated with methadone and the authors speculated that this was due to reduced peripheral perfusion after opioid administration (Hellebrekers et al. 1989). In summary, methadone reduces ISOMAC in a dose-dependent fashion and the magnitude of the inhalant sparing effect is reduced over the course of 5 hours after opioid administration. The higher dose of methadone (1.0 mg kg)1) resulted in more intense and prolonged reductions in ISOMAC, whereas the reduction induced by 0.5 mg kg)1 of methadone at 5 hours may have little clinical relevance (<20% in most animals). Both doses of methadone were accompanied by a dose-dependent decrease in HR, while a slight metabolic acidosis was associated only with the highest dose. Acknowledgement Partial Funding was provided by ‘Fundac¸a˜o de Amparo a` Pesquisa de Sa˜o Paulo’. References Bauer H, Schmidt G, Holle F (1976) Combined anesthesia with propionylpromazine (Combelen) and methadone (Polamivet). A sure simple method of anesthesia in gastrointestinal surgery in dogs. Z Gastroenterol 14, 277–279. Chui PT, Gin T (1992) A double-blind randomized trial comparing postoperative analgesia after perioperative loading doses of methadone or morphine. Anaesth Intensive Care 20, 46–51. Eap CB, Buclin T, Baumann P (2002) Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 41, 1153–1193. Ebert B, Andersen S, Krogsgaard-Larsen P (1995) Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 187, 165– 168. Eger EI II, Saidman LJ, Brandstater B (1965a) Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 26, 756–763. Eger EI II, Saidman LJ, Brandstater B (1965b) Temperature dependence of halothane and cyclopropane anesthesia
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in dogs: correlation with some theories of anesthetic action. Anesthesiology 26, 764–770. Eisele JH, Eger EI II, Muallem M (1967) Narcotic properties of carbon dioxide in the dog. Anesthesiology 28, 856– 865. Gourlay GK, Wilson PR, Glynn CJ (1982) Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology 57, 458–467. Hall RI, Murphy MR, Hug CC Jr (1987a) The enflurane sparing effect of sufentanil in dogs. Anesthesiology 67, 518–525. Hall RI, Szlam F, Hug CC Jr (1987b) The enflurane-sparing effect of alfentanil in dogs. Anesth Analg 66, 1287– 1291. Hellebrekers LJ, van den Brom WE, Mol JA (1989) Plasma arginine vasopressin response to intravenous methadone and naloxone in conscious dogs. J Pharmacol Exp Ther 248, 329–333. Ilkiw JE, Pascoe PJ, Haskins SC et al. (1993) The cardiovascular sparing effect of fentanyl and atropine, administered to enflurane anesthetized dogs. Can J Vet Res 57, 248–253. KuKanich B, Borum SL (2008a) The disposition and behavioral effects of methadone in Greyhounds. Vet Anaesth Analg 35, 242–248. KuKanich B, Borum SL (2008b) Effects of ketoconazole on the pharmacokinetics and pharmacodynamics of morphine in healthy Greyhounds. Am J Vet Res 69, 664– 669. KuKanich B, Lascelles BDX, Aman AM et al. (2005a) The effects of inhibiting cytochrome P450 3A, p-glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs. J Vet Pharmacol Ther 28, 461–466. KuKanich B, Lascelles BDX, Papich MG (2005b) Pharmacokinetics of morphine and plasma concentrations of morphine-6-glucuronide following morphine administration to dogs. J Vet Pharmacol Ther 28, 371–376. KuKanich B, Lascelles BDX, Papich MG (2005c) Use of a von Frey device for evaluation of pharmacokinetics and pharmacodynamics of morphine after intravenous administration as an infusion or multiple doses in dogs. Am J Vet Res 66, 1968–1974. Leibetseder EN, Mosing M, Jones RS (2006) A comparison of extradural and intravenous methadone on intraoperative isoflurane and postoperative analgesia requirements in dogs. Vet Anaesth Analg 33, 128–136. Machado CE, Dyson DH, Grant-Maxie M (2006) Effects of oxymorphone and hydromorphone on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 33, 70–77. Maiante AA, Teixeira Neto FJ, Beier SL et al. (2009) Comparison of the cardiorespiratory effects of methadone and morphine in conscious dogs. J Vet Pharmacol Ther 32, 317–328. Monteiro ER, Figueroa CD, Choma JC et al. (2008) Effects of methadone, alone or in combination with acepro-
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mazine or xylazine, on sedation and physiologic values in dogs. Vet Anaesth Analg 35, 519–527. Muir WW, Woolf CJ (2001) Mechanisms of pain and their therapeutic implications. J Am Vet Med Assoc 219, 1346–1356. Murphy MR, Hug CC Jr (1982) The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC. Anesthesiology 57, 485–488. Mutoh T, Nishimura R, Kim HY et al. (1997) Cardiopulmonary effects of sevoflurane, compared with halothane, enflurane, and isoflurane, in dogs. Am J Vet Res 58, 885–890. Quasha AL, Eger EI II, Tinker JH (1980) Determination and applications of MAC. Anesthesiology 53, 315–334. Roizen MF, Horrigan RW, Frazer BM (1981) Anesthetic doses blocking adrenergic (stress) and cardiovascular responses to incision-MAC BAR. Anesthesiology 54, 390–398. Schmidt N, Brune K, Williams KM et al. (1994) Stereoselective pharmacokinetics of methadone in beagle dogs. Chirality 6, 492–495.
