Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs

Tokiko Kushiro Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210

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Ashley J. Wiese Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210

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Mark C. Eppler Fort Dodge Animal Health, 9 Deer Park Dr, Monmouth Junction, NJ 08852

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William W. Muir III Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210

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Abstract

Objective—To determine the effect of IV administration of perzinfotel on the minimum alveolar concentration (MAC) of isoflurane in dogs.

Animals—6 healthy sexually intact male Beagles.

Procedures—Dogs were instrumented with a telemetry device that permitted continuous monitoring of heart rate, arterial blood pressure, and body temperature. Dogs were anesthetized with propofol (4 to 6 mg/kg, IV) and isoflurane for 30 minutes before determination of MAC of isoflurane. Isoflurane MAC values were determined 4 times, separated by a minimum of 7 days, before and after IV administration of perzinfotel (0 [control], 5, 10, and 20 mg/kg). Bispectral index and percentage hemoglobin saturation with oxygen (SpO2) were monitored throughout anesthesia.

Results—Isoflurane MAC was 1.32 ± 0.14%. Intravenous administration of perzinfotel at 0, 5, 10, and 20 mg/kg decreased isoflurane MAC by 0%, 24%, 30%, and 47%, respectively. Perzinfotel significantly decreased isoflurane MAC values, compared with baseline and control values. The bispectral index typically increased with higher doses of perzinfotel and lower isoflurane concentrations, but not significantly. Heart rate, body temperature, and SpO2 did not change, but systolic, mean, and diastolic arterial blood pressures significantly increased with decreases in isoflurane MAC after administration of perzinfotel at 10 and 20 mg/kg, compared with 0 and 5 mg/kg.

Conclusions and Clinical Relevance—IV administration of perzinfotel decreased isoflurane MAC values. Improved hemodynamics were associated with decreases in isoflurane concentration.

Abstract

Objective—To determine the effect of IV administration of perzinfotel on the minimum alveolar concentration (MAC) of isoflurane in dogs.

Animals—6 healthy sexually intact male Beagles.

Procedures—Dogs were instrumented with a telemetry device that permitted continuous monitoring of heart rate, arterial blood pressure, and body temperature. Dogs were anesthetized with propofol (4 to 6 mg/kg, IV) and isoflurane for 30 minutes before determination of MAC of isoflurane. Isoflurane MAC values were determined 4 times, separated by a minimum of 7 days, before and after IV administration of perzinfotel (0 [control], 5, 10, and 20 mg/kg). Bispectral index and percentage hemoglobin saturation with oxygen (SpO2) were monitored throughout anesthesia.

Results—Isoflurane MAC was 1.32 ± 0.14%. Intravenous administration of perzinfotel at 0, 5, 10, and 20 mg/kg decreased isoflurane MAC by 0%, 24%, 30%, and 47%, respectively. Perzinfotel significantly decreased isoflurane MAC values, compared with baseline and control values. The bispectral index typically increased with higher doses of perzinfotel and lower isoflurane concentrations, but not significantly. Heart rate, body temperature, and SpO2 did not change, but systolic, mean, and diastolic arterial blood pressures significantly increased with decreases in isoflurane MAC after administration of perzinfotel at 10 and 20 mg/kg, compared with 0 and 5 mg/kg.

Conclusions and Clinical Relevance—IV administration of perzinfotel decreased isoflurane MAC values. Improved hemodynamics were associated with decreases in isoflurane concentration.

The detection of a harmful (ie, noxious) stimulus, nociception, is initiated by activating high-threshold pain receptors (nociceptors) located on the peripheral terminals of unmyelinated (C-fiber) and thinly myelinated (AD-fiber) sensory neurons. Both uni- and polymodal primary sensory neurons transfer electrical potentials from nociceptors to neurons in the dorsal horn of the spinal cord that project to the brain.1 The severity of tissue or nerve damage determines the frequency and duration of electrical potentials generated and transferred to the dorsal horn and, as a result, determines the quantity and type of centrally acting neurotransmitters released. Mild to moderate noxious stimuli trigger release of glutamate, which acts predominantly at postsynaptic A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainite receptors to produce fast excitatory synaptic potentials in the dorsal horn. More intense or chronically repeated C-fiber activation results in progressively greater increases in nociceptive neuronal activity and temporal summation, resulting in structural modification (phosphorylation) and removal of Mg2+ from NMDA receptors. Dorsal horn synaptic signaling is amplified by neuropeptides that are coreleased with glutamate, such as substance P and brain-derived neurotrophic factor.2 Activation of dorsal horn NMDA receptors is believed to be the primary factor in the development of central sensitization, as manifested by exaggerated and amplified responses to noxious stimuli (hyperalgesia), the expansion of hypersensitivity to noninjured tissues (secondary hyperalgesia), and a reduction in threshold required for eliciting pain (allodynia).3

