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Effects of dexmedetomidine combined with ropivacaine on sciatic and femoral nerve blockade in dogs

  • Thomas A. Trein
    Correspondence
    Correspondence: Thomas A Trein, Departamento de Clínica, Cirurgia e Reprodução Animal, Faculdade de Medicina Veterinária de Araçatuba, Universidade Estadual Paulista, Rua Clóvis Pestana, no. 793, Araçatuba 16050-680, SP, Brazil.
    Affiliations
    Department of Animal Clinic, Surgery and Reproduction, Faculty of Veterinary Medicine of Araçatuba (FMVA), São Paulo State University (UNESP), Araçatuba, Brazil
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  • Beatriz P. Floriano
    Affiliations
    Department of Animal Clinic, Surgery and Reproduction, Faculty of Veterinary Medicine of Araçatuba (FMVA), São Paulo State University (UNESP), Araçatuba, Brazil
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  • Juliana T. Wagatsuma
    Affiliations
    Department of Animal Clinic, Surgery and Reproduction, Faculty of Veterinary Medicine of Araçatuba (FMVA), São Paulo State University (UNESP), Araçatuba, Brazil
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  • Joana Z. Ferreira
    Affiliations
    Department of Animal Clinic, Surgery and Reproduction, Faculty of Veterinary Medicine of Araçatuba (FMVA), São Paulo State University (UNESP), Araçatuba, Brazil
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  • Guilherme L. da Silva
    Affiliations
    Department of Animal Clinic, Surgery and Reproduction, Faculty of Veterinary Medicine of Araçatuba (FMVA), São Paulo State University (UNESP), Araçatuba, Brazil
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  • Paulo S.P. dos Santos
    Affiliations
    Department of Animal Clinic, Surgery and Reproduction, Faculty of Veterinary Medicine of Araçatuba (FMVA), São Paulo State University (UNESP), Araçatuba, Brazil
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  • Sílvia H.V. Perri
    Affiliations
    Department of Support, Production and Animal Health, Faculty of Veterinary Medicine of Araçatuba (FMVA), São Paulo State University (UNESP), Araçatuba, Brazil
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  • Valéria NLS. Oliva
    Affiliations
    Department of Animal Clinic, Surgery and Reproduction, Faculty of Veterinary Medicine of Araçatuba (FMVA), São Paulo State University (UNESP), Araçatuba, Brazil
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Published:February 22, 2017DOI:https://doi.org/10.1111/vaa.12399

      Abstract

      Objective

      To evaluate motor and sensory blockade of combining dexmedetomidine with ropivacaine, administered perineurally or systemically, for femoral and sciatic nerve blocks in conscious dogs.

      Study design

      Randomized, controlled, experimental study.

      Animals

      Seven healthy Beagle dogs, aged 3.3 ± 0.1 years and weighing 11.0 ± 2.4 kg.

      Methods

      Dogs were anesthetized with isoflurane on three separate occasions for unilateral femoral and sciatic nerve blocks and were administered the following treatments in random order: perineural ropivacaine 0.75% (0.1 mL kg–1) on each nerve and intramuscular (IM) saline (0.2 mL kg–1) (GCON); perineural dexmedetomidine (1 μg mL–1) and ropivacaine 0.75% (0.1 mL kg–1) on each nerve and IM saline (0.2 mL kg–1) (GDPN); and perineural ropivacaine 0.75% (0.1 mL kg–1) on each nerve and IM dexmedetomidine (1 μg mL–1, 0.2 mL kg–1) (GDIM). Nerve blocks were guided by ultrasound and electrical stimulation and dogs were allowed to recover from general anesthesia. Sensory blockade was evaluated by response to clamp pressure on the skin innervated by the saphenous/ femoral, common fibular and tibial nerves. Motor blockade was evaluated by observing the ability to walk and proprioception. Sensory and motor blockade were evaluated until their full recovery.

      Results

      No significant differences in onset time to motor and sensory blockade were observed among treatments. Duration of motor blockade was not significantly different among treatments; however, duration of tibial sensory blockade was longer in the GDPN than in the GDIM treatment.

      Conclusions and clinical relevance

      Although a longer duration of sensory blockade was observed with perineural dexmedetomidine, a significant increase compared with the control group was not established. Other concentrations should be investigated to verify if dexmedetomidine is a useful adjuvant to local anesthetics in peripheral nerve blocks in dogs.

