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Evaluation of Nociception, Sedation, and Cardiorespiratory Effects of a Constant Rate Infusion of Xylazine Alone or in Combination with Lidocaine in Horses
Journal of Equine Veterinary Science 32 (2012) 339-345
Journal of Equine Veterinary Science journal homepage: www.j-evs.com
Original Research
Evaluation of Nociception, Sedation, and Cardiorespiratory Effects of a Constant Rate Infusion of Xylazine Alone or in Combination with Lidocaine in Horses Juliano Ferreira Fernandes de Souza MV, MS a, Eduardo Raposo Monteiro MV, PhD a , Daniela Campagnol MV, PhD a, Renata Conti Ramos MV a, Antonio Manoel Ferreira Frasson PhD b a b
School of Veterinary Medicine, Universidade Vila Velha, Vila Velha, Espírito Santo, Brazil Department of Electrical Engineering, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 July 2011 Received in revised form 17 October 2011 Accepted 6 November 2011 Available online 21 December 2011
This study aimed to evaluate the effects of a constant rate infusion (CRI) of xylazine or xylazine in combination with lidocaine on nociception, sedation, and physiologic values in horses. Six horses were given intravenous (IV) administration of a loading dose (LD) of 0.55 mg/kg of xylazine followed by a CRI of 1.1 mg/kg/hr. The horses were randomly assigned to receive three treatments, on different occasions, administered 10 minutes after initiation of the xylazine CRI, as follows: control, physiologic saline; lidocaine low CRI (LLCRI), lidocaine (LD: 1.3 mg/kg, CRI: 0.025 mg/kg/min); and lidocaine high CRI (LHCRI), lidocaine (LD: 1.3 mg/kg, CRI: 0.05 mg/kg/min). A blinded observer assessed objective and subjective data for 50 minutes during the CRIs. In all treatments, heart and respiratory rates decreased, end-tidal carbon dioxide concentration increased, and moderate to intense sedation was observed, but no significant treatment effect was detected in these variables. Ataxia was significantly higher in LHCRI than in the control treatment at 20 minutes of infusion. Compared with baseline values, nociceptive threshold increased to as much as 79% in the control, 190% in LLCRI, and 158% in LHCRI. Nociceptive threshold was significantly higher in LLCRI (at 10 and 50 minutes) and in LHCRI (at 30 minutes) than in the control treatment. The combination of CRIs of lidocaine with xylazine produced greater increases in nociceptive threshold compared with xylazine alone. The effects of xylazine on sedation and cardiorespiratory variables were not enhanced by the coadministration of lidocaine. The potential to increase ataxia may contraindicate the clinical use of LHCRI, in combination with xylazine, in standing horses. Ó 2012 Elsevier Inc. All rights reserved.
Keywords: a2-Adrenoceptor Agonists Equine Analgesia Sedative Effects Antinociception
1. Introduction Several complications, such as hypotension, hypoxemia, myositis, and nerve paralysis, may arise in horses as a result of the effects of general anesthetics on the cardiovascular
Corresponding author at: Eduardo Raposo Monteiro, MV, PhD, School of Veterinary Medicine, Universidade Vila Velha, Vila Velha, Espírito Santo, Brazil. Rua Comissário José Dantas de Melo, 21, Boa Vista, Espírito Santo, Brazil. E-mail address: [email protected] (E. Raposo Monteiro). 0737-0806/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jevs.2011.11.010
and respiratory system and also because of recumbency and positioning [1]. To avoid such complications, many surgical and diagnostic procedures can be performed in the standing horse under sedation and local anesthesia [2]. The a2-adrenoceptor agonists comprise the class of drugs most frequently used to facilitate standing medical procedures in horses. This class of drugs is known to produce sedation, analgesia, and muscle relaxation [2]. However, monotherapy with a2-adrenoceptor agonists may result in insufficient analgesia for some surgical procedures; in such circumstances, the a2-adrenoceptor
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agonists are administered in combination with opioids or local anesthetics to improve analgesia. Systemic administration of opioids was shown to produce short-term antinociception in horses [3], but its use was associated with decreased gastrointestinal motility [4]. Although administration of opioids has also been shown to cause excitement and increased locomotor activity in horses [3], there is evidence that these effects can be prevented if these drugs are administered in combination with sedatives such as a2-adrenoceptor agonists [5]. Lidocaine has been used as a constant rate infusion (CRI), with the aim to provide intraoperative analgesia during surgery [6-8] and to reduce the requirement of inhalational anesthetics for maintenance of anesthesia in horses [6,9]. Administration of lidocaine CRI has also been reported in conscious horses and was associated with thermal antinociception [10]. To the authors’ knowledge, the use of lidocaine CRI in combination with a2-adrenoceptor agonists has not been reported in conscious horses. The study reported here aimed to evaluate the effects of CRIs of xylazine alone or in combination with lidocaine on nociception, sedation, and physiologic values in standing horses. We hypothesized that the combination of xylazine with lidocaine would result in greater antinociception than xylazine alone. 2. Materials and Methods 2.1. Animals The study was approved by the Institutional Animal Care and Use Committee (protocol 103/2010). Five mixed breed mares and one stallion (Mangalarga Marchador), weighing 307 49 kg (mean SD), were used in this study. Horses were judged to be in good health on the basis of results of physical examination, complete blood count (CBC), and serum biochemistry analyses. Horses with preexisting lameness were excluded from the study. Food, but not water, was withheld from horses for 12 hours before each experiment. 