Various drugs and drug combinations have been shown to provide analgesia and reduce the amount of injectable or inhalation general anesthetics required for surgical planes of anesthesia.1–4 Studies examining the effect of analgesic drugs on volatile anesthetic requirements usually use the MAC as the standard measure. The MAC of an inhalation anesthetic was originally developed as a standard of anesthetic potency and is defined as the minimum steady-state alveolar concentration of an inhalation anesthetic required to prevent gross purposeful movement to a noxious stimulus in 50% of patients.5,6 A reduction in the adverse cardiovascular effects of inhalation anesthetics has been demonstrated by a reduction in the MAC.1–4,7 Isoflurane produces dose-dependent cardiovascular and respiratory adverse effects that include an increase in heart rate, decrease in blood pressure, and decrease in cardiac output.7 Therefore, a decrease in the isoflurane concentration needed for general anesthesia would reduce the dose-dependent adverse effects and improve the safety of general anesthesia for a patient.7 A decrease in the end-tidal concentration of an inhalation anesthetic is used to determine the analgesic or anesthetic effect of that agent.5,6,8,9 For MAC, a reduction in inhalation anesthetic requirements of ≥ 20%7 are generally considered clinically relevant. For example, the addition of IV administration of morphine to the anesthetic protocol has been shown to reduce isoflurane MAC by 48% in dogs.4
Findings in numerous studies10–13 support the fact that periodontal disease affects many canine and feline patients. Despite improvements in veterinary oral health products and owner compliance with periodontal homecare (tooth brushing), many animals develop severe stages of periodontal disease that require periodontal surgery, root canal treatment, or extraction.
Stimulation of the tooth pulp, known as dental dolorimetry, has been used experimentally as a source of noxious stimulus in dogs and cats.14–17 This technique is an established clinical pain model.14–17 Dental dolorimetry has been used to assess changes in pain threshold in awake dogs14 and horses15 in response to injectable analgesic agents.
Blockade of the infraorbital nerve at the level of the infraorbital canal has effectively provided regional anesthesia of the canine tooth in dogs18 and cats.19 Anesthesia has been documented by the loss of reflex-evoked muscle action potentials in the digastricus muscle during noninvasive stimulation of the tooth pulp.18,19 In these studies, a loss of the reflex muscle movements associated with a painful stimulus was attributed to the analgesic effects of local anesthetics. However, clinically, the effect could also be attributed to a blocked motor response secondary to the local anesthetic. Other studies have not evaluated the potential for a decrease in the MAC of inhalant anesthetics as a result of local anesthetic administration.
Surgical manipulation associated with dental extraction includes stimulation of not only the tooth pulp, but also the gingiva and alveolar mucosa. Therefore, to assess pain associated with commonly performed surgical tooth extractions, dental dolorimetry must be modified to include stimulation of the tooth pulp, gingiva, and alveolar mucosa. The infraorbital nerve is a continuation of the maxillary branch of the trigeminal nerve. It is established that branches of the trigeminal nerve provide sensation to the cutaneous tissues of the head, alveolar mucosa, and buccal gingiva and, within the infraorbital canal, provide branches responsible for sensation involving the maxillary teeth (ipsilateral incisor to molar teeth).20,21 Nervous innervation to these tissues is established, but to our knowledge, there have not been studies to date documenting the fact that the use of nerve blocks to achieve regional anesthesia can result in a reduction in the inhalation anesthetic requirements needed for general anesthesia during dental procedures.
Nerve blocks, with a variety of local anesthetics, are commonly used in veterinary dentistry for their analgesic effects. Mepivacaine was chosen on the basis of its short onset of action (5 to 10 minutes) and duration of action (2 hours).22 By determining whether infraorbital nerve blocks can, in addition to providing analgesia, improve the safety of anesthesia by reducing the dose-dependent cardiorespiratory adverse effects, a large population of canine patients could benefit from a technique impacting commonly performed dental procedures. If the MAC of inhalation anesthetics can be reduced by the addition of regional anesthesia, its use may be beneficial in improving inhalation anesthetic safety.
