Accepted Manuscript

Neostigmine combined or not with lidocaine for epidural anesthesia in mares

Rodrigo C. Valadares, DVM, PhD, Cahuê F.R. Paz, DVM, MSc, Sérgio S. Rocha
Junior, DVM, MSc, Tatiana C. Castro, DVM, Rafael R. Faleiros, DVM, MSc, PhD

PII: S0737-0806(17)30107-7
DOI: 10.1016/j.jevs.2017.06.001
Reference: YJEVS 2334

To appear in: Journal of Equine Veterinary Science

Received Date: 12 March 2017

Revised Date: 9 June 2017
Accepted Date: 9 June 2017

Please cite this article as: Valadares RC, Paz CFR, Rocha Junior SS, Castro TC, Faleiros RR,
Neostigmine combined or not with lidocaine for epidural anesthesia in mares, Journal of Equine
Veterinary Science (2017), doi: 10.1016/j.jevs.2017.06.001.

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1 Neostigmine combined or not with lidocaine for epidural anesthesia in mares

3 Rodrigo C. Valadares, DVM, PhDa; Cahuê F.R. Paz, DVM, MSca; Sérgio S. Rocha Junior,

4 DVM, MSca; Tatiana C. Castro DVMa; Rafael R. Faleiros, DVM, MSc, PhDa,b*

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6 Department of Veterinary Clinic and Surgery, Universidade Federal de Minas Gerais, Belo

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7 Horizonte, MG, Brazil
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8 CNPq and FAPEMIG Fellow, Belo Horizonte, MG, Brazil

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10 Corresponding author at: Rafael Resende Faleiros, DVM, MSc, PhD.

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Departamento de Clínica e Cirurgia Veterinárias, Escola de Veterinária da Universidade
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12 Federal de Minas Gerais. Av. Antonio Carlos, 6627. CEP 31270-901, Belo Horizonte, MG,
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13 Brazil. E-mail address: faleirosufmg@gmail.com

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1 ABSTRACT

2 Only a few studies have examined the effect of neostigmine combined with lidocaine on

3 epidural anesthesia in gelding horses. The purpose of this investigation was to evaluate

4 clinical effects, ataxia, and the sensory block duration caused by adding neostigmine to

5 epidural lidocaine in mares. Three independent treatments including neostigmine (NEOST),

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6 2% lidocaine (LIDO), or 2% lidocaine combined with neostigmine (LIDO + NEOST) were

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7 administered to six mares using epidural catheters. Each animal received all treatments. A

8 cutaneous pinprick nociception test with fine needle was used in perianal, sacral, and lumbar

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9 dermatomes in both antimeres. The response (attempt to kick, movement of the limbs, tail, or

10 head towards the stimulus) was assessed immediately before and after each treatment (every

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15 min in the first hour, and then every 30 min thereafter until the animal would go back to
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12 basal response). ANOVA (P < 0.05) was used to compare the treatment responses. The
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13 NEOST group did not show sign of anesthesia in any of the dermatomes. The LIDO and

14 LIDO + NEOST groups showed sensory block of the perianal and sacral dermatomes, but not
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15 of the lumbar dermatome. The mean duration of anaesthesia on perineal dermatomes was 58.4
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16 minutes using lidocaine alone and 64.2 minutes when neostigmine were added to lidocaine

17 with no significant difference between these 2 treatments (P > 0.05). No relevant changes in
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18 clinical and behavioral parameters were observed. In conclusion, adding neostigmine to

19 lidocaine has not brought any relevant benefits to the epidural anesthesia in clinically normal
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20 mares.

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22 Keywords: horse; pain; neuroaxial anesthesia
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24 1. Introduction

25 Sensory blocks of the spinal cord and nerves roots are known to produce anesthesia in

26 humans and animals. The types of neuroaxial anesthesia used in horses include epidural and
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1 intrathecal injections of anesthetic solutions by means of a single or continuous administration

2 via catheters [1].

3 The use of pharmaceutical adjuvants such as opioids and alpha-2 agonists is effective

4 in reducing the dosage of local anesthetics and increase anesthesia duration in neuraxial

5 anesthesia; however, the adverse effects of these compounds can limit their use [1]. The use of

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6 spinal opioids can cause pruritus, nausea, respiratory depression, and reduction of digestive

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7 motility. The use of alpha-2 agonists can result in bradycardia, hypotension, and sedation.