2.2. Instrumentation During the study, the horses were restrained in stocks by a loose lead rope attached to their halter. Horses were instrumented with a 14-gauge jugular venous catheter for subsequent drug administration. The catheter was connected to a three-way stopcock and was secured in place with suture. The horses were allowed to acclimate for 30 minutes before each experiment was started. Thereafter, heart rate (HR), respiratory rate (fR), end-tidal carbon dioxide concentration (ETCO2), head height, and nociceptive threshold were determined for use as baseline values. HR was measured by auscultation with a stethoscope, whereas fR and ETCO2 were monitored by a side-stream capnograph (M2000, J.G. Moriya, São Paulo, Brazil) whose sampling tube was positioned inside the horse’s nostrils. Head height was considered the distance from the ground to the lowest point of the lower lip and was determined using a tape measure attached to the stocks. Degree of sedation was assessed by using a subjective scale ranging from 0 to 3, with 0: no sedation; 1: mild sedation with head only slightly lowered; 2: moderate sedation with the head
lowered below the manubrium but with the horse responsive to an audible stimulus (by clapping hands behind the animal); and 3: intense sedation with the head lowered below the manubrium and no response to an audible stimulus. Degree of ataxia was also evaluated by using a subjective scale with 0: no ataxia; 1: the horse was stable but slightly swaying; 2: the horse was swaying and leaning against the stock; and 3: the horse was leaning against the stock and swaying with its hind limbs crossed and its forelimbs buckling at the carpal joints. To evaluate nociceptive threshold, an electrical stimulus (50 Hz and 0.3 ms) was applied to the horse by the use of two electrodes connected to a transcutaneous electrical nerve stimulation (TENS) device (Physiotonus Four, Bioset, Rio Claro, São Paulo, Brazil). Electrodes were placed on the clipped skin over the lateral palmar nerve of the right forelimb after previous local application of conductive gel. The positive electrode was placed on the abaxial surface of the right proximal sesamoid, and the negative electrode was placed 3 cm proximal to the positive electrode. Electrodes were kept in place by an adhesive wrap around the limb. During testing, the electrical current was gradually increased until a clear avoidance response (lifting of the leg) was apparent. At that moment, the stimulus was stopped, and the corresponding intensity of the stimulus provided by the TENS device was recorded. At least two measurements of nociceptive threshold were obtained at each time point. If a different value was obtained during the first and second measurements, a third measurement was obtained, and all values were averaged for the analysis. Although the TENS unit allows the gradual increase of the electrical stimulus, the display of the device provides arbitrary units and not the output current. To determine the current intensity delivered in each level, the electrodes of the TENS unit were connected to a two-channel digital storage oscilloscope (DS5062MA, Rigol, Oakwood Village, OH). The level of stimulus was progressively increased, and the corresponding current intensity (in mA) registered by the oscilloscope was recorded. Four sets of measurements were performed, and percentage variations among the four measurements, obtained for each level of stimulus, were calculated. These procedures did not use animals and were performed after all the experiments with horses were concluded. Values of nociceptive threshold determined in the horses (in arbitrary units), before (baseline) and after administration of each of the three treatments, were converted to the corresponding current intensity (in mA) determined with the oscilloscope. 2.3. Study Design and Treatments The study was designed as a randomized, placebocontrolled, and blinded crossover study. Horses received a loading dose (LD) of xylazine (0.55 mg/kg, IV; Sedazine, Fortdodge, Campinas, São Paulo, Brazil), administered over 1 minute, followed by a CRI of xylazine (1.1 mg/kg/hr) using a syringe pump (ST 670, Samtronic, São Paulo, Brazil). Ten minutes after the beginning of the xylazine CRI, each horse was randomly assigned to receive one of three treatments IV as an LD (administered over 5 minutes), followed by a CRI: control treatment, physiologic saline (LD: 0.125 mL/kg, CRI 1 mL/kg/hr); lidocaine low CRI (LLCRI), lidocaine (LD: 1.3
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Fig. 1. Mean SD values of heart rate (HR), head height, respiratory rate (fR), and end-tidal carbon dioxide concentration (ETCO2) in six horses before (baselineeBL) and after administration of xylazine (0.55 mg/kg LD followed by 1.1 mg/kg/hr constant rate infusion [CRI]) in combination with physiologic saline (control treatment) or lidocaine. In LLCRI and LHCRI treatments, horses received an LD of lidocaine (1.3 mg/kg administered over 5 minutes) followed by a CRI of 0.025 and 0.05 mg/kg/min, respectively. Measurements at time point XYL were performed within 10 minutes after the beginning of the xylazine CRI. Measurements at time points 10, 20, 30, 40, and 50 minutes were performed during CRIs of xylazine and lidocaine. At time points 65, 80, and 110 minutes, measurements were performed within 15, 30, and 60 minutes after discontinuation of CRIs, respectively. Within each treatment group: brackets that follow the symbol (*) indicate the time points that are significantly different from BL (P < .05). Among treatment groups, y indicate significant difference between LHCRI and the control treatment (P < .05).