The utility of NMDA antagonists in surgical analgesia and anesthesia is well established.4 Their preferred molecular targets are the glutamate-activated, Ca2+-permeable NMDA receptors known to be involved in central mechanisms of pain transmission. These are formed by various combinations of 3 families of NMDA receptor subunits (NR1, NR2, and NR3). Although many combinations are possible, the NR1-NR2A and NR1-NR2B combinations are most relevant physiologically because NR1, NR2A, and NR2B subunits are widely distributed throughout the dorsal horn of the spinal cord. The NR2C subunits are found predominantly in the cerebellum, and NR2D subunits have been identified only in small concentrations in the thalamus and brainstem.5-7 Presently available NMDA antagonists, including ketamine, dextromethorphan, dizocilpine, and memantine, are not subunit-selective ion channel blockers. They are known to reduce temporal summation and windup central sensitization and have been administered clinically to reduce hypersensitivity and allodynia.8 Ketamine also reduces the MAC of isoflurane; for example, MAC reductions as high as 25% can be safely achieved in dogs.9,10 The clinical use of most NMDA antagonists, however, is hampered by short duration of action, low therapeutic index, and narrow separation between effective analgesia and adverse effects that include sedation, psychotomimitic activity, muscle rigidity, hypersalivation, and seizures.8,11

Efforts to produce less toxic NMDA antagonists with greater analgesic efficacy and reduced adverse effects focused on compounds with NMDA subunit selectivity. It has been suggested that drugs with NR1-NR2B selectivity are more effective for alleviating mechanical and thermal hypersensitivity and have fewer adverse effects, compared with nonselective NMDA antagonists.4-6 Results of other studies suggest that the NR2A receptor subunit is upregulated to a greater extent than the NR2B subunit and plays a greater role in inflammatory pain.12

Perzinfotel ([2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid) is a novel, selective, and competitive NMDA antagonist with approximately 10 times the selectivity for NR1-NR2A, compared with NR1-NR2B and NR1-NR2C subunit combinations.13 The half maximal inhibitory concentration for perzinfotel on the NR1-NR2A subunit suggests a potency of at least 10 times that for the nonselective NMDA antagonist ketamine.14,15 Perzinfotel blocks thermal and tactile hypersensitivities induced by prostaglandin E2, capsaicin, and spinal nerve lesions and prevents glutamate-induced neurotoxicosis without inducing inhibition of A-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid or kainite receptors.13 In addition, perzinfotel has a much wider therapeutic window and longer half-life than other NMDA receptor antagonists, no known adverse cardiorespiratory effects, and a better adverse effect profile, compared with all other competitive and noncompetitive NMDA receptor antagonists.13

The MAC of an inhalant anesthetic is defined as the amount of inhaled anesthetic required to prevent gross purposeful movement to a noxious supramaximal stimulus in 50% of the subjects.16 The MAC is a measure of anesthetic potency and provides a guide to the concentration of inhaled anesthetic needed to induce unconsciousness and immobility. Bispectral processing is a proprietary method for analyzing the degree of sedation and hypnosis.17,18 Bispectral analysis examines the harmonic and phase relation of EEG signals and quantifies the amount of synchronization in the EEG. The BIS is a numeric value derived from the EEG and provides a reasonably accurate index of anesthetic depth and the presence or absence of consciousness.19 Values < 70 generally are associated with pronounced sedation, and values < 60 indicate unconsciousness from which the animal cannot be aroused. Changes in BIS values are used to indicate a return to consciousness during inhalant anesthesia and to distinguish between druginduced analgesic and hypnotic effects. The purpose of the study reported here was to determine whether perzinfotel would decrease the MAC of isoflurane in dogs and whether the decrease was associated with a change in BIS values.

Materials and Methods

Animal care and instrumentation—The study was approved by the Institutional Animal Care and Use Committee of The Ohio State University. Six healthy sexually intact male Beagles, 13 to 15 months of age and weighing 8.6 to 10.2 kg (mean ± SD, 9.1 ± 0.5 kg), were the subjects of this study. Each dog was equipped with a telemetry device that had been surgically implanted at least 3 months before beginning the study. The telemetry device permitted the simultaneous and continuous monitoring of respirations, the ECG, arterial (femoral artery) blood pressure, and body temperature.

