Effects of perzinfotel, butorphanol tartrate, and a butorphanol-perzinfotel combination on the minimum alveolar concentration of isoflurane in cats

Raphael J. Zwijnenberg From Pfizer Animal Health Australia, PO Box 57, West Ryde, NSW 2114, Australia.

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 DVM, MVPHMgt
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Carlos L. del Rio Q Test Labs, PO Box 12381, Columbus, OH 43212.

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Robert A. Pollet Pfizer Animal Health, PO Box 5366, Princeton, NJ 08543.

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William W. Muir Q Test Labs, PO Box 12381, Columbus, OH 43212.

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Abstract

Objective—To determine the effects of perzinfotel, butorphanol, and their combination on the minimal alveolar concentration (MAC) of isoflurane in cats.

Animals—7 healthy sexually intact cats (4 males and 3 females), aged 12 to 17 months and weighing 2.8 to 4.6 kg.

Procedures—In a crossover design, saline (0.9% NaCl) solution, perzinfotel (2.5 to 15 mg/kg; IV, IM, and SC), butorphanol tartrate (0.2 mg/kg, IM), or a combination of 5 mg of perzinfotel/kg and 2 mg of butorphanol tartrate/kg (both IM) was administered to 6 cats before 7 separate episodes of anesthesia with isoflurane in oxygen. Heart rate, arterial blood pressure, bispectral index (BIS), and inspiration and expiration concentrations of isoflurane were continuously monitored. The isoflurane MAC was determined twice during anesthesia.

Results—IV, IM, and SC administration of perzinfotel at 2.5 to 15 mg/kg resulted in a significant decrease in mean isoflurane MAC by 43.3% to 68.0%. The BIS significantly increased after perzinfotel administration via the same routes at 2.5 to 15 mg/kg and after perzinfotelbutorphanol administration IM. Blood pressure was significantly higher after perzinfotel was administered at 5 mg/kg, IM; 10 mg/kg, IV; and 10 mg/kg, SC than after saline solution administration.

Conclusions and Clinical Relevance—Perzinfotel administration decreased the isoflurane MAC and increased several BIS and blood pressure values in anesthetized cats. Administration of perzinfotel prior to isoflurane anesthesia may improve anesthetic safety by reducing inhalant anesthetic requirements and improving cardiovascular function during anesthesia. (Am J Vet Res 2010;71:1270–1276)

Abstract

Objective—To determine the effects of perzinfotel, butorphanol, and their combination on the minimal alveolar concentration (MAC) of isoflurane in cats.

Animals—7 healthy sexually intact cats (4 males and 3 females), aged 12 to 17 months and weighing 2.8 to 4.6 kg.

Procedures—In a crossover design, saline (0.9% NaCl) solution, perzinfotel (2.5 to 15 mg/kg; IV, IM, and SC), butorphanol tartrate (0.2 mg/kg, IM), or a combination of 5 mg of perzinfotel/kg and 2 mg of butorphanol tartrate/kg (both IM) was administered to 6 cats before 7 separate episodes of anesthesia with isoflurane in oxygen. Heart rate, arterial blood pressure, bispectral index (BIS), and inspiration and expiration concentrations of isoflurane were continuously monitored. The isoflurane MAC was determined twice during anesthesia.

Results—IV, IM, and SC administration of perzinfotel at 2.5 to 15 mg/kg resulted in a significant decrease in mean isoflurane MAC by 43.3% to 68.0%. The BIS significantly increased after perzinfotel administration via the same routes at 2.5 to 15 mg/kg and after perzinfotelbutorphanol administration IM. Blood pressure was significantly higher after perzinfotel was administered at 5 mg/kg, IM; 10 mg/kg, IV; and 10 mg/kg, SC than after saline solution administration.

Conclusions and Clinical Relevance—Perzinfotel administration decreased the isoflurane MAC and increased several BIS and blood pressure values in anesthetized cats. Administration of perzinfotel prior to isoflurane anesthesia may improve anesthetic safety by reducing inhalant anesthetic requirements and improving cardiovascular function during anesthesia. (Am J Vet Res 2010;71:1270–1276)

N-methyl-D-aspartate receptors are a class of glutamate-gated ion channels that regulate the transmembrane flux of sodium and calcium ions. The receptors have received considerable attention experimentally and clinically because of their important roles in excitatory synaptic transmission, neuronal plasticity, and prevention of neurodegeneration in the CNS.1,2 There is considerable evidence that pain caused by peripheral tissue or nerve injury involves NMDAR activation.3 Such receptors have been identified on myelinated and unmyelinated axons in peripheral somatic tissues.4–6

N-methyl-D-aspartate receptors are comprised of NR1 (8 splice variants) and NR2 (A, B, C, and D subtypes) subunits with additional variation possibly provided by the recently discovered NR3 (A and B) subunits. These subunits represent a class of structurally different binding sites with different affinities for receptor agonists and antagonists. Recent evidence suggests that activation of NR2B and NR3A subtypes plays important roles in perception of pain and neuronal injury, respectively.1