      Keywords

      Introduction

      In humans, inclusion of locoregional techniques in the anesthetic protocol improves intraoperative analgesia and decreases the requirements of opioids and inhalation anesthetics during surgical interventions, thereby reducing the magnitude of their undesirable effects (
      • Roberts S.
      Ultrasonographic guidance in pediatric regional anesthesia.
      ,
      • Hebl J.R.
      • Dilger J.A.
      • Byer D.E.
      • et al.
      A pre-emptive multimodal pathway featuring peripheral nerve block improves perioperative outcomes after major orthopedic surgery.
      ). Similarly, locoregional techniques are used to provide multimodal analgesia to small animals during surgery and similar benefits have been attained (
      • Wenger S.
      • Moens Y.
      • Jäggin N.
      • et al.
      Evaluation of the analgesic effect of lidocaine and bupivacaine used to provide a brachial plexus block for forelimb surgery in 10 dogs.
      ,
      • Mosing M.
      • Reich H.
      • Moens Y.
      Clinical evaluation of the anaesthetic sparing effect of brachial plexus block in cats.
      ).
      Epidural anesthesia is probably the most frequently used technique to provide analgesia for orthopedic surgical procedures in small animals. Peripheral nerve blockade of the pelvic limb is an alternative for neuroaxial anesthesia and provides a similar degree of analgesia (
      • Campoy L.
      • Martin-Flores M.
      • Ludders J.W.
      • et al.
      Comparison of bupivacaine femoral and sciatic nerve block versus bupivacaine and morphine epidural for stifle surgery in dogs.
      ,
      • Caniglia A.M.
      • Driessen B.
      • Puerto D.A.
      • et al.
      Intraoperative antinociception and postoperative analgesia following epidural anesthesia versus femoral and sciatic nerve blockade in dogs undergoing stifle joint surgery.
      ).
      Local anesthetic agents are widely used in veterinary practice; however, the development of the ideal drug is still anticipated. Even though currently used local anesthetic agents are efficient and safe for most scenarios, their durations of effect may not preclude the need for opioids for postoperative analgesia. In an effort to extend the duration of nerve blockade, combinations of other drugs with local anesthetics are being investigated.
      Clonidine, an α2-adrenergic agonist drug, has been studied as an adjuvant to local anesthetics in humans to prolong the duration of sensory blockade, with inconsistent results (
      • Singelyn F.J.
      • Gouverneur J.M.
      • Robert A.
      A minimum dose of clonidine added to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block.
      ,
      • Duma A.
      • Urbanek B.
      • Sitzwohl C.
      • et al.
      Clonidine as an adjuvant to local anaesthetic axillary brachial plexus block: a randomized, controlled study.
      ). Dexmedetomidine, the active isomer of medetomidine, is approximately seven times more selective for the α2-receptor than clonidine (
      • Kamibayashi T.
      • Maze M.
      Clinical uses of α2-adrenergic agonists.
      ). The addition of dexmedetomidine to a local anesthetic, such as bupivacaine, levobupivacaine and ropivacaine, was found to extend the duration of sensory blockade in peripheral nerves in humans (
      • Esmaoglu A.
      • Yegenoglu F.
      • Akin A.
      • et al.
      Dexmedetomidine added to levobupivacaine proIongs axillary plexus block.
      ,
      • Rancourt M.M.
      • Albert N.T.
      • Côté M.
      • et al.
      Posterior tibial nerve sensory blockade duration prolonged by adding dexmedetomidine to ropivacaine.
      ,
      • Marhofer D.
      • Kettner S.C.
      • Marhofer P.
      • et al.
      Dexmedetomidine as an adjuvant to ropivacaine proIongs peripheral nerve block: a volunteer study.
      ,
      • Agarwal S.
      • Agarwal R.
      • Gupta P.
      Dexmedetomidine prolongs the effect of bupivacaine in supraclavicular brachial plexus block.
      ,
      • Gurav S.Y.
      • Kulkarni A.M.
      Dexmedetomidine added to levobupivacaine prolongs the duration of anaesthesia and analgesia after axillary brachial plexus block.
      ,
      • Nema N.
      • Badgaiyan H.
      • Raskaran S.
      • et al.
      Effect of addition of dexmedetomidine to ropivacaine hydrochloride (0.75%) in brachial plexus block through supraclavicular route in upper limb surgeries: a clinical comparative study.
      ) and in experimental animals (
      • Brummett C.M.
      • Padda A.K.
      • Amodeo F.S.
      • et al.
      Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve block in rat.
      ,
      • Brummett C.M.
      • Hong E.K.
      • Janda A.M.
      • et al.
      Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current.
      ). Nevertheless, no published studies were found that evaluated the sensory and motor effects of local anesthetic with or without dexmedetomidine for peripheral nerve blocks in dogs.
      The purpose of this study was to investigate the effects on motor and sensory blockade of adding dexmedetomidine to ropivacaine, administered either perineurally or intramuscularly (IM), for femoral and sciatic nerve blocks in awake dogs. Our hypothesis was that perineural dexmedetomidine combined with ropivacaine would offer a faster onset time and a longer duration of sensory blockade, with a similar duration of motor blockade compared with IM administration of dexmedetomidine or perineural administration of ropivacaine alone.

      Materials and methods

      Animals

      Following approval by the Ethics Committee on the Use of Animals of the Faculty of Odontology of Araçatuba, São Paulo State University (UNESP), Brazil (FOA no. 2014-00772), seven purpose-bred Beagle dogs, two males and five females, aged 3.3 ± 0.1 (3.3-3.4) years [mean ± standard deviation (SD) (range)] and weighing 11.0 ± 2.4 (7.8-15.0) kg were enrolled in this prospective experimental study. Dogs were already acclimatized for over a year. Commercial dry food was fed twice daily and water was available ad libitum. All dogs were deemed healthy based on physical examination, complete blood count and biochemical serum tests (creatinine and alanine aminotransferase).