Materials and Methods
Animal care and instrumentation—The present study was approved by The Animal Care and Use Committee of the University of Wisconsin, Madison, Wis. Eight young adult healthy Beagles (5 sexually intact females and 3 sexually intact males) were used. Animals were considered to be in good health on the basis of the results of general physical examination, hemogram evaluation, serum biochemical analysis, and thoracic auscultation. Dogs had a mean ± SD body weight of 9.2 ± 2.0 kg (20.24 ± 4.4 lb; range, 6.6 to 12.2 kg [14.52 to 26.84 lb]) and ranged in age from 8 to 14 months (mean, 10 months).
Each dog was anesthetized once, with data collection occurring during 2 phases. Phase 1 consisted of isoflurane MAC determination during isoflurane anesthesia alone (control treatment), and phase 2 consisted of isoflurane MAC determination during isoflurane anesthesia with regional anesthesia via an infraorbital nerve block (mepivacaine treatment).
Food, but not water, was withheld for a minimum of 12 hours prior to anesthesia. The right cephalic vein was percutaneously catheterized to facilitate anesthetic induction and fluid administration. Electrolyte solution was administered IV through the cephalic catheter at a rate of 10 mL/kg/h (4.5 mL/lb/h) for the duration of anesthesia. Anesthesia was induced with IV administration of propofola to effect (mean ± SD, 8.7 ± 1.2 mg/kg [3.95 ± 0.55 mg/lb]). All dogs were endotracheally intubated with a cuffed endotracheal tube and then positioned in left lateral recumbency. An esophageal temperature probe was inserted, and core body temperature was continuously monitored and maintained from 37° to 38°C (98.6° to 100.4°F) via a warm water circulating tabletop heating pad. Anesthesia was maintained with isofluraneb in oxygen delivered by an out-of-circle agent-specific vaporizer and a semiclosed anesthetic circle rebreathing system. The oxygen flow rate was kept at 2 L/min for anesthetic induction, and the end-tidal isoflurane concentration was initially maintained between 1.7% and 1.8%. Following anesthetic induction, the oxygen flow rate was maintained at 1 L/min for the duration of the experiment. Controlled ventilation was used to ensure a constant end-tidal isoflurane concentration and to maintain the end-tidal partial pressure of carbon dioxide between 37 and 43 mm Hg.
An anesthetic analyzerc was calibrated before each anesthetic procedure and was used to monitor inspired and expired gas samples continuously to provide end-tidal concentrations of isoflurane (%), oxygen (%), and partial pressure of carbon dioxide (mm Hg). Dogs were instrumented with lead II ECG leads, a pulse oximeter, and an oscillometric monitor, with cuff placement over the metatarsal region for indirect measurements of arterial blood pressure. Heart rate (beats/min) and rhythm, oxygen saturation (%), and systolic arterial blood pressure, diastolic arterial blood pressure, and MAP (mm Hg) were measured continuously. Heart and respiratory rates, esophageal body temperature (°C), inspired isoflurane concentration (%), oxygen saturation measured by pulse oximetry (%), end-tidal carbon dioxide concentration, end-tidal isoflurane concentration, and systolic arterial blood pressure, diastolic arterial blood pressure, and MAP (mm Hg) were recorded. Variables were monitored continuously and recorded at each isoflurane concentration just prior to the noxious stimulus and immediately following noxious stimulus. The experiment took place a minimum of 10 days following administration of any analgesic.