8 Thus, an ideal adjuvant for use as a neuraxial anesthetic agent has yet to be identified [2].

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9 Intrathecal injection of muscarinic receptor agonists caused antinociception in rats,

10 and this effect was reversed by intrathecal administration of atropine. Moreover, post-surgery

11 analgesia was observed in humans

Uafter systemic use of physostigmine, an
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12 acetylcholinesterase inhibitor that crosses the blood-brain barrier. Following pre-clinical
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13 toxicity studies, the use of spinal neostigmine was introduced in clinical studies in 1995 [3].

14 In the equine literature, a limited number of studies have addressed the use of
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15 neostigmine combined with lidocaine in castrated males [4,5]. However, the effect of this
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16 combination in mares has not been documented in the international literature. The main

17 purpose of this study was to evaluate whether the addition of neostigmine to lidocaine in
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18 caudal epidural anesthesia would lead to an increase in the duration of the sensory block in

19 mares. Furthermore, the safety of neostigmine administration in caudal epidural anesthesia

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20 was also assessed by evaluating cardio-respiratory parameters in a blinded randomized study.

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22 2. Materials and Methods

23 Six non-pregnant mix breed aged (mean ± SD) 12 + 2 years, with weight of 350 + 26

24 Kg and with mean body condition score of 6 + 1/9 were selected to participate in the study.

25 Mares were stabled in individual stalls for a 2-week acclimatization period consuming grass
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1 hay and water. The experimental protocol was approved by the University Animal Ethics

2 Committee (protocol number 99/2012)

3 A crossover experimental design was used, where each animal underwent three

4 treatments via caudal epidural administration, through a previously implanted catheter. In

5 order to avoid eventual residual effects among treatments, a 72-hour period was established

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6 from one treatment to the next.

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7 Treatment 1 (NEOST) consisted of 4µg/Kg of neostigmine 0.5 mg/mL (neostigmine

8 methylsulfate, Cristália, São Paulo, Brasil), treatment 2 (LIDO) consisted of 0.35 mg/Kg of

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9 lidocaine 2% with no vasoconstrictor (Lidocaine hydrochlorate, Cristália, São Paulo, Brasil)

10 and treatment 3 (LIDO + NEOST) consisted of 4µg/Kg of neostigmine and 0.35 mg/Kg of

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lidocaine 2%. The final volume of each treatment was standardized to be 10 mL adding
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12 sodium chloride at 0.9%. Treatments were administered at a speed of 0.1 mL/second for the
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13 standardization of pharmaceutical distribution within the epidural space. For catheter

14 implantation, the animals were maintained under the following fasting conditions: 6 h without
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15 food and 2 h without water. Following this period, the animals were sedated with 10%
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16 xylazine (0.5 mg/kg, intravenous IV).

17 The region corresponding to the first intercoccygeal space was identified and was
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18 surgically prepared, and the skin and the subcutaneous tissue were desensitized by infiltration

19 with 3.0 mL of 2% lidocaine. A Tuohy 18-G needle was used to penetrate the epidural space,
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20 using the technique of loss of resistance to air to identify this space. Then, an epidural catheter

21 18G was introduced cranially until it reached 10 cm from the tip of the needle. Before

22 removing the needle, lidocaine 2% (1mL/ 100 Kg of bwt) was injected through the catheter in

23 order to verify the correct location of the catheter, by the the loss of sensitivity to cutaneous

24 pinprick of the perineum and the absence of tail tonus. Catheters were fixed to the skin using

25 the tunnelling technique. A dressing with sterile gauze with a chlorhexidine solution 2% was
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1 done on the site where the catheter was inserted and changed daily during the experimental

2 period. In order to avoid catheter flow obstruction, it was flushed daily with 0.5 mL of saline

3 solution 0.9% with heparin at 10 UI. During each treatment, the catheter was flushed only

4 after the end of the evaluation period in order to avoid the interference of the washing solution

5 with the treatment.

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6 During the treatments, mares went through clinical data collection by one researcher

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7 on a single-blinded study protocol. Animals were blindfolded during the evaluation period to

8 avoid their conditioning during the stimulus with fine needle. Heart rate was measured by a

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9 continuous electrocardiogram in derivation I, where electrodes were positioned according to

10 the base apex derivation (Dixtal DX 2010 multi-parameter monitor, Dixtal Biomédica, São

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Paulo, Brazil). In order to measure oscillometric blood pressure, tail-base circumference was
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12 determined in centimetres and a cuff was chosen according to this circumference, when this
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13 was placed on this region. Respiratory rate and ETCO2 were measured by sidestream

14 capnography probe (Capnosat, Drägerwerk, Lübeck, Germany) in one of the animal’s nostril,
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15 where it was kept for 30 seconds to validate the information. In order to record rectal
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16 temperature, the digital thermometer sensor (digital thermometer, BD, São Paulo, Brazil) was