      Treatments

      Dogs were randomly allocated to three treatments using a random number generator (Excel 2010; Microsoft Corp., WA, USA), with a minimum washout period of 7 days between treatments. Each treatment included unilateral perineural administrations around the femoral and sciatic nerves and an IM injection. The limb to be blocked (left or right pelvic limb) was randomized in the same manner for the first treatment and alternated for subsequent treatments. The solutions were prepared on the day of the procedure by an individual not involved in the assessment. The perineural solutions were prepared by adding 9.9 mL of ropivacaine (Ropi, 0.75%; Cristália Produtos Químicos e Farmacêuticos Ltda, SP, Brazil) to 0.1 mL of dexmedetomidine (Precedex, 0.01%; Hospira Produtos Hospitalares Ltda, SP, Brazil) or 0.1 mL of saline, providing ropivacaine 7.425 mg mL-1. The IM solutions containing dexmedetomidine were prepared by adding 9.9 mL of saline to 0.1 mL of 0.01% dexmedetomidine.
      Treatments included the following: control treatment (GCON), ropivacaine (0.1 mL kg-1 of prepared solution, 0.7425 mg kg-1) administered perineurally at each nerve and saline (0.2 mL kg-1) administered IM; perineural dexmedetomidine treatment (GDPN), ropivacaine and dexmedetomidine (0.1 mL kg-1 of the prepared solution; 0.7425 mg kg-1 of ropivacaine, 0.1 μg kg-1 of dexmedetomidine) administered perineurally at each nerve and saline (0.2 mL kg-1) IM; and IM dexmedetomidine treatment (GDIM), ropivacaine (0.1 mL kg–1 of prepared solution, 0.7425 mg kg–1) administered perineurally at each nerve and dexmedetomidine (0.2 mL kg–1 of prepared IM solution, 0.2 μg kg–1) IM.

      Procedure

      On the day before the procedure, hair was clipped from the region over the cephalic veins, palmar surface of a distal thoracic limb, and inguinal and proximal third of the lateral aspect of the pelvic limb to be blocked. Food was withheld for 12 hours and water for 2 hours before each experiment and the dogs were weighed. No premedication was administered. A 22 gauge catheter (Safelet; Nipro Medical Ltda, SP, Brazil) was percutaneously placed into one cephalic vein for fluid therapy. After a resting period of 20 minutes, baseline data were collected. Subsequently, anesthesia was induced with isoflurane (Isoforine; Cristália Produtos Químicos e Farmacêuticos Ltda) (inspired concentration of 7.9 ± 2.3%) in oxygen 3 L minute–1 using a universal vaporizer delivered by face mask and a circle rebreathing circuit (Anesthesia System 800; Oxigel Materiais Hospitalares Ind. Com. Ltda, SP, Brazil). Following endotracheal intubation, anesthesia was maintained at an end-tidal isoflurane concentration (Fe′Iso) of 1.5 ± 0.3% in oxygen (1 L minute–1) for the duration of the nerve block procedures. Lactated Ringer's solution (Ringer Lactato; JP Indústria Farmacêutica SA, SP, Brazil) was administered intravenously (IV) at 10 mL kg–1 hour–1 throughout the procedure.
      Combined ultrasound- and nerve stimulator-guided perineural blocks were performed sequentially and unilaterally on the femoral and sciatic nerves by a single individual unaware of the treatment group. During the year before the study, this individual received training in the use of ultrasound and electrostimulation for regional nerve blocks and practiced using cadavers and dogs prior to euthanasia. Ultrasonography was performed using a high-frequency 9-15 MHz linear array transducer (LA523; Esaote Healthcare do Brasil, SP, Brazil) and an ultrasound system (MyLab 70 VETXV; Esaote Healthcare do Brasil). Isopropyl alcohol 70% was used as an acoustic coupling agent. Insulated needles (22 gauge 50 mm Stimuplex-A Insulated Needle; B. Braun Brasil, RJ, Brazil) connected to a peripheral nerve stimulator (Stimuplex HNS12; B. Braun Brasil) were used to inject the anesthetic solution perineurally. Electrical stimuli of 1 mA current, 0.1 ms duration at a frequency of 1 Hz were delivered. The skin where echolocation was to be performed and the site of needle insertion were surgically prepared. Echolocation was used to direct the needle to the nerve by an in-plane technique and electrostimulation was used to confirm that the needle tip was proximate to the relevant nerve once typical and evident muscle contractions appeared at 0.4 mA. To avoid intraneural injection, absence of muscular contraction was checked at 0.2 mA. The injections were carried out using a single-hand technique by another individual unaware of the treatment only when blood could not be aspirated and when there was no resistance to injection. The deposition of local anesthetic was observed with ultrasound.
      Femoral and sciatic nerve blocks were accomplished according to the published technique (
      • Campoy L.
      • Bezuidenhout A.J.
      • Gleed R.D.
      • et al.
      Ultrasound-guided approach for axillary brachial plexus, femoral nerve, and sciatic nerve blocks in dogs.
      ). For the femoral nerve block, the dog was positioned in lateral recumbency with the limb to be blocked uppermost, abducted 90° and extended caudally. The femoral triangle (delimited by the sartorius muscle, pectineus muscle and iliopsoas muscle) was scanned ultrasonographically and a hyperechoic nodular structure deep and cranial to the femoral artery and caudal to the fascia of the rectus femoris muscle was presumed to be the femoral nerve. The needle was introduced through the quadriceps femoris muscle and advanced towards the femoral nerve until there was sonographic evidence of close proximity of the tip of the needle to the nerve and characteristic extension of the stifle could be observed. At this point the solution was administered. For the sciatic block, the animal remained in the same recumbency with the limb to be blocked extended and in a natural position. The area immediately distal to the ischiatic tuberosity and greater trochanter was scanned ultrasonographically and a hyperechoic, double ellipsoid-shaped structure, presumably the sciatic nerve, was observed medial to the fascia of the biceps femoris muscle and cranial to the fascia of the semimembranosus muscle. The needle was introduced through the semimembranosus and abductor muscles and advanced towards the sciatic nerve until there was sonographic evidence of close proximity of the tip of the needle to the nerve and characteristic dorsiflexion or plantar extension of the foot could be observed. At this point the solution was administered, followed immediately by the IM injection in the triceps muscle of the uppermost thoracic limb. Isoflurane administration was stopped immediately after the blocks were performed and the dogs were allowed to recover from anesthesia.