Steffey EP, Howland D Jr (1978) Potency of enflurane in dogs: comparison with halothane and isoflurane. Am J Vet Res 39, 573–577. Steffey EP, Mama KR (2007) Inhalation anesthetics. In: Lumb & Jones’ Veterinary Anesthesia (4th edn). Thurmon JC, Tranquilli WJ, Grimm GJ (eds). Blackwell Publishing, Oxford, UK. pp. 355–393. Steffey EP, Eisele JH, Baggot JD et al. (1993) Influence of inhaled anesthetics on the pharmacokinetics and pharmacodynamics of morphine. Anesth Analg 77, 346– 351. Valverde A, Morey TE, Herna´ndez 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. Yamamura T, Kimura T, Furukawa K (1983) Effects of halothane, thiamylal, and ketamine on central sympathetic and vagal tone. Anesth Analg 62, 129–134. Received 11 September 2008; accepted 20 February 2009.
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doi:10.1111/j.1467-2995.2010.00528.x
RESEARCH PAPER
Effects of methadone on the minimum alveolar concentration of isoflurane in dogs Renato G Credie*, Francisco J Teixeira Neto*, Tatiana H Ferreira*, Antoˆnio JA Aguiar*, Fabio C Restitutti & Jose´ E Correnteà *Departamento de Cirurgia e Anestesiologia Veterina´ria, Faculdade de Medicina Veterina´ria e Zootecnia, Universidade Estadual Paulista, Botucatu, SP, Brazil Department of Veterinary Clinical Sciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland àDepartmento de Bioestatı´stica, Instituto de Biocieˆncias, Universidade Estadual Paulista, Botucatu, SP, Brazil
Correspondence: Francisco J Teixeira Neto, Departamento de Cirurgia e Anestesiologia Veterina´ria, Faculdade de Medicina Veterina´ria e Zootecnia, Universidade Estadual Paulista, Distrito de Rubia˜o Jr S/N, CEP 18618-000, Botucatu, SP, Brazil. E-mail: [email protected]
Abstract Objective To investigate the effects of methadone on the minimum alveolar concentration of isoflurane (ISOMAC) in dogs. Study design Prospective, randomized cross-over experimental study. Animals Six adult mongrel dogs, four males and two females, weighing 22.8 ± 6.6 kg. Methods Animals were anesthetized with isoflurane and mechanically ventilated on three separate days, at least 1 week apart. Core temperature was maintained between 37.5 and 38.5 C during ISOMAC determinations. On each study day, ISOMAC was determined using electrical stimulation of the antebrachium (50 V, 50 Hz, 10 mseconds) at 2.5 and 5 hours after intravenous injection of physiological saline (control) or one of two doses of methadone (0.5 or 1.0 mg kg)1). Results Mean (±SD) ISOMAC in the control treatment was 1.19 ± 0.15% and 1.18 ± 0.15% at 2.5 and 5 hours, respectively. The 1.0 mg kg)1 dose of methadone reduced ISOMAC by 48% (2.5 hours) and by 30% (5 hours), whereas the 0.5 mg kg)1 dose caused smaller reductions in ISOMAC (35% and 15%
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reductions at 2.5 and 5 hours, respectively). Both doses of methadone decreased heart rate (HR), but the 1.0 mg kg)1 dose was associated with greater negative chronotropic actions (HR 37% lower than control) and mild metabolic acidosis at 2.5 hours. Mean arterial pressure increased in the MET1.0 treatment (13% higher than control) at 2.5 hours. Conclusions and clinical relevance Methadone reduces ISOMAC in a dose-related fashion and this effect is lessened over time. Although the isoflurane sparing effect of the 0.5 mg kg)1 dose of methadone was smaller in comparison to the 1.0 mg kg)1 dose, the lower dose is recommended for clinical use because it results in less evidence of cardiovascular impairment. Keywords isoflurane, methadone, minimum alveolar concentration.
Introduction Inhalant anesthetics allow rapid and precise control of anesthetic drug concentration at the effect site (central nervous system, CNS) via monitoring endtidal inhalant anesthetic concentrations. Modern inhalant agents are also devoid of cumulative effects and this characteristic allows fast recoveries that are not substantially influenced by the duration of anes-
Methadone and isoflurane MAC in dogs RG Credie et al.
