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Caudal epidural anesthesia in mares after bicarbonate addition to a lidocaine–epinephrine combination
Accepted Manuscript Caudal epidural anesthesia in mares after bicarbonate addition to a lidocaineepinephrine combination Patricia C. Duarte, Cahuê FR. Paz, Alvaro PL. Oliveira, Thairê P. Maróstica, Leticia O. Cota, Rafael R. Faleiros PII:
S1467-2987(17)30055-7
DOI:
10.1016/j.vaa.2016.11.003
Reference:
VAA 81
To appear in:
Veterinary Anaesthesia and Analgesia
Received Date: 17 August 2016 Revised Date:
2 November 2016
Accepted Date: 4 November 2016
Please cite this article as: Duarte PC, Paz CF, Oliveira AP, Maróstica TP, Cota LO, Faleiros RR, Caudal epidural anesthesia in mares after bicarbonate addition to a lidocaine-epinephrine combination, Veterinary Anaesthesia and Analgesia (2017), doi: 10.1016/j.vaa.2016.11.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT RESEARCH PAPER
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PC Duarte et al.
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Lidocaine-bicarbonate equine epidural block
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Caudal epidural anesthesia in mares after bicarbonate addition to a lidocaine-
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epinephrine combination
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Patricia C Duarte, Cahuê FR Paz, Alvaro PL Oliveira, Thairê P Maróstica, Leticia O Cota &
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Rafael R Faleiros
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Department of Veterinary Clinics and Surgery, Universidade Federal de Minas Gerais, Belo
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Horizonte, Brazil
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Correspondence: Rafael R Faleiros, Escola de Veterinária da Universidade Federal de
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Minas Gerais, Departamento de Clínica e Cirurgia Veterinárias, Av. Antônio Carlos 6627,
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caixa postal 567, Campus Pampulha da UFMG, Belo Horizonte, Minas Gerais, Brasil, 31270-
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901. E-mail: [email protected]
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Abstract
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Objective To investigate the nociceptive and clinical effects of buffering a lidocaine-
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epinephrine solution with sodium bicarbonate in caudal epidural block in mares.
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Study design Prospective randomized controlled trial.
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Animals Six mixed-breed mares weighing 350–440 kg.
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Methods Each animal was administered two caudal epidural injections, 72 hours apart, using
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different solutions prepared immediately before injection. The control solution was 7 mL 2%
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lidocaine hydrochloride with epinephrine hemitartrate (1:200 000) added to 3 mL sterile
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ACCEPTED MANUSCRIPT water for injection (pH 2.9). The alkalinized solution was 7 mL of lidocaine-epinephrine
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solution added to 2.3 mL sterile water for injection and 0.7 mL 8.4% sodium bicarbonate (pH
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7.4). Nociception was evaluated by response to skin pinching at 31 sites in the sacral region
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and around the perimeter of the anogenital area (distances of 10, 15, and 20 cm) before and 5,
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10 and 15 minutes after epidural injection, then every 15 minutes until the return of
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nociception in all evaluated sites. The onset and duration times, and intensity of ataxia
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(grades 0 to 3) were recorded. The paired t test was used to compare the onset and duration of
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anesthesia and ataxia (p < 0.05).
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Results Alkalization of the solution resulted in significant decreases in the average time of
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onset of loss of nociception in the sacral region (40%) and around the perimeter of the
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anogenital area extending up to 5 cm (36%) and from 5 to 10 cm (32%) from the anus and
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vulva. Alkalization also decreased the average duration of ataxia (33%), without affecting the
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duration and extent of anesthesia or the degree of ataxia.
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Conclusions and clinical relevance Alkalization of lidocaine-epinephrine solution is
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advantageous in shortening the duration of ataxia and hastening the onset of anesthesia in
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areas adjacent to the anogenital area, without reducing the duration of epidural anesthesia, in
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mares.
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Keywords epinephrine, equine, local anesthetic, nociception, sodium bicarbonate.
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ACCEPTED MANUSCRIPT Introduction
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Lidocaine is a local anesthetic with rapid onset and moderate duration of activity and
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moderate toxicity, and is therefore the most widely used agent for local anesthesia in
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veterinary medicine (Garcia 2015). Although concerns exist about the risk of ischemia and
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tissue necrosis when vasoconstrictors are added to the epidural solution (Moyer et al. 2011;
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Garcia 2015), epinephrine may increase duration of equine epidural anesthesia when added to
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lidocaine (Carpenter & Byron 2015; Garcia 2015).
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Epidural anesthesia can be performed in the standing horse, avoiding the risks of decubitus
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and arising from general anesthesia (Robinson & Natalini 2002; Garcia 2015). However, the
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onset of epidural anesthesia with lidocaine can be particularly long in horses compared with
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other domestic species (Hall et al. 2001; Garcia 2015). This may lead to the false conception
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that the epidural space was not reached (Hall et al 2001) or a long onset time may be a
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problem in patient management, especially for a restless horse requiring physical restraint
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and sedation and in emergency situations.
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Commercially available local anesthetic with vasoconstrictor solutions are formulated to be
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acidic to avoid oxidation of epinephrine and increase shelf life (Moore 1981; Lambert 2002;
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Garcia 2015). This low pH results in predominance of the ionized hydrophilic form,
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diminishing diffusion of the anesthetic through cell membranes and delaying its arrival at the
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site of action (Garcia 2015). The medical and veterinary literature reports quicker onset of
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anesthesia (DiFazio et al. 1986; Fernando & Jones 1991; Patel et al. 1996) and reduced pain
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on injection (McKay et al. 1987; Eccarius et al. 1990) when sodium bicarbonate is added to a
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local anesthetic thereby increasing the pH to a physiologic value.
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This study aimed to evaluate and compare the onset, duration and sites anesthetized in the
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anogenital region, and some clinical effects, with caudal epidural anesthesia in horses
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performed using lidocaine with epinephrine, with and without sodium bicarbonate added as
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an alkalizing agent. The hypothesis was that adjusting the pH of the epidural injectate to
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within the physiological range before administration can reduce the anesthesia latency time.
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Materials and methods
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Animals
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The study was approved by the Ethics Committee on Animal Use of the Universidade Federal
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de Minas Gerais, Brazil (no. 200/2013). Six mixed-breed mares were selected from a group
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of 8 horses. They were aged [mean ± standard deviation (SD)] 12.8 ± 2.8 years (range: 8–16
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years), with body condition score of 6.5 ± 1 (range: 5–8) out of 9, and weight of 397 ± 40 kg
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(range: 350–440 kg). All six mares were considered physically healthy on clinical
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examination and had been proved to have a predictable anesthetic response to caudal epidural
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injection of lidocaine 2% using the technique described below. The mares were kept in a
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group paddock, where they were fed with Tifton hay and had access to water ad libitum.
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Anesthetic solutions
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Each animal was administered two treatments at an interval of at least 72 hours. The order of
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treatments was randomized (toss of a coin) for each mare without the knowledge of the
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evaluator, in a crossover design. The control solution (treatment CON) was 7 mL lidocaine
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hydrochloride
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Pharmaceuticals Ltd., Brazil) and 3 mL sterile water for injection (Equiplex Pharmaceutical
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Industry, Brazil). The alkalinized solution (treatment ALC) was 7 mL lidocaine
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hydrochloride with epinephrine hemitartrate 1:200 000, 0.7 mL sodium bicarbonate (8.4%
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sodium bicarbonate; Samtec Biotechnology, Brazil) and 2.3 mL sterile water for injection
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with
epinephrine
hemitartrate
1:200 000
(Xylestesin
2%;
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(equivalent to 0.005 mEq bicarbonate per mg of lidocaine). The solutions were prepared by
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an assistant at the time of epidural administration. The pH and density of both solutions were
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measured with a pH meter (mPA210; MS Tecnopon Instrumentation, Brazil) and a
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refractometer (RHC-200ATC; Megabrix, Brazil), respectively.
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Assessments
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The sites to be tested were demarcated on the horse (Fig.1). Four concentric ellipses were
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drawn 5, 10, 15, and 20 cm outside the virtual ellipse delimited by anus and vulva. In
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addition, two lines were drawn parallel to the ground, the first at the level of the anal
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sphincter and the second at the ventral vulvar commissure, and two lines were drawn parallel
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to the longitudinal axis of the sacral vertebrae at the level of the lateral borders of the tail.
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The test sites were located at the centers of the delimited areas on both antimeres and the
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sacrum, and at the anal sphincter, perineum, dorsal and ventral vulvar commissures. For
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analysis purposes, the test sites were grouped in six concentric anatomic regions as follows:
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the anogenital (AG) region, sacral (SC) region, and perianogenital regions corresponding to
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the ellipses 5, 10, 15, and 20 cm outside the anogenital region (P5-P20). In addition, the sites
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were grouped on the basis of a dorsal–ventral distribution in anatomic thirds: dorsal (DT),
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middle (MT) and ventral (VT) (Fig. 1).
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The nociception was tested with the horse confined in a stocks by using a pinching technique
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with an Adson thumb forceps, and systematically applying stimulation at the 31 defined sites.