      Data collection

      Two trained evaluators, blinded to the treatment administered, assessed each dog for motor and sensory blockade. A visual clinical evaluation was used to assess motor and sensory blockade, based on the method described by
      • Portela D.A.
      • Otero P.E.
      • Tarragona L.
      • et al.
      Combined paravertebral plexus block and parasacral sciatic block in healthy dogs.
      . The proprioceptive response and ability to walk were used to assess motor blockade. Proprioceptive response was tested by observing the orientation of the treated limb while walking and dorsiflexion of the paw, and a score from 1 to 3 was given as follows: 1, no effect, normal motor response; 2, partial loss, delayed response and alteration of limb orientation while walking; 3, complete loss, absence of response and alteration of limb orientation while walking. Ability to walk was assessed by observing the dog walk in a straight line on a non-slippery surface and a score 1 or 2 was given: 1, normal, no alteration in locomotion; 2, dog walks with ataxia of treated limb. Sensory blockade was evaluated by observing the response to a noxious stimulus applied with pressure from a Kelly clamp on the skin over the medial aspect of the thigh (innervated by the sensory branch of the femoral nerve, the saphenous nerve), over the caudal aspect of the metatarsus (innervated by the tibial nerve) and over the third phalanx of the fourth digit (innervated by the common fibular nerve). The response was scored from 1 to 3, as follows: 1, no effect, normal response, vigorous or rapid withdrawal of the limb and/or vocalization; 2, partial block, attenuated response, slower withdrawal of the limb without vocalization; 3, complete block, absence of response, without limb movement or head movement toward the stimulated area. The jaws of the clamp were covered with pieces of plastic from an IV administration set and the stimulus was applied sharply by the same investigator, closed just before the first ratchet, for a maximum of 5 seconds to avoid excessive tissue trauma. Following the blocks, scores were determined by evaluation of the treated limb compared with the untreated limb.
      From these scores, onset time and duration of motor and sensory blockade were determined. The onset time of sensory blockade was the time elapsed from perineural administration to the first moment a partial or complete blockade (scores 2 or 3) was detected on the dermatome of the respective nerve. The onset time of motor blockade was the time elapsed from the end of sciatic perineural administration to the first moment any level of blockade (scores 2 or 3 for proprioceptive response and 2 for ability to walk) was detected. The total duration of sensory blockade was the time elapsed during which the dog presented any level of blockade (scores 2 or 3). The total duration of motor blockade was the time elapsed during which the dog presented any level of blockade (scores 2 and 3 for proprioceptive response). The duration of complete motor blockade was the time elapsed during which the dog presented only complete blockade (score 3 proprioception response). The duration of complete sensory blockade was the time elapsed during which the dog exhibited only complete blockade (score 3). Onset times were only considered when the dog could stand on at least three legs.
      Motor and sensory blockades were assessed at baseline (TB), 5 minutes after the end of isoflurane administration (T5), at T15 and then every 15 minutes until total recovery of limb activity. Motor and sensory activities were evaluated 24 and 72 hours following the procedure to assess possible neural deficits.
      Monitoring during general anesthesia included heart rate and arterial blood oxygen saturation using a pulse-oximeter sensor on the tongue; respiratory rate, Fe′Iso and end-tidal carbon dioxide partial pressure using a multiparameter monitor (Cardiocap 5, D-O; GE Healthcare Finland Oy, Finland); and systolic arterial pressure using ultrasonic Doppler (811-B; Parks Medical Electronics Inc., OR, USA) and an aneroid sphygmomanometer (804; American Diagnostic Corporation, NY, USA) at 5 minute intervals. The time required to perform each perineural administration (from needle puncture of the skin until end of injection), the total time under general anesthesia (from intubation until end of isoflurane administration) and the time to extubation (from end of isoflurane administration to extubation) were recorded.

      Statistical analysis

      Statistical analysis was carried out using commercially available software (SAS 2013; SAS Institute Inc., NC, USA). Each variable was tested for normality using the Shapiro-Wilk test. Differences in onset times and durations of sensory and motor blockade and time required to perform the blocks among treatments were evaluated using Friedman's test and the Student–Newman–Keuls post hoc test. Differences in cardiopulmonary variables among treatments were analyzed with repeated-measures anova and Tukey's post hoc test. Differences were considered statistically significant when p < 0.05.