thesia (Steffey & Mama 2007). Although inhalation anesthetics produce unconsciousness and some degree of muscle relaxation, that is sufficient for performing surgical procedures, many of the more modern drugs do not provide a specific analgesic effect. Surgical procedures carried out under inhalant anesthesia alone may result in hyperalgesia during the postoperative period because of central sensitization of the CNS caused by the surgical trauma (Muir & Woolf 2001). Inhalant anesthetics inhibit autonomic outflow (Yamamura et al. 1983) and cause dose-related cardiorespiratory depression (Steffey & Howland 1978; Mutoh et al. 1997). Relatively, high doses of inhalant anesthetics are necessary to inhibit the cardiovascular responses to nociception (Roizen et al. 1981) and when these drugs are used at concentrations necessary to produce surgical anesthesia, hypotension and substantial decreases in cardiac output/tissue oxygen delivery may follow. The minimum alveolar concentration (MAC), defined as the end-tidal concentration of an inhalant anesthetic required to prevent purposeful movement in response to a supramaximal noxious stimulus in 50% of a population, is useful to assess objectively changes in inhalant anesthetic requirements caused by drugs used during anesthesia (Quasha et al. 1980). In dogs, pure l-opioid agonists decrease the MAC of volatile anesthetics to a maximum of 65–70% (Murphy & Hug 1982; Hall et al. 1987a,b). Methadone is drug that acts as a competitive agonist at l-opioid receptors. The mechanism of methadone-induced analgesia also appears to involve a noncompetitive antagonism of NMDA receptors located in the CNS (Ebert et al. 1995). In human patients, methadone is considered a long-acting opioid because it has a long elimination half-life (22–35 hours) and produces postoperative analgesia that lasts longer than morphine (Gourlay et al. 1982; Chui & Gin 1992; Eap et al. 2002). Dogs differ from humans because methadone is more rapidly eliminated from the body due to a high clearance. In dogs, methadone elimination half-lives recorded after intravenous administration ranged from 1.53 to 4.3 hours (Schmidt et al. 1994; KuKanich et al. 2005a; KuKanich & Borum 2008a). Because methadone is more rapidly eliminated in dogs than in humans, one may expect that this opioid would need to be administered more frequently in this species. Few controlled studies assessing the perioperative use of methadone are available in small animals, yet
this drug has become popular as a premedicant before general anesthesia in some countries (Bauer et al. 1976; Monteiro et al. 2008). In isofluraneanesthetized dogs undergoing cranial cruciate ligament repair, when epidural methadone (0.3 mg kg)1) was compared to the same dose administered intravenously (IV), epidural opioid administration resulted in greater reduction of inhalant anesthetic requirements for maintaining surgical anesthesia than the intravenous route of administration (Leibetseder et al. 2006). The hypothesis of the study reported here was that methadone would induce dose-related reductions in the MAC of isoflurane. Materials and methods Animals This study was carried out after obtaining approval of the University Animal Care and Use Committee (Protocol number 35/2005 CEEA). A total of six adult healthy mongrel dogs (four castrated male and two spayed female) weighing 22.8 ± 6.6 kg (mean ± SD) were selected for this study. Health status was assessed via physical examination, complete blood cell count and serum biochemistry values within reference intervals. Experimental protocol All animals randomly received three treatments administered IV: saline (control), 0.5 mg kg)1 of methadone (MET0.5), and 1.0 mg kg)1 of methadone (MET1.0). Each treatment was administered on a different experimental day, allowing a minimum washout period of 7 days between experiments. Food was withheld for 12 hours, with water ad libitum. Anesthesia was induced and maintained with isoflurane (Isoforine; Crista´lia, Brazil). During induction of anesthesia, a vaporized concentration of 5% of isoflurane diluted in 4–5 L of oxygen was delivered to the animal via a face-mask connected to a circle breathing circuit (Linea C; Intermed, Brazil). After an adequate depth of anesthesia was achieved, a cuffed orotracheal tube was placed in the dog’s trachea, the oxygen flow rate was reduced to values between 1 and 2 L minute)1, and the precision vaporizer was adjusted to maintain a moderate depth of anesthesia, on the basis of clinical assessment. Animals were placed in lateral recumbency
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and a cephalic vein and a dorsal pedal artery were catheterized (Insyte; Becton Dickinson, Brazil). Intravenous fluid therapy with lactated Ringer’s solution (5 mL kg)1 hour)1) was maintained throughout anesthesia using a peristaltic infusion pump (LF2001; Lifemed). For recording systolic, diastolic, and mean arterial blood pressures (SAP, DAP, and MAP), the catheter placed in the dorsal pedal artery was connected to a multiparametric monitor (AS3 Monitor; Datex-E¨ngstrom, Finland) via a pressure transducer filled with heparinized saline (TruWave; Edwards Lifesciences, CA, USA) that was previously zeroed at the level of the manubrium. Accuracy of the pressure transducer was checked with a mercury manometer before each experiment. Blood samples were drawn from the arterial catheter into heparinized syringes and analyzed immediately by an automated blood-gas analyzer (Model 348; Chiron Diagnostics, UK). Displayed blood-gas values were corrected on the basis of core temperature, which was recorded by a probe placed in the thoracic portion of the esophagus. Adhesive electrodes were placed according to a Lead II orientation and the ECG tracing was stored on a PC computer using an interface (ECGPC; Tecnologia Eletroˆnica Brasileira, Brazil). A sampling line was attached between the orotracheal tube and the anesthetic breathing circuit for continuous aspiration of