The NMDARs contain various sites at which endogenous ligands and subunit-selective drugs modulate receptor activity. Local injections of glutamate or N-methyl-D-aspartate result in nociceptive behaviors in rats that can be attenuated by the peripheral administration of NMDAR antagonists.7–10 These NMDAR antagonists effectively alleviate pain in experimental and clinical situations in animals11,12; however, their use as analgesics may be limited by adverse effects such as memory impairment,13 psychotomimetic effects,14 ataxia, and motor incoordination.15 Antinociceptive selective antagonists of NR2B-containing NMDARs (eg, ifenprofil) have fewer adverse effects than some other NMDAR antagonists.12

Perzinfotel (EAA-090) is a potent NMDAR antagonist.16 Results of in vivo evaluation17 suggest that perzinfotel is 10 times as potent at blocking NR2A-versus NR2B-or NR2C-containing NMDARs and protected chick embryo retina slices and cultured rat hippocampal and cortical neurons from glutamate-and N-methyl -D-aspartate-induced neurotoxic effects. In rats, a bolus dose of perzinfotel administered IV after permanent occlusion of the middle cerebral artery resulted in a reduction in infarct size by 57%, compared with no perzinfotel administration.18 When compared with uncompetitive channel blockers (eg, memantin, dizocilpine, and ketamine), an NR2B-selective antagonist (eg, ifenprodil), and other glutamate antagonists (eg, selfotel, 3-[2-carboxypiperazin-4-yl]propyl-1-phosphonic acid, and CGP-39653), perzinfotel had superior therapeutic ratios for effectiveness in treating pain versus adverse behavioral effects.18

The MAC of an inhalant anesthetic is defined as the amount of inhaled anesthetic required to prevent gross purposeful movement to a noxious stimulus in 50% of the subjects.19 A measure of anesthetic potency, the MAC provides a guide to the concentration of inhaled anesthetic needed to induce unconsciousness and immobility. Administration of NMDAR antagonists may reduce the amount of inhaled anesthetic needed to maintain anesthesia (ie, an anesthetic-sparing effect) in addition to resulting in analgesic effects. When NMDAR antagonists, such as ketamine, are administered, the MAC of isoflurane needed to keep dogs anesthetized can be reduced by up to 25%.20,21 Recently, perzinfotel was shown to have similar or greater anesthetic-sparing effects in dogs than NMDAR antagonists, such as ketamine.22,23 The effects of perzinfotel administration in cats have not been reported to our knowledge.

Butorphanol, a synthetic morphinan derivative and opioid receptor agonist-antagonist, is commonly administered alone or in conjunction with other sedatives as a preanesthetic medication prior to anesthesia in cats.24,25 Current opinion is that butorphanol acts as a partial μ-receptor agonist and antagonist, pure δ-receptor agonist, and κ-receptor antagonist, although species differences have been reported.26 In 1 study,27 a 19% reduction in isoflurane requirements was achieved in cats that received butorphanol prior to anesthesia.

Bispectral index processing is a proprietary method for analyzing the degree of sedation and hypnosis in subjects.28,29 Bispectral analysis examines the harmonic and phase relation of EEG signals and quantifies the amount of synchronization in the EEG. The index is a numeric value derived from the EEG and provides a reasonably accurate index of anesthetic depth and the presence or absence of consciousness.30 Changes in BIS values are used to indicate a return to consciousness during inhalant anesthesia and to help identify differences between drug-induced analgesic and hypnotic effects.

The purpose of the study reported here was to determine the anesthetic-sparing effects of perzinfotel in cats when administered IM, IV, or SC before induction of anesthesia with isoflurane. We also sought to evaluate the effects of IM perzinfotel administration after butorphanol administration in similar anesthetic conditions.

Materials and Methods

Animals and instrumentation—Seven healthy sexually intact domestic shorthair cats (4 males and 3 females) aged 12 to 17 months and weighing 2.8 to 4.6 kg were included in the study. Two weeks before beginning phase 1 of the study, each cat had been surgically implanted with a telemetry device that permitted the simultaneous and continuous monitoring of respiration, ECG data, arterial (femoral artery) blood pressure, and rectal temperature. The study protocols were approved by the institutional animal care and use committee of the study facility.

Experimental design—In phase 1, the effects of perzinfotel administration were determined. To do so, 6 cats underwent 7 treatments as follows: saline (0.9% NaCl) solution (0.2 mL/kg), then perzinfotel at 5 mg/kg, IM; 10 mg/kg, IM; 15 mg/kg, IM; 10 mg/kg, IV; and 10 mg/kg, SC. Each treatment was separated by a minimum washout period of 7 days. Saline solution was administered first to determine the baseline MAC (MAC0) and other variables during isoflurane anesthesia. The order of the 6 remaining treatments was determined via a Latin square crossover design. Each treatment was administered 30 minutes before anesthetic induction with isoflurane. The isoflurane MAC was determined twice for each treatment approximately 30 minutes after anesthesia onset (MAC1) and 2 hours later (MAC2).