      Results

      Perineural blocks

      The induction of anesthesia with isoflurane was smooth and rapid. The durations of general anesthesia (mean ± SD) were 19.6 ± 7.3, 19.3 ± 5.5 and 20.8 ± 5.7 minutes for GCON, GDPN and GDIM, respectively, and were not statistically different among treatments (p = 0.8866).
      A total of 42 perineural blocks were performed and no complications (resistance during injection or blood aspiration) were observed during the procedure. The times [median (range)] taken to perform the femoral and sciatic blocks were 3.5 (0.7–11.1) and 3.1 (1.4–9.0) minutes for GCON, 3.3 (1.7–6.8) and 3.8 (1.5–10.3) minutes for GDPN, and 5.8 (1.6-16.3) and 4.1 (0.8–14.5) minutes for GDIM, respectively, with no statistically significant difference between treatments or nerves. Target nerves were observed with ultrasound in all occasions. Perineural deposition around the femoral nerve was not observed in one dog in GDIM, even though extension of the stifle was observed at 0.4 mA. This was counted as a block failure and data regarding saphenous/femoral sensory blockade from this dog in the other two treatments were removed from the analysis. Dorsiflexion of the paw was observed with 0.4 mA in all sciatic nerve blocks, except in one dog which only exhibited the characteristic muscular contraction with 0.6 mA in all treatments. The ultrasonographic images from this dog presented adequate perineural administration of the solution and were considered successful. No degree of sensory blockade of the areas innervated by the tibial and common fibular nerves could be detected in one dog in GCON, even though the characteristic muscle contractions were observed with electrostimulation, and perineural deposition of the solution was observed with ultrasound. This was considered to be a block failure, and data regarding tibial and common fibular sensory blockade from this dog in the other two treatments were also removed from analysis. Dogs recovered uneventfully and the times to extubation (mean ± SD) were 2.6 ± 1.4, 2.5 ± 1.0 and 2.3 ± 1.4 minutes for GCON, GDPN and GDIM, respectively, with no statistically significant difference among treatments (p = 0.9240).

      Motor blockade

      All dogs had normal proprioception scores (score 1) and no signs of ataxia at baseline. All three treatments resulted in proprioceptive blockade (scores 2 or 3), with complete blockade (score 3) in four dogs in GCON, six dogs in GPDN and five dogs in GDIM. No significant differences were observed among treatments with regard to onset time and duration of proprioceptive blockade (p = 0.5073 and p = 0.3679, respectively) (Table 1).
      Table 1Median (range) onset time and total duration of partial and complete proprioceptive blockade (score 2 and 3) and duration of complete proprioceptive blockade (score 3), and onset time and duration of ataxia in seven Beagle dogs submitted to femoral and sciatic blocks with perineural ropivacaine (GCON), perineural dexmedetomidine and ropivacaine (GDPN), and perineural ropivacaine and intramuscular dexmedetomidine (GDIM) (n = 7 except where indicated)
      VariableGroup
      GCONGDPNGDIM
      Proprioception
       Onset time (minutes)30 (5–90)45 (15–105)30 (0–75)
       Duration of partial and complete blockade (minutes)300 (10–375)225 (15–270)300 (105–355)
       Duration of complete blockade (minutes)233 (165–330) (n = 4)128 (90–195) (n = 6)150 (30–240) (n = 5)
      Ability to walk
       Onset time of ataxia (minutes)5 (5–30)5 (5–30)5 (5–15)
       Duration of ataxia (minutes)400 (180–565)390 (285–520)315 (270–490)
      n, number of dogs; score 1, no effect and normal motor response; score 2, partial loss, delayed response and alteration of limb orientation while walking; score 3, complete loss, absence of response and alteration of limb orientation while walking.
      Ataxia was observed in all dogs after perineural injections in the three treatments. The onset time and duration of altered ability to walk were similar among treatments and no significant differences were detected (p = 0.7251 and p = 0.3679, respectively) (Table 1).