airway gases (200 mL minute)1) into an infrared gas analyzer (M-Caio; Datex-E¨ngstrom) for recording end-tidal isoflurane (E¢ISO) and end-tidal CO2 (PE¢CO2) concentrations. The infrared gas analyzer was calibrated with a reference gas mixture containing 3% anesthetic agent (CHF3 as enflurane substitute), 55% O2, 33% N2O, 5% CO2 and N2 balance (Quick Cal 755582; Datex-E¨ngstrom). With the anesthetic agent monitor used, calibration for all halogenated anesthetics (e.g. isoflurane) is automatically adjusted when the calibration procedure is performed with the enflurane substitute. Gas calibration was performed prior and during each experiment; the percent volume of inhalant anesthetic was found not to drift by more than 0.03% (absolute values) from the reference value (3%) on the same experimental day. Core temperature was maintained between 37.5 and 38.5 C throughout the experimental procedure by means of a warm air blanket (Warmtouch; Mallinkrodt, CA, USA) and an electrically heated pad. Eucapnia (PaCO2 between 35 and 45 mmHg, 4.7 and 6 kPa) was maintained throughout anesthesia by positive pressure ventila242
tion. To maintain PaCO2 levels within the desired range, the ventilator (Linea C) was adjusted to deliver a peak inspiratory pressure ranging between 9 and 16 cmH2O and a respiratory rate between 8 and 18 breaths minute)1, while the inspiration to expiration ratio was held constant (1:2). To facilitate ventilator adjustments, PE¢CO2 values were used as estimates of PaCO2 values. Because the difference between arterial and PE¢CO2 may vary substantially among individuals, the arterial to PE¢CO2 gradient [P(a-E¢)CO2] was determined for each animal during anesthesia and PE¢CO2s were considered acceptable estimates of PaCO2 when an alveolar plateau could be identified on the capnographic waveform. During the procedure for determining isoflurane MAC (ISOMAC), spontaneous respiratory efforts are commonly observed during supramaximal noxious stimulation or during substantial reduction in E¢ISO values. During the noxious stimulation, the inspiratory flow sensitivity of the ventilator was adjusted to trigger-assisted ventilatory cycles between the controlled breaths. After the end of the instrumentation, E¢ISO values were stabilized at 1.8% for 15 minutes and each animal randomly received one of three intravenous treatments. In the control treatment, 0.9% saline solution (0.2 mL kg)1) was administered as a placebo; whereas in the MET0.5 and in the MET1.0 treatment groups, methadone (Metadon; Crista´lia, SP, Brazil) was administered as an IV bolus over 1 minute at 0.5 and 1.0 mg kg)1, respectively. Determination of isoflurane minimum alveolar concentration Two 22-gauge stainless steel hypodermic needles transfixing skin on the lateral aspect of the middle third of the antebrachium at a distance of 5 cm from each other were used for electrical stimulation during ISOMAC determinations. The needles were connected to an electrical stimulator (Grass S48 Stimulator; Astromed Inc, RI, USA) that was adjusted to deliver a 50 V stimulus, at 50 Hz with a 10 msecond pulse duration. The noxious stimulation consisted of four stimuli administered at 5 second intervals (two simple stimuli and two continuous stimuli lasting 3 seconds each). In a previous study, this electrical stimulation pattern was characterized as supramaximal, yielding ISOMAC values that did not differ from those obtained with a tail clamp in dogs (Valverde et al. 2003). The electrical stimulation was interrupted if the animal had
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gross purposeful movement before the entire stimulation sequence was completed. Obvious lifting of the head and neck, twisting movements of the trunk, and gross repetitive limb movements (paddling) observed during noxious stimulation or up to 1 minute after the end of the stimulation sequence were considered positive motor responses. Negative responses included: retraction/movement of the limb undergoing electrical stimulation, arching of the back, discrete and repetitive movements of the limbs (flexion of the metacarpal and/or metatarsal joints only), slight flexion of the neck and/or head, and spontaneous respiratory efforts (Quasha et al. 1980; Valverde et al. 2003). Two experienced individuals who were unaware of the treatment administered to the animal were responsible for assessing the presence or absence of gross movement in response to noxious stimulation. If there was disagreement between them with regard to the classification of the motor response, the electrical stimulation was repeated 1 minute after the first stimulation for redefining motor response. Fifteen minutes after drug administration, E¢ISO was adjusted to maintain moderate depth of anesthesia on the basis of clinical judgment (relaxation of the mandible, absence of palpebral reflexes, absence of spontaneous respiratory efforts during mechanical ventilation). Noxious stimulation was applied after the E¢ISO was stable for 15 minutes. If a negative motor response was initially observed, the E¢ISO concentration was reduced by 0.2% decrements and the noxious stimulation was repeated after an additional 15 minute re-equilibration period at the new E¢ISO level. When a positive motor response was observed, the E¢ISO was then increased in 0.1% increments and noxious stimulation was repeated after 15 minute equilibration periods at each new E¢ISO until the motor response was inhibited. If the motor response to the first noxious stimulation was positive, the changes in E¢ISO were performed in the opposite direction using the same steps until a negative response was obtained. The ISOMAC was calculated as the arithmetic mean of the highest E¢ISO concentration that allowed a gross purposeful movement in response to noxious stimulation and the lowest E¢ISO that prevented such response, with a difference of 0.1% in the E¢ISO values that resulted in this alternating pattern of response to stimulation (Quasha et al. 1980). The altitude of our laboratory is 785 m above sea level, with an average barometric pressure of