17 placed in contact with the rectal mucosa until the value of this variable was recorded.
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18 Sedation, behaviour and ataxia were evaluated by means of scores [6]. For the sedation: 1 –

19 no variation in the head position; 2 – lower the head to the level of the elbow and 3 – lower
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20 the head to the level of the carpus or even lower. For the behaviour: 1 – calm and alert; 2 –

21 restless (moderate movement within the trunk); 3 – excited (violent movement within the

22 trunk). For ataxia: 1 – normal body posture, normal reaction to lateral pressure, normal gait; 2

23 – moderate rocking, delay to lateral pressure; 3 – severe rocking, rest against trunk, severe

24 variation on gait or unable to move; 4 – fall. These pieces of information were reported
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1 immediately before and every 15 minutes during the first hour after administering the

2 treatments, and then, every 30 minutes until the scores would turn back to baseline.

3 Evaluation of the anesthesia was performed by cutaneous pinprick test stimulating the

4 skin with a fine needle (25 mm x 0.7mm; 22 G) in perineal (1, 2 and 8), sacral (3 and 4) and

5 lumbar dermatomes (9) bilaterally the median sagittal plane (Fig. 1) [7]. The dermatome was

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6 considered anesthetized when the mares did not respond to the stimulus. The painful stimulus

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7 was performed in each time point stimulating the surface of the epidermis once with the

8 needle. The reactions considered in this evaluation were the movement of limbs, head turning

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9 towards the location of the stimulus or an attempt to kick. In case the anesthesia occurred in

10 any dermatome, this would be evaluated every 15 minutes until the animal produced a

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positive response to the stimulus with a fine needle. Then the total duration of the anesthesia
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12 was recorded for each dermatome.
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14 2.1 Statistical Analysis

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15 Data obtained from clinical parameters, dermatome, sedation, and ataxia testing were
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16 subjected to the Kolmogorov–Smirnov test, which showed a normal distribution. The data are

17 presented as the means and the standard error of the means. Data from clinical parameters
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18 (within and between treatments) and data from dermatome testing (within treatments) were

19 subjected to analysis of variance for mean comparisons by using the ANOVA test. In this case,
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20 Tukey’s test was used as a post-test to determine the significance of the difference between

21 means. For the data obtained from dermatome testing, the t-test was used to compare means

22 and to determine the significance of the difference between treatments. The non-parametric

23 data obtained from sedation, behavior, and ataxia scores were subjected to Friedman’s test,

24 and Dunn’s test was used to determine the significance of the difference between means. P
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1 values <0.05 were considered significant. Statistical analysis was performed by using

2 GraphPad Prism 5 (GraphPad Software, Inc., La Jolla, CA) software.

4 3. Results

5 During the catheter implementation phase, three mares were discarded from the study.

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6 The reason to exclude these animals was the fact that, after injecting 1 mL of lidocaine 2% for

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7 each 100 Kg of body weight to confirm the positioning of the catheter, there was a sensorial

8 block of the perineal and sacral dermatomes only on one side of the mean sagittal plane,

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9 suggesting an uneven distribution of the medicine within the space. Three new animals

10 substituted the ones that were excluded, and had an appropriate response to the positioning

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test of the epidural catheter with an injection of lidocaine 2%.
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12 Comparison of the means obtained from dermatome desensitization tests, within and
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13 between treatments, was performed only between the LIDO and LIDO + NEOST groups

14 because the group that received only NEOST did not show anesthesia of any of the tested
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15 dermatomes. Anaesthesia was observed in demartomes 1, 2, 3, 4 and 8. The evaluation of the

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16 duration of analgesia between the dermatomes revealed a significant difference (P < 0.05)

17 between the dermatome 3 and the others, with the former showing a shorter analgesia
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18 duration (Figure 2). No statistical difference were observed between groups in each

19 dermatome.
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20 The effect of time in each of the treatments was not statistically verified in any of the

21 clinical variables tested. However, when comparing the effects of treatments among groups, at

22 each time, some differences became evident. Heart rate (Fig. 3) was lower in the NEOST

23 group than that in the LIDO group from 45 to 60 minutes (35.33 + 6.12 versus 43.83 + 6.96;

24 34.50 + 4.55 versus 41.67 + 8.45, respectively; mean + standard deviation). ETCO2 (Fig. 4)

25 was greater in the NEOST treatment from 15 to 45 minutes when compared to the LIDO
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1 group (50 + 4.05 versus 41.50 + 3.61; 48.83 + 3.97 versus 39.67 + 5.61; 47.33 + 3.67 versus

2 38.67 + 5.57; 47 + 2.75 versus 40.83 + 5.19, respectively at 15, 30 and 45 minutes; mean +

3 standard deviation). Respiratory rate, systolic, diastolic and mean blood pressure and rectal

4 temperature are not influenced by the time or by the treatments (P>0.05). There was statistical

5 difference between sedation scores and behavior among treatments. NEOST treatment has not

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6 induced ataxia at any moment of evaluation, whereas LIDO and LIDO + NEOST treatments

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7 induced ataxia from 15 to 60 minutes, differing from the NEOST treatment (data not show).