In phase 2, the effects of IM administration of a low dose of perzinfotel and a combination of perzinfotel and butorphanol were determined. Because of dysfunction of one of the telemeters, 1 of the original 6 cats was replaced for this phase. As in phase 1, saline solution was first administered at a dose of 0.2 mL/kg to allow determination of the MAC0 and other variables in all cats to control for possible confounding effects (ie, lessening of anesthetic requirements) resulting from habituation to the laboratory environment, the noxious stimulation protocol, or the repeated anesthesia (ie, temporal factors). For the second treatment in all cats, the low-dose perzinfotel (2.5 mg/kg, IM) was administered 30 minutes before induction of anesthesia. For the first and second treatments, the isoflurane MAC was determined at MAC1 and MAC2. For the third treatment in all cats, butorphanol tartrate (0.2 mg/kg, IM) was administered 30 minutes before induction of anesthesia. Then, after the isoflurane MAC was first determined at MAC1, a higher dose of perzinfotel (5 mg/kg, IM) was administered. Two hours later, the second isoflurane MAC (MAC2) measurement was made.

Experimental procedures—Food was withheld from cats for 12 hours and water was withheld for 2 hours prior to preanesthetic treatment administration. After the aforementioned preanesthetic treatments were administered, anesthesia was induced with isofluranea in oxygen in an induction box and cats were orotracheally intubated and positioned in right lateral recumbency. Isoflurane in oxygen was used to maintain anesthesia through an out-of-circle, agent-specific vaporizerb in a semiclosed anesthetic circle rebreathing system.c The Petco2 was maintained between 35 and 45 mm Hgd by means of controlled breathing. The ECG, heart rate, various measures of blood pressure (SAP, DAP, and MAP), ETISO, Petco2, Po2, rectal temperature, and inspiration and expiration isoflurane concentrations were continuously monitored.e,f Heating padsg and hot water blankets were used during anesthesia to maintain rectal temperature between 37.5° and 38.5°C.

Determination of isoflurane MAC—Isoflurane MAC was determined by delivering a noxious supramaximal electrical stimulus to the buccal mucosa of each cat.18 Two 24-gauge, 10-mm insulated stimulating electrodesh were inserted 1 cm apart into the buccal mucosa at a location dorsal and caudal to the incisors. The opposite ends of the electrodes were connected to an electrical stimulatori that delivered a predetermined stimulus of 50 V, 5 Hz, and 10-millisecond duration. Stimulation continued for 1 minute unless the cat had signs of gross purposeful movement (ie, lifting of the head and repeated movement of the limbs) before completion of the 1-minute stimulation. The ETISO was initially set at 1.5% for each cat's first control MAC determination and at 1.2 times each cat's control MAC value during subsequent days when experimental treatments were administered. When a cat did not respond to the stimulus, the ETISO was decreased by 20% and allowed to equilibrate for at least 15 minutes before the stimulus was reapplied. This process was continued until the cat responded with gross purposeful movement. The ETISO was then increased by increments of 10% until the cat failed to have gross purposeful movement. The MAC was considered to be the mean of the lowest ETISO value that did not result in gross purposeful movement and the highest ETISO value that did result in gross purposeful movement.18

Determination of BIS—The BIS value was derived by continuously monitoring EEG activity. An EEG was obtained via platinum subdermal needle electrodes by use of a 3-lead referential montage, arranged in a bifrontal configuration with the reference electrode positioned on the midline of the head rostral to the medial canthus of the eyes. The ground electrode was positioned on the midline in the atlantooccipital region.30 The EEG and BIS values were continuously acquired and displayed by use of a proprietary BIS monitor,j with the high-frequency filter set at 70 Hz and the low-frequency filter set at 2 Hz. The BIS number was automatically calculated and digitally displayed every 5 seconds and represented the EEG activity during the previous 60 seconds. Eight BIS values were recorded during a 2-minute period before and after buccal mucosal stimulation.

Interval to sternal recumbency—Interval to sternal recumbency was defined as the interval between extubation (laryngeal cough reflex) and attainment of sternal recumbency. Time was measured with a digital clock.

Statistical analysis—Values for MAC, BIS, and all cardiopulmonary variables (at MAC level) for each cat and treatment are reported as mean ± SD. For phase 1 of the study, control values for all variables were first compared with baseline values. Because no significant (P > 0.05) differences were detected, effects of all drug treatments included in the Latin square design were compared with each other and with those of the saline solution control treatment. For phase 2, effects of the drug treatments were compared with each other and with baseline values. Control MACs for the 2 phases were compared to verify whether equivalence existed, and a combined analysis was conducted for the 2 phases in which the effect of all drug treatments could be compared. Comparisons were made by means of ANOVA, with least squares means of groups compared with each other via a 2-sided Student t test.k Values of P ≤ 0.05 were considered significant.

Table 1—

Values for isoflurane MAC, HR, and BIS in 6 healthy cats measured twice before (baseline] and after treatment with saline (0.9% NaCl] solution (saline] or with various doses and administration routes of perzinfotel.

Isoflurane MACHRBIS
TreatmentMean ± SDPercentage change*Mean ± SDPercentage change*Mean ± SDPercentage change*
Saline baseline1.54 ± 0.15173.7 ± 27.6 54.8 ± 14. 5 
Saline control1.50 ± 0.17177.6 ± 35.4a67.0 ± 12.1b
5 mg of perzinfotel/kg, IM0.63 ± 0.08-58.0161.6 ± 15.2a-10.075.7 ± 12.6a13.0
10 mg of perzinfotel/kg, IM0.51 ± 0.13-66.0163.8 ± 13.0a-7.876.8 ± 6.1a14.6
15 mg of perzinfotel/kg, IM0.52 ± 0.20-65.3163.4 ± 9.3a-8.077.9 ± 3.8a16.3
10 mg of perzinfotel/kg, IV0.48 ± 0.04-68.0166.3 ± 11.8a-6.477.3 ± 3.0a15.4
10 mg of perzinfotel/kg, SC0.62 ± 0.19-58.7163.2 ± 15.6a-8.175.3 ± 4.0a12.4

Because there was no difference (ie, P > 0.05) between the saline solution control and baseline treatments, baseline treatment values were not included in the statistical comparisons between pairs of treatments.