MAC of isoflurane without regional anesthesia—Phase 1 of the treatment protocol involved establishing the MAC of isoflurane for each dog before performing the infraorbital nerve block. Each dog was maintained at an end-tidal isoflurane concentration of 1.5% for a minimum of 20 minutes before determining the MAC of isoflurane. A modification of noninvasive dental dolorimetry19 was used as the noxious stimulus for isoflurane MAC determination. An alligator clip anodal electrode was attached to the right maxillary canine tooth and coated with electrode gel extending to the buccal-free gingival margin. A platinum needle cathodal electrode was inserted in the adjacent alveolar mucosa at the level of the tooth root. The electrodes were connected to an electrical stimulating deviced that provided a supramaximal stimulus for delivery of a noxious stimulus. As described, a 0.5-millisecond square wave pulse stimulus of 10 to 20 mA at a frequency of 0.5 Hz19 was administered to the preplaced electrodes for a maximum of 1 minute or until gross purposeful movement was elicited.8 Gross purposeful movement resulted in discontinuation of the electrical stimulus. Gross purposeful movements were defined as repetitive movement of the limbs, pawing at the face, or lifting of the head. Movements not considered gross purposeful movements included muscle twitching, arching of the back, swallowing, blinking, and nystagmus. Without a gross purposeful response, the electrical stimulus was discontinued after 1 minute and the end-tidal isoflurane concentration was decreased by 20% of the preceding end-tidal isoflurane concentration. The dog was then allowed to equilibrate to the new end-tidal isoflurane concentration for a minimum of 15 minutes, and the noxious stimulus was repeated. The process of reducing end-tidal isoflurane concentration and stimulation was repeated until gross purposeful movement was elicited. Once elicited, the isoflurane was increased by 10% of the preceding end-tidal isoflurane concentration and allowed to equilibrate for 15 minutes and the noxious stimulus was applied. Each individual MAC of isoflurane was calculated as the mean value of the highest end-tidal isoflurane concentration associated with a gross purposeful movement response and the lowest end-tidal isoflurane concentration associated with no gross purposeful movement.5,6
MAC of isoflurane with regional anesthesia—Once the control treatment isoflurane MAC was determined, the end-tidal isoflurane concentration was increased to its original setting for phase 2 of the treatment protocol. Regional anesthesia via an infraorbital nerve block was administered ipsilateral to the canine tooth being stimulated. The infraorbital nerve block was performed in each dog by the same board-certified veterinary dentist (CJS). The infraorbital foramen was located by palpation between the dorsal border of the zygomatic process and the gingiva of the canine tooth.22,23 A 25-gauge, 1-inch-long needle was inserted intraorally approximately 0.5 cm into the infraorbital foramen, with the needle tip angled slightly medially. After needle placement, negative pressure was generated by withdrawing the syringe plunger to inspect for the presence of blood, which would signify needle placement in an artery or vein. The needle was then rotated 90° along the long access 4 times, each time stopping to inspect with negative pressure for the presence of blood. Once the operator was satisfied that the needle bevel was not placed intravascularly, a 2% solution of mepivacaine hydrochloridee (0.3 mL; 0.49 to 0.91 mg/kg [0.22 to 0.41 mg/lb]) was injected into the infraorbital canal. The needle was withdrawn, and digital pressure was placed over the injection site for 1 minute to prevent outward flow of mepivacaine and to prevent hematoma formation. Twenty minutes was allowed for complete onset of action of the mepivacaine before repeating the protocol of phase 1 to determine the isoflurane MAC with regional anesthesia. Dogs were allowed to recover from anesthesia.
Statistical analysis—Data are reported as mean ± SD, with values of P < 0.05 considered significant. The effect of the treatment on the isoflurane MAC, cardiorespiratory variables, and end-tidal isoflurane concentration was determined via an ANOVA for repeated measures. When differences were detected, the Dunnett and Tukey post tests were performed to identify differences within and between control and mepivacaine treatments, respectively.
Results
All 8 dogs tolerated the procedure well and recovered from anesthesia uneventfully. No dog developed adverse effects, systemically or locally, from the regional mepivacaine anesthesia. Mean ± SD isoflurane MAC in response to control and mepivacaine treatments was 1.12 ± 0.13% and 0.86 ± 0.11%, respectively; the addition of regional anesthesia resulted in a significant (P = 0.001) reduction of 23% in the isoflurane MAC. For both mepivacaine and control treatments, heart rate and MAP increased in dogs when the end-tidal isoflurane concentration was decreased. Lifting the head or shaking the head was the most common positive response to the noxious stimulus. Occasionally, dogs pawed at their muzzle in response to the noxious stimulus. Body temperature was kept between 37° and 38°C for the duration of anesthesia. Oxygen saturation measured by pulse oximetry remained > 90% in all dogs.
Measurements of heart rate and MAP were obtained at the following time points: after anesthetic induction and anesthetic equilibration (time 1; baseline), at the lowest end-tidal isoflurane concentration that did not elicit purposeful movement (time 2), and at the lowest end-tidal isoflurane concentration in which purposeful movement could be elicited (time 3; Table 1).