680 mmHg. Isoflurane MAC was corrected to values at sea level (barometric pressure: 760 mmHg) according to the formula: Altitude corrected ISOMAC ðvol%Þ ¼ measured ISOMAC ðvol%Þ 680=760:
Times of ISOMAC determination The ISOMAC measurements were made at 2.5 ± 0.5 and 5 ± 0.5 hours. If ISOMAC could not be determined within these pre-defined time intervals, the experiment was aborted and the same treatment was repeated after a minimum interval of 1 week until ISOMAC determinations could be concluded within the pre-defined time intervals. If an additional experiment was necessary to fulfill these time criteria, the E¢ISO first used during ISOMAC determinations was modified to values that were thought to be closer to the ISOMAC during each targeted time. Cardiorespiratory evaluation Cardiovascular data (HR, SAP, DAP, and MAP), arterial blood-gases (pH, PaCO2, PaO2, HCO3)) and core body temperature were recorded for each ISOMAC determination (2.5 and 5.0 hours). The physiological data corresponding to each time were calculated as the arithmetic mean of the two sets of values recorded immediately before the noxious stimulation that gave origin to the ISOMAC. Characteristics of recovery from anesthesia After the last MAC determination was concluded, isoflurane administration was discontinued and the times for endotracheal tube removal (performed upon the return of the swallowing reflex) and to standing were recorded. These variables were measured as the time elapsed from turning off the isoflurane vaporizer. Statistical analysis Normal distribution of data was verified by using the Kolgomorov–Smirnov test. Using a computer software program (SAS for Windows v. 8.02; SAS Institute Inc, NC, USA), a split-plot design was used for the analysis of the effects of treatments (control, MET0.5 or MET1.0) on ISOMAC and on physiologic variables, considering time as plot and treatment as
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subplot. The F-value of the ANOVA table was used for analyzing the effect of time, treatment, and treatment · time interaction. Using the PDIFF option of the PROC GLM, a multiple comparison test was used for comparing the effects of treatment drug and time on the continuous variables. An ANOVA followed by a Tukey’s test compared the times until orotracheal tube removal and until standing. The null hypothesis (no effect of methadone on ISOMAC, on physiologic variables, and on times to recover from anesthesia) was rejected when p < 0.05. Results Isoflurane MAC values were not determined within the pre-defined time intervals (2.5 ± 0.5 and 5.0 ± 0.5 hours) in three animals treated with 1 mg kg)1 of methadone. In one of these animals, the determination of ISOMAC was also obtained outside the time intervals after the administration of 0.5 mg kg)1 of methadone. After treatment was repeated in these same animals on a second occasion, ISOMAC was successfully determined within the targeted time periods. A small but statistically significant difference in the real times of ISOMAC determination was observed when the control and the MET0.5 treatment groups were compared at 5.0 hours (Table 1). The ISOMAC values did not change over time in the control treatment. Both doses of methadone significantly reduced ISOMAC values in comparison to the control treatment at 2.5 and 5 hours. The reduction in ISOMAC induced by methadone was directly related to the dose administered, with the
1.0 mg kg)1 dose resulting in significantly greater reductions in ISOMAC than the 0.5 mg kg)1 dose at 2.5 hours (decreased by 35 ± 15% and 48 ± 18% for MET0.5 and MET1.0, respectively) and at 5.0 hours (decreased by 15 ± 11% and 30 ± 12% for MET0.5 and MET1.0, respectively). The reduction in ISOMAC caused by methadone was also inversely related to time; the ISOMAC reduction induced by both doses of methadone was significantly less at 5.0 hours than at 2.5 hours. With the exception of one animal that had episodes of bradycardia (HR < 60 beats minute)1) with heart rates (HRs) between 49 and 55 beats minute)1 during the experimental period, there were no changes in HR or rhythm in the control treatment. Bradycardia was recorded in all animals after receiving methadone. Minimum HRs for individual animals recorded throughout the experimental procedure ranged from 34 to 42 beats minute)1 in the MET0.5 treatment group and from 31 to 42 beats minute)1 in the MET1.0 treatment group. Two animals that received methadone (0.5 and 1.0 mg kg)1) had bradycardia and episodes of sinus arrest. In these two animals, the episodes of sinus arrest were still present immediately prior to noxious stimulations used for ISOMAC determinations at 2.5 and 5 hours. Another animal had a ventricular escape rhythm associated with third degree atrioventricular block and isolated ventricular escape beats after receiving 0.5 and 1.0 mg kg)1 of methadone. During the first ISOMAC determination (2.5 hours), these arrhythmias persisted in the MET1.0 treatment, but were not observed during
Table 1 Changes in isoflurane minimum alveolar concentration (ISOMAC, mean ± SD) recorded approximately 2.5 and 5 hours after intravenous administration of 0.9% NaCl solution (Control) or two doses of methadone [0.5 mg kg)1 (MET0.5) or 1.0 mg kg)1 (MET1.0)] to six dogs. Actual times for ISOMAC determination are shown within parenthesis (mean ± SD)
Treatment
Variable
Control
ISOMAC at 2.5 hours (%) Actual time (hours) ISOMAC at 5 hours (%) Actual time (hours)
1.19 (2.61 1.18 (4.82
± ± ± ±
0.15A 0.16) 0.15A 0.11B)
MET0.5
0.78 (2.48 1.01 (5.08
± ± ± ±
MET1.0 0.21B 0.19) 0.18*B 0.17A)
0.61 (2.44 0.82 (4.99
± ± ± ±
0.17C 0.23) 0.14*C 0.34AB)
For a given variable (rows), treatment mean values followed by different superscript letters are significantly different from each other (p < 0.05) (A > B > C). *For a given treatment (columns), mean ISOMAC at 5 hours is significantly higher than at 2.5 hours (p < 0.05).