= Not applicable.

Values with different superscript letters within a column are significantly (P ≤ 0.05) different. Heart rate and BIS were measured when the MAC had been attained.

Results

MAC—Control MAC values remained stable throughout phase 1, in which the effects of perzinfotel administered at various doses were determined. The mean ± SD baseline MAC value for isoflurane was 1.54 ± 0.15, whereas the mean control MAC value during the trial was 1.50 ± 0.17 (Table 1). Intravenous, SC, and IM administration of perzinfotel 30 minutes before anesthetic induction significantly decreased the mean isoflurane MAC values by 58.0% to 68.0% for all doses of perzinfotel. The decrease after administration of all different doses and routes of administration of perzinfotel was equivalent (P > 0.05), and no evidence of dose dependency was detected.

In phase 2, in which the effects of IM administration of a low dose of perzinfotel and a combination of perzinfotel and butorphanol were determined, IM administration of 2.5 mg of perzinfotel/kg 30 minutes before anesthetic induction significantly reduced the isoflurane MAC by 43.3%, compared with the control MAC (Table 2). Intramuscular administration of 0.2 mg of butorphanol/kg 30 minutes before anesthetic induction provided a significant reduction of isoflurane MAC by 15.3%, whereas IM administration of 5 mg of perzinfotel/kg 30 minutes before MAC2 was measured resulted in a significant reduction in MAC of 58.0%, compared with baseline.

When the results of phase 1 and phase 2 were combined and analyzed, a dose dependency was evident. The dose of 2.5 mg of perzinfotel/kg resulted in a significantly higher isoflurane MAC than did the higher (5, 10, and 15 mg/kg) doses.

BIS—All BIS values were measured after the isoflurane MAC had been attained. In phase 1, BIS values significantly increased after all perzinfotel treatments, relative to BIS values for the saline solution control treatment (Table 1). However, all doses and routes of perzinfotel administration resulted in a similar, albeit insignificant, increase of approximately 15% relative to baseline. In phase 2, the BIS values for perzinfotel at 2.5 mg/kg, IM, and for the butorphanol-perzinfotel combination, also administered IM, were similar and were significantly higher than the control treatment value (Table 2). Administration of butorphanol alone resulted in a nonsignificant increase in BIS.

Table 2—

Values for isoflurane MAC, HR, and BIS in 6 healthy cats measured twice before (baseline) and after treatment with saline solution (saline) or with various doses and administration routes of perzinfotel and butorphanol.

Isoflurane MACHRBIS
TreatmentTotal No. of measurementsMean ± SDPercentage change*Mean ± SDPercentage change*Mean ± SDPercentage change*
Saline control121.50 ± 0.17a172.6 ± 28.2a66.7 ± 11.7b 
2.5 mg of perzinfotel/kg, IM120.85 ± 0.17c−43.3164.9 ± 13.9a77.7 ± 3.3a16.5 
0.2 mg of butorphano/kg, IM61.27 ± 0.10b-15.3180.0 ± 47.9a4.374.7 ± 7.8a,b12.0
0.2 mg of butorphanol/kg and 5 mg of perzinfotel/kg, IM6-58.0161.2 ± 24.5a-6.680.8 ± 5.3a21.1 

See Table 1 for key.

Table 3—

Values for DAR, SAP; and MAP in 6 healthy isoflurane-anesthetized cats measured twice before (baseline) and after treatment with saline solution (control) or with various doses and administration routes of perzinfotel.

DAPSAPMAP
TreatmentMean ± SDPercentage change*Mean ± SDPercentage change*Mean ± SDPercentage change*
Baseline75.3 ± 11.9105.1 ± 15.289.2 ± 14.2
Control84.1 ± 22.5b113.8 ± 25.9b97.6 ± 24.3
5 mg of perzinfotel/kg, IM95.9 ± 19.6a14.0127.3 ± 20.5a11.9109.9 ± 19.912.6
10 mg of perzinfotel/kg, IM95.7 ± 18.3a13.8124.8 ± 22.2a,b9.7108.5 ± 19.5a,b10.0
15 mg of perzinfotel/kg, IM94.0 ± 11.9a,b11.8122.4 ± 17.4a,b7.6106.7 ± 13.6a,b9.3
10 mg of perzinfotel/kg, IV97.7 ± 12.5a16.2128.8 ± 10.3a13.2111.5 ± 11.814.2
10 mg of perzinfotel/kg, SC97.9 ± 15.3a16.4126.7 ± 21.7a11.3109.6 ± 15.812.3

See Table 1 for key.