Experimental design—Isoflurane MAC values were repeatedly determined for each dog 4 times separated by a minimum washout period of 7 days. Isoflurane MAC was determined before and after administration of saline (0.9% NaCl) solution for the first time (0.0 mg/kg [control group]) and before and after treatment with 1 of 3 doses (5, 10, or 20 mg/kg, IV) of perzinfotela administered randomly for 1 of the 3 remaining experimental times (treatment groups). The investigator was not masked to the dose of perzinfotel administered. The dose of perzinfotel was selected on the basis of results of previous studies conducted in rats13 and dogs (pilot study). The volume of fluid (saline solution) used to dilute and administer perzinfotel was identical. The authors had previously determined that doses of perzinfotel up to 20 mg/kg, IV, did not induce changes in behavior, locomotor activity, respiratory rate, heart rate, arterial blood pressure, or body temperature in clinically normal conscious dogs. Isoflurane MAC values were determined at approximately 1.5 ± 0.25 hours and 4.5 ± 0.25 hours after induction of anesthesia on the first time (0.0 mg/kg) and at 0 (before treatment), 1.5 ± 0.25 hours, and 4.5 ± 0.25 hours (after treatment) after induction of anesthesia on each of the subsequent treatment days to identify changes in duration of the effect of perzinfotel.

Experimental procedures—Food was withheld for 12 hours and water for 2 hours on the day of the experiment. A cephalic vein was catheterized and anesthesia induced by administering propofolb (4 to 6 mg/kg, IV, to effect). Each dog was orotracheally intubated and positioned in right lateral recumbency. Anesthesia was maintained with isofluranec in oxygen delivered by use of an out-of-circle, agent-specific vaporizerd in a semiclosed anesthetic circle rebreathing system.e Breathing was controlled to maintain the ETCO2 between 35 and 45 mm Hg.f Inspired and expired concentrations of isoflurane were continuously monitored.g The ECG; heart rate (beats/min); systolic, mean, and diastolic direct arterial blood pressure (mm Hg); ETISO; ETCO2; oxygen saturation of hemoglobin by pulse oximetry (%); and core body temperature (°C) were continuously monitored and periodically recorded.h Core body temperature was maintained between 37.5° and 38.5°C throughout anesthesia by use of a hot water circulating heating padi and blankets.

Determination of isoflurane MAC—Isoflurane MAC was determined by delivering a supramaximal electrical stimulus to the buccal mucosa.10 Two 24-gauge, 10-mm, insulated stimulating electrodesj 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 stimulatork that delivered a predetermined stimulus of 50 V and 5 Hz for 10 milliseconds. Stimulation continued for 1 minute unless the dog had gross purposeful movement before completion of the 1-minute stimulation. Lifting of the head and repeated movement of the limbs were considered gross purposeful movement. Slight paw movement, arching of the back, chewing, swallowing, blinking, opening of the eyes, and nystagmus were not considered gross purposeful movement (negative response). The ETISO was set at 1.5% during each dog's first MAC determination (0.0 mg/kg [control group]) and at 1.1 times each dog's control MAC value during subsequent drug treatment days. If a negative response to the stimulus was obtained, the ETISO was decreased by 20% and allowed to equilibrate for at least 15 minutes before applying the stimulus. This process was continued until the dog responded with gross purposeful movement. The ETISO was then increased by increments of 10% until the dog failed to have gross purposeful movement. The MAC was considered to be the mean of the lowest ETISO value that did not induce gross purposeful movement and the highest ETISO value that induced gross purposeful movement.10

Determination of BIS—The BIS value was derived by continuously monitoring EEG activity. The EEG was obtained from platinum subdermal needle electrodes in 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.10 The EEG and BIS values were continuously acquired and displayed by use of a proprietary BIS monitor,l 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.

Statistical analysis—Data are reported as mean ± SD and were analyzed by use of 1- and 2-way repeated-measures ANOVA with Bonferonni correction.m Comparisons were considered significant at P < 0.05.