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9 4. Discussion

10 Our results demonstrated that the use of pure neostigmine solution in caudal epidural

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space at a dosage of 4 µg/kg did not produced any sign of anesthetic effect in clinically
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12 normal mares. It is believed that neostigmine can produce analgesia at medullar level by
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13 increasing the concentration of acetylcholine, which binds muscarinic and nicotinic receptors

14 activating the descending pathways that inhibited pain [8]. However, the analgesic effect of
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15 epidural injected neostigmine remains unclear and may be related to a central action because
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16 it apparently does not cross the duramater due to its hydrophilic properties [8]. In fact,

17 neostigmine has been most used as an adjunct for neuroaxial anesthesia performed with local
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18 anesthetic agents or in combination with classic analgesic drugs to provide obstetric and post-

19 operative analgesia [9,10].

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20 The use of lidocaine was effective in promoting anesthesia of dermatomes 1, 2, 4, and

21 8; in contrast, it had a minimal effect in dermatome 3 and no effect in dermatome 9. These

22 findings were bilaterally homogeneous in the dermatomes and occurred in all animals, with a

23 mean anesthesia time of 54.2 min. Longer mean duration times (70 min) in perianal

24 dermatomes were reported in studies that used a lower dosage (0.2 mg/kg) of epidural

25 lidocaine in geldings [4,5]. The authors of this previous study also used a nociception model
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1 with a fine needle; however, unlike our study in which the skin was superficially stimulated,

2 the needle seemed to be deepened until penetration of the skin and muscle tissue. The type of

3 pain stimulus appears to have a strong influence on the duration of the analgesic effect of

4 epidural lidocaine in horses. For example, LeBlanc et al. [11] used a nociception model

5 through neurostimulation of the perianal dermatomes, and found that the mean duration of the

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6 sensorial block for epidural lidocaine was 150 minutes. This is much higher than the mean

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7 durations reported in the present study as well as those reported in other studies [4,5], which

8 used a fine needle stimulus.

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9 The addition of neostigmine did not effectively prolong the effect of epidural lidocaine

10 of any tested dermatome in the present study. In contrast, other studies using a similar model

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showed that the addition of neostigmine at dosages ranging from 1 to 2 µg/kg led to an
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12 increase in the duration of the sensory block of epidural lidocaine, reaching mean duration
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13 values of 150 minutes [4,5].

14 Despite the similarity between the model used in this study and other using geldings
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15 [4,5], important methodological differences may explain the discrepancy in the results among
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16 studies. In the present study, we considered only the absence or the presence of the response

17 to fine needle punctures, while reduced responses were also considered evidence of analgesia
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18 in previous studies [4,5]. Also the differences in gender should be carefully considered in pain

19 and analgesia studies. According to recently published reports regarding the influence of
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20 gender in the perception of pain, female animals were found to be more sensitive to

21 nociceptive stimulus than were males [12]. Moreover, the International Association for the

22 Study of Pain published a consensus review stating that it should not be assumed that results

23 obtained in pain studies using males can be generalized to a female population. They also

24 recommend that studies designed to evaluate pain should include both male and female

25 subjects; and, if this is not practically achievable, it should include only female subjects [13].
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1 The administration of neostigmine (4 µg/kg) did not affect the baseline cardiovascular

2 parameters. When compared to the group that received only lidocaine, the heart rate values

3 were lower at 45 and 60 min following administration; however, all parameters remained

4 within physiological limits. Similarly, no changes in heart rate or blood pressure were

5 observed by DeRossi et al. [4] following administration of epidural neostigmine (1 µg/kg)

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6 combined with lidocaine in horse. However, the use of 2 µg/kg neostigmine combined with

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7 lidocaine via the epidural route caused the heart rate and diastolic and mean arterial pressure

8 to decrease in horses [5]. In humans, the use of epidural neostigmine as an adjuvant anesthetic

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9 for women in labor did not lead to alterations in maternal and fetal blood pressure or heart

10 rate [14,15]. In sheep, the prior use of intrathecal neostigmine in spinal analgesia with

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clonidine led to an increase in heart rate, thus preventing the arterial hypotension caused by
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12 this alpha agonist [16].
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13 In an attempt to explain these discrepancies, the fact that the cardiovascular effect of

14 neostigmine appears to be variable and to depend upon the route of administration must be
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15 considered. The low liposolubility of epidural neostigmine may cause it to progress slowly to
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16 the hemodynamic sites in the spinal cord, which are responsible for stimulating the circulatory

17 parameters. Instead, it can be systemically absorbed and cause parasympathomimetic effects

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18 in the circulatory system [16].