mg/kg, CRI 0.025 mg/kg/min); or lidocaine high CRI (LHCRI), lidocaine (LD: 1.3 mg/kg, CRI 0.05 mg/kg/min). In all cases, the volume of the LD was 0.125 mL/kg. Saline solution was used as vehicle where applicable. Each horse was tested with each of the three treatments in a 7-day interval. The lidocaine solutions were prepared by injecting 750 mg (LLCRI) or 1,500 mg (LHCRI) of 2% lidocaine hydrochloride (Hipolabor, Sabará, Minas Gerais, Brazil) into a 500-mL bag of physiologic saline (NaCl 0.9%). In all treatments, the solutions were administered at a rate of 1 mL/kg/hr using a peristaltic infusion pump (Nutrimat II, B-Braun, São Gonçalo, Rio de Janeiro, Brazil). 2.4. Assessments Measurements were performed before drug administration (baseline values), within 10 minutes after initiation of the xylazine CRI (time point XYL) and every 10 minutes after initiation of the CRI of the experimental treatment (time points 10, 20, 30, 40, and 50). When data collection was completed at 50 minutes, the infusions of xylazine and the experimental treatment were discontinued, and measurements were performed again within 15, 30, and 60 minutes after discontinuing the infusions (time points 65, 80, and 110). A single blinded assessor was responsible for assessing objective and subjective data throughout the study. 2.5. Statistical Analysis Normal distribution of data was checked with a KolgomoroveSmirnov test. For each horse, head heights
after treatment administration were converted to percentages of the baseline heights. Comparisons among treatments in cardiorespiratory variables and head height were performed by using a 2-way repeated-measures analysis of variance with time (baseline, XYL, 10, 20, 30, 40, 50, 65, 80, and 110) and treatment (control, LLCRI, and LHCRI) as main factors. When a significant treatment effect was detected, treatment comparison was performed by using a Bonferroni correction for multiple pairwise comparisons to identify the time points at which the treatments differed. To evaluate the time-related effects, a 1-way repeated-measures analysis of variance was performed within each treatment. When a significant effect was detected, values at each time point (XYL through 110) were compared with baseline values by use of a Dunnett test. Comparisons among treatments and over time in sedation, ataxia, and nociceptive threshold were analyzed by use of Friedman and Dunn’s multiple comparison test. For all analysis, differences were considered significant at values of P < .05. 3. Results There was no significant difference among treatments in baseline values of HR, fR, ETCO2, head height, and nociceptive threshold. In all cases, the horses were assigned sedation and ataxia scores of 0 at baseline (Figs. 1 and 2, Table 1). HR decreased in all treatments after administration of xylazine (time point XYL). HR values were also lower than baseline from 10 to 50 minutes in the control treatment, from 20 to 30 minutes in the LLCRI treatment, and only at
In treatments LLCRI and LHCRI, horses received an LD of lidocaine (1.3 mg/kg administered over 5 minutes) followed by a CRI of 0.025 and 0.05 mg/kg/min, respectively. See Figure 1 for remainder of key. a Significant difference compared with value for the baseline. b Significant difference compared with value for the control treatment (P < .05).
7.4 (5.9-9.2) 7.6 (7.4-14.0) 9.7 (7.2-11.3) 11.3 (8.3-13.2)a 10.3 (9.6-13.3)a 10.1 (9.0-13.1)a 9.9 (8.7-10.9) 8.6 (7.2-11.3) 7.9 (6.1-9.7) 11.0 (8.4-12.2)a 18.2 (11.5-22.5)a 19.2 (11.3-25.6)a 21.2 (10.3-26.4)a,b 11.1 (8.7-21.2) 7.6 (7.6-18.1) 17.8 (9.4-25.6)a,b 18.7 (9.3-24.5)a a a a,b a a b 17.7 (12.2-25.5) 19.1 (14.7-25.9) 11.8 (9.4-15.4) 11.6 (8.3-13.8) 17.0 (11.3-22.0) 19.1 (12.3-23.0) 16.2 (13.2-23.8) (7.6-14) (8.5-14.8) (8.9-13.0)
0.0 (0.0-0.0) 0.0 (0.0-0.0) 0.0 (0.0-0.25) 0.0 (0.0-0.25) 0.0 (0.0-0.25) 0.5 (0.0-1.0) 0.5 (0.0-1.0) 0.5 (0.0-1.0) 1.0 (1.0-1.25) 1.0 (0.75-1.0) 1.5 (1.0-2.0)a 2.0 (1.75-2.0)a 1.0 (0.75-1.0) 1.0 (1.0-1.25) 2.0 (1.75-2.0)a 1.0 (0.0-1.0) 2.0 (1.0-2.0)a 2.0 (1.0-2.25)a 1.0 (1.0-1.25)a 2.0 (1.0-2.25)a 2.5 (1.75-3.0)a (1.0-1.25)a (1.0-1.0) (1.0-2.0)
1.0 (1.0-1.0) 2.0 (1.0-2.25)a 2.0 (2.0-2.25)a,b
1.0 (0.75-1.0) 0.0 (0.0-0.25) 1.0 (0.0-2.0) 0.0 (0.0-0.3) 1.0 (0.75-1.25) 0.0 (0.0-0.25) 1.5 (0.75-2.0) 2.0 (1.0-2.0) 2.0 (2.0-2.0) 2.0 (1.75-3.0)a 2.0 (2.0-3.0)a 2.0 (2.0-2.25)a 2.0 (1.75-3.0)a 2.0 (2.0-2.3)a 2.0 (2.0-2.0) 2.0 (1.75-3.0)a 2.0 (2.0-2.3)a 2.5 (2.0-3.0)a 1.75 (2.0-3.0)a 2.0 (2.0-3.0)a 2.0 (2.0-3.0)a 2.0 (2.0-3.0)a 2.0 (2.0-2.25)a 2.0 (2.0-2.25)a