      Sensory blockade

      All dogs had normal sensory activity scores (score 1) at baseline. In the area innervated by the saphenous nerve, all treatments resulted in complete blockade, except in one dog in GDIM as described earlier. Onset time of blockade did not differ significantly among treatments (p = 0.4169). The median total duration of blockade (scores 2 and 3) and duration of complete blockade (score 3) were longer in GDPN than in the other treatments, but did not reach statistical significance (p = 0.1146 and p = 0.0695, respectively) (Table 2). In the area innervated by the common fibular nerve, GCON resulted in complete blockade in five dogs and partial blockade in one dog, GDPN resulted in complete blockade in six dogs and partial blockade in one dog, and GDIM resulted in complete blockade in five dogs and partial blockade in two dogs. Onset times and total durations of blockade (scores 2 and 3) in the region innervated by the common fibular nerve did not differ significantly among treatments (p = 0.5818 and p = 0.5134, respectively) (Table 2). In the area innervated by the tibial nerve, GCON resulted in complete blockade in five dogs and partial blockade in one dog, GDPN resulted in complete blockade in six dogs and partial blockade in one dog, and GDIM resulted in complete blockade in four dogs and partial blockade in three dogs. Onset times to sensory blockade were similar among treatments and did not differ statistically (p = 0.3247). The duration of partial and complete blockade (scores 2 and 3) was significantIy longer in GDPN than in GDIM [323 (240–360) versus 255 (105–345) minutes; p = 0.0302], and no significant differences were detected between GDPN and GCON or between GCON and GDIM (TabIe 2).
      Table 2Median (range) onset time and duration of partial and complete sensory blockade (score 2 and 3) and duration of complete sensory blockade (score 3) of the areas innervated by the saphenous nerve, common fibular nerve and tibial nerve of seven Beagle dogs submitted to femoral and sciatic blocks with perineural ropivacaine (GCON), perineural dexmedetomidine and ropivacaine (GDPN), and perineural ropivacaine and intramuscular dexmedetomidine (GDIM) (n = 6 except where indicated)
      Area of innervationGroup
      GCONGDPNGDIM
      Saphenous (femoral) nerve
       Onset time (minutes)10 (7–67)11 (8–28)13 (8–80)
       Duration of partial and complete blockade (minutes)278 (90–510)365 (265–460)208 (150–370)
       Duration of complete blockade (minutes)260 (75–370)275 (190–370)148 (90–235)
      Common fibular nerve
       Onset time (minutes)32 (16–46)24 (16–47)31 (16–32)
       Duration of partial and complete blockade (minutes)285 (120–405)300 (225–375)203 (195–450)
       Duration of complete blockade (minutes)240 (60–330) (n = 5)173 (60–285)180 (15–255) (n = 5)
      Tibial nerve
       Onset time (minutes)31 (16–45)39 (19–62)32 (30–62)
       Duration of partial and complete blockade (minutes)233ab (120–570)323a (240–360)255b (105–345)
       Duration of complete blockade (minutes)210 (75–330) (n = 5)173 (30–225)143 (105–240) (n = 4)
      Different superscript letters indicate significant difference between treatments (p < 0.05). n, number of dogs; score 1, no effect, normal response, vigorous or rapid withdrawal of the limb and/or vocalization; score 2, partial block, attenuated response, slower withdrawal of the limb without vocalization; score 3, complete block, absence of response, without limb movement or head movement toward the stimulated area.