Mean ± SD heart rate and MAP values measured at specific time points in the determination of MAC for isoflurane alone (control treatment) and for isoflurane with the addition of an infraorbital nerve block (mepivacaine treatment) immediately before and after dental dolorimetry in 8 healthy adult anesthetized Beagles.
| Variable | Treatment | Heart rate (beats/min) | MAP (mm Hg) | ||
|---|---|---|---|---|---|
| Before | After | Before | After | ||
| Time 1 | |||||
| Control | 94.75 ± 17.1 | 146.3 ± 21.6‡ | 48.8 ± 11.3 | 69.3 ± 12.2‡ | |
| Mepivacaine | 108.2 ± 13.4 | 118.5 ± 10.9† | 45.3 ± 3.1 | 53 ± 7.0†‡ | |
| Time 2 | |||||
| Control | 106.6 ± 19.9 | 175 ± 30.2*‡ | 57.9 ± 16.2 | 87.9 ± 19.2*‡ | |
| Mepivacaine | 109.0 ± 25.7 | 160.8 ± 29.2*‡ | 69.6 ± 11.3* | 86.1 ± 19.3* | |
| Time 3 | |||||
| Control | 113.3 ± 23.5 | 185.4 ± 30.5*‡ | 65.1 ± 16.6* | 102.8 ± 19.9*‡ | |
| Mepivacaine | 108.0 ± 28.3 | 158.8 ± 26.1*‡ | 72.3 ± 11.5* | 98.0 ± 23.1*‡ | |
Significantly (P < 0.05) different from baseline value (time 1) within a treatment.
Significantly (P < 0.05) different from control treatment at the same time point.
Significantly (P < 0.05) different from before value within a treatment (control or mepivacaine) for a given time point.
Time 1 = After anesthetic induction and anesthetic equilibration (baseline). Time 2 = At the lowest end-tidal isoflurane concentration that did not elicit purposeful movement. Time 3 = At the lowest end-tidal isoflurane concentration at which purposeful movement could be elicited.
The heart rate at time 2 (lowest end-tidal isoflurane concentration without purposeful movement) after stimulus was significantly higher than the heart rate at baseline for both control and mepivacaine treatments. The MAP at time 2 after stimulus was significantly higher than the MAP at baseline for both control and mepivacaine treatments; the MAP at time 2 before stimulus was also significantly higher than the MAP at baseline for mepivacaine treatment (Table 1).
The heart rate at time 3 (lowest end-tidal isoflurane concentration with purposeful movement) after stimulus was significantly higher than the heart rate at baseline for both control and mepivacaine treatments. The MAP at time 3 after stimulus was significantly higher than the MAP at baseline for both control and mepivacaine treatments; the MAP at time 3 before stimulus was also significantly higher than the MAP at baseline for both control and mepivacaine treatments (Table 1).
At baseline after stimulus, heart rate and MAP were significantly higher for control treatment, compared with those for mepivacaine treatment. With the exception of heart rate with mepivacaine treatment at baseline and MAP with mepivacaine treatment at time 2, heart rate and MAP significantly increased within each treatment after noxious stimulus, compared with heart rate and MAP before noxious stimulus (Table 1). For most time points and treatments, heart rate and MAP increased both as the inhalant anesthetic concentration decreased and following noxious stimulus.
With the addition of regional anesthesia via an infraorbital nerve block, 2 of the 8 dogs spontaneously woke up prior to the application of the noxious stimulus. These 2 dogs had achieved an MAC of isoflurane at which consciousness returned.
Discussion
Findings of the present study indicated that the addition of regional mepivacaine anesthesia via an infraorbital nerve block decreased the MAC of isoflurane from control values in a modified dental dolorimetric model of pain. The MAC of isoflurane after placement of an infraorbital nerve block significantly decreased from baseline by 23%. Regional mepivacaine anesthesia via an infraorbital nerve block significantly reduced the isoflurane MAC in dogs without adversely affecting hemodynamics or inducing obvious adverse effects.