Results

Isoflurane MAC values determined at 1.5 ± 0.25 hours and 4.5 ± 0.25 hours after administration of saline solution varied only slightly over time and among dogs (mean ± SD, 1.32 ± 0.14%). The IV administration of perzinfotel at 5, 10, and 20 mg/kg significantly decreased MAC values at 1.5 ± 0.25 hours and 4.5 ± 0.25 hours to 1.03 ± 0.08% and 0.99 ± 0.07%, 0.93 ± 0.12% and 0.93 ± 0.10%, and 0.72 ± 0.12% and 0.70 ± 0.12%, respectively, compared with control MAC values. No significant differences were found between the 2 MAC values obtained at 1.5 and 4.5 hours at each dose. Mean MAC values following administration of perzinfotel at 5, 10, and 20 mg/kg were 1.01 ± 0.05%, 0.93 ± 0.10%, and 0.71 ± 0.15%, respectively. These MAC values were significantly lower than control MAC values and were significantly different from each other. One dog given perzinfotel at 5 mg/kg vomited 3 times during recovery from isoflurane anesthesia. Three dogs that recieved perzinfotel at 20 mg/kg had periods of nystagmus, salivation, mild excitement, and hind limb muscle fasciculations during recovery from isoflurane anesthesia. These responses were not treated and lasted for 15 to 20 minutes. All dogs in all groups were able to walk back to their cage within 1 hour after recovering from isoflurane anesthesia.

The BIS values increased after noxious stimulus, regardless of the dose of perzinfotel administered. The mean BIS values were 63 ± 14 and 68 ± 17 in dogs that recieved perzinfotel at 0 and 5 mg/kg, respectively. The BIS values typically increased, compared with baseline values, to 74 ± 15 in dogs that recieved perzinfotel at 10 mg/kg and to 79 ± 15 in dogs that recieved perzinfotel at 20 mg/kg, but these differences were not significant. One dog given perzinfotel at 5 mg/kg and 2 dogs that recieved perzinfotel at 20 mg/kg had brief (< 3 seconds) periods of burst suppression.

Heart rate; respiratory rate; and systolic, diastolic, and mean arterial blood pressures were significantly increased after administration of 10 and 20 mg/kg, respectively, compared with control and baseline values (Table 1). End-tidal concentration of oxygen2, ETCO2, percentage of hemoglobin saturated with oxygen, and body temperature did not change. Some dogs panted for various durations at lower isoflurane concentrations, resulting in temporary decreases in ETCO2.

Table 1—

Mean ± SD values for variables measured during a study of the effects of perzinfotel on the MAC of isoflurane in 6 dogs.

Table 1—

Discussion

Administration of the selective competitive NMDA receptor antagonist, perzinfotel, induced dose-dependent decreases in isoflurane MAC values that were associated with decreases in hypnosis and improvement in hemodynamic values. Doses of perzinfotel administered did not induce clinically important adverse effects.

The MAC of inhaled anesthetic required to prevent gross purposeful movement in 50% of the subjects in response to a supramaximal noxious stimulus is used as a clinical index of drug potency and a guide to selection of the inhalant anesthetic concentration required for general anesthesia.16 Development of a standard noxious testing procedure in this regard is imperative because MAC values are higher when noxious stimuli are applied for longer periods and because determination of MAC is subjective, requiring the investigator to determine when the subject has gross purposeful movement.16 The stability, repeatability, and lack of significant difference in the control (1.32 ± 0.14%) and baseline (1.33 ± 0.16%) values reported here and the similarity to other reported values (1.38 ± 0.08%)20-22 were encouraging. The mechanism whereby perzinfotel reduces isoflurane MAC, however, remains to be elucidated. Although it would seem axiomatic that perzinfotel reduces isoflurane MAC by depressing temporal summation, windup, and pain perception secondary to blockade of NMDA receptors in the dorsal horn of the spinal cord, other investigations cast doubt on this conclusion.23,24 The infusion of the NMDA antagonists ketamine and dizocilpine markedly suppresses temporal summation and windup in the dorsal horn of the spinal cord in conjunction with marked decreases in isoflurane MAC values.25 Targeted-controlled IV infusions of ketamine that result in plasma concentrations varying from 1.07 to 22.8 μg/mL reduce isoflurane MAC values in dogs by 10.89% to 95.42%.9 Those study results, however, do not prove cause and effect. The conclusion that NMDA receptor antagonists reduce MAC by reducing windup becomes less certain after considering that a previous study26 found either no change or an increase in windup after NMDA receptor antagonism and that suppression of dorsal horn neurons is not an important mechanism for inducing anesthetic-induced immobility. Furthermore, evidence suggests that injectable and inhalant anesthetics induce immobility not by blocking NMDA receptors in the dorsal horn, but by impairing motor components in the ventral horn of the spinal cord.23,24 Further studies are required to determine whether NMDA receptor antagonists reduce MAC by suppressing peripheral nociceptors (halothane and isoflurane sensitize peripheral nociceptors) or dorsal horn neurons (central) or whether they, like the inhalant anesthetics, act at a more ventral site within the spinal cord.