      Discussion

      The results obtained in this study do not support the hypothesis that perineural dexmedetomidine combined with ropivacaine decreases onset time and increases duration of sensory blockade.
      The locoregional technique used in the present study has been successful in both cadaveric, through evaluation of nerve staining, and clinical trials (
      • Campoy L.
      • Bezuidenhout A.J.
      • Gleed R.D.
      • et al.
      Ultrasound-guided approach for axillary brachial plexus, femoral nerve, and sciatic nerve blocks in dogs.
      ,
      • Campoy L.
      • Martin-Flores M.
      • Ludders J.W.
      • et al.
      Comparison of bupivacaine femoral and sciatic nerve block versus bupivacaine and morphine epidural for stifle surgery in dogs.
      ). In the clinical setting, these blocks provide analgesia distal to and including the stifle. Only two out of the 42 perineural blocks (4.8%) failed to result in at least a partial sensory blockade. The high success rate in this study is attributed to performing the blocks under ultrasound and electrical stimulation guidance, techniques that offer anatomical and electrophysiological confirmation of the target nerve and allow visualization of the needle and deposition of the local anesthetic solution (
      • Marhofer P.
      • Greher M.
      • Kapral S.
      Ultrasound guidance in regional anaesthesia.
      ,
      • Campoy L.
      • Bezuidenhout A.J.
      • Gleed R.D.
      • et al.
      Ultrasound-guided approach for axillary brachial plexus, femoral nerve, and sciatic nerve blocks in dogs.
      ). In the instance of the unsuccessful femoral blockade, it is probable that the needle failed to penetrate the fascia iliaca that lies over the nerve (
      • Echeverry D.F.
      • Gil F.
      • Laredo F.
      • et al.
      Ultrasound-guided block of the sciatic and femoral nerves in dogs: a descriptive study.
      ).
      Ropivacaine is a long-acting amide local anesthetic which was chosen because it provides a duration of action between those of bupivacaine and lidocaine (
      • Sakonju I.
      • Maeda K.
      • Maekawa R.
      • et al.
      Relative nerve blocking properties of bupivacaine and ropivacaine in dogs undergoing brachial plexus block using a nerve stimulator.
      ,
      • Martin-Flores M.
      Clinical pharmacology and toxicology of local anesthetics and adjuncts.
      ), providing sufficient time to perform most surgical procedures. Advantages of ropivacaine over bupivacaine include lower systemic toxicity (
      • Feldman H.S.
      • Arthur R.
      • Covino B.G.
      Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine and lidocaine in the conscious dog.
      ,
      • Moller R.
      • Covino B.G.
      Cardiac electrophysiologic properties of bupivacaine and lidocaine with those of ropivacaine, a new amide local anesthetic.
      ) and lower motor blocking efficacy (
      • Merson N.
      A comparison of motor block between ropivacaine and bupivacaine for continuous labor epidural analgesia.
      ). However, in our study, the durations of sensory blockade of the areas innervated by the femoral and sciatic nerves and motor blockade were similar. The lack of selectivity may result from the use of 0.75% ropivacaine, as a greater degree of motor blockade is reported with higher concentrations (
      • Merson N.
      A comparison of motor block between ropivacaine and bupivacaine for continuous labor epidural analgesia.
      ).
      Onset time to sensory and motor blockade did not differ among treatments, regardless of the route of dexmedetomidine administration. This is in agreement with studies in humans (
      • Rancourt M.M.
      • Albert N.T.
      • Côté M.
      • et al.
      Posterior tibial nerve sensory blockade duration prolonged by adding dexmedetomidine to ropivacaine.
      ,
      • Marhofer D.
      • Kettner S.C.
      • Marhofer P.
      • et al.
      Dexmedetomidine as an adjuvant to ropivacaine proIongs peripheral nerve block: a volunteer study.
      ,
      • Zhang Y.
      • Wang C.
      • Shi J.
      • et al.
      Perineural administration of dexmedetomidine in combination with ropivacaine prolongs axillary brachial plexus block.
      ) and dogs (
      • Lamont L.A.
      • Lemke K.A.
      The effects of medetomidine on radial nerve blockade with mepivacaine in dogs.
      ). In the latter study, the authors reported that perineural or IM medetomidine (10 μg kg−1) also caused significant sedation, which might have influenced the evaluation (
      • Lamont L.A.
      • Lemke K.A.
      The effects of medetomidine on radial nerve blockade with mepivacaine in dogs.
      ). The findings of the present study are in contrast to the results of others that reported a significant decrease in onset time to sensory and motor blockade in humans with perineural dexmedetomidine (
      • Esmaoglu A.
      • Yegenoglu F.
      • Akin A.
      • et al.
      Dexmedetomidine added to levobupivacaine proIongs axillary plexus block.
      ,
      • Kaygusuz K.
      • Kol I.O.
      • Duger C.
      • et al.
      Effects of adding dexmedetomidine to levobupivacaine in axillary brachial plexus block.
      ,
      • Agarwal S.
      • Agarwal R.
      • Gupta P.
      Dexmedetomidine prolongs the effect of bupivacaine in supraclavicular brachial plexus block.
      ,
      • Gurav S.Y.
      • Kulkarni A.M.
      Dexmedetomidine added to levobupivacaine prolongs the duration of anaesthesia and analgesia after axillary brachial plexus block.
      ,
      • Nema N.
      • Badgaiyan H.
      • Raskaran S.
      • et al.
      Effect of addition of dexmedetomidine to ropivacaine hydrochloride (0.75%) in brachial plexus block through supraclavicular route in upper limb surgeries: a clinical comparative study.
      ). The authors of the present study believe that onset times to sensory and motor blockade were unaffected by residual sedation from isoflurane anesthesia or dexmedetomidine administration, as all the dogs recovered rapidly from anesthesia and none of the dogs exhibited signs of sedation during the evaluation period.
      The durations of sensory blockade in the control and IM dexmedetomidine treatments were similar to those recorded in dogs after injection of 0.75% ropivacaine for brachial plexus block (
      • Sakonju I.
      • Maeda K.
      • Maekawa R.
      • et al.
      Relative nerve blocking properties of bupivacaine and ropivacaine in dogs undergoing brachial plexus block using a nerve stimulator.
      ). However, the addition of dexmedetomidine perineurally did not increase the duration of sensory or motor blockade compared with perineural administration of ropivacaine. This is in contrast to previous studies conducted in humans, in which the addition of dexmedetomidine to ropivacaine for brachial plexus and tibial nerve blocks prolonged sensory blockade and increased the duration of motor blockade (
      • Rancourt M.M.
      • Albert N.T.
      • Côté M.
      • et al.
      Posterior tibial nerve sensory blockade duration prolonged by adding dexmedetomidine to ropivacaine.
      ,
      • Zhang Y.
      • Wang C.
      • Shi J.
      • et al.
      Perineural administration of dexmedetomidine in combination with ropivacaine prolongs axillary brachial plexus block.
      ). None of these studies included subjects submitted to systemic administration of dexmedetomidine and therefore we cannot conclude that the effects were due to peripheral mechanisms. Conversely,
      • Marhofer D.
      • Kettner S.C.
      • Marhofer P.
      • et al.
      Dexmedetomidine as an adjuvant to ropivacaine proIongs peripheral nerve block: a volunteer study.