20 10
(1.75-2.25)a (2.0-2.0) (2.0-3.0)a
Sedation Control 0.0 (0.0-0.0) 2.0 LLCRI 0.0 (0.0-0.0) 2.0 LHCRI 0.0 (0.0-0.0) 2.0 Ataxia Control 0.0 (0.0-0.0) 1.0 LLCRI 0.0 (0.0-0.0) 1.0 LHCRI 0.0 (0.0-0.0) 1.5 Nociceptive threshold (mA) Control 6.3 (5.7-8.2) 9.3 LLCRI 7.3 (5.7-10.8) 11.0 LHCRI 7.4 (5.9-9.3) 12.2
BL
XYL
Time Points (Minutes)
30
40
50
65
80
110
J.F. Fernandes de Souza et al. / Journal of Equine Veterinary Science 32 (2012) 339-345 Table 1 Medians (interquartile range) sedation scores, ataxia scores, and nociceptive threshold in six horses before (baselineeBL) and after administration of xylazine (0.55 mg/kg LD followed by 1.1 mg/kg/hr CRI) in combination with physiologic saline (control treatment) or lidocaine
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10 minutes in LHCRI. There was no significant difference among treatments in HR during the infusions. Thirty minutes after discontinuation of the CRIs (time point 80), HR was lower in LHCRI than in the control treatment (Fig. 1). Compared with baseline values, there was a significant decrease in fR in all treatments at time point XYL. Respiratory rate remained significantly lower than baseline in all treatments until completion of the study (time point 110). At time point XYL, values of ETCO2 increased compared with the value for the baseline only in the control treatment, but from 10 to 110 minutes, values of ETCO2 were higher in all treatments than the values for the baseline. There was no significant difference among treatments at any time point in fR and ETCO2 values (Fig. 1). Head height decreased in all treatments after administration of xylazine and remained lower than baseline until 80 minutes. At 110 minutes, head height returned to baseline values in all treatments. No significant difference among treatments was observed in head height throughout the study (Fig. 1). Administration of xylazine caused moderate to intense sedation in most horses. Although median sedation scores were the same in all treatments at time point XYL (median ¼ 2.0), sedation scores were higher than baseline in the control and LHCRI treatments but not in LLCRI. Sedation scores were significantly higher than baseline values in all treatments during most of the infusion period. Compared with baseline, there was no significant difference in sedation scores in any treatment after discontinuation of the infusions (time points 65, 80, and 110). However, some horses still presented mild to moderate sedation until 30 minutes after the CRIs were stopped. Sedation scores did not differ among treatments at any time point (Table 1). During the study, mild ataxia was observed in most horses in the control treatment group. The highest ataxia scores observed in these horses were (at least in one time point during the study) as follows: 1 in five of six horses and 2 in one of six horses. Moderate to intense ataxia was observed in LLCRI and LHCRI treatments. In LLCRI, the highest ataxia scores were as follows: 1 in one of six horses, 2 in four of six horses, and 3 in one of six horses. The highest ataxia scores recorded in LHCRI were as follows: 2 in three of six horses and 3 in three of six horses. Ataxia scores were higher in the control treatment than the value for the baseline at XYL and 10 minutes. In LLCRI and LHCRI treatments, ataxia was higher than at baseline during most time points from 10 to 50 minutes. At 20 minutes, ataxia score was higher in LHCRI than in the control treatment. In all treatments, ataxia scores did not differ compared with baseline values from 65 to 110 minutes, and most horses did not show apparent signs of ataxia within 30 minutes after discontinuation of the infusions (time point 80, Table 1). Connection of the TENS unit to an oscilloscope revealed that the increase in output current varied from 0.5 to 1.5 mA between two consecutive levels of stimulus. The use of the oscilloscope also demonstrated that an identical current intensity is expected to be delivered when the same level of stimulus is selected on the same TENS unit. Deviations among measurements for each level of stimulus performed on four different occasions ranged from 3% to þ3%.