Regardless of the mechanism, results of the present study clearly indicated that perzinfotel induces dose-dependent decreases in isoflurane MAC in dogs. There were no differences between the 2 control isoflurane MAC values obtained at approximately 1.5 and 4.5 hours after saline solution administration and baseline MAC values, suggesting that MAC values are reproducible and remain stable over time. Importantly, the decreases in isoflurane MAC values induced by perzinfotel were usually associated with increases in consciousness (increased BIS values) and improved hemodynamics. Lower BIS values are associated with greater degrees of sedation and unconsciousness and vice versa. Increasing BIS values are indicative of increased consciousness and suggest a decrease in anesthetic-associated depression of consciousness. Increased BIS values may be beneficial in animals if appropriate anesthetic depth can be maintained. We detected a decrease in isoflurane MAC and a gradual, albeit insignificant, increase in BIS values with increasing doses of perzinfotel, suggesting that the level of consciousness either improved or that perzinfotel induces excitatory EEG activity. Furthermore, increasing doses of perzinfotel resulted in increases in heart rate and arterial blood pressure in conjunction with decreases in isoflurane concentration and increases in BIS values, suggesting a reduction in anesthetic induced–depression of hemodynamics. Alternatively, the effects of perzinfotel on BIS and hemodynamics, like those of ketamine, could have been caused by direct stimulation of the CNS, increased sympathetic nervous system activity, and increased plasma concentrations of epinephrine and norepinephrine.27-29 Ketamine infusion, for example, causes increases in BIS values during anesthesia with stable concentrations of sevoflurane and dose-dependent improvements in ventilation, oxygenation, hemodynamics, and oxygen delivery in isoflurane-anesthetized dogs.29 We do not believe that the improvements in hemodynamics detected in isoflurane-anesthetized dogs were caused by perzinfotel administration because perzinfotel is not a stimulant, did not change hemodynamics in consciousness dogs during pilot experiments, and did not change the EEG at stable concentrations of isoflurane and because the improvements in hemodynamics were not evident until isoflurane concentrations were reduced. Further studies are required to determine the effects of graded doses of perzinfotel on the EEG and cardiorespiratory values in conscious dogs.

Several dogs had adverse effects during recovery from isoflurane anesthesia. No dog, however, required treatment for these events. Because similar adverse effects were not observed when perzinfotel was administered at identical dosages to conscious dogs (data not presented), it is believed that recovery events we observed were typical of unpremedicated dogs recovering from isoflurane anesthesia. One dog given perzinfotel IV at 5 mg/kg vomited during recovery, and 3 dogs given perzinfotel IV at 20 mg/kg developed hypersalivation, nystagmus, and hind limb muscle fasciculations. These adverse effects were minimal following IV administration of perzinfotel at 5 and 10 mg/kg. Additional studies are required to determine whether larger doses of perzinfotel exaggerate the adverse effects we observed during recovery from isoflurane anesthesia.

Perzinfotel induced a dose-dependent decrease in isoflurane MAC values in sexually intact male dogs that lasted for at least 4 hours. The decreases in isoflurane MAC were associated with improvement in hemo-dynamics. Further investigations, including clinical trials, are warranted to verify that these results are transferable to dogs requiring surgery for naturally occurring disease.

ABBREVIATIONS

NMDA

N-methyl-D-aspartate

MAC

Minimum alveolar concentration

EEG

Electroencephalogram

BIS

Bispectral index

ETCO2

End-tidal concentration of carbon dioxide

ETISO

End-tidal concentration of isoflurane

a.

Fort Dodge Animal Health, Monmouth Junction, NJ.

b.

PropoFlo, Abbott Laboratories, North Chicago, Ill.

c.

IsoFlo, Abbott Laboratories, North Chicago, Ill.

d.

Isotec 3, Ohmeda, Madison, Wis.

e.

LEI Medical, Boring, Ore.

f.

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

g.

Passport 2, Datascope, Montvale, NJ.

h.

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

i.

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

j.

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

k.

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

l.

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

m.

Prism 4, GraphPad Software Inc, San Diego, Calif.

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