      performed ulnar nerve blocks in human patients using perineural ropivacaine, perineural ropivacaine plus dexmedetomidine (20 μg) or perineural ropivacaine plus IM dexmedetomidine (20 μg), similar to the present study. The results indicated an increased duration of sensory blockade in both groups treated with dexmedetomidine compared with the control, as well as an increase in the perineural dexmedetomidine group compared with the IM group, which may indicate a peripheral mechanism of action of dexmedetomidine. In dogs, however, the addition of 10 μg kg-1 of medetomidine to mepivacaine for radial nerve block, administered perineurally or IM, increased the duration of sensory blockade compared with the control (
      • Lamont L.A.
      • Lemke K.A.
      The effects of medetomidine on radial nerve blockade with mepivacaine in dogs.
      ). However, the difference between the two routes of administration was not statistically significant. It is possible that, due to the elevated dose of medetomidine used in that study, the potential peripheral effects were concealed by the systemic analgesic effects of the adjuvant when administered perineurally.
      A possible mechanism of action of perineural dexmedetomidine is blockade of the hyperpolarization-activated cation (Ih) current, not by interaction with α2-receptors (
      • Brummett C.M.
      • Hong E.K.
      • Janda A.M.
      • et al.
      Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current.
      ). The Ih current is an important mechanism to re-establish the resting potential of a nerve and, if blocked, will result in prolonged hyperpolarization and sensory blockade (
      • Brummett C.M.
      • Hong E.K.
      • Janda A.M.
      • et al.
      Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current.
      ). This mechanism may also result in a selective sensory blockade by having a greater effect on C fibers than on Aα fibers (
      • Gaumann D.M.
      • Brunet P.C.
      • Jirounek P.
      Hyperpolarizing afterpotentials in C fibers and local anesthetic effects of clonidine and lidocaine.
      ).
      Although the median durations of sensory blockade of all three nerves were increased in GDPN, statistical significance was only achieved for the tibial nerve compared with GDIM, which was not expected. It is possible that the dose of dexmedetomidine used in the present study was too low to produce any significant effect, as studies in humans have employed higher doses of dexmedetomidine and the increase in sensory blockade appears to be dose-dependent (
      • Brummett C.M.
      • Padda A.K.
      • Amodeo F.S.
      • et al.
      Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve block in rat.
      ). An effective concentration of dexmedetomidine in local anesthetic solutions for perineural blockade is currently under investigation. In a case series, dogs submitted to orthopedic surgery were managed with femoral and sciatic nerve blocks using dexmedetomidine (0.5 μg mL-1) added to ropivacaine or bupivacaine (0.1 mL kg-1 per nerve) and IV infusion of propofol and dexmedetomidine during the procedure (
      • Campoy L.
      • Martin-Flores M.
      • Ludders J.W.
      • et al.
      Procedural sedation combined with locoregional anesthesia for orthopedic surgery of the pelvic limb in 10 dogs: a case series.
      ). No rescue analgesia was necessary within 10 hours after the blockade. However, the dogs were administered a non-steroidal anti-inflammatory drug and the study did not evaluate the effects of addition of dexmedetomidine to bupivacaine, and thus cannot be directly compared with the present study. Another possible explanation is heterogeneous deposition of the anesthetic solution around the nerves, even though the same person executed all the blocks, using the same end point to determine the correct needle placement. The administrations were carried out as a single injection and the needle was not relocated to attempt a circumferential spread (doughnut sign) around the nerve. Although the doughnut sign is considered a good indicator of a successful block (
      • Van Geffen G.J.
      • Gielen M.
      Ultrasound-guided subgluteal sciatic nerve blocks with stimulating catheters in children: a descriptive study.
      ), the single injection technique was observed in canine cadavers to result in adequate staining of the nerves with methylene blue (
      • Echeverry D.F.
      • Laredo F.G.
      • Gil F.
      • et al.
      Ultrasound-guided 'two-in-one' femoral and obturator nerve block in a dog: an anatomical study.
      ). There may also be anatomical variation among the dogs, such as different fascia thickness, which could alter the diffusion of dexmedetomidine and ropivacaine to the nerves and may explain the high variation in duration of sensory blockade within treatments. Moreover, the small sample size may have affected the ability to determine statistically significant differences between GCON and GDPN.
      Other limitations of this study include the type of noxious stimulus employed to evaluate sensory activity and the failure to achieve complete sensory blockade in all the dogs. Small myelinated Aδ fibers may be more susceptible to anesthetic blockade than larger myelinated Aδ fibers (
      • Ford D.J.
      • Raj P.P.
      • Singh P.
      • et al.
      Differential peripheral nerve block by local anesthetics in the cat.
      ). Therefore, it is possible that some dogs may have responded to the pressure of the clamp and not to the nociception per se, as suggested by
      • Portela D.A.
      • Otero P.E.
      • Tarragona L.
      • et al.
      Combined paravertebral plexus block and parasacral sciatic block in healthy dogs.
      , and the block may still be effective in a clinical scenario. Complete sensory blockade of the sciatic branches may have been 100% effective if plantar flexion was obtained instead of dorsiflexion during nerve stimulation for the sciatic block. This response is characteristic of tibial nerve stimulation, which is significantly thicker than the common fibular nerve and predicts a more frequent success rates in humans (
      • Taboada M.
      • Atanassoff P.G.
      • Rodríguez J.
      • et al.
      Plantar flexion seems more reliable than dorsiflexion with Labat's sciatic nerve block: a prospective, randomized comparison.
      ).
      In conclusion, administration of dexmedetomidine, perineurally or IM, combined with perineural 0.75% ropivacaine for femoral and sciatic nerve blocks at the doses used in this study did not significantly change the onset time to sensory or motor blockade, or prolong the duration of motor blockade. The duration of sensory blockade was prolonged by perineural addition of dexmedetomidine compared with IM or no administration of dexmedetomidine, but the duration was only significantly increased for the tibial nerve when compared with IM administration. The results of the present study warrant further investigation with higher concentrations of dexmedetomidine added to the local anesthetic to determine whether dexmedetomidine has a concentration effect in perineural blockade in dogs.

      Acknowledgements

      The authors thank the Coordination for the Improvement of Higher Education Personnel (CAPES) and the São Paulo Research Foundation (FAPESP) , grant numbers 2014/10449-8 and 2014/24043-0 , for the Masters scholarship provided to TAT and financial support, respectively.

      Authors' contributions

      TAT: conception, design, execution of the technique, data interpretation and preparation of manuscript. BPF: design, data collection, data interpretation and proofreading. JTW: design, data collection and data interpretation. JZF: design, data collection and data management. GLS: data collection and data management. PSPS: design, data interpretation, preparation of manuscript and proofreading. SHVP: statistical analysis and data interpretation. VNLSO: conception, design, data interpretation, preparation of manuscript and proofreading.

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