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Baseline values of nociceptive threshold did not differ among treatments. In the control treatment, nociceptive threshold was increased compared with the baseline value from 10 to 40 minutes, whereas in LLCRI and LHCRI treatments, nociceptive threshold was increased from 10 to 50 minutes. Maximum percentage increases above baseline in median values were 79% in control (at 20 minutes), 190% in LLCRI (at 50 minutes), and 158% in LHCRI (at 20 and 50 minutes). Compared with values for the control treatment, nociceptive threshold was significantly higher in LLCRI at 10 and 50 minutes and higher in LHCRI at 30 minutes. Fifteen minutes after discontinuation of the infusions, nociceptive threshold was higher in LHCRI than at baseline. In the remaining treatments, nociceptive threshold did not differ significantly from baseline after discontinuation of the infusions (Table 1). 4. Discussion Under the conditions of this study, the administration of xylazine as a CRI produced moderate to intense sedation and increased the nociceptive threshold in response to electrical stimulation (up to 79% increase in median) in horses; these effects were accompanied by mild ataxia, decreased HR and fR, and increased ETCO2. The combination of lidocaine with xylazine resulted in greater increases in nociceptive threshold (up to 190% increase in median), but this effect was not influenced by the infusion rate of lidocaine. The effects of xylazine on HR, fR and ETCO2 were not enhanced by the coadministration of lidocaine, but the degree of ataxia appeared to be increased, especially in the LHCRI treatment. In the present study, horses were not assigned to a lidocaine-only group. The inclusion of this additional experimental treatment would have provided useful information. However, only treatments that might be used in clinical practice were included in this study. Although lidocaine CRI has been shown to provide analgesia in horses [10], it does not induce adequate sedation for most procedures in standing horses. One limitation of the study reported here was the fact that serum lidocaine and xylazine concentrations were not determined. To evaluate the effect of a given drug administered as a CRI on nociception, it is important that plasma/ serum concentrations of the drug or drugs being tested have achieved a steady state. It has been reported that in awake and in sevoflurane-anesthetized horses, steady lidocaine serum concentrations are achieved within 30 minutes after LD (1.3 mg/kg) followed by a CRI of 0.05 mg/kg/min [11,12]. This infusion regimen is similar to that administered in the LHCRI treatment. Therefore, it is likely that steady state lidocaine concentrations were achieved in the LHCRI treatment in this study. Conversely, there is no evidence to support that a steady state was reached in the LLCRI treatment, and this shortcoming may be a reason why no major differences were observed between the two lidocaine dose groups. The a2-adrenoceptor agonists produce sedation by activation of presynaptic a2 receptors within the central nervous system, which inhibits neurotransmitter release and decreases the discharge rate of central and peripheral neurons [2]. In the present study, administration of a LD of
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xylazine (0.55 mg/kg) resulted in moderate to intense sedation, which had a rapid onset, as judged by our subjective scale. Sedation scores were consistently stable throughout the xylazine CRI (1.1 mg/kg/hr) and returned to near baseline values within 60 minutes after discontinuing the CRI. These results suggest that the xylazine LD and CRI used in this study can be administered to produce stable and predictable sedation in standing horses, with fast recovery without the use of antagonists. To the authors’ knowledge, there are no studies reporting pharmacokinetic data about xylazine CRI. In a recently published study, it was reported that xylazine 0.5 mg/kg (LD) followed by 0.40 mg/kg/hr CRI, in combination with either butorphanol or morphine and ketamine, was enough to maintain a sufficient level of sedation to perform common carotid translocation in standing horses [13]. The LD used in the present study and the study by Benredouane et al. [13] was similar, but the xylazine CRI used in our study was much higher (1.1 mg/kg/hr vs. 0.40 mg/kg/hr). When a2-adrenoceptor agonists are administered in combination with drugs that possess analgesic and/or sedating properties, such as opioids, the dose of the a2-adrenoceptor agonist can be reduced. A ceiling effect appears to exist after which, further increases in the dose of the a2-adrenoceptor agonist increase the duration but not the depth of sedation [5,14]. In the present study, the LD and CRI administered to horses in the control treatment was the same for treatments LLCRI and LHCRI. The findings that sedation did not differ among treatments and that ataxia was increased in treatment LHCRI suggest that, for the use in clinical practice, a reduction in the dose of xylazine CRI is necessary when administered in combination with a CRI of lidocaine. Administration of a CRI of lidocaine in isofluraneanesthetized dogs resulted in smooth recovery from anesthesia [15]. Similarly, in horses anesthetized with isoflurane and a CRI of lidocaine, recoveries were incident-free, whereas in horses anesthetized with isoflurane alone, some horses showed excitement during recovery [6]. In a previous study by Meyer et al. [16], the authors reported that conscious horses given a CRI of lidocaine appeared mildly