19 The breathing rate was not significantly affected as a function of time or between
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20 treatments. The ETCO2 values remained within physiological limits and time had no effect on

21 them. However, the ETCO2 values for the NEOST group were higher than were those of the

22 other groups at 15 and 45 min. Although this difference is not clinically significant, several

23 facts should be considered. Neostigmine is known to promote sedation and respiratory

24 depression because of its activity on the muscarinic receptors of the brain stem [17].
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1 In this study, no statistical difference among the scores obtained for sedation for any of

2 the treatments was found. Similar studies that used epidural neostigmine in males also did not

3 report sedation or respiratory depression [4]. The increased higher ETCO2 values obtained for

4 the NEOST group compared with LIDO group could be hypothetically explained by cranial

5 migration of neostigmine towards the brain stem or by its systemic absorption, which would

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6 cause a decrease in the nerve impulses to respiratory muscles.

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7 Neuroaxial neostigmine have been used in humans for more than 20 years in a wide

8 range of doses varying from 50 to 750µg [8,18]. In the present study a dose 4µg/kg was

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9 chosen based of evidences that doses exceeding 30 µg/kg can cause higher incidence of

10 gastrointestinal discomfort in children [19], and that even lower doses (1 to 2 µg/kg) can be

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effective in increasing the duration of lidocaine-induced epidural anesthesia in geldings [4,5].
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12 The nociceptive findings from the present study should be taken considering that the
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13 experimental design was limited to evaluate the effect of adding a single dose of neostigmine

14 in the duration of epidural anesthesia with lidocaine in pain free mares. Future studies using
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15 different type of nociceptive stimulus (pressure on the skin and tissues, temperature changes,
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16 electrical stimulation, etc…) are warrant to evaluate potential beneficial analgesic effects of

17 epidural neostigmine associated with local anesthetist drugs in clinically normal and ill mares.
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18 5. Conclusions

19 Caudal epidural administration of 4µg/kg of neostigmine diluted for the final volume
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20 of 10 mL in spite of not producing adverse clinical effects, was not able neither to promote

21 anesthesia nor to prolong the anesthetic effects of lidocaine in clinically normal mares.

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23 Acknowledgements
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1 This work was supported by CNPq (302929/2015-0), FAPEMIG (PPM-00847-15), CAPES,

2 and the Office of the Dean for Research at Universidade Federal de Minas Gerais (PRPq-

3 UFMG).

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1 Figure 1 – Caudal dermatomes location, adapted from Polydoro [7]. 1 = Perineal dermatome

2 innervated by coccygeal nerve. 2 = perineal dermatome innervated by sacral nerves S3 e S4.

3 3 = sacral dermatome innervated by sacral nerves S1 to S5. 4 = sacral dermatome innervated

4 by spinal nerves L6, S1 e S2. 8 = perineal dermatome innervated by lumbar nerve L3; 9 =

5 lumbar dermatome innervated by spinal nerves L1 to L6.

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6

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7 Figure 2 - Mean (±SEM) times of sensorial block in skin dermatomes from mares treated

8 with epidural lidocaine combined or not with neostigmine. *Differ from the other dermatomes

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9 in the same group.

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Figure 3 - Mean (±SEM) heart rates from mares subjected to epidural infiltration of
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12 neostigmine and lidocaine combined or not with neostigmine. *Bars followed by same letter
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13 did not differ in the same time (P<0.05).

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15 Figure 4 - Mean (±SEM) ETCO2 values from mares subjected to epidural infiltration of
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16 neostigmine and lidocaine combined or not with neostigmine. *Bars followed by same letter

17 did not differ in the same time (P<0.05).

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Highlights
• Only a few studies have examined the effect of neostigmine combined with
lidocaine on epidural anesthesia in geldings.
• A cross over controlled study was used to test epidural anesthesia time with
lidocaine combined or not with neostigmine in mares.
• No relevant changes in clinical and behavioral parameters were observed.
• Differently from gelding studies, adding neostigmine to lidocaine has not
brought any relevant benefits to the epidural anesthesia in mares.

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