Introduction
Regional anesthesia permits surgery without the need for general anesthesia, decreases anesthetic requirements when surgery is performed with the patient anesthetized, provides postoperative analgesia, and provides temporary relief of pain from a painful medical condition. However, the relatively short duration of action of local anesthetics necessitates repeatedly instilling the local anesthetic perineurally, with the use of either a hypodermic needle or a perineural catheter. Both techniques are time-consuming and inconvenient, and administering a local anesthetic through a catheter can result in infection at the site of catheterization.1 Alternatively, analgesia can be provided by administering an analgesic drug systemically or epidurally, but administering analgesic drugs by these routes is not as efficacious or safe as regional anesthesia. Systemically administered opioids have been associated with ileus, and nonsteroidal anti-inflammatory drugs have been associated with gastrointestinal ulceration and impaired renal function.2,3
A long-acting local anesthetic or a combination of a local anesthetic and a drug that prolongs the action of the local anesthetic would, therefore, be useful for administering regional anesthesia. Bupivacaine, a long-acting local anesthetic, when used to anesthetize the femoral and sciatic nerves in humans, provides a mean complete sensory blockade of 412 minutes.4 In contrast, bupivacaine, when used to anesthetize the palmar digital nerves (PDNs) of horses, provides a mean sensory blockade of only 90 to 180 minutes, depending on the experimental model used.5,6 Liposomal bupivacaine, when used to the anesthetize the PDNs of horses, provides a mean duration of sensory blockage of 240 minutes.7
The duration of sensory block of the PDNs of horses with mepivacaine, a local anesthetic commonly used to provide regional anesthesia to horses, appears to be similar to that provided by bupivacaine.5,6,8,9 One study8 shows that lameness of horses caused by naturally occurring foot pain was ameliorated for up to 120 minutes when the PDNs were anesthetized with mepivacaine. Another study indicates that lameness of horses caused by experimentally induced foot pain was ameliorated for 169 minutes and skin sensation was blocked for 195 minutes when the PDNs were anesthetized with mepivacaine.9
Research in humans and animals has found that the duration of desensitization provided by a regional nerve block can be increased by adding an adjuvant, such as an α2-adrenoceptor agonist.10,11,12,13,14 Studies show that dexmedetomidine, an α2-adrenoceptor agonist, added to bupivacaine or ropivacaine prolongs the duration of sensory and motor blockade by up to 2-fold in rats12,13,14 and that dexmedetomidine added to ropivacaine administered perineurally can increase the duration of action of ropivacaine by 60% in humans.11
On the basis of a literature search we conducted, the duration of effect of a combination of dexmedetomidine and mepivacaine hydrochloride administered perineurally to horses has not been studied. The aim of the study reported here was to compare the duration of action of a combination of mepivacaine and dexmedetomidine with mepivacaine alone or dexmedetomidine alone when administered perineurally for PDN blockade in horses. The study was designed to test the hypothesis that dexmedetomidine would prolong the duration of action of mepivacaine when mepivacaine is used to anesthetize the PDNs of horses.
Materials and Methods
Animals
All protocols were reviewed and approved by the University of Tennessee Institutional Animal Care and Use Committee (protocol No. 2693 0304 19). Eight mares (4 American Quarter Horses, 1 Thoroughbred, 1 Missouri Fox Trotter, 1 American Paint Horse, and 1 American Quarter Horse–Pony cross) from the University of Tennessee’s teaching herd were used in the study. The mares ranged in age from 6 to 23 years (median, 18 years) and in weight from 364 to 568 kg (median, 500 kg). Horses were determined to have had no signs of lameness at a walk, and the digits of the right forelimb of all horses had clinically normal sensation, as determined by observing purposeful withdrawal of that forelimb when a force of 70 N was applied between the heel bulbs.
Study design
The study was conducted with a randomized, blinded, crossover design. Each horse was assigned to a randomized (SAS version 9.4 TS1M4; SAS Institute Inc) sequence of 3 treatments in which the PDNs of the right forelimb were anesthetized at the level of the proximal sesamoid bones (ie, an abaxial sesamoid nerve block).15 Each treatment within the sequence was administered after a washout period of at least 14 days. The 3 treatments were perineural administration of either 1.5 mL of 2% mepivacaine hydrochloride (Carbocaine-V; 30 mg) combined with 0.5 mL of saline (0.9% NaCl) solution (mepivacaine alone), 0.5 mL of 0.05% dexmedetomidine (Dexdomitor; 250 µg) combined with 1.5 mL of saline solution (dexmedetomidine alone), or 1.5 mL of 2% mepivacaine (30 mg) combined with 0.5 mL of 0.05% dexmedetomidine (250 µg; mepivacaine combined with dexmedetomidine) over each PDN in the treated limb. Treatments were prepared by an investigator (JS) not involved in the assessment of the mechanical nociceptive threshold (MNT).