Isoflurane has been associated with dose-dependent cardiovascular and respiratory adverse effects that include a decrease in blood pressure and has been shown to cause a decrease in cardiac output.7 Therefore, decreasing the concentration of isoflurane required for general anesthesia would reduce the dose-dependent adverse effects and improve the safety of general anesthesia for the patient.7 The amount of inhalation anesthesia necessary for maintaining a surgical plane of anesthesia correlates to the MAC. The MAC is defined as the minimum steady-state alveolar concentration that will prevent 50% of patients from responding to a noxious stimulus with gross purposeful movement.5–8 In the study reported here, the end-tidal concentration of the inhalation anesthetic was maintained for a minimum of 15 minutes to permit the alveolar concentration of isoflurane to equilibrate with arterial blood and brain concentrations.5–7 The MAC for an individual patient can be influenced by a number of variables, such as age, body temperature, and metabolic status.5,6 Therefore, these individual patient variables were kept constant to minimize the variability of isoflurane MAC in dogs of the present study. However, there is evidence that the MAC of an individual can vary over time. The MAC of halothane has been shown to vary by a mean of 8% during successive weeks in the same animal.24 Additionally, it has been demonstrated that additional analgesic administration serves to reduce the MAC of an inhalation anesthetic.5 A reduction in MAC by a minimum of 20% is clinically relevant for the patient. When translating the findings of the study reported here to clinical relevance, an MAC reduction by 20% implies that 95% of patients receiving the original MAC dose would remain anesthetized following a noxious stimulus.7
The MAC of isoflurane at which consciousness returns has been reported to be 1.0 ± 0.1%.25 In the study reported here, the isoflurane MAC with the regional mepivacaine anesthesia was 0.86 ± 0.11%, with 2 of 8 dogs spontaneously waking up. Determining the MAC of isoflurane at which consciousness returns was not the purpose of our study; however, our population of dogs appeared to have a lower MAC of isoflurane at which consciousness returns than did dogs of the other study.25
In the present study, body temperature and the respiratory rates were kept constant throughout anesthesia with a heating pad and ventilator, respectively, to minimize isoflurane MAC variability. In terms of cardiovascular variables, heart rate and blood pressure increased as the end-tidal concentration of isoflurane decreased, in some cases significantly. Additionally, for most time points of both control and mepivacaine treatments, the addition of the noxious stimulus caused the heart rate and blood pressure to increase (before stimulus vs after stimulus). The addition of regional mepivacaine anesthesia did not significantly alter the heart rate or blood pressure (except at baseline after noxious stimulus) from the control period. It appears, from our results, that the addition of the regional mepivacaine anesthesia via an infraorbital nerve block did not have any systemic adverse cardiorespiratory effects associated with systemic uptake of the drug.
Periodontal disease has been reported to be extremely prevalent in the veterinary population, involving as much as 80% of dogs > 2 years of age.10–13,26 Despite the improvements in veterinary oral health products and owner compliance with periodontal homecare, many animals have such periodontally compromised teeth that periodontal surgery, root canal treatment, or extractions are warranted. Although all of these procedures typically require general anesthesia, the addition of regional anesthetic techniques can help minimize adverse effects associated with deep planes of general anesthesia. One mechanism with which the anesthetic management of these patients can be influenced is through the regional blockade of A-delta and C-fiber nociceptor stimulation.
Research studies16–19 have been conducted, and through dental dolorimetry, teeth were electrically stimulated and a reflex-evoked muscle action potential was measured. These movements occurred through a reflex contraction of the digastricus muscles.21 Because this is a reflex pathway, the presence of a reflex-evoked muscle action potential demonstrates the plane of anesthesia is sufficient to suppress or demonstrate the reflex, but this does not correlate with the patient's perception of a pain stimulus. In the study reported here, we expected to see suppression of reflexive muscular activity at deep planes of anesthesia, with or without the nerve block. As the depth of anesthesia was reduced, the dogs had reflexive muscular activity associated with the electrical stimulus without responding to the painful stimulus with gross purposeful movement. All dogs of the present study had reflexive muscular activity at lighter planes of anesthesia regardless of gross purposeful movement. The electrical stimulus incited reflex muscle activity, not purposeful movement. However, the muscular activity could have been stimulatory enough to cause consciousness without pain.