HR—All HRs were measured after the isoflurane MAC had been attained. During phase 1, mean HRs of cats when treated with perzinfotel were 6.4% to 10.0% less than the control treatment value; however, these differences between values were not significant (Table 1). During phase 2, mean HRs of cats when treated with perzinfotel were slightly lower (4.5% to 6.6%) than the control treatment value, whereas HR was somewhat higher (4.3%) after butorphanol was administered (Table 2). However, again these changes were not significant.

Table 4—

Values for DAP, SAR, and MAP in 6 healthy isoflurane-anesthetized cats measured after treatment with saline solution (control) or with various doses and administration routes of perzinfotel and butorphanol.

DAPSAPMAP
TreatmentTotal No. of TreatmentMean ± SDPercentage change*Mean ± SDPercentage change*Mean ± SDPercentage change*
Control1278.7 ± 17.6a106.1 ± 23.4a91.0 ± 20.3a
2.5 mg of perzinfotel/kg, IM1286.3 ± 16.9a9.7114.8 ± 18.1a8.298.1 ± 17.7a7.8
0.2 mg of butorphanol/kg, IM669.8 ± 15.7a-11.397.7 ± 16.5a-7.981.8 ± 16.3a−10.1
0.2 mg of butorphanol/kg and 5 mg of perzinfotel/kg, IM679.8 ± 18.1a1.4110.8 ± 25.2a4.493.2 ± 21.2a2.4

See Table 1 for key.

Table 5—

Mean ± SD intervals from extubation to sternal recumbency in 6 healthy cats anesthetized with isoflurane before (baseline) and after treatment with saline solution (control) or with various doses and administration routes of perzinfotel.

Phase 1 treatmentTime (s)Phase 2 treatmentTime (s)
Baseline124 ± 148Control83 ± 44a
Control68 ± 35b
5 mg of perzinfotel/kg, IM127 ± 117b2.5 mg of perzinfotel/kg, IM88 ± 32a
10 mg of perzinfotel/kg, IM259 ± 209b0.2 mg of butorphanol/kg and 5 mg of perzinfotel/kg, IM296 ± 374a
15 mg of perzinfotel/kg, IM724 ± 737a
10 mg of perzinfotel/kg, IV400 ± 548a,b
10 mg of perzinfotel/kg, SC232 ± 139b

See Table 1 for key.

Blood pressure—All measures of blood pressure were made after the isoflurane MAC had been attained. During phase 1, treatment with perzinfotel at the various doses resulted in a consistent increase in DAP (11.8% to 16.4%), SAP (7.6% to 13.2%), and MAP (9.3% to 14.2%) relative to control values during isoflurane anesthesia (Table 3). Relative to control values, increases in DAP, SAP, and MAP were significant for perzinfotel at 5 mg/kg, IM; 10 mg/kg, IV; and 10 mg/kg, SC. Administration of perzinfotel at a dose of 10 mg/kg, IM, also yielded a significant increase in DAP. In phase 2, DAP, SAP, and MAP increased 9.7%, 8.2%, and 7.8%, respectively, after administration of perzinfotel at 2.5 mg/kg, IM. After administration of 0.2 mg of butorphanol/kg, IM, DAP, SAP, and MAP values were 11.3%, 7.9%, and 10.1% lower than control values, respectively. Intramuscular administration of 5 mg of perzinfotel/kg after IM administration of 0.2 mg of butorphanol/kg caused an increase in DAP, SAP, and MAP of 1.4%, 4.4%, and 2.4% relative to control values (Table 4). However, all changes in blood pressure were insignificant in phase 2.

Interval from sternal recumbency to extubation—Administration of perzinfotel alone yielded some sedative effects such as sleepiness and a decreased ability to react to external stimuli in cats during the 30 minutes prior to anesthetic induction, particularly at the higher (10 to 15 mg/kg, IM) doses. Dose-dependent increases were evident in the interval required for cats to achieve sternal recumbency after extubation (Table 5). In control conditions, the cats required a mean of 68 ± 35 seconds to reach a sternal position after isoflurane anesthesia in phase 1. Premedication with perzinfotel at the various doses (5 mg/kg, IM; 10 mg/kg, IM; 10 mg/kg, SC; and 10 mg/kg, IV) increased this interval; however, the treatment values did not differ significantly from the control value. Only administration of perzinfotel at 15 mg/kg, IM, led to a significant increase in the interval to sternal recumbency (724 ± 737 seconds). During phase 2, cats in the control conditions required 83 ± 44 seconds to reach a sternal position. This interval did not significantly change after IM treatment with perzinfotel at 2.5 mg/kg or with the butorphanol-perzinfotel combination (296 ± 374 seconds). No adverse reactions were observed during anesthesia or anesthetic recovery.

Discussion

Results of the present study provided evidence of the anesthetic-sparing effects of perzinfotel in healthy cats. Administration of all doses of perzinfotel resulted in lower isoflurane MAC values relative to control values, regardless of route of administration. Intramuscularly administered doses of 5, 10, and 15 mg of perzinfotel/kg did not cause a dose-dependent reduction in isoflurane MAC values (58.0% to 68% reduction relative to control values), indicating that a plateau might have been reached. However, perzinfotel when administered IM at a dose of 2.5 mg/kg lowered the isoflurane MAC less than it did at the other doses (43.3% reduction), signifying a dose-dependent effect when compared with the higher doses. The isoflurane MAC reduction of 15.3% after administration of butorphanol was similar to that reported in earlier studies.24 Intramuscular administration of 5 mg of perzinfotel/kg to butorphanol-treated cats resulted in an isoflurane MAC reduction of 58.0%, which was equivalent to the effect of the same dose of perzinfotel administered alone.