sedated. The results of previous studies suggest that lidocaine administered as a CRI possesses sedating properties. Conversely, in the study reported here, sedation scores did not differ between horses in the control treatment and horses given lidocaine. It is possible that, at the doses used in this study, no additive or synergistic effect is obtained by the combination of lidocaine with xylazine or the subjective scale used to assess the degree of sedation was not sufficiently sensitive to detect differences among treatments. Lidocaine CRI administered IV has been associated with the occurrence of muscle tremors in conscious horses [17-19], and this effect was considered as a sign of drug toxicity [16-19]. Serum concentrations that resulted in muscle fasciculations ranged from 1.85 to 4.53 ng/mL [16]. Lidocaine serum concentrations in the range of 2 ng/mL are expected in awake horses given an LD of 1.3 mg/kg (0.087 mg/ kg/min for 15 minutes) followed by a CRI of 0.05 mg/kg/min [11,12,17]. It has been reported that serum lidocaine concentrations were even higher in sevoflurane-anesthetized horses than awake horses given the same infusion regimen,
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because of decreased clearance of lidocaine secondary to decreased cardiac output and hepatic blood flow [11]. Clinical signs of lidocaine toxicosis were not reported in this latter study, but the authors suggested that general anesthesia may have masked neurologic signs of toxicosis. Although lidocaine serum concentrations of lidocane were not measured in the present study, it is likely that lidocaine toxic levels have been achieved because a fast infusion rate (0.30 mg/kg/min) was administered during 5 minutes as an LD. Xylazine is known to decrease cardiac output [20-22]; therefore, administration of xylazine in combination with lidocaine may decrease the clearance of lidocaine and increase serum concentrations of this drug. Although clinical signs of toxicity were not observed in this study, it is possible that neurologic manifestations of toxicosis may have been masked by the sedative effects of xylazine. When administered at recommended doses, ataxia in horses given a2-adrenoceptor agonists is usually not a concern. However, coadministration of drugs that possess analgesic and/or sedating properties, such as opioids, enhance sedation and ataxia and increase the danger for horses to fall over [5,14]. In this study, more horses given lidocaine were assigned ataxia scores of 2 (moderate ataxia) and 3 (intense ataxia) compared with horses in the control treatment. The median ataxia scores were numerically higher in LLCRI and LHCRI than in the control treatment during most of the infusion period, although a significant difference was observed only between LHCRI and the control treatment (time point 20). These results suggest that, as reported with opioids, administration of lidocaine CRI increases the degree of ataxia caused by xylazine. This effect appears to be dose-related. To the authors’ knowledge, the use of a TENS device with the aim of assessing nociception in horses has not been reported previously. In the study reported here, the use of a TENS unit produced avoidance responses in conscious horses, which were consistent with those reported in other studies [23-25]. Moreover, baseline values of nociceptive threshold observed in this study (converted to mA) were very close to those reported in a previous study that used a gold standard electrical stimulus to evaluate nociception in horses [23]. Although in this study, the output current delivered in each level of intensity was not measured at the moment that the stimulus was applied to the horses, the use of a digital oscilloscope revealed that when the same level of stimulus is selected on the same TENS unit, on different occasions, an identical current intensity is expected to be delivered. The use of the TENS merits further investigation, but results of this study suggest that it can be a feasible technique to evaluate nociception in horses. Xylazine, detomidine, and romifidine were shown to cause antinociception in conscious horses [23,25,26]. After administration of a single bolus, the maximum antinociceptive effect of a2-adrenoceptor agonists appeared to occur within 15 minutes after drug administration, and nociceptive thresholds gradually decreased thereafter [23,25]. In the present study, administration of a CRI of xylazine increased the nociceptive threshold to electrical stimulus from 10 to 40 minutes. Unlike the antinociceptive effect of single bolus administration, in our study, the increase in nociceptive threshold remained constant during most of the xylazine infusion (increases of 57%-79% in
medians for the control treatment from 10 to 50 minutes). These results indicate that administration of a CRI of xylazine produces stable analgesic effect compared with the administration of a single bolus of a2-adrenoceptor agonists. The administration of an LD of 2 mg/kg lidocaine followed by 0.05 mg/kg/min CRI produced thermal, but not visceral, antinociception in conscious horses [10]. Results of this latter study suggest that systemic administration of lidocaine may produce somatic analgesia in conscious animals. In the present study, the increase in electrical nociceptive threshold was significantly higher for the combination of the low and high doses of lidocaine with xylazine than for xylazine alone. In addition to the thermal antinociception effect reported by Robertson et al. [10], results of this study indicate that lidocaine CRI also produces antinociception