Other studies16–19 involving dental dolorimetry involved the placement of an anode via an alligator clip on a specific tooth and a platinum-coated cathode into the alveolar mucosa overlying the tooth's root tip. Enamel is made up of > 96% inorganic material consisting primarily of apatite crystals.27 With < 4% organic substance (collagen and water), enamel has high electrical resistance and capacitance.28 The methodology used in 2 studies16,17 to deal with the electrical resistance of enamel was to remove or abrade enamel to expose the dentin. Dentin contains roughly 30% organic material and water,27 which is more efficient than enamel at electrical conduction. There has been a great deal of interest in exploring the mechanism with which tooth sensitivity occurs. Once enamel is removed and dentin is exposed, the dentin with its tubule arrangement contains fluid and extensions of odontoblastic processes. The hydrodynamic hypothesis states that fluid shifts within the dentinal tubules and subsequent movement of the odontoblastic processes result in stimulation of the odontoblast and closely associated A-delta nerve fibers.29 Dentinal tubules have been shown to contain cellular processes from the odontoblast cell bodies (located at the dentinal-pulp junction), but unmyleinated nerve endings have been shown to also penetrate into dentinal tubules.30,31 Despite various theories for the mechanism of tooth sensitivity, the most commonly performed treatment for diseased teeth in veterinary dentistry remains to be extraction. In some studies16,17 that involved use of dental dolorimetry, enamel was removed to facilitate electrical conduction through dentin and into pulp. The acute removal of enamel and exposure of dentinal tubules result in the exposure of odontoblastic processes within those tubules. Rather than considering implications of dentin exposure within the design of the present study, it was determined to be more clinically appropriate to evaluate the effect of the nerve block on the stimulation of the tooth and periodontal and soft tissue structures, which would all be involved in commonly performed dental procedures and extractions. By applying the noxious stimulus to the tooth and closely associated hard and soft tissues, an experimentally induced stimulus designed to mimic surgical stimulus was created. The 23% reduction in the isoflurane MAC with the addition of regional mepivacaine anesthesia supports the idea that nerve blocks substantially reduce the MAC of isoflurane. Therefore, isoflurane's dose-dependent adverse effects are reduced with the implication that painful dental procedures can be performed more safely under lighter planes of anesthesia.
More complete sensory blockade may have occurred by performing a caudal maxillary nerve block, which would have also provided sensory blockade to the major palatine branch of the maxillary nerve prior to the maxillary nerve entering the infraorbital canal as the infraorbital nerve. The major palatine nerve is responsible for sensory innervation to hard palatal mucosa.20
The best opportunity for complete anesthesia of the teeth, supporting periodontal tissues, and soft tissues of the alveolar mucosa and palatal mucoperiosteum stems from caudal maxillary nerve blocks administered caudal to the infraorbital canal ramifications supplying the dental structures (caudal, middle, and rostral superior alveolar nerves) and soft tissue structures of the lip. Multiple studies32–35 in humans have established that there are also accessory nerves that cross midline and innervate the contralateral incisors and that bilateral nerve blocks are frequently required to completely anesthetize teeth closer to midline. It is unknown whether the dogs of the study reported here may have had an increased reduction in MAC if the nerve block were applied to both sides, thus eliminating the potential for crossover innervation in the area of the root apex of the maxillary canine tooth. Further investigation into both of these alternatives is needed. The use of various premedications has been shown to reduce the MAC of inhalation anesthetics,36 but the use of regional anesthesia in conjunction with premedications has yet to be investigated.
ABBREVIATIONS
| MAC | Minimum alveolar concentration |
| MAP | Mean arterial blood pressure |
Propofol, Ben Venue Laboratories Inc, Bedford, Ohio.
Isoflo, Abbot, North Chicago, Ill.
Cardiocap/5, Datex Ohmeda, Louisville, Colo.
GRASS SD9 Square Pulse Stimulator, Astro-Med Inc, West Warwick, RI.
2% mepivacaine hydrochloride USP, Carbocaine-V, Pfizer, New York, NY.
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