The MAC of an inhaled anesthetic is used as a clinical index of drug potency and a guide to selection of the inhalant anesthetic concentration required for general anesthesia.18 The repeatability and stability over time of the control MAC values reported here indicated that the measured decrease in isoflurane MAC values is scientifically valid. The decrease in isoflurane MAC values was associated with significant increases in BIS values for all doses and routes of perzinfotel, suggesting a reduction in CNS-and anesthetic-associated depression but adequate analgesia to prevent gross purposeful movement in response to a noxious stimulus. A lack of change in BIS and hemodynamic values, among all treatment groups, when the isoflurane concentration was held constant at 1.5% suggested that the decrease in the isoflurane concentration was responsible for the changes detected.

Perzinfotel administration caused a nonsignificant (4.5% to 10%) decrease in HR, compared with control treatment administration in our study cats. In dogs, perzinfotel administration reportedly increases the HR, although not significantly.22,23 The reason for this apparent discrepancy is unclear and might be species related.

The DAP, MAP, and SAP values in the anesthetized healthy cats in our study were higher than control values when they received perzinfotel and the butorphanol-perzinfotel combination as preanesthetic treatments. These increases were consistent for all doses of perzinfotel and were significant during phase 1 for doses of 5 mg/kg, IM, and 10 mg/kg, SC and IV; the dose of 10 mg/kg, IM, caused a significant increase in DAP. Hypotension as a function of cardiovascular management during anesthesia is an important contributor to anesthetic-related death in humans and other animals.31 The ability of perzinfotel to increase blood pressure could therefore potentially improve anesthetic safety. Such hemodynamic effects appeared to be secondary (dependent) effects in our study and were most likely attributable to a decrease in inhaled isoflurane concentrations.

Recovery from isoflurane anesthesia was significantly longer when cats were pretreated with perzinfotel only at the highest dose (15 mg/kg, IM). This finding suggested that perzinfotel administration may have resulted in some immobilizing activity when combined with inhalant anesthetics and supports findings of another study32 suggesting that NMDAR inhibition contributes part of the immobilizing activity of aromatic volatile anesthetics. Because the cats in our study had smooth and unremarkable recoveries, the longer recovery intervals would be of little or no practical importance at a therapeutic dose in a clinical setting.

Ketamine is an NMDAR antagonist approved for use in feline medicine for restraint (11 mg/kg, IM) and anesthesia (22 to 33 mg/kg, IM).33 In the present study, perzinfotel was evaluated for a different use, as a premedication, which resulted in a significant isofluranesparing effect and an increase in arterial blood pressure, thereby enhancing cardiopulmonary safety during anesthesia. At a therapeutic dose of 5 mg/kg, perzinfotel administration had a negligible sedative effect. Unlike ketamine, perzinfotel can be administered IV, IM, or SC and, at the dose range used in our study, may provide a much greater anesthetic-sparing effect21 and cause less adverse effects (eg, dysphoria and difficult anesthetic recovery) than ketamine.

Findings of the present study were somewhat limited because of the small number of cats used. Increases in DAP, MAP, and SAP after perzinfotel administration, although a consistent finding throughout phase 2, were not significant but might have been had more cats been evaluated.

Abbreviations

BIS

Bispectral index

DAP

Diastolic arterial blood pressure

EEG

Electroencephalogram

ETiso

End-tidal concentration of isoflurane

HR

Heart rate

MAC

Minimum alveolar concentration

MAP

Mean arterial blood pressure

NMDAR

N-methyl-d-aspartate receptor

Petco2

End-tidal partial pressure of carbon dioxide

SAP

Systolic arterial blood pressure

a.

IsoFlo, Abbott Laboratories, North Chicago, Ill.

b.

Isotec 3, Ohmeda, Madison, Wis.

c.

LEI Medical, Boring, Ore.

d.

Veterinary Anesthesia Ventilator Model 2KIE, Hallowell Engineering and Manufacturing Corp, Pittsfield, Mass.

e.

DSI Physio Tel D70-PCT transmitter, Data Sciences International, Saint Paul, Minn.

f.

Passport 2, Datascope Corp, Montvale, NJ.

g.

T/Pump, Gaymar Industries Inc, Orchard Park, NY.

h.

Genuine grass platinum subdermal needle electrodes, Astro-Med Inc, West Warwick, RI.

i.

Grass SD9 Stimulator, Grass Medical Instruments, Quincy, Mass.

j.

A-1000 EEG Monitor, Aspect Medical Systems Inc, Newton, Mass.

k.

SAS, version 8.2, SAS Institute Inc, Cary, NC.

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  • 2.

    Pozzi A, Muir WW, Traverso F. Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists. J Am Vet Med Assoc 2006; 228:5360.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Doubell TP, Mannion RJ, Woolf CJ. The dorsal horn: state-dependent sensory processing, plasticity and the generation of pain. In: Wall PD, Melzack R, eds. Textbook of pain. London: Churchill Livingstone Inc, 1999; 165181.