in response to electrical stimulation. Because the effect of lidocaine on nociception in this study was not assessed alone, it was not possible to determine whether the combination of lidocaine with xylazine has additive or synergistic effects. Lidocaine reduces the minimum alveolar concentration of inhalational anesthetics in a dose-dependent manner in dogs [15] and in ponies [9]. However, the effect of the dose of lidocaine on antinociception could not be demonstrated in this study. Nociceptive threshold was significantly higher in LHCRI than in the control treatment at 30 minutes, whereas in LLCRI, a significant difference was observed at 10 and 50 minutes. It is likely that the reason no major differences were observed between the two lidocaine dose groups is that plasma concentrations did not differ significantly, given the LD and the short time (50 minutes) over which data were assessed. It is possible that, after only 50 minutes, lidocaine serum concentrations were higher than at a steady state in LLCRI because a high infusion rate was used as an LD (0.30 mg/kg/min for 5 minutes). In the present study, HR decreased by 15%-20% in all treatments after administration of xylazine. It has been reported that administration of a2-adrenoceptor agonists has the potential to produce significant decreases in both HR and cardiac output [20-22]. This class of drugs was also shown to produce a biphasic effect on arterial blood pressure characterized by initial increase followed by a decrease to near baseline values [20-22]. Although significant, the cardiovascular effects caused by administration of a2-adrenoceptor agonists are well tolerated by healthy animals [2]. Blood pressure was not measured in this study, but all horses were considered to be in good health, and cardiovascular complications were not observed during this study or in the short-term follow-up. Lidocaine has been used as a CRI to provide intraoperative analgesia in horses. Lidocaine administered at an LD of 2.0-2.5 mg/kg followed by a CRI of 0.05 mg/kg/min to isoflurane-anesthetized horses did not result in cardiovascular side effects [6-8]. In one study, administration of lidocaine (1.3 mg/kg LD followed by 0.05 mg/kg/min CRI) to sevoflurane-anesthetized horses did not result in deterioration or improvement in cardiac output and arterial blood pressure compared with anesthesia with equipotent concentrations of sevoflurane alone [27]. In another study, the effects of lidocaine on the electrocardiogram (ECG), HR, and blood pressure were studied in conscious horses [16]. The authors did not report significant changes on HR and
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blood pressure at serum lidocaine concentrations below the levels that produce signs of intoxication, defined as the onset of muscle tremors. Although significant changes were observed in ECG parameters, all variables remained within normal limits for horses [16]. During the infusion period in the present study, no significant difference in HR was observed between horses in the control treatment compared with horses given lidocaine (LLCRI and LHCRI treatments). These results suggest that the combination of lidocaine with xylazine, at the doses used, did not enhance the effect of xylazine on HR. After discontinuation of the CRIs, HR appeared to return faster to values for the baseline in control than in LLCRI and LHCRI treatments. Thirty minutes after the CRIs were discontinued, HR was higher in the control treatment than in LHCRI. Although significant, this difference cannot be considered as clinically relevant. Administration of xylazine resulted in significant decreases in fR, which were accompanied by increases in ETCO2 in the control treatment (time point XYL). It has been reported that administration of a2-adrenoceptor agonists to horses causes a reduction in fR [20], tidal volume, and minute volume, which are followed by transient decreases in arterial oxygen tension (PaO2) and increases in arterial carbon dioxide tension (PaCO2) [21,22,28]. The effects of xylazine on the respiratory system were not enhanced by administration of lidocaine CRI, as fR and ETCO2 did not differ among treatments throughout this study. Also, in all treatments, the effects on fR and ETCO2 persisted for 60 minutes after discontinuation of the CRIs, which is different from the effect on HR. Despite causing a significant effect on the respiratory system, respiratory depression observed after administration of xylazine does not seem to be a concern in conscious horses [2]. In conclusion, the combination of CRIs of lidocaine with xylazine produces greater increases in nociceptive threshold in response to electrical stimulation compared with xylazine alone. The effects of xylazine on sedation and cardiorespiratory variables were not enhanced by the coadministration of lidocaine. The potential to increase ataxia may contraindicate the clinical use of LHCRI, in combination with xylazine, in standing horses.