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ISOMAC determination at 5 hours. With 0.5 mg kg)1 of methadone in this animal, these arrhythmias were of shorter duration and were not seen during the ISOMAC determinations at 2.5 and 5 hours. During the noxious stimulation that was applied at the E¢ISO values that gave origin to the ISOMAC, there was an increase in HR from pre-stimulation values and the arrhythmias could no longer be detected in all animals, regardless of the treatment group. In the control treatment, mean values of HR, SAP, DAP, and MAP did not change over the time between the two time points measured (2.5 and 5 hours) (Table 2). Both doses of methadone decreased HR in comparison to control values. During the first ISOMAC determination (2.5 hours), the decrease in HR induced by methadone was directly related to the dose administered (mean HR values after 1.0 mg kg)1 were significantly lower than mean HR values after 0.5 mg kg)1). Mean SAP values 2.5 hours after administering 0.5 mg kg)1 of methadone were significantly high-
er than mean SAP values recorded in the control treatment. There were no significant differences for DAP. During the first ISOMAC determination (2.5 hours), animals that received 1.0 mg kg)1 of methadone showed that MAPs were significantly higher than the control treatment. Five hours after drug administration, MAPs were significantly lower than values recorded at 2.5 hours for both doses of methadone. During the ISOMAC determination at 2.5 hours, methadone was associated with a significant decrease in arterial pH values in comparison to the control group (differences in mean pH values ranging from 0.05 to 0.09). At 2.5 hours, concomitantly to a dose-dependent decrease in pH induced by methadone, there was also a dose-dependent decrease in HCO3) levels; while PaCO2 tensions did not differ among treatment groups. During the second ISOMAC determination (5 hours), pH values were also lower in methadone-treated animals than in the control treatment but HCO3) values were not significantly altered. At 5 hours, PaCO2 was higher in methadone-treated animals in comparison to the
Table 2 Physiological variables (mean ± SD) recorded 2.5 and 5.0 hours after intravenous administration of 0.9% NaCl (Control) or one of two doses of methadone (0.5 and 1.0 mg kg)1 in the MET0.5 and MET1.0 treatment groups, respectively) at equipotent concentrations of isoflurane (1 · ISOMAC) in six dogs Treatment
Variable
Time (hours)
Control
MET0.5
HR (beats minute)1)
2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0
75 ± 8A 73 ± 13A 126 ± 17B 128 ± 20 52 ± 9 51 ± 7 69 ± 9B 67 ± 9 7.40 ± 0.02A 7.41 ± 0.02A 37 ± 1 (4.9 ± 0.1) 36 ± 1A (4.8 ± 0.1) 486 ± 38 (64.6 ± 5.1) 476 ± 39 (63.3 ± 5.2) 22.2 ± 1.3A 22.1 ± 1.2 37.7 ± 0.2AB 37.7 ± 0.2B
54 60 145 138 55 50 74 67 7.35 7.38 39 39 474 474 20.5 21.8 38.0 38.1
SAP (mmHg) DAP (mmHg) MAP (mmHg) pH PaCO2 mmHg (kPa) PaO2 mmHg (kPa) HCO3) (mmol L)1) Temperature (oC)
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
7B 8B 24A 29 4 3 4AB 5* 0.02B 0.03*B 2 (5.2 ± 0.3) 2B (5.2 ± 0.3) 46 (63.0 ± 6.1) 42 (63.0 ± 5.6) 1.4B 0.9 0.4A 0.2A
MET1.0
47 55 135 126 58 51 78 70 7.31 7.36 39 39 476 463 18.9 21.4 37.7 37.9
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
9C 12B 13AB 15 8 6 8A 6* 0.03C 0.01*B 3 (5.2 ± 0.4) 2B (5.2 ± 0.3) 46 (63.3 ± 6.1) 32 (61.6 ± 4.3) 0.8C 1.2* 0.3B 0.4AB
HR, heart rate; SAP, systolic arterial blood pressure; DAP, diastolic arterial blood pressure; MAP, mean arterial blood pressure. Mean values (rows) followed by different superscript letters differ significantly from each other (A > B > C) (p < 0.05). *Mean values (columns) at 5.0 hours are significantly different from mean values recorded at 2.5 hours (p < 0.05).