    • Search Google Scholar
    • Export Citation
  • 4.

    Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett 1995; 197:2528.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Coggeshall RE, Carlton SM. Ultrastructural analysis of NMDA, AMPA, and kanaite receptors on unmyelinated and myelinated axons in the periphery. J Comp Neurol 1998; 391:7886.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Lascelles BD, Gaynor JS & Smith ES, et al. Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. J Vet Intern Med 2008; 22:5359.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Jackson DL, Graff CB & Richardson JD, et al. Glutamate participates in the peripheral modulation of thermal hyperalgesia in rats. Eur J Pharmacol 1995; 284:321325.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Zhou S, Bonasera L, Carlton SM. Peripheral administration of NMDA, AMPA or KA results in pain behaviors in rats. Neuroreport 1996; 7:895900.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Lawand NB, Willis WD, Westlund KN. Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats. Eur J Pharmacol 1997; 324:169177.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Chizh BA, Headley PM, Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol Sci 2001; 22:636642.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Fisher K, Coderre TJ, Hagen NA. Targeting N-methyl-D-aspartate receptor for chronic pain management: preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage 2000; 20:358373.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Hewitt DJ. The use of NMDA receptor antagonists in the treatment of chronic pain. Clin J Pain 2000; 16:S73S76.

  • 13.

    Kim AH, Kerchner GA, Choi DW. Blocking excitotoxicity. In: Marcoux FW, Choi DW, eds. CNS neuroprotection. New York: Springer, 2002; 336.

  • 14.

    Pomarol-Clotet E, Honey GD & Murray GK, et al. Psychological effects of ketamine in healthy volunteers. Phenomenological study. Br J Psychiatry 2006; 189:173179.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Rockstroh S, Emre M & Tarral A, et al. Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans. Psychopharmacology (Berl) 1996; 124:261266.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Kinney WA, Abou-Gharbia M & Garrison DT, et al. Design and synthesis of (2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-Cyclobutene-1,2-dione as an achiral ?-amino acid bioisostere. J Med Chem 1998; 41:236246.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Sun L, Chiu D & Kowal D, et al. Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-?-Amino-5-chloro-1-(phospohonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride). J Pharmacol Exp Ther 2004; 310:563570.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Brandt MR, Cummons TA & Potestio L, et al. Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel [EAA-090; (2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethyl]phosphonic acid] on chemically induced thermal hypersensitivity. J Pharmacol Exp Ther 2005; 313:13791386.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Antognini JF, Cartens E. Measuring minimum alveolar concentration: more than meets the tail (lett). Anesthesiology 2005; 103:679680.

  • 20.

    Solano AM, Pyendop BH & Boscan PL, et al. Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs. Am J Vet Res 2006; 67:2125.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Muir WW III, Wiese AJ, March PA. Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane. Am J Vet Res 2003; 64:11551160.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Kushiro T, Wiese AJ & Eppler MC, et al. Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs. Am J Vet Res 2007; 68:12941299.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Zwijnenberg RJG, Del Rio CL & Pollet RA, et al. Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs when administered as a preanesthetic via various routes or in combination with butorphanol. Am J Vet Res 2010; 71:604609.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Lamont LA, Mathews KA. Opiods, nonsteroidal antiinflammatories, and analgesic adjuvants. In: Veterinary anesthesia and analgesia. 4th ed. Oxford, England: Blackwell Science Ltd, 2007; 250251.

    • Search Google Scholar
    • Export Citation
  • 25.

    Hewson CJ, Dohoo IR, Lemke KA. Perioperative use of analgesics in dogs and cats by Canadian veterinarians in 2001. Can Vet J 2006; 47:352359.

    • Search Google Scholar
    • Export Citation
  • 26.

    Commiskey S, Fan LW & Ho IK, et al. Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci 2005; 98:109116.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Ilkiw JE, Pascoe PJ, Tripp LD. Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 2002; 63:11981202.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Kissin I. Depth of anesthesia and bispectral index monitoring. Anesth Analg 2000; 90:11141117.

  • 29.

    Johansen JW. Update on Bispectral Index monitoring. Best Pract Res Clin Anaesthesiol 2006; 20:8199.

  • 30.

    March PA, Muir WW III. Bispectral analysis of the electroencephalogram: a review of its development and use in anesthesia. Vet Anaesth Analg 2005; 32:241255.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Arbous MS, Grobbee DE & van Kleef JW, et al. Mortality associated with anaesthesia: a qualitative analysis to identify risk factors. Anaesthesia 2001; 56:11411153.

    • Search Google Scholar
    • Export Citation
  • 32.

    Sewell JC, Raines DE & Eger EI II, et al. A comparison of the molecular bases for N-methyl-D-aspartate-receptor inhibition versus immobilizing activities of volatile aromatic anesthetics. Anesth Analg 2009; 108:168175.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    US FDA. Ketamine. Available at: www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118102.htm. Accessed Oct 14, 2009.

    • Search Google Scholar
    • Export Citation
  • 1.

    Petrenko AB, Yamakura T & Baba H, et al. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003; 97:11081116.

    • Search Google Scholar
    • Export Citation
  • 2.