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Nociception was always assessed by the same evaluator blinded to the treatment. To avoid
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distractions in the environment on the behavior of the mare, a blindfold was applied over the
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eyes of each animal during the nociception test. In the week previous to the experimental
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period, all the horses were acclimatized in the stocks with a blindfold once a day for 3 hours.
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ACCEPTED MANUSCRIPT Positive reactions to the noxious stimulus were raising and pricking the ears, turning the head
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towards the croup, tucking the croup, and threatening to kick.
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Tests for nociception were performed before anesthesia (T0); 5 (T1), 10 (T2), and 15 (T3)
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minutes after epidural injection; and 15 minutes thereafter until positive reactions to the
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noxious stimulus were observed in all tested areas. Heart rate (HR), respiratory rate (fR), and
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rectal temperature (RT) were measured before nociception testing at T0, T3, and T4 and
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every 30 minutes thereafter. At these same time points, after nociceptive testing, the horse
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was unmasked and encouraged to walk out of the stocks. Ataxia was scored 0-3: 0, walking
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and turning firmly; 1, mild ataxia, walking with some limb weakness; 2, moderate ataxia,
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walking with support, staggering, risk of falling when turned; 3, marked ataxia, inability to
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walk or exit the stocks without risk of falling, falling when turned (Taylor et al. 2014). Mares
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were only returned to the group paddock when pain sensation and motor function were
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considered totally normal.
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Epidural technique
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With the mare restrained in the stocks, the sacrococcygeal region was shaved. The site for
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needle insertion was identified by moving the tail up and down and palpation of the first
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articulation caudal to the sacrum. After the shaved area had been prepared according to a
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surgical antisepsis technique, a 1.7 × 50 mm needle with no stilette (Angiocath, BD Medical,
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Brazil) was inserted in the center of the palpated depression at a 90° angle to the skin plane.
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The correct placement of the needle in the epidural space was confirmed using the hanging-
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drop method and sensing a lack of resistance in the syringe plunger during solution infusion.
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The same researcher (PD) performed all the epidural injections.
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ACCEPTED MANUSCRIPT Statistical analysis
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The nociception data were analyzed in two ways. First, the effect of the treatment on the
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onset and duration of anesthesia was analyzed by comparing the values of each site and the
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values of each region (the arithmetic mean of all sites in the region) between treatments.
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Second, the effect of the treatment on the distribution of the anesthetic solution was analyzed
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in each treatment by comparing the values for the onset and duration of the anesthesia among
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the dorsal, middle, and ventral thirds and between antimeres. The paired t test was used to
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compare values between treatments or antimeres. A repeated measures ANOVA was used to
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compare values among thirds within treatments.
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The clinical variables (HR, fR and RT) were subjected to a two-way repeated measures
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ANOVA followed by the Tukey’s post hoc test. Ataxia was compared between treatments by
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using the Mann–Whitney test for degree data and the paired t test for duration data.
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For all parametric analyses, normality was assessed using the Shapiro–Wilk test and, if
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necessary, data were transformed before analysis by using the natural logarithms. Statistical
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analyses were performed using the SigmaStat 4.0 software (Systat Software, CA, USA) and
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GraphPad Prism 5.0 (GraphPad Software, CA, USA), and p < 0.05 was considered
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significant.
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Results
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From an initial group of eight mares, two mares were rejected. The perineum in the first mare
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could not be anesthetized and in the second, epidural anesthesia always appeared to be
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unilateral.
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The pH and density of the epidural solutions were pH 2.98 and 1010 g L-1 in CON and pH
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7.44 and 1012 g L-1 in ALC. The onset of anesthesia was significantly shorter in ALC than in 7
ACCEPTED MANUSCRIPT CON, by 40% in the SC region, 36% in P5, and 32% in P10 (p = 0.029, p = 0.003 and p =
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0.005, respectively) (Table 1). There were no significant differences between treatments in
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the duration of anesthesia, or between the left and right antimeres.
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Failures of desensitization occurred in both treatments with the sum of 18 unblocked areas
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within each treatment. In CON, there was one unblocked area in AG, two in P5, four in P15,
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and 11 in P20. In ALC, there was one unblocked area in P5, three in P15, and 14 in P20.
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Failures of desensitization occurred predominantly in the ventral areas.
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There was a reduced time of onset and extended duration of anesthesia in the dorsal region
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compared with the middle (p = 0.012 and p = 0.028, respectively) and ventral (p = 0.045 and
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p = 0.048, respectively) regions in CON and a significantly greater duration of anesthesia in
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the dorsal (p = 0.016) and middle (p = 0.008) regions compared with the ventral region in
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ALC (Table 2). Onset of anesthesia was not different between these regions in ALC (Table
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2). Times of onset and duration of anesthesia for all tested sites in both treatments are
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presented in Table 3.
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HR, fR and RT did not change between baseline and the subsequent times in both treatments.
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There were no statistical differences in ataxia scores between treatments. Ataxia was first
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detected at 15 minutes after epidural injection in both treatments. Duration of ataxia was
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shorter in ALC (84.0 ± 29.2 minutes) than in CON ( 125.8 ± 51.0 minutes) (p = 0.033). Two
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animals were assigned ataxia scores of 2 and one animal a score of 1 in both treatments. Two
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more animals displayed ataxia in both treatments; one animal was scored 3 in CON and 2 in
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ALC, and the other animal was scored 2 in CON and 1 in ALC. The sixth animal was scored
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2 in CON but displayed no ataxia in ALC.
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Discussion 8
ACCEPTED MANUSCRIPT The present study results show that alkalization of a commercial solution of lidocaine-
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epinephrine to a physiological pH value results in a shorter time of onset of anesthesia close
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to the anogenital area in epidural anesthesia in mares. The alkalization of local anesthetics
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with sodium bicarbonate was first reported in 1901, resulting in increased potency and shorter
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onset of action of procaine (Patel et al. 1996). Similarly, lidocaine combined with sodium
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bicarbonate for pH adjustment resulted in faster onset of anesthesia and surgical anesthesia,
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as well as faster spread of sensory blockade (DiFazio et al. 1986).
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The addition of carbon dioxide (carbonization) to lidocaine has also been shown to hasten the
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onset and improve epidural anesthesia in humans (Bromage 1965; Schelling & Klein 1985;
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Garcia 2015). However, its epidural use in horses did not alter the time of onset, the duration,
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or the extent of the block (Schelling & Klein 1985). A commercially available lidocaine-
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epinephrine solution, which has a lower pH to avoid oxidation of epinephrine and increase
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shelf life (Moore 1981; Lambert 2002; Garcia 2015), was used in our study. Thus, the marked
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difference in the pH of tested solutions (2.98 to 7.44) in the present study when compared to
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those from the study that used carbonization (5.3 to 6.5) may explain such discrepancies.
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In comparison, epidural block with lidocaine in cattle may take less than 5 minutes to develop
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complete perineal analgesia (Bigham et al. 2010), whereas the block may take up to 20
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minutes to develop in horses (Hall et al. 2001). The longer time for developing epidural
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anesthesia in horses after lidocaine epidural injection may induce the veterinarian to falsely
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conclude that the epidural space was not reached (Hall et al. 2001). A reasonable explanation
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for this difference was not found in the literature. However, this study showed that
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alkalization of the anesthetic solution may provide more consistent epidural anesthesia in
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horses.
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ACCEPTED MANUSCRIPT In the present study, the treatments were applied at least 72 hours apart. Considering that the
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total body clearance of intravenously infused lidocaine in horses is 29 mL kg-1 minute-1
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(Garcia 2015), the horses in this experiment would have taken 16 to 21 hours to have blood
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free of circulating lidocaine. In humans, the slow absorption half-life of lidocaine-
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epinephrine solution is 6.6 hours; therefore, it takes approximately 24 hours for 20 mL to be
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completely absorbed from the epidural space (Tucker & Mather 1979). Nevertheless, the
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order of treatments was randomly selected for each mare to offset possible effects of one
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treatment on the other.
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In the comparisons among the dorsal, middle, and ventral thirds within each treatment, the
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onset of anesthesia was longer in the middle and ventral thirds compared with the dorsal third
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in the CON treatment. In the ALC treatment such differences were not significant. This may
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be explained by the improved absorption of anesthetic solutions with a physiological pH.
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This homogeneity in the onset of action observed in the dorsal, middle and ventral thirds may
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be considered another advantage of anesthetic solution pH adjustment for epidural
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administration in mares. The duration of anesthesia, however, differed to a greater extent
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between regions in the ALC than CON treatment. Further study is needed to determine the
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mechanisms responsible for the greater heterogeneity of block duration with the ALC
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solution.
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Although individual asymmetries were observed in most animals, there were no significant
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differences in the time of onset or duration of anesthetic action between the right and left
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antimeres in either of the treatments. A finding of predominant asymmetry, consistent
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desensitization of one antimere more than the other, could have indicated incorrect technique,
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eg. angling the needle during insertion. Previous studies have reported that individual
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variation in desensitized areas and asymmetries are common findings for epidural anesthesia
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ACCEPTED MANUSCRIPT in horses (Skarda & Muir 1983; Schelling & Klein 1985). The presence of congenital
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membranes or adhesions in the epidural space could explain the unilateral anesthesia
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(Robinson & Natalini 2002), but no further investigation was made in these mares. To ensure
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greater reliability in the comparison between treatments in this study, only mares with
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symmetric and predictable responses in the pre-study testing were included in the
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experimental protocol.