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metabolic parameters and stress-related hormones in horses undergoing surgery. J Vet Med A Physiol Pathol Clin Med 2003; 50:190-5. Valverde A, Gunkelt C, Doherty TJ, Giguère S, Pollak AS. Effect of a constant rate infusion of lidocaine on the quality of recovery from sevoflurane or isoflurane general anaesthesia in horses. Equine Vet J 2005;37:559-64. Valverde A, Rickey E, Sinclair M, Rioja E, Pedernera J, Hathway A, et al. Comparison of cardiovascular function and quality of recovery in isoflurane-anaesthetised horses administered a constant rate infusion of lidocaine or lidocaine and medetomidine during elective surgery. Equine Vet J 2010;42:192-9. Doherty TJ, Frazier DL. Effect of intravenous lidocaine on halothane minimum alveolar concentration in ponies. Equine Vet J 1998;30: 300-3. Robertson SA, Sanchez LC, Merritt AM, Doherty TJ. Effect of systemic lidocaine on visceral and somatic nociception in conscious horses. Equine Vet J 2005;37:122-7. Feary DJ, Mama KR, Wagner AE, Thomasy S. Influence of general anesthesia on pharmacokinetics of intravenous lidocaine infusion in horses. Am J Vet Res 2005;66:574-80. Feary DJ, Mama KR, Thomasy SM, Wagner AE, Enns RM. Influence of gastrointestinal tract disease on pharmacokinetics of lidocaine after intravenous infusion in anesthetized horses. Am J Vet Res 2006;67: 317-22. Benredouane K, Ringer SK, Fourel I, Lepage OM, Portier KG, Bettschart-Wolfensberger R. Comparison of xylazine-butorphanol and xylazine-morphine-ketamine infusions in horses undergoing a standing surgery. Vet Rec 2011;169:364. Cruz FS, Carregaro AB, Machado M, Antonow RR. Sedative and cardiopulmonary effects of buprenorphine and xylazine in horses. Can J Vet Res 2011;75:35-41. Valverde A, Doherty TJ, Hernández J, Davies W. Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 2004;31:264-71. Meyer GA, Lin HC, Hanson RR, Hayes TL. Effects of intravenous lidocaine overdose on cardiac electrical activity and blood pressure in the horse. Equine Vet J 2001;33:434-7. Milligan M, Kukanich B, Beard W, Waxman S. The disposition of lidocaine during a 12-hour intravenous infusion to postoperative horses. J Vet Pharmacol Ther 2006;29:495-9. Brianceau P, Chevalier H, Karas A, Court MH, Bassage L, KirkerHead C, et al. Intravenous lidocaine and small-intestinal size, abdominal fluid, and outcome after colic surgery in horses. J Vet Intern Med 2002;16:736-41. Malone E, Ensink J, Turner T, Wilson J, Andrews F, Keegan K, et al. Intravenous continuous infusion of lidocaine for treatment of equine ileus. Vet Surg 2006;35:60-6. Muir WW, Skarda RT, Sheehan W. Hemodynamic and respiratory effects of a xylazine-acetylpromazine drug combination in horses. Am J Vet Res 1979;40:1518-22. Wagner AE, Muir WW, Hinchcliff KW. Cardiovascular effects of xylazine and detomidine in horses. Am J Vet Res 1991;52:651-7. Yamashita K, Tsubakishita S, Futaok S, Ueda I, Hamaguchi H, Seno T, et al. Cardiovascular effects of medetomidine, detomidine and xylazine in horses. J Med Vet Sci 2000;62:1025-32. Moens Y, Lanz F, Doherr MG, Schatzmann U. A comparison of the antinociceptive effects of xylazine, detomidine and romifidine on experimental pain in horses. Vet Anaesth Analg 2003;30:183-90. Natalini CC, Robinson EP. Evaluation of the analgesic effects of epidurally administered morphine, alfentanil, butorphanol, tramadol, and U50488H in horses. Am J Vet Res 2000;61:1579-86. Schatzmann U, Armbruster S, Stucki F, Busato A, Kohler I. Analgesic effect of butorphanol and levomethadone in detomidine sedated horses. J Vet Med A Physiol Pathol Clin Med 2001;48:337-42. Rohrbach H, Korpivaara T, Schatzmann U, Spadavecchia C. Comparison of the effects of the alpha-2 agonists detomidine, romifidine and xylazine on nociceptive withdrawal reflex and temporal summation in horses. Vet Anaesth Analg 2009;36:384-95. Wagner AE, Mama KR, Steffey EP, Ferreira TH, Rezende ML. Comparison of the cardiovascular effects of equipotent anesthetic doses of sevoflurane alone and sevoflurane plus an intravenous infusion of lidocaine in horses. Am J Vet Res 2011;72:452-60. Reitemeyer H, Klein HJ, Deegen E. The effect of sedatives on lung function in horses. Acta Vet Scand Suppl 1986;82:111-20.
Journal of Equine Veterinary Science journal homepage: www.j-evs.com
Original Research
Evaluation of Nociception, Sedation, and Cardiorespiratory Effects of a Constant Rate Infusion of Xylazine Alone or in Combination with Lidocaine in Horses Juliano Ferreira Fernandes de Souza MV, MS a, Eduardo Raposo Monteiro MV, PhD a , Daniela Campagnol MV, PhD a, Renata Conti Ramos MV a, Antonio Manoel Ferreira Frasson PhD b a b
School of Veterinary Medicine, Universidade Vila Velha, Vila Velha, Espírito Santo, Brazil Department of Electrical Engineering, Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 July 2011 Received in revised form 17 October 2011 Accepted 6 November 2011 Available online 21 December 2011
This study aimed to evaluate the effects of a constant rate infusion (CRI) of xylazine or xylazine in combination with lidocaine on nociception, sedation, and physiologic values in horses. Six horses were given intravenous (IV) administration of a loading dose (LD) of 0.55 mg/kg of xylazine followed by a CRI of 1.1 mg/kg/hr. The horses were randomly assigned to receive three treatments, on different occasions, administered 10 minutes after initiation of the xylazine CRI, as follows: control, physiologic saline; lidocaine low CRI (LLCRI), lidocaine (LD: 1.3 mg/kg, CRI: 0.025 mg/kg/min); and lidocaine high CRI (LHCRI), lidocaine (LD: 1.3 mg/kg, CRI: 0.05 mg/kg/min). A blinded observer assessed objective and subjective data for 50 minutes during the CRIs. In all treatments, heart and respiratory rates decreased, end-tidal carbon dioxide concentration increased, and moderate to intense sedation was observed, but no significant treatment effect was detected in these variables. Ataxia was significantly higher in LHCRI than in the control treatment at 20 minutes of infusion. Compared with baseline values, nociceptive threshold increased to as much as 79% in the control, 190% in LLCRI, and 158% in LHCRI. Nociceptive threshold was significantly higher