    Pozzi A, Muir WW, Traverso F. Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists. J Am Vet Med Assoc 2006; 228:5360.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Doubell TP, Mannion RJ, Woolf CJ. The dorsal horn: state-dependent sensory processing, plasticity and the generation of pain. In: Wall PD, Melzack R, eds. Textbook of pain. London: Churchill Livingstone Inc, 1999; 165181.

    • Search Google Scholar
    • Export Citation
  • 4.

    Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett 1995; 197:2528.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Coggeshall RE, Carlton SM. Ultrastructural analysis of NMDA, AMPA, and kanaite receptors on unmyelinated and myelinated axons in the periphery. J Comp Neurol 1998; 391:7886.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Lascelles BD, Gaynor JS & Smith ES, et al. Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. J Vet Intern Med 2008; 22:5359.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Jackson DL, Graff CB & Richardson JD, et al. Glutamate participates in the peripheral modulation of thermal hyperalgesia in rats. Eur J Pharmacol 1995; 284:321325.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Zhou S, Bonasera L, Carlton SM. Peripheral administration of NMDA, AMPA or KA results in pain behaviors in rats. Neuroreport 1996; 7:895900.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Lawand NB, Willis WD, Westlund KN. Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats. Eur J Pharmacol 1997; 324:169177.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Chizh BA, Headley PM, Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol Sci 2001; 22:636642.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Fisher K, Coderre TJ, Hagen NA. Targeting N-methyl-D-aspartate receptor for chronic pain management: preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage 2000; 20:358373.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Hewitt DJ. The use of NMDA receptor antagonists in the treatment of chronic pain. Clin J Pain 2000; 16:S73S76.

  • 13.

    Kim AH, Kerchner GA, Choi DW. Blocking excitotoxicity. In: Marcoux FW, Choi DW, eds. CNS neuroprotection. New York: Springer, 2002; 336.

  • 14.

    Pomarol-Clotet E, Honey GD & Murray GK, et al. Psychological effects of ketamine in healthy volunteers. Phenomenological study. Br J Psychiatry 2006; 189:173179.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Rockstroh S, Emre M & Tarral A, et al. Effects of the novel NMDA-receptor antagonist SDZ EAA 494 on memory and attention in humans. Psychopharmacology (Berl) 1996; 124:261266.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Kinney WA, Abou-Gharbia M & Garrison DT, et al. Design and synthesis of (2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-Cyclobutene-1,2-dione as an achiral ?-amino acid bioisostere. J Med Chem 1998; 41:236246.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Sun L, Chiu D & Kowal D, et al. Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-?-Amino-5-chloro-1-(phospohonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride). J Pharmacol Exp Ther 2004; 310:563570.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Brandt MR, Cummons TA & Potestio L, et al. Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel [EAA-090; (2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethyl]phosphonic acid] on chemically induced thermal hypersensitivity. J Pharmacol Exp Ther 2005; 313:13791386.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Antognini JF, Cartens E. Measuring minimum alveolar concentration: more than meets the tail (lett). Anesthesiology 2005; 103:679680.

  • 20.

    Solano AM, Pyendop BH & Boscan PL, et al. Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs. Am J Vet Res 2006; 67:2125.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Muir WW III, Wiese AJ, March PA. Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane. Am J Vet Res 2003; 64:11551160.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Kushiro T, Wiese AJ & Eppler MC, et al. Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs. Am J Vet Res 2007; 68:12941299.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Zwijnenberg RJG, Del Rio CL & Pollet RA, et al. Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs when administered as a preanesthetic via various routes or in combination with butorphanol. Am J Vet Res 2010; 71:604609.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Lamont LA, Mathews KA. Opiods, nonsteroidal antiinflammatories, and analgesic adjuvants. In: Veterinary anesthesia and analgesia. 4th ed. Oxford, England: Blackwell Science Ltd, 2007; 250251.

    • Search Google Scholar
    • Export Citation
  • 25.

    Hewson CJ, Dohoo IR, Lemke KA. Perioperative use of analgesics in dogs and cats by Canadian veterinarians in 2001. Can Vet J 2006; 47:352359.

    • Search Google Scholar
    • Export Citation
  • 26.

    Commiskey S, Fan LW & Ho IK, et al. Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci 2005; 98:109116.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Ilkiw JE, Pascoe PJ, Tripp LD. Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 2002; 63:11981202.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Kissin I. Depth of anesthesia and bispectral index monitoring. Anesth Analg 2000; 90:11141117.

  • 29.

    Johansen JW. Update on Bispectral Index monitoring. Best Pract Res Clin Anaesthesiol 2006; 20:8199.

  • 30.

    March PA, Muir WW III. Bispectral analysis of the electroencephalogram: a review of its development and use in anesthesia. Vet Anaesth Analg 2005; 32:241255.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Arbous MS, Grobbee DE & van Kleef JW, et al. Mortality associated with anaesthesia: a qualitative analysis to identify risk factors. Anaesthesia 2001; 56:11411153.

    • Search Google Scholar
    • Export Citation
  • 32.

    Sewell JC, Raines DE & Eger EI II, et al. A comparison of the molecular bases for N-methyl-D-aspartate-receptor inhibition versus immobilizing activities of volatile aromatic anesthetics. Anesth Analg 2009; 108:168175.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    US FDA. Ketamine. Available at: www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118102.htm. Accessed Oct 14, 2009.

    • Search Google Scholar
    • Export Citation

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