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It has been proposed that increasing the volume or concentration of local anesthetic will
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speed the onset of epidural anesthesia and the addition of sodium bicarbonate may be of little
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value (Lambert 2002). However, the pH of commercially available lidocaine solutions vary
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and the lidocaine-epinephrine solution used in this study has a low pH. The results of this
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study indicate that for this lidocaine preparation, correcting the acidity of the solution to a
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physiologic pH is advantageous.
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In the present study, no precipitation was observed in the anesthetic solution after bicarbonate
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solution addition. However, precipitation after autoclaving has been reported in lidocaine
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solutions with a pH above 7.4 (Zehetmayer et al. 1997; Fuchsjäger-Mayrl et al. 2002).
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The specific gravity of solutions used in epidural anesthesia has been reported as an
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influencing factor in time of onset. In addition, the density of a solution is not affected by the
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concentration of anesthetic or volume administered. In their study of epidural anesthesia in
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horses, DeRossi et al. (2005) attributed a more rapid onset with hyperbaric 5% lidocaine than
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2% lidocaine to the difference in specific gravity. The densities of the solutions used in the
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present study were similar, 1010 g L-1 and 1012 g L-1, and exceeded the density of equine
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cerebrospinal fluid (1006 g L-1) (Polydoro et al. 2008). Therefore, the specific gravity of the
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ALC and CON solutions was not considered an influencing factor in the reduced time of
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onset in the ALC treatment.
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ACCEPTED MANUSCRIPT Epinephrine, used as an additive for many local anesthetics, could potentially cause
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cardiovascular effects when absorbed systemically, such as increased HR (Kozody et al.
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1984; Garcia 2015) and decreased peripheral resistance (Niwa et al. 1991). In this study, HR
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fluctuations remained within physiologic limits for the species and no adverse reactions,
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other than ataxia, were induced by the anesthetic solutions.
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The occurrence of ataxia is relatively common during epidural anesthesia in horses because
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of the development of motor block (Hall et al. 2001; Robinson & Natalini 2002; Skarda et al.
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2005; Carpenter & Byron 2015). In the present study, the animals showed a significantly
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shorter duration of ataxia with the ALC than CON treatment. This may be interpreted as
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differential block between motor and sensory fibers, because the duration of anesthesia did
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not differ between treatments. A similar phenomenon was observed by Sadegh & Shafiei
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(2008), who reported no ataxia in horses undergoing epidural block with lidocaine combined
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with magnesium sulfate. Differences in ataxia among studies may be related to the different
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additives, as there was no difference in anesthetic concentration between treatments in the
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present study to explain the phenomenon. Medical reports have shown conflicting results
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about the motor effects of adding sodium bicarbonate to lidocaine-epinephrine solution in
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epidural anesthesia. Fukuda & Naito (1994) found no statistical difference in the intensity of
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motor block, while Arakawa et al. (2002) and Curatolo et al. (1998) reported increased motor
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block with an alkalinized solution.
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The limited number of horses, the use of a standard volume of anesthetic for all mares, and
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the lack of additional tests to differentiate sensory and motor block were considered
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limitations of the present study. It is possible that the ALC solution may have yielded
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statistical differences in the duration and extent of anesthesia if a larger number of horses had
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been used.
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Conclusion
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Epidural anesthesia was compared in six mares administered either lidocaine-epinephrine
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(lidocaine 0.35 mg kg-1, epinephrine 1:200,000, pH 2.98) or lidocaine-epinephrine-sodium
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bicarbonate (pH 7.44) by caudal epidural injection. The solution treated with sodium
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bicarbonate resulted in reduction in the duration of ataxia and onset time of anesthesia in
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areas adjacent to the anogenital region (within a radius of 10 cm), without reducing the
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duration of epidural anesthesia. In addition, there was greater uniformity in the onset time of
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anesthesia among the studied areas. The findings suggest that pH adjustment of lidocaine-
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epinephrine solution prior to epidural injection may be advantageous for clinical use in
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mares. Further elucidation about differential block, dose, duration, and spread of block with
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alkalinized local anesthetics is necessary.
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Acknowledgments
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The authors thank Dr. Rodrigo Valadares for background research and the insight about pH
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buffering, and CNPq (Research Productivity), CAPES (MSscholarship), FAPEMIG
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(Pesquisador Mineiro), and Pro Reitoria de Pesquisa UFMG for funding the research.
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Authors declare no conflict of interest.
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Authors’ contributions
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PCD: conduction of the experiment, data analysis, manuscript preparation. CFRP, APLO:
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data collection and analysis. TPM, LOC: data collection, tabulation of data, animal handling.
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RRF: study design, statistical analysis, manuscript preparation.
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ACCEPTED MANUSCRIPT References
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Fuchsjäger-Mayrl G, Zehetmayer M, Plass H, Turnheim K (2002) Alkalinization increases
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penetration of lidocaine across the human cornea. J Cataract Refract Surg 28, 692–696.
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ACCEPTED MANUSCRIPT Fukuda T, Naito H (1994) The effect of pH adjustment of 1% lidocaine on the onset of
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sensory and motor blockade of epidural anesthesia in nonpregnant gynecological patients. J
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Anesth 8, 293–296.
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Garcia ER (2015) Local anesthetics. In: Lumb & Jones Veterinary Anesthesia and Analgesia
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(5th edn). Grimm KA, Lamont LA, Tranquilli WJ et al. (eds). John Wiley & Sons, Iowa,
337
USA, pp. 332–354.
338
Hall LW, Clarke KW, Trim CM (2001) General principles of local analgesia: anaesthesia of
339
the horse. In: Veterinary Anaesthesia (10th edn). Hall LW, Clarke KW, Trim CM (eds). W.
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B. Saunders, UK. pp. 224–313.
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Kozody R, Palahniuk RJ, Wade JG et al. (1984) The effect of subarachnoid epinephrine and
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phenylephrine on spinal cord blood flow. Can Anaesth Soc J 31, 503–508.
343
Lambert DH (2002) Clinical value of adding sodium bicarbonate to local anesthetics. Region
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Anesth Pain Med 27, 328–329.
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McKay W, Morris R, Mushlin P (1987) Sodium bicarbonate attenuates pain on skin
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infiltration with lidocaine, with or without epinephrine. Anesth Analg 66, 572–574.
347
Moore DC (1981) The pH of local anesthetic solutions. Anesth Analg 60, 833-834.
348
Moyer W, Schumacher J, Schumacher J (2011) Epidural Anesthesia. In: Equine Joint
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Injection and Regional Anesthesia (2nd edn). Moyer W, Schumacher J, Schumacher J (eds).
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Academic Veterinary Solutions, USA. pp. 140–143.
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Niwa H, Hirota Y, Sibutani T et al. (1991) The effects of epinephrine and norepinephrine
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administered during local anesthesia on left ventricular diastolic function. Anesth Prog 38,
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221–226.
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ACCEPTED MANUSCRIPT Patel M, Craig R, Laishley R (1996) A comparison between epidural anaesthesia using
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alkalinized solution and spinal (combined spinal/epidural) anaesthesia for elective caesarean
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section. Int J Obstet Anesth 5, 236–239.
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Polydoro AS, Raiser AG, Natalini CC et al. (2008) Making of an in vitro experimental model
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of equine subarachnoid space to test hyperbaric opioids. Cienc Rural 38, 384–388.
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Robinson EP, Natalini CC (2002) Epidural anesthesia and analgesia in horses. Vet Clin North
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Am Equine Pract 18, 61–82.
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Sadegh AB, Shafiei Z (2008) Comparison of caudal epidural anesthesia with lidocaine–
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distilled water and lidocaine–MgSO4 mixture in horses. J Equine Vet Sci 28, 341–344.
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Schelling CG, Klein LV (1985) Comparison of carbonated lidocaine and lidocaine
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hydrochloride for caudal epidural anesthesia in horses. Am J Vet Res 46, 1375–1377.
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Skarda RT, Muir WW (1983) Continuous caudal epidural and subarachnoid anesthesia in
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mares: a comparative study. Am J Vet Res 44, 2290–2298.
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Skarda RT, Grosenbaugh DA, Muir WW (2005) Caudal regional anaesthesia in
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horses. Equine Vet Educ 15, 108–116.
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Taylor P, Coumbe K, Henson F et al. (2014) Evaluation of sedation for standing clinical
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procedures in horses using detomidine combined with buprenorphine. Vet Anaesth Analg 41,
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14–24.
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Tucker GT, Mather LE (1979) Clinical pharmacokinetics of local anaesthetics. Clin
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Pharmacokinet 4, 241–278.
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Zehetmayer M, Rainer G, Turnheim K et al. (1997) Topical anesthesia with pH-adjusted
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versus standard lidocaine 4% for clear corneal cataract surgery. J Cataract Refract Surg 23,
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1390–1393.