Treatment administration
For treatment, each horse was restrained with a halter attached to a lead rope. None was sedated for treatment. The injection sites were prepared with chlorhexidine soap and 70% isopropyl alcohol prior to injection. A lip twitch was applied to restrain the horse for insertion of the needle and injection of the assigned treatment over the medial and lateral PDNs (ie, 2 mL per nerve, 4 mL per digit) of the right forelimb with the use of a 25-gauge, 1.6-cm-long needle attached to a 3-mL syringe. The distal portion of the limb was held off the ground for injections. All injections were performed by the same nonblinded investigator (JS).
Determination of the MNT
The MNT was determined, as previously described,7 by use of digital force gauge (Digital Force Dial; Wagner Instruments) with a 6-mm-diameter, flat, circular tip. For each horse, force was applied to the region between the heel bulbs until the horse withdrew its limb or until a maximum force of 70 N was reached. The horse’s line of sight to the person applying the noxious stimulus was blocked by blinders (Dura-Tech Blinker Hood; Schneider Saddlery) to prevent the horse from anticipating the application of force. The MNT was obtained before treatment (baseline) and then every 15 minutes after the treatment injection, until the horse withdrew its limb at an MNT of ≤ 30 N. At each testing, 3 consecutive MNT readings were obtained at 1-minute intervals, and the mean MNT value was recorded as the value for that time point. An MNT of 30 N was chosen to represent the return to baseline because it approximated the highest baseline MNT.
Sedation was evaluated at baseline (before treatment) and at 15-minute intervals after treatment with the use of a 4-point scoring system reported by Seddighi et al16 and based on the horse’s head droop, posture, and degree of ataxia. A score of 1 was characterized by no evidence of sedation, whereas a score of 4 was characterized by marked signs of drowsiness, a wide-based stance, and low carriage of the head (ie, the horse’s chin lowered to the level of the horse’s carpi). Measurement of the MNT and evaluation of sedation were performed by the same blinded evaluator (CLN). This same investigator inspected the sites of injection daily for 7 days after treatment for signs of inflammation (eg, swelling, heat, or signs of pain when the injection sites were palpated) or lameness (ie, when the horse was walked in a straight line and a tight circle).
Statistical analysis
The effect of treatment on the duration of the PDN block was examined with the use of a mixed model analysis for crossover design. To confirm whether data met linear model assumptions, the Shapiro-Wilk test was conducted on residuals saved from model fitting to verify the normality model assumption, and the Levene test was used to verify the equal variance model assumption. Post hoc multiple comparisons were performed with a Tukey adjustment. Statistical significance was identified at P < 0.05. Available software analyses were conducted with SAS 9.4 TS1M4 (SAS Institute Inc).
Results
All 8 horses completed the study. No horse developed lameness at the walk in a straight line or tight circle after any treatment, and in the 7 days after treatment, none developed signs of inflammation at the sites of injections or application of the force gauge. No horse showed signs of sedation after treatment; all had sedation scores16 of 1.
The mean ± SE baseline MNT was 24.7 ± 1.1 N, 26.0 ± 1.5 N, and 21.3 ± 1.7 N for treatments with dexmedetomidine alone, mepivacaine alone, and mepivacaine combined with dexmedetomidine, respectively, and the values did not differ significantly (P ≥ 0.05). The mean ± SE duration of complete sensory blockade of the digit (ie, an MNT of 70 N associated with failure of the horse to withdraw the limb) was significantly (P < 0.001) longer after treatment with mepivacaine combined with dexmedetomidine (371 ± 22 minutes) than for mepivacaine alone (186 ± 14 minutes; Figure 1). Perineural treatment with 500 µg of dexmedetomidine (0.9 to 1.4 µg/kg) alone was not associated with detectable sedation and did not increase the MNT over baseline values. The mean ± SE time for the MNT to return to baseline (≤ 30 N) was significantly (P < 0.001) longer after perineural treatment with mepivacaine combined with dexmedetomidine (409 ± 20 minutes), compared with mepivacaine alone (225 ± 12 minutes; Figure 2). Clinically apparent inflammation at the sites of injections was not observed within 7 days after treatment, indicating that no horse incurred tissue damage at the injection sites. Similarly, no horse had evidence of tissue damage after a force of 70 N was applied between the heel bulbs.