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control treatment. Mean PaCO2 remained within reference intervals (35–45 mmHg, 4.7–6 kPa) in all treatment groups throughout the study. Significant differences in core temperature were observed between treatment groups at 2.5 and 5 hours (maximum differences in mean temperature values: 0.4 C). There was no significant difference among treatments for the variables recorded during recovery from anesthesia (Table 3). Complications such as emesis or excitation during recovery were not observed. Discussion The present study showed that methadone decreases ISOMAC in a dose-related manner and that the magnitude of the inhalant sparing effect induced by a single bolus administration of this opioid is reduced over time. The ISOMAC reduction was more intense and prolonged with the use of a higher dose of the opioid (1 mg kg)1), as the ISOMAC was still reduced by 30 ± 12% 5 hours after administration of 1 mg kg)1 of methadone. The inhalant anesthetic sparing effect induced by methadone in the study reported here appeared to be more intense and prolonged than the ISOMAC reduction reported with the use of morphine in dogs. In a previous study, Steffey et al. (1993) observed that, 30 minutes after intravenous morphine administration (1 mg kg)1), ISOMAC was reduced by 39% (Steffey et al. 1993). In that same study, authors reported that the isoflurane sparing effect was no longer significant (<10%) 4 hours
Table 3 Time until orotracheal tube removal (time to extubation) and time until regaining standing position (mean ± SD) recorded in six isoflurane-anesthetized dogs that received intravenous administration of 0.9% NaCl (Control) or one of two doses of methadone (0.5 and 1.0 mg kg)1 in the MET0.5 and MET1.0 treatment groups, respectively) for minimum alveolar concentration of isoflurane determinations at 2.5 and 5 hours after treatment administration
Treatments
Variable
Control
MET0.5
MET1.0
Time to extubation (minutes) Time until standing (minutes)
12 ± 6 16 ± 7
14 ± 8 26 ± 12
18 ± 10 24 ± 14
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after opioid administration (Steffey et al. 1993). A difference in the pharmacokinetic profile of methadone and morphine could explain the longer duration of ISOMAC reduction provided by methadone in the study reported here. The mean elimination halflives reported after the intravenous administration of 0.5 mg kg)1 of methadone (1.5–4.3 hours) are longer than the mean elimination half-lives reported after the administration of the same dose of intravenous morphine (0.87–1.28 hours) (Schmidt et al. 1994; KuKanich et al. 2005a,b,c; KuKanich & Borum 2008a,b). The magnitude and duration of ISOMAC reduction induced by the higher dose of methadone (1 mg kg)1) seemed not to differ substantially from the magnitude and duration of ISOMAC reduction reported after the use of hydromorphone in dogs (Machado et al. 2006). In the study presented here, ISOMAC was reduced by 48 ± 18% and 30 ± 12% at 2.5 and 5 hours after administration of 1 mg kg)1 of methadone, respectively; while Machado et al. (2006) reported that intravenous hydromorphone (0.1 mg kg)1) reduced ISOMAC by 48 ± 6% and by 34 ± 7% 2 and 4 hours after opioid administration, respectively (Machado et al. 2006). The magnitude of ISOMAC reduction induced by the 0.5 mg kg)1 dose of methadone was significantly less than at the 1 mg kg)1 dose. Despite a statistically significant reduction in ISOMAC at 2.5 (35 ± 15%) and at 5 hours (15 ± 11%) recorded after administration of 0.5 mg kg)1 of methadone, the inhalant sparing effect recorded at 5 hours may not be considered of clinical relevance (<20% reduction in ISOMAC in 4/6 animals). On the basis of these findings, during prolonged anesthetic procedures in dogs given 0.5 mg kg)1 of methadone, there would be a need for re-administering the same dose of methadone, 2.5 hours after the first dose, to maintain a 30% reduction in inhalant anesthetic requirements. In the control treatment, ISOMAC was constant over a 2.5-hour interval between measurements (1.19 ± 0.15% and 1.18 ± 0.15% after 2.5 and 5 hours of 0.9% NaCl administration). This repeatability over time is expected and is in agreement with previous studies (Eger et al. 1965a). In the present study, some factors that are known to influence the MAC of inhalant anesthetics were controlled (temperature, PaCO2, PaO2). In dogs, as temperature is reduced from 38 to 28 C, halothane MAC decreases in a rectilinear fashion by 5% for
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each 1 C decrease in core temperature (Eger et al. 1965b). In the present study, mean temperatures were maintained within a narrow range (37.7– 38.1 C) and such small variation probably did not bear a significant influence on ISOMAC values. A statistically significant but clinically unimportant difference was also observed in PaCO2 values (mean PaCO2s ranged from 36 to 39 mmHg, 4.8– 5.2 kPa). It was unlikely that this variation in PaCO2 could have biased ISOMAC as only extreme changes in PaCO2 (<10 mmHg or >95 mmHg) reduced the MAC of inhalant anesthetics (Eisele et al. 1967; Quasha et al. 1980). As the temporal factor may influence the magnitude of MAC reduction induced by a drug administered as a single bolus due to decreasing plasma concentrations (Steffey et al. 1993; Machado et al. 2006), comparison of the effect of different doses of one drug on MAC should to be performed at similar time periods. In the study reported here, this confounder was controlled by determining ISOMAC values within pre-established times (2.5 and 5 hours after treatment drug administration). It was not possible to conclude ISOMAC determinations within the limits of tolerance for each targeted time (± 0.5 