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Table 1 Onset time and duration of epidural anesthesia in the sacral, anogenital, and
380
perianogenital regions in six mares treated with 10 mL of lidocaine-epinephrine solution with
381
(ALC, pH 7.4) or without (CON, pH 2.9) alkalization. Onset (minutes)
Duration (minutes)
ALC
p-value
CON
SC
12.5 ± 2.7
7.5 ± 2.9
0.029
113.9 ± 57.0
AG
19.1 ± 7.9
16.5 ± 13.2
0.496
101.2 ± 62.0
P5
20.2 ± 9.4
13.0 ± 8.2
0.003
102.2 ± 64.6
P10
18.6 ± 6.4
12.6 ± 6.2
0.005
P15
23.9 ± 10.2
18.5 ± 12.6
P20
24.4 ± 13.3
30.2 ± 26.3
p-value
110 ± 53.2
0.905
94.8 ± 44.3
0.770
103.3 ± 43.5
0.960
103.5 ± 63.3
106.5 ± 39.9
0.902
0.283
87.6 ± 57.1
71.4 ± 39.4
0.466
0.779
63.9 ± 57.5
48.7 ± 52.0
0.431
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ALC
SC
CON
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Region
Values are shown as means ± standard deviation.
384
SC, sacral region; AG, anogenital region; P5-P20, perianogenital region 5, 10, 15, or 20 cm
385
outside the anogenital region; CON, control treatment; ALC, alkalinized treatment.
386
p-values < 0.05 indicate significant difference between treatments for that region.
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Table 2 Onset time and duration of epidural anesthesia in the dorsal, middle, and ventral
394
thirds of the perianogenital region in six mares treated with 10 mL of lidocaine-epinephrine
395
solution with (ALC, pH 7.4) or without (CON, pH 2.9) alkalization. Onset (minutes) CON
ALC
Duration (minutes) CON
ALC
RI PT
Area
16.2 ± 2.4a
13.6 ± 9.1a
107.5 ± 51.8a
98.2 ± 3.0a
Middle
23.4 ± 4.2b
18.0 ± 9.2a
87.9 ± 51.6b
84.9 ± 9.7a
Ventral
28.1 ± 9.8b
21.9 ± 9.3a
72.5 ± 46.8b
62.9 ± 18.4b
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SC
Dorsal
Data are means ± standard deviations.
398
Means with the same letter do not differ within each treatment (p < 0.05).
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Table 3 Onset time and duration of epidural anesthesia in perianogenital sites of six mares
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treated with 10 mL of lidocaine-epinephrine solution with (ALC, pH 7.4) or without (CON,
403
pH 2.9) alkalization.
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Onset (minutes)
Duration (minutes) CON
RI PT
Tested site
ALC
p-value
ALC
p-value
SCP10
10.8 ± 2.0
5.8 ± 2.0
0.011
121.7 ± 55.9 119.2 ± 50.9
0.935
SCP15
12.5 ± 4.2
8.3 ± 2.6
0.042
112.5 ± 54.9 109.2 ± 53.1
0.920
SCP20
14.2 ± 2.0
8.3 ± 4.1
0.034
107.5 ± 60.1 101.7 ± 55.6
0.868
Anus
15.0 ± 8.4
9.2 ± 4.9
0.058
117.5 ± 58.6 118.3 ± 36.6
0.966
Perineum
17.5 ± 6.1
12.5 ± 9.3
0.041
110.0 ± 62.0 102.5 ± 46.8
0.802
Dorsal VC
20.0 ± 7.7
19.2 ± 20.3
0.908
97.5 ± 59.8
93.3 ± 53.3
0.874
Ventral VC 24.0 ± 13.4 25.0 ± 20.0
1.000
80.0 ± 67.5
65.0 ± 40.7
0.480
P5TDe
13.3 ± 2.6
8.3 ± 4.1
0.012
129.2 ± 53.5 124.2 ± 47.8
0.842
P5TDd
15.8 ± 7.4
8.3 ± 4.1
0.007
116.7 ± 67.3 126.7 ± 50.4
0.721
P5TMe
16.0 ± 8.2
10.0 ± 4.5
0.206
104.2 ± 70.1 112.5 ± 42.0
0.725
P5TMd
26.0 ± 13.9 16.7 ± 10.8
0.071
90.8 ± 66.0
98.3 ± 41.8
0.772
P5TVe
25.0 ± 12.2
17.5 ± 9.9
0.030
87.5 ± 66.7
90.0 ± 30.5
0.900
P5TVd
25.0 ± 12.2 17.0 ± 15.6
0.512
85.0 ± 64.1
68.3 ± 48.6
0.550
P10TDe
15.0 ± 7.7
7.5 ± 2.7
0.060
120.0 ± 53.9 120.0 ± 47.7
1.000
P10TDd
12.5 ± 2.7
7.5 ± 2.7
0.041
110.0 ± 63.9 125.0 ± 42.1
0.615
P10TMe
15.0 ± 0.0
10.8 ± 3.8
0.042
107.5 ± 66.0 119.2 ± 45.9
0.574
P10TMd
19.1 ± 8.6
14.2 ± 8.6
0.111
98.3 ± 64.5
100.8 ± 37.1
0.927
P10TVe
27.5 ± 11.3 16.7 ± 10.8
0.016
92.5 ± 67.4
103.3 ± 35.4
0.640
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ACCEPTED MANUSCRIPT 22.5 ± 8.2
19.2 ± 8.6
0.235
92.5 ± 63.9
70.8 ± 31.2
0.465
P15TDe
12.5 ± 2.7
8.3 ± 2.6
0.093
117.5 ± 49.1
94.2 ± 48.3
0.345
P15TDd
16.7 ± 6.8
17.5 ± 21.1
0.932
103.3 ± 63.5
77.5 ± 27.9
0.353
P15TMe
22.5 ± 8.2
12.5 ± 2.7
0.049
100.0 ± 59.0
90.0 ± 52.2
0.737
P15TMd
22.5 ± 8.2
18.3 ± 20.9
0.611
92.5 ± 59.6
66.7 ± 28.0
0.389
P15TVe
30.0 ± 15.0 22.0 ± 11.5
0.560
52.5 ± 60.6
66.7 ± 49.6
0.389
P15TVd
39.0 ± 20.1 32.5 ± 16.6
0.754
60.0 ± 51.1
33.3 ± 30.6
0.396
P20TDe
24.0 ± 8.2
31.2 ± 30.9
0.739
72.5 ± 54.8
64.2 ± 69.4
0.648
P20TDd
20.0 ± 9.3
31.0 ± 26.8
0.813
90.8 ± 64.1
54.2 ± 32.8
0.164
P20TMe
22.5 ± 8.7
38.7 ± 29.3
0.562
55.0 ± 57.4
51.7 ± 64.5
0.861
P20TMd
33.7 ± 22.5 31.2 ± 25.6
0.093
55.0 ± 50.8
39.2 ± 38.3
0.487
P20TVe
20.0 ± 8.7
17.5 ± 17.7
0.500
62.5 ± 69.3
49.2 ± 60.9
0.628
P20TVd
26.2 ± 22.5 31.7 ± 27.5
0.874
47.5 ± 48.8
34.2 ± 46.3
0.515
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Data are means ± standard deviations.
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Each tested site is represented by letter and number combinations: SC, sacral region; P5-P20,
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perianogenital region at 5, 10, 15, and 20 cm outside the anogenital region; TD, dorsal third;
409
TV, ventral third; TM, middle third; e, left; d, right; VC, vulvar commissure.
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p-values < 0.05 indicate a significant difference between treatments for that region.
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ACCEPTED MANUSCRIPT Figure Legends
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Figure 1 Delineation of areas around the anogenital region. (a) Four concentric ellipses were
415
drawn at 5 cm (P5), 10 cm (P10), 15 cm (P15) and 20 cm (P20) outside the virtual ellipse
416
delimiting the anus and vulva (anogenital; AG region). Two lines were drawn parallel to the
417
floor, the first level with the anal sphincter and the second level with the ventral vulvar
418
commissure, separating the test area into dorsal (TD), middle (TM) and ventral (TV) thirds.
419
Two lines were drawn parallel to the longitudinal axis of the sacral vertebrae at the level of
420
the lateral borders of the tail, delimited the sacral (SC) region. The white spots indicate the
421
test sites located at the centers of the areas delimited in both antimeres and the sacrum, and at
422
the anal sphincter, perineum, dorsal vulvar commissure, and ventral vulvar commissure. (b)
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Testing areas were drawn on the horse before conducting the experiment.
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ACCEPTED MANUSCRIPT
S1467-2987(17)30055-7
DOI:
10.1016/j.vaa.2016.11.003
Reference:
VAA 81
To appear in:
Veterinary Anaesthesia and Analgesia
Received Date: 17 August 2016 Revised Date:
2 November 2016
Accepted Date: 4 November 2016
Please cite this article as: Duarte PC, Paz CF, Oliveira AP, Maróstica TP, Cota LO, Faleiros RR, Caudal epidural anesthesia in mares after bicarbonate addition to a lidocaine-epinephrine combination, Veterinary Anaesthesia and Analgesia (2017), doi: 10.1016/j.vaa.2016.11.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT RESEARCH PAPER
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PC Duarte et al.