Box-and-whisker plots of the duration of complete palmar digital nerve (PDN) blockade in 8 mares with no signs of lameness evaluated with a 6-mm flat-tipped force gauge to determine their mechanical nociceptive threshold (MNT) immediately before and every 15 minutes after treatment with either a combination of mepivacaine (30 mg) and dexmedetomidine (250 µg) or mepivacaine (30 mg) alone. Complete blockade of the PDN was defined as lack of withdrawal of the limb when a force of 70 N was applied to a region between the heel bulbs with the described force gauge. In each plot, the central line in the box represents the median, the diamond represents the mean, the box indicates the interquartile (25th to 75th percentile) range, the whiskers represent the range, and each dot represents the duration of complete PDN blockade for an individual horse. *The mean duration of complete PDN blockade was significantly (P < 0.001) shorter when horses were treated with mepivacaine alone versus mepivacaine combined with dexmedetomidine.
Citation: American Journal of Veterinary Research 83, 2; 10.2460/ajvr.20.10.0188
Box-and-whisker plots of the duration to return to baseline MNT after PDN blockade in the 8 horses as described in Figure 1. Return to baseline was defined as withdrawal of the limb when a force of ≤ 30 N was applied to a region between the heel bulbs with the use of a force gauge with a 6-mm flat tip. *The mean duration to return to baseline MNT was significantly (P < 0.001) shorter when horses were treated with mepivacaine alone versus mepivacaine combined with dexmedetomidine.See Figure 1 for the key.
Citation: American Journal of Veterinary Research 83, 2; 10.2460/ajvr.20.10.0188
Discussion
In this randomized, blinded study, perineural treatment of horses with mepivacaine combined with dexmedetomidine yielded a longer duration of sensory blockade of the PDNs, as measured by the time from treatment to the withdrawal of the limb when force was applied to the foot, than did treatment with mepivacaine alone. Perineural injection of dexmedetomidine alone was not associated with a clinically substantial increase in the MNT over baseline MNT and did not result in clinical signs of sedation.
The mean duration of sensory blockade of 186 minutes provided by anesthesia of the PDNs of 1 limb of horses with 2 mL of 1.5% mepivacaine alone in our study was longer than the 120-minute mean duration of sensory blockade provided by anesthesia of the PDNs of 1 limb of horses with 1.5 mL of 2% mepivacaine reported by authors of a previous study.8 Differences in the duration of action of mepivacaine between that study8 and the present study may have been attributable to differences in the experimental model or our use of a larger volume of injectate (2 mL). However, the duration of effect of 1.5 mL of 2% mepivacaine alone for a PDN block in a recent study9 was similar to the duration of effect of 2 mL of 1.5% mepivacaine in our study. In that previous study,9 the mean time to return of sensitivity in response to force applied with a force gauge was 195 minutes. A shorter duration of action of mepivacaine (75 to 120 minutes) was reported in a study17 examining the effect of anesthesia of the median and ulnar nerves in ameliorating naturally occurring lameness of horses, and the authors surmised that shorter duration of action may reflect faster absorption of mepivacaine from a more vascular site (around the median and ulnar nerves vs around the PDNs).
The duration of action of mepivacaine alone in our study was similar to or longer than what has been reported for the duration of action of bupivacaine in relation to blockade of the PDNs of horses.5,6 Anesthesia of the PDNs of horses with bupivacaine lasted approximately 180 minutes in a thermal model of nociception5; however, in an experimental model of foot pain, in which the pain was induced by tightening a metal clamp around the hoof wall, bupivacaine decreased the intensity of lameness for approximately 90 minutes.6 Differences in the duration of action between that study6 and the present study may have been due to differences in the models. In a study7 that used a model similar to that used in our study, liposomal bupivacaine provided a mean duration of action of anesthesia of the PDNs of 240 minutes, and this longer duration was expected given the extended duration of action of liposomal bupivacaine.18
In horses of the present study, treatment with mepivacaine combined with dexmedetomidine yielded approximately 2-fold duration of PDN anesthesia, and this finding was consistent with other reports10,11,12,13,14 of α2-adrenoceptor agonists prolonging the action of local anesthetics. For instance, dexmedetomidine prolonged the duration of action of ropivacaine in an in vivo sciatic nerve block model in rats,13 and this prolongation was attributed to blockade of the current (Ih) produced by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels because the effect of dexmedetomidine was inhibited by the administration of forskolin, an Ih current enhancer. This effect was not related to dexmedetomidine’s α-adrenergic actions because the prolongation of action was not reversed by either prazosin (an α1-adrenoceptor antagonist) or idazoxan (an α2-adrenoceptor antagonist). The HCN channels are a subfamily of membrane proteins within the superfamily of pore-loop cationic channels and are expressed in peripheral and central sensory neurons.19,20,21 Opening of HCN channels causes the cellular membrane to depolarize, facilitating the generation of an action potential by moving the membrane potential toward threshold. The Ih current is a mixed cationic (Na+ and K+) current that is activated during the phase of hyperpolarization of the action potential and serves to reset the nerve for succeeding action potentials.22
In the present study, treatment with dexmedetomidine alone was not associated with a substantial change in MNT over baseline values. This finding is consistent with findings of a study14 in which dexmedetomidine failed to produce sensory blockade of the sciatic nerve of rats but potentiated the sensory and motor blockade of bupivacaine.