hours) during the first anesthetic in three animals treated with 1.0 mg kg)1 of methadone and in one animal treated with 0.5 mg kg)1 of methadone. The initial difficulty in fulfilling the time criteria in some animals that received methadone was attributed to the fact that in those animals the E¢ISO concentrations at baseline were very different from those concentrations used for calculating ISOMAC. On the second occasion, ISOMAC determinations were concluded within the pre-defined time intervals because the E¢ISO concentrations were adjusted to values that were closer to those used for determining ISOMAC. Despite the efforts to conclude ISOMAC measurements at constant time periods, the actual time for concluding ISOMAC at 5 hours in the MET0.5 treatment (5.08 ± 0.17 hours) was significantly longer than the actual time recorded in the control treatment (4.82 ± 0.11 hours). However, it is unlikely that this difference had a substantial influence in the ISOMAC values because the absolute difference in mean times for ISOMAC measurements was relatively small (0.26 hours or 16 minutes). The bradycardia, conduction disturbances (sinus arrest and third degree atrioventricular blockade) and ventricular escape beats induced by methadone
are explained by the central vagotonic action typically induced by l-opioid agonists. The higher dose of methadone (1 mg kg)1) was associated with more intense negative chronotropic effects than the 0.5 mg kg)1 dose at 2.5 hours after opioid administration. Studies performed in conscious dogs have shown that 1.0 mg kg)1 of methadone may result in more significant hemodynamic changes than the changes induced by the administration of 0.5 mg kg)1 of methadone (27% and 52% reduction in cardiac index from baseline values for the 0.5 and 1.0 mg kg)1 doses of methadone, respectively) (Maiante et al. 2009). One of the beneficial effects of combining opioids and inhalant anesthetics is to lessen the cardiovascular depression induced by inhalant anesthetics by reducing the amount of inhalant anesthetic required for maintaining anesthesia (Ilkiw et al. 1993). The increases in arterial blood pressure values recorded after methadone could be caused primarily by the reduction in isoflurane requirements induced by the opioid, or to an increase in systemic vascular resistance associated with methadone (Maiante et al. 2009). The negative chronotropic effects induced by opioids may mask or attenuate an overall improvement in hemodynamic function (increased cardiac output, oxygen delivery, and arterial pressure) (Ilkiw et al. 1993). The administration of high doses of fentanyl (15.9 lg kg)1 minute)1 for 20 minutes, followed by 1.065 lg kg)1 minute)1), despite reducing enflurane requirements by 65%, did not result in increases in cardiac output and tissue oxygen delivery because of opioid-induced bradycardia; improvements in these variables were evident after reversal of opioid-induced bradycardia with atropine (Ilkiw et al. 1993). Although no detailed hemodynamic monitoring was used in the study reported here, it is likely that methadone-induced bradycardia also resulted in significant decreases in cardiac output. At 2.5 hours after administering the 1.0 mg kg)1 dose of methadone, mean values for pH (7.31 ± 0.03) and HCO3) (18.9 ± 0.8 mmol L)1) were not only significantly lower than values recorded in the control treatment group and in the MET0.5 treatment group, but were also lower than reference intervals (7.35–7.45 for pH; and 20–26 mmol L)1 for bicarbonate). As PaCO2 did not change significantly at this time (mean PaCO2 values ranged from 37 to 39 mmHg at 2.5 hours), these blood-gas changes suggest that a mild metabolic acidosis was in progress after 2.5 hours of administration of the
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higher dose of the opioid. In another study performed in conscious dogs, administration of 1 mg kg)1 of methadone resulted in a discrete increase in PaCO2 (Hellebrekers et al. 1989). In that study, reductions in HCO3) concentrations were also associated with methadone and the authors speculated that this was due to reduced peripheral perfusion after opioid administration (Hellebrekers et al. 1989). In summary, methadone reduces ISOMAC in a dose-dependent fashion and the magnitude of the inhalant sparing effect is reduced over the course of 5 hours after opioid administration. The higher dose of methadone (1.0 mg kg)1) resulted in more intense and prolonged reductions in ISOMAC, whereas the reduction induced by 0.5 mg kg)1 of methadone at 5 hours may have little clinical relevance (<20% in most animals). Both doses of methadone were accompanied by a dose-dependent decrease in HR, while a slight metabolic acidosis was associated only with the highest dose. Acknowledgement Partial Funding was provided by ‘Fundac¸a˜o de Amparo a` Pesquisa de Sa˜o Paulo’. References Bauer H, Schmidt G, Holle F (1976) Combined anesthesia with propionylpromazine (Combelen) and methadone (Polamivet). A sure simple method of anesthesia in gastrointestinal surgery in dogs. Z Gastroenterol 14, 277–279. Chui PT, Gin T (1992) A double-blind randomized trial comparing postoperative analgesia after perioperative loading doses of methadone or morphine. Anaesth Intensive Care 20, 46–51. Eap CB, Buclin T, Baumann P (2002) Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 41, 1153–1193. Ebert B, Andersen S, Krogsgaard-Larsen P (1995) Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 187, 165– 168. Eger EI II, Saidman LJ, Brandstater B (1965a) Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 26, 756–763. Eger EI II, Saidman LJ, Brandstater B (1965b) Temperature dependence of halothane and cyclopropane anesthesia
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