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Lidocaine-bicarbonate equine epidural block
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Caudal epidural anesthesia in mares after bicarbonate addition to a lidocaine-
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epinephrine combination
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Patricia C Duarte, Cahuê FR Paz, Alvaro PL Oliveira, Thairê P Maróstica, Leticia O Cota &
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Rafael R Faleiros
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Department of Veterinary Clinics and Surgery, Universidade Federal de Minas Gerais, Belo
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Horizonte, Brazil
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Correspondence: Rafael R Faleiros, Escola de Veterinária da Universidade Federal de
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Minas Gerais, Departamento de Clínica e Cirurgia Veterinárias, Av. Antônio Carlos 6627,
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caixa postal 567, Campus Pampulha da UFMG, Belo Horizonte, Minas Gerais, Brasil, 31270-
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901. E-mail: [email protected]
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Abstract
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Objective To investigate the nociceptive and clinical effects of buffering a lidocaine-
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epinephrine solution with sodium bicarbonate in caudal epidural block in mares.
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Study design Prospective randomized controlled trial.
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Animals Six mixed-breed mares weighing 350–440 kg.
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Methods Each animal was administered two caudal epidural injections, 72 hours apart, using
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different solutions prepared immediately before injection. The control solution was 7 mL 2%
24
lidocaine hydrochloride with epinephrine hemitartrate (1:200 000) added to 3 mL sterile
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ACCEPTED MANUSCRIPT water for injection (pH 2.9). The alkalinized solution was 7 mL of lidocaine-epinephrine
26
solution added to 2.3 mL sterile water for injection and 0.7 mL 8.4% sodium bicarbonate (pH
27
7.4). Nociception was evaluated by response to skin pinching at 31 sites in the sacral region
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and around the perimeter of the anogenital area (distances of 10, 15, and 20 cm) before and 5,
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10 and 15 minutes after epidural injection, then every 15 minutes until the return of
30
nociception in all evaluated sites. The onset and duration times, and intensity of ataxia
31
(grades 0 to 3) were recorded. The paired t test was used to compare the onset and duration of
32
anesthesia and ataxia (p < 0.05).
33
Results Alkalization of the solution resulted in significant decreases in the average time of
34
onset of loss of nociception in the sacral region (40%) and around the perimeter of the
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anogenital area extending up to 5 cm (36%) and from 5 to 10 cm (32%) from the anus and
36
vulva. Alkalization also decreased the average duration of ataxia (33%), without affecting the
37
duration and extent of anesthesia or the degree of ataxia.
38
Conclusions and clinical relevance Alkalization of lidocaine-epinephrine solution is
39
advantageous in shortening the duration of ataxia and hastening the onset of anesthesia in
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areas adjacent to the anogenital area, without reducing the duration of epidural anesthesia, in
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mares.
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Keywords epinephrine, equine, local anesthetic, nociception, sodium bicarbonate.
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ACCEPTED MANUSCRIPT Introduction
46
Lidocaine is a local anesthetic with rapid onset and moderate duration of activity and
47
moderate toxicity, and is therefore the most widely used agent for local anesthesia in
48
veterinary medicine (Garcia 2015). Although concerns exist about the risk of ischemia and
49
tissue necrosis when vasoconstrictors are added to the epidural solution (Moyer et al. 2011;
50
Garcia 2015), epinephrine may increase duration of equine epidural anesthesia when added to
51
lidocaine (Carpenter & Byron 2015; Garcia 2015).
52
Epidural anesthesia can be performed in the standing horse, avoiding the risks of decubitus
53
and arising from general anesthesia (Robinson & Natalini 2002; Garcia 2015). However, the
54
onset of epidural anesthesia with lidocaine can be particularly long in horses compared with
55
other domestic species (Hall et al. 2001; Garcia 2015). This may lead to the false conception
56
that the epidural space was not reached (Hall et al 2001) or a long onset time may be a
57
problem in patient management, especially for a restless horse requiring physical restraint
58
and sedation and in emergency situations.
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Commercially available local anesthetic with vasoconstrictor solutions are formulated to be
60
acidic to avoid oxidation of epinephrine and increase shelf life (Moore 1981; Lambert 2002;
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Garcia 2015). This low pH results in predominance of the ionized hydrophilic form,
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diminishing diffusion of the anesthetic through cell membranes and delaying its arrival at the
63
site of action (Garcia 2015). The medical and veterinary literature reports quicker onset of
64
anesthesia (DiFazio et al. 1986; Fernando & Jones 1991; Patel et al. 1996) and reduced pain
65
on injection (McKay et al. 1987; Eccarius et al. 1990) when sodium bicarbonate is added to a
66
local anesthetic thereby increasing the pH to a physiologic value.
67
This study aimed to evaluate and compare the onset, duration and sites anesthetized in the
68
anogenital region, and some clinical effects, with caudal epidural anesthesia in horses
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ACCEPTED MANUSCRIPT 69
performed using lidocaine with epinephrine, with and without sodium bicarbonate added as
70
an alkalizing agent. The hypothesis was that adjusting the pH of the epidural injectate to
71
within the physiological range before administration can reduce the anesthesia latency time.
72
Materials and methods
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Animals
75
The study was approved by the Ethics Committee on Animal Use of the Universidade Federal
76
de Minas Gerais, Brazil (no. 200/2013). Six mixed-breed mares were selected from a group
77
of 8 horses. They were aged [mean ± standard deviation (SD)] 12.8 ± 2.8 years (range: 8–16
78
years), with body condition score of 6.5 ± 1 (range: 5–8) out of 9, and weight of 397 ± 40 kg
79
(range: 350–440 kg). All six mares were considered physically healthy on clinical
80
examination and had been proved to have a predictable anesthetic response to caudal epidural
81
injection of lidocaine 2% using the technique described below. The mares were kept in a
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group paddock, where they were fed with Tifton hay and had access to water ad libitum.
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Anesthetic solutions
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Each animal was administered two treatments at an interval of at least 72 hours. The order of
86
treatments was randomized (toss of a coin) for each mare without the knowledge of the
87
evaluator, in a crossover design. The control solution (treatment CON) was 7 mL lidocaine
88
hydrochloride
89
Pharmaceuticals Ltd., Brazil) and 3 mL sterile water for injection (Equiplex Pharmaceutical
90
Industry, Brazil). The alkalinized solution (treatment ALC) was 7 mL lidocaine
91
hydrochloride with epinephrine hemitartrate 1:200 000, 0.7 mL sodium bicarbonate (8.4%
92
sodium bicarbonate; Samtec Biotechnology, Brazil) and 2.3 mL sterile water for injection
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with
epinephrine
hemitartrate
1:200 000
(Xylestesin
2%;
Cristália
4
ACCEPTED MANUSCRIPT 93
(equivalent to 0.005 mEq bicarbonate per mg of lidocaine). The solutions were prepared by
94
an assistant at the time of epidural administration. The pH and density of both solutions were
95
measured with a pH meter (mPA210; MS Tecnopon Instrumentation, Brazil) and a
96
refractometer (RHC-200ATC; Megabrix, Brazil), respectively.
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Assessments
99
The sites to be tested were demarcated on the horse (Fig.1). Four concentric ellipses were
100
drawn 5, 10, 15, and 20 cm outside the virtual ellipse delimited by anus and vulva. In
101
addition, two lines were drawn parallel to the ground, the first at the level of the anal
102
sphincter and the second at the ventral vulvar commissure, and two lines were drawn parallel
103
to the longitudinal axis of the sacral vertebrae at the level of the lateral borders of the tail.
104
The test sites were located at the centers of the delimited areas on both antimeres and the
105
sacrum, and at the anal sphincter, perineum, dorsal and ventral vulvar commissures. For
106
analysis purposes, the test sites were grouped in six concentric anatomic regions as follows:
107
the anogenital (AG) region, sacral (SC) region, and perianogenital regions corresponding to
108
the ellipses 5, 10, 15, and 20 cm outside the anogenital region (P5-P20). In addition, the sites
109
were grouped on the basis of a dorsal–ventral distribution in anatomic thirds: dorsal (DT),
110
middle (MT) and ventral (VT) (Fig. 1).
111
The nociception was tested with the horse confined in a stocks by using a pinching technique
112
with an Adson thumb forceps, and systematically applying stimulation at the 31 defined sites.
113
Nociception was always assessed by the same evaluator blinded to the treatment. To avoid
114
distractions in the environment on the behavior of the mare, a blindfold was applied over the
115
eyes of each animal during the nociception test. In the week previous to the experimental
116
period, all the horses were acclimatized in the stocks with a blindfold once a day for 3 hours.
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ACCEPTED MANUSCRIPT Positive reactions to the noxious stimulus were raising and pricking the ears, turning the head
118
towards the croup, tucking the croup, and threatening to kick.