Administration of 500 µg of dexmedetomidine (0.9 to 1.4 µg/kg) perineurally (SC) to the horses in our study was not associated with detectable sedation. The low dose of dexmedetomidine and the expected slow absorption of it from a subcutaneous site presumably resulted in inadequate effect-site concentrations to produce sedation. Additionally, an IV dose of dexmedetomidine of 3 to 5 µg/kg is generally required to achieve moderate to deep sedation of short duration in horses.23
Clinically apparent inflammation at the injection sites was not observed within the 7 days after treatment. This finding was in keeping with the anti-inflammatory effects of α2-adrenoceptor agonists reported in a study involving rats.24 Moreover, administration of dexmedetomidine perineurally at a high concentration to rats was not associated with histologic changes in peripheral nerves 24 hours and 14 days after injection. Horses in our study incurred no tissue damage when a force of 70 N was applied to the heel with the use of a force gauge with a blunt tip, whereas tissue was damaged in a previous study9 when a force of 65 N was applied between the heel bulbs with the use of a force gauge with a pointed tip.
A limitation of the present study was that only 1 dose of dexmedetomidine was investigated. We do not know whether a smaller dose of dexmedetomidine would have produced similar effects or been less efficacious or whether a higher dose would have been more efficacious. The dose of dexmedetomidine administered perineurally in combination with mepivacaine was chosen because it approximated 0.5 µg/kg/nerve, which was within the dose range used in human patients when dexmedetomidine is combined with local anesthetics for peripheral nerve blocks.8 A potential limitation of our study was that a control treatment of perineural injection of the saline solution alone was not studied. We chose not to use a control treatment and instead compared the MNT values for baseline versus after treatment because that seemed more appropriate. In addition, a previous study13 that used a similar method to determine MNT shows that perineural injection of isotonic saline solution was not associated with a change in the MNT over baseline values and that the MNT did not change significantly over time. Another limitation was that the model used in the present study did not evaluate pain in the deep tissues of the digit. Sensation in deep tissues of the digit was likely abolished with the PDN block; anesthesia of the PDNs with the use of mepivacaine has been shown to resolve experimentally induced lameness in horses.6 Nevertheless, another model may have produced different results, and determining how the model used in our study related to clinical disease of the digit was not possible. Our testing at 15-minute intervals may have resulted in small inaccuracies in determining the duration of effect of treatments; however, this testing interval was similar to that used in another study9 and more frequent testing may have contributed to cutaneous damage, which may have influenced the results. Intervals of 15 minutes were used to monitor the duration of complete sensory blockade and the time for the MNT to return to baseline, rather than analyzing each as an independent variable. The MNT data for each individual 15-minute data point were not analyzed further because determining the total duration of time for the MNT to return to baseline was our primary goal.
In our study, the addition of 250 µg of dexmedetomidine to the dose of mepivacaine (30 mg) was associated with a 2-fold increase in the duration of anesthesia of the PDNs over that provided by mepivacaine alone. Thus, the combination of mepivacaine and dexmedetomidine should be considered as an option for providing perineural anesthesia in horses when a prolonged duration of action is desired. Studies to determine whether the duration of effect of dexmedetomidine is dose-dependent and its interaction with purportedly longer-acting local anesthetics are indicated to identify a combination that can provide an even longer duration of action.
Acknowledgments
The study was funded by the University of Tennessee’s Department of Large Animal Clinical Sciences. The authors declare that there were no conflicts of interest.
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