119
Tests for nociception were performed before anesthesia (T0); 5 (T1), 10 (T2), and 15 (T3)
120
minutes after epidural injection; and 15 minutes thereafter until positive reactions to the
121
noxious stimulus were observed in all tested areas. Heart rate (HR), respiratory rate (fR), and
122
rectal temperature (RT) were measured before nociception testing at T0, T3, and T4 and
123
every 30 minutes thereafter. At these same time points, after nociceptive testing, the horse
124
was unmasked and encouraged to walk out of the stocks. Ataxia was scored 0-3: 0, walking
125
and turning firmly; 1, mild ataxia, walking with some limb weakness; 2, moderate ataxia,
126
walking with support, staggering, risk of falling when turned; 3, marked ataxia, inability to
127
walk or exit the stocks without risk of falling, falling when turned (Taylor et al. 2014). Mares
128
were only returned to the group paddock when pain sensation and motor function were
129
considered totally normal.
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Epidural technique
132
With the mare restrained in the stocks, the sacrococcygeal region was shaved. The site for
133
needle insertion was identified by moving the tail up and down and palpation of the first
134
articulation caudal to the sacrum. After the shaved area had been prepared according to a
135
surgical antisepsis technique, a 1.7 × 50 mm needle with no stilette (Angiocath, BD Medical,
136
Brazil) was inserted in the center of the palpated depression at a 90° angle to the skin plane.
137
The correct placement of the needle in the epidural space was confirmed using the hanging-
138
drop method and sensing a lack of resistance in the syringe plunger during solution infusion.
139
The same researcher (PD) performed all the epidural injections.
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ACCEPTED MANUSCRIPT Statistical analysis
142
The nociception data were analyzed in two ways. First, the effect of the treatment on the
143
onset and duration of anesthesia was analyzed by comparing the values of each site and the
144
values of each region (the arithmetic mean of all sites in the region) between treatments.
145
Second, the effect of the treatment on the distribution of the anesthetic solution was analyzed
146
in each treatment by comparing the values for the onset and duration of the anesthesia among
147
the dorsal, middle, and ventral thirds and between antimeres. The paired t test was used to
148
compare values between treatments or antimeres. A repeated measures ANOVA was used to
149
compare values among thirds within treatments.
150
The clinical variables (HR, fR and RT) were subjected to a two-way repeated measures
151
ANOVA followed by the Tukey’s post hoc test. Ataxia was compared between treatments by
152
using the Mann–Whitney test for degree data and the paired t test for duration data.
153
For all parametric analyses, normality was assessed using the Shapiro–Wilk test and, if
154
necessary, data were transformed before analysis by using the natural logarithms. Statistical
155
analyses were performed using the SigmaStat 4.0 software (Systat Software, CA, USA) and
156
GraphPad Prism 5.0 (GraphPad Software, CA, USA), and p < 0.05 was considered
157
significant.
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Results
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From an initial group of eight mares, two mares were rejected. The perineum in the first mare
161
could not be anesthetized and in the second, epidural anesthesia always appeared to be
162
unilateral.
163
The pH and density of the epidural solutions were pH 2.98 and 1010 g L-1 in CON and pH
164
7.44 and 1012 g L-1 in ALC. The onset of anesthesia was significantly shorter in ALC than in 7
ACCEPTED MANUSCRIPT CON, by 40% in the SC region, 36% in P5, and 32% in P10 (p = 0.029, p = 0.003 and p =
166
0.005, respectively) (Table 1). There were no significant differences between treatments in
167
the duration of anesthesia, or between the left and right antimeres.
168
Failures of desensitization occurred in both treatments with the sum of 18 unblocked areas
169
within each treatment. In CON, there was one unblocked area in AG, two in P5, four in P15,
170
and 11 in P20. In ALC, there was one unblocked area in P5, three in P15, and 14 in P20.
171
Failures of desensitization occurred predominantly in the ventral areas.
172
There was a reduced time of onset and extended duration of anesthesia in the dorsal region
173
compared with the middle (p = 0.012 and p = 0.028, respectively) and ventral (p = 0.045 and
174
p = 0.048, respectively) regions in CON and a significantly greater duration of anesthesia in
175
the dorsal (p = 0.016) and middle (p = 0.008) regions compared with the ventral region in
176
ALC (Table 2). Onset of anesthesia was not different between these regions in ALC (Table
177
2). Times of onset and duration of anesthesia for all tested sites in both treatments are
178
presented in Table 3.
179
HR, fR and RT did not change between baseline and the subsequent times in both treatments.
180
There were no statistical differences in ataxia scores between treatments. Ataxia was first
181
detected at 15 minutes after epidural injection in both treatments. Duration of ataxia was
182
shorter in ALC (84.0 ± 29.2 minutes) than in CON ( 125.8 ± 51.0 minutes) (p = 0.033). Two
183
animals were assigned ataxia scores of 2 and one animal a score of 1 in both treatments. Two
184
more animals displayed ataxia in both treatments; one animal was scored 3 in CON and 2 in
185
ALC, and the other animal was scored 2 in CON and 1 in ALC. The sixth animal was scored
186
2 in CON but displayed no ataxia in ALC.
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187 188
Discussion 8
ACCEPTED MANUSCRIPT The present study results show that alkalization of a commercial solution of lidocaine-
190
epinephrine to a physiological pH value results in a shorter time of onset of anesthesia close
191
to the anogenital area in epidural anesthesia in mares. The alkalization of local anesthetics
192
with sodium bicarbonate was first reported in 1901, resulting in increased potency and shorter
193
onset of action of procaine (Patel et al. 1996). Similarly, lidocaine combined with sodium
194
bicarbonate for pH adjustment resulted in faster onset of anesthesia and surgical anesthesia,
195
as well as faster spread of sensory blockade (DiFazio et al. 1986).
196
The addition of carbon dioxide (carbonization) to lidocaine has also been shown to hasten the
197
onset and improve epidural anesthesia in humans (Bromage 1965; Schelling & Klein 1985;
198
Garcia 2015). However, its epidural use in horses did not alter the time of onset, the duration,
199
or the extent of the block (Schelling & Klein 1985). A commercially available lidocaine-
200
epinephrine solution, which has a lower pH to avoid oxidation of epinephrine and increase
201
shelf life (Moore 1981; Lambert 2002; Garcia 2015), was used in our study. Thus, the marked
202
difference in the pH of tested solutions (2.98 to 7.44) in the present study when compared to
203
those from the study that used carbonization (5.3 to 6.5) may explain such discrepancies.
204
In comparison, epidural block with lidocaine in cattle may take less than 5 minutes to develop
205
complete perineal analgesia (Bigham et al. 2010), whereas the block may take up to 20
206
minutes to develop in horses (Hall et al. 2001). The longer time for developing epidural
207
anesthesia in horses after lidocaine epidural injection may induce the veterinarian to falsely
208
conclude that the epidural space was not reached (Hall et al. 2001). A reasonable explanation
209
for this difference was not found in the literature. However, this study showed that
210
alkalization of the anesthetic solution may provide more consistent epidural anesthesia in
211
horses.
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9
ACCEPTED MANUSCRIPT In the present study, the treatments were applied at least 72 hours apart. Considering that the
213
total body clearance of intravenously infused lidocaine in horses is 29 mL kg-1 minute-1
214
(Garcia 2015), the horses in this experiment would have taken 16 to 21 hours to have blood
215
free of circulating lidocaine. In humans, the slow absorption half-life of lidocaine-
216
epinephrine solution is 6.6 hours; therefore, it takes approximately 24 hours for 20 mL to be
217
completely absorbed from the epidural space (Tucker & Mather 1979). Nevertheless, the
218
order of treatments was randomly selected for each mare to offset possible effects of one
219
treatment on the other.
220
In the comparisons among the dorsal, middle, and ventral thirds within each treatment, the
221
onset of anesthesia was longer in the middle and ventral thirds compared with the dorsal third
222
in the CON treatment. In the ALC treatment such differences were not significant. This may
223
be explained by the improved absorption of anesthetic solutions with a physiological pH.
224
This homogeneity in the onset of action observed in the dorsal, middle and ventral thirds may
225
be considered another advantage of anesthetic solution pH adjustment for epidural
226
administration in mares. The duration of anesthesia, however, differed to a greater extent
227
between regions in the ALC than CON treatment. Further study is needed to determine the
228
mechanisms responsible for the greater heterogeneity of block duration with the ALC
229
solution.
230
Although individual asymmetries were observed in most animals, there were no significant
231
differences in the time of onset or duration of anesthetic action between the right and left
232
antimeres in either of the treatments. A finding of predominant asymmetry, consistent
233
desensitization of one antimere more than the other, could have indicated incorrect technique,
234
eg. angling the needle during insertion. Previous studies have reported that individual
235
variation in desensitized areas and asymmetries are common findings for epidural anesthesia
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10
ACCEPTED MANUSCRIPT in horses (Skarda & Muir 1983; Schelling & Klein 1985). The presence of congenital
237
membranes or adhesions in the epidural space could explain the unilateral anesthesia
238
(Robinson & Natalini 2002), but no further investigation was made in these mares. To ensure
239
greater reliability in the comparison between treatments in this study, only mares with
240
symmetric and predictable responses in the pre-study testing were included in the
241
experimental protocol.
242
It has been proposed that increasing the volume or concentration of local anesthetic will
243
speed the onset of epidural anesthesia and the addition of sodium bicarbonate may be of little
244
value (Lambert 2002). However, the pH of commercially available lidocaine solutions vary
245
and the lidocaine-epinephrine solution used in this study has a low pH. The results of this
246
study indicate that for this lidocaine preparation, correcting the acidity of the solution to a
247
physiologic pH is advantageous.
248
In the present study, no precipitation was observed in the anesthetic solution after bicarbonate
249
solution addition. However, precipitation after autoclaving has been reported in lidocaine
250
solutions with a pH above 7.4 (Zehetmayer et al. 1997; Fuchsjäger-Mayrl et al. 2002).
251
The specific gravity of solutions used in epidural anesthesia has been reported as an
252
influencing factor in time of onset. In addition, the density of a solution is not affected by the
253
concentration of anesthetic or volume administered. In their study of epidural anesthesia in
254
horses, DeRossi et al. (2005) attributed a more rapid onset with hyperbaric 5% lidocaine than
255
2% lidocaine to the difference in specific gravity. The densities of the solutions used in the
256
present study were similar, 1010 g L-1 and 1012 g L-1, and exceeded the density of equine
257
cerebrospinal fluid (1006 g L-1) (Polydoro et al. 2008). Therefore, the specific gravity of the
258
ALC and CON solutions was not considered an influencing factor in the reduced time of
259
onset in the ALC treatment.
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11
ACCEPTED MANUSCRIPT Epinephrine, used as an additive for many local anesthetics, could potentially cause
261
cardiovascular effects when absorbed systemically, such as increased HR (Kozody et al.
262
1984; Garcia 2015) and decreased peripheral resistance (Niwa et al. 1991). In this study, HR
263
fluctuations remained within physiologic limits for the species and no adverse reactions,
264
other than ataxia, were induced by the anesthetic solutions.
265
The occurrence of ataxia is relatively common during epidural anesthesia in horses because
266
of the development of motor block (Hall et al. 2001; Robinson & Natalini 2002; Skarda et al.
267
2005; Carpenter & Byron 2015). In the present study, the animals showed a significantly
268
shorter duration of ataxia with the ALC than CON treatment. This may be interpreted as
269
differential block between motor and sensory fibers, because the duration of anesthesia did
270
not differ between treatments. A similar phenomenon was observed by Sadegh & Shafiei
271
(2008), who reported no ataxia in horses undergoing epidural block with lidocaine combined
272
with magnesium sulfate. Differences in ataxia among studies may be related to the different
273
additives, as there was no difference in anesthetic concentration between treatments in the
274
present study to explain the phenomenon. Medical reports have shown conflicting results
275
about the motor effects of adding sodium bicarbonate to lidocaine-epinephrine solution in
276
epidural anesthesia. Fukuda & Naito (1994) found no statistical difference in the intensity of
277
motor block, while Arakawa et al. (2002) and Curatolo et al. (1998) reported increased motor
278
block with an alkalinized solution.
279
The limited number of horses, the use of a standard volume of anesthetic for all mares, and
280
the lack of additional tests to differentiate sensory and motor block were considered
281
limitations of the present study. It is possible that the ALC solution may have yielded
282
statistical differences in the duration and extent of anesthesia if a larger number of horses had
283
been used.
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ACCEPTED MANUSCRIPT 284
Conclusion
286
Epidural anesthesia was compared in six mares administered either lidocaine-epinephrine
287
(lidocaine 0.35 mg kg-1, epinephrine 1:200,000, pH 2.98) or lidocaine-epinephrine-sodium
288
bicarbonate (pH 7.44) by caudal epidural injection. The solution treated with sodium
289
bicarbonate resulted in reduction in the duration of ataxia and onset time of anesthesia in
290
areas adjacent to the anogenital region (within a radius of 10 cm), without reducing the
291
duration of epidural anesthesia. In addition, there was greater uniformity in the onset time of
292
anesthesia among the studied areas. The findings suggest that pH adjustment of lidocaine-
293
epinephrine solution prior to epidural injection may be advantageous for clinical use in
294
mares. Further elucidation about differential block, dose, duration, and spread of block with
295
alkalinized local anesthetics is necessary.
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Acknowledgments
298
The authors thank Dr. Rodrigo Valadares for background research and the insight about pH
299
buffering, and CNPq (Research Productivity), CAPES (MSscholarship), FAPEMIG
300
(Pesquisador Mineiro), and Pro Reitoria de Pesquisa UFMG for funding the research.
301
Authors declare no conflict of interest.
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Authors’ contributions
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PCD: conduction of the experiment, data analysis, manuscript preparation. CFRP, APLO:
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data collection and analysis. TPM, LOC: data collection, tabulation of data, animal handling.
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RRF: study design, statistical analysis, manuscript preparation.
307
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ACCEPTED MANUSCRIPT References
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improves blockade of the first sacral segment–a brief report. Can J Anaesth 49, 566-570.
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Bigham AS, Habibian S, Ghasemian F, Layeghi S (2010) Caudal epidural injection of
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lidocaine, tramadol, and lidocaine–tramadol for epidural anesthesia in cattle. J Vet Pharmacol
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Bromage, PR (1965) A comparison of the hydrochloride and carbon dioxide salts of lidocaine
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and prilocaine in epidural analgesia. Acta Anaesthesiol Scand 16, 55-69.
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Carpenter RE, Byron CR (2015) Equine local anesthetic and analgesic techniques. In: Lumb
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WJ et al. (eds). John Wiley & Sons, USA. pp. 886–911.
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Curatolo M, Petersen-Felix S, Arendt-Nielsen L et al. (1998) Adding sodium bicarbonate to
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DeRossi R, Frazílio FO, Kassab TA (2005) Comparison of 2% lidocaine and hyperbaric 5%
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DiFazio CA, Carron H, Grosslight KR et al. (1986) Comparison of pH-adjusted lidocaine
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solutions for epidural anesthesia. Anesth Analg 65, 760–764.
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Eccarius SG, Gordon ME, Parelman JJ (1990) Bicarbonate-buffered lidocaine–epinephirine–
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hyaluronidase for eyelid anesthesia. Ophthalmology 97, 1499–1501.
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Fernando R, Jones HM (1991) Comparison of plain and alkalinized local anaesthetic
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mixtures of lignocaine and bupivacaine for elective extradural caesarean section. Br J
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Fuchsjäger-Mayrl G, Zehetmayer M, Plass H, Turnheim K (2002) Alkalinization increases
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penetration of lidocaine across the human cornea. J Cataract Refract Surg 28, 692–696.
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(5th edn). Grimm KA, Lamont LA, Tranquilli WJ et al. (eds). John Wiley & Sons, Iowa,
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Hall LW, Clarke KW, Trim CM (2001) General principles of local analgesia: anaesthesia of
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the horse. In: Veterinary Anaesthesia (10th edn). Hall LW, Clarke KW, Trim CM (eds). W.
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B. Saunders, UK. pp. 224–313.
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Kozody R, Palahniuk RJ, Wade JG et al. (1984) The effect of subarachnoid epinephrine and
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phenylephrine on spinal cord blood flow. Can Anaesth Soc J 31, 503–508.
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Lambert DH (2002) Clinical value of adding sodium bicarbonate to local anesthetics. Region
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Anesth Pain Med 27, 328–329.
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McKay W, Morris R, Mushlin P (1987) Sodium bicarbonate attenuates pain on skin
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infiltration with lidocaine, with or without epinephrine. Anesth Analg 66, 572–574.
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Moore DC (1981) The pH of local anesthetic solutions. Anesth Analg 60, 833-834.
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Moyer W, Schumacher J, Schumacher J (2011) Epidural Anesthesia. In: Equine Joint
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Injection and Regional Anesthesia (2nd edn). Moyer W, Schumacher J, Schumacher J (eds).
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Academic Veterinary Solutions, USA. pp. 140–143.
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Niwa H, Hirota Y, Sibutani T et al. (1991) The effects of epinephrine and norepinephrine
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Polydoro AS, Raiser AG, Natalini CC et al. (2008) Making of an in vitro experimental model
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Robinson EP, Natalini CC (2002) Epidural anesthesia and analgesia in horses. Vet Clin North
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Sadegh AB, Shafiei Z (2008) Comparison of caudal epidural anesthesia with lidocaine–
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distilled water and lidocaine–MgSO4 mixture in horses. J Equine Vet Sci 28, 341–344.
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Schelling CG, Klein LV (1985) Comparison of carbonated lidocaine and lidocaine
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hydrochloride for caudal epidural anesthesia in horses. Am J Vet Res 46, 1375–1377.
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Skarda RT, Muir WW (1983) Continuous caudal epidural and subarachnoid anesthesia in
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mares: a comparative study. Am J Vet Res 44, 2290–2298.
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Skarda RT, Grosenbaugh DA, Muir WW (2005) Caudal regional anaesthesia in
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horses. Equine Vet Educ 15, 108–116.
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Taylor P, Coumbe K, Henson F et al. (2014) Evaluation of sedation for standing clinical
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procedures in horses using detomidine combined with buprenorphine. Vet Anaesth Analg 41,
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Tucker GT, Mather LE (1979) Clinical pharmacokinetics of local anaesthetics. Clin
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Pharmacokinet 4, 241–278.
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Zehetmayer M, Rainer G, Turnheim K et al. (1997) Topical anesthesia with pH-adjusted
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versus standard lidocaine 4% for clear corneal cataract surgery. J Cataract Refract Surg 23,
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1390–1393.
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Table 1 Onset time and duration of epidural anesthesia in the sacral, anogenital, and
380
perianogenital regions in six mares treated with 10 mL of lidocaine-epinephrine solution with
381
(ALC, pH 7.4) or without (CON, pH 2.9) alkalization. Onset (minutes)
Duration (minutes)
ALC
p-value
CON
SC
12.5 ± 2.7
7.5 ± 2.9
0.029
113.9 ± 57.0
AG
19.1 ± 7.9
16.5 ± 13.2
0.496
101.2 ± 62.0
P5
20.2 ± 9.4
13.0 ± 8.2
0.003
102.2 ± 64.6
P10
18.6 ± 6.4
12.6 ± 6.2
0.005
P15
23.9 ± 10.2
18.5 ± 12.6
P20
24.4 ± 13.3
30.2 ± 26.3
p-value
110 ± 53.2
0.905
94.8 ± 44.3
0.770
103.3 ± 43.5
0.960
103.5 ± 63.3
106.5 ± 39.9
0.902
0.283
87.6 ± 57.1
71.4 ± 39.4
0.466
0.779
63.9 ± 57.5
48.7 ± 52.0
0.431
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ALC
SC
CON
RI PT
Region
Values are shown as means ± standard deviation.
384
SC, sacral region; AG, anogenital region; P5-P20, perianogenital region 5, 10, 15, or 20 cm
385
outside the anogenital region; CON, control treatment; ALC, alkalinized treatment.
386
p-values < 0.05 indicate significant difference between treatments for that region.
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ACCEPTED MANUSCRIPT 393
Table 2 Onset time and duration of epidural anesthesia in the dorsal, middle, and ventral
394
thirds of the perianogenital region in six mares treated with 10 mL of lidocaine-epinephrine
395
solution with (ALC, pH 7.4) or without (CON, pH 2.9) alkalization. Onset (minutes) CON
ALC
Duration (minutes) CON
ALC
RI PT
Area
16.2 ± 2.4a
13.6 ± 9.1a
107.5 ± 51.8a
98.2 ± 3.0a
Middle
23.4 ± 4.2b
18.0 ± 9.2a
87.9 ± 51.6b
84.9 ± 9.7a
Ventral
28.1 ± 9.8b
21.9 ± 9.3a
72.5 ± 46.8b
62.9 ± 18.4b
396
SC
Dorsal
Data are means ± standard deviations.
398
Means with the same letter do not differ within each treatment (p < 0.05).
399
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Table 3 Onset time and duration of epidural anesthesia in perianogenital sites of six mares
402
treated with 10 mL of lidocaine-epinephrine solution with (ALC, pH 7.4) or without (CON,
403
pH 2.9) alkalization.
404
Onset (minutes)
Duration (minutes) CON
RI PT
Tested site
ALC
p-value
ALC
p-value
SCP10
10.8 ± 2.0
5.8 ± 2.0
0.011
121.7 ± 55.9 119.2 ± 50.9
0.935
SCP15
12.5 ± 4.2
8.3 ± 2.6
0.042
112.5 ± 54.9 109.2 ± 53.1
0.920
SCP20
14.2 ± 2.0
8.3 ± 4.1
0.034
107.5 ± 60.1 101.7 ± 55.6
0.868
Anus
15.0 ± 8.4
9.2 ± 4.9
0.058
117.5 ± 58.6 118.3 ± 36.6
0.966
Perineum
17.5 ± 6.1
12.5 ± 9.3
0.041
110.0 ± 62.0 102.5 ± 46.8
0.802
Dorsal VC
20.0 ± 7.7
19.2 ± 20.3
0.908
97.5 ± 59.8
93.3 ± 53.3
0.874
Ventral VC 24.0 ± 13.4 25.0 ± 20.0
1.000
80.0 ± 67.5
65.0 ± 40.7
0.480
P5TDe
13.3 ± 2.6
8.3 ± 4.1
0.012
129.2 ± 53.5 124.2 ± 47.8
0.842
P5TDd
15.8 ± 7.4
8.3 ± 4.1
0.007
116.7 ± 67.3 126.7 ± 50.4
0.721
P5TMe
16.0 ± 8.2
10.0 ± 4.5
0.206
104.2 ± 70.1 112.5 ± 42.0
0.725
P5TMd
26.0 ± 13.9 16.7 ± 10.8
0.071
90.8 ± 66.0
98.3 ± 41.8
0.772
P5TVe
25.0 ± 12.2
17.5 ± 9.9
0.030
87.5 ± 66.7
90.0 ± 30.5
0.900
P5TVd
25.0 ± 12.2 17.0 ± 15.6
0.512
85.0 ± 64.1
68.3 ± 48.6
0.550
P10TDe
15.0 ± 7.7
7.5 ± 2.7
0.060
120.0 ± 53.9 120.0 ± 47.7
1.000
P10TDd
12.5 ± 2.7
7.5 ± 2.7
0.041
110.0 ± 63.9 125.0 ± 42.1
0.615
P10TMe
15.0 ± 0.0
10.8 ± 3.8
0.042
107.5 ± 66.0 119.2 ± 45.9
0.574
P10TMd
19.1 ± 8.6
14.2 ± 8.6
0.111
98.3 ± 64.5
100.8 ± 37.1
0.927
P10TVe
27.5 ± 11.3 16.7 ± 10.8
0.016
92.5 ± 67.4
103.3 ± 35.4
0.640
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ACCEPTED MANUSCRIPT 22.5 ± 8.2
19.2 ± 8.6
0.235
92.5 ± 63.9
70.8 ± 31.2
0.465
P15TDe
12.5 ± 2.7
8.3 ± 2.6
0.093
117.5 ± 49.1
94.2 ± 48.3
0.345
P15TDd
16.7 ± 6.8
17.5 ± 21.1
0.932
103.3 ± 63.5
77.5 ± 27.9
0.353
P15TMe
22.5 ± 8.2
12.5 ± 2.7
0.049
100.0 ± 59.0
90.0 ± 52.2
0.737
P15TMd
22.5 ± 8.2
18.3 ± 20.9
0.611
92.5 ± 59.6
66.7 ± 28.0
0.389
P15TVe
30.0 ± 15.0 22.0 ± 11.5
0.560
52.5 ± 60.6
66.7 ± 49.6
0.389
P15TVd
39.0 ± 20.1 32.5 ± 16.6
0.754
60.0 ± 51.1
33.3 ± 30.6
0.396
P20TDe
24.0 ± 8.2
31.2 ± 30.9
0.739
72.5 ± 54.8
64.2 ± 69.4
0.648
P20TDd
20.0 ± 9.3
31.0 ± 26.8
0.813
90.8 ± 64.1
54.2 ± 32.8
0.164
P20TMe
22.5 ± 8.7
38.7 ± 29.3
0.562
55.0 ± 57.4
51.7 ± 64.5
0.861
P20TMd
33.7 ± 22.5 31.2 ± 25.6
0.093
55.0 ± 50.8
39.2 ± 38.3
0.487
P20TVe
20.0 ± 8.7
17.5 ± 17.7
0.500
62.5 ± 69.3
49.2 ± 60.9
0.628
P20TVd
26.2 ± 22.5 31.7 ± 27.5
0.874
47.5 ± 48.8
34.2 ± 46.3
0.515
M AN U
SC
RI PT
P10TVd
TE D
405
Data are means ± standard deviations.
407
Each tested site is represented by letter and number combinations: SC, sacral region; P5-P20,
408
perianogenital region at 5, 10, 15, and 20 cm outside the anogenital region; TD, dorsal third;
409
TV, ventral third; TM, middle third; e, left; d, right; VC, vulvar commissure.
410
p-values < 0.05 indicate a significant difference between treatments for that region.
412
AC C
411
EP
406
20
ACCEPTED MANUSCRIPT Figure Legends
414
Figure 1 Delineation of areas around the anogenital region. (a) Four concentric ellipses were
415
drawn at 5 cm (P5), 10 cm (P10), 15 cm (P15) and 20 cm (P20) outside the virtual ellipse
416
delimiting the anus and vulva (anogenital; AG region). Two lines were drawn parallel to the
417
floor, the first level with the anal sphincter and the second level with the ventral vulvar
418
commissure, separating the test area into dorsal (TD), middle (TM) and ventral (TV) thirds.
419
Two lines were drawn parallel to the longitudinal axis of the sacral vertebrae at the level of
420
the lateral borders of the tail, delimited the sacral (SC) region. The white spots indicate the
421
test sites located at the centers of the areas delimited in both antimeres and the sacrum, and at
422
the anal sphincter, perineum, dorsal vulvar commissure, and ventral vulvar commissure. (b)
423
Testing areas were drawn on the horse before conducting the experiment.
M AN U
SC
RI PT
413
AC C
EP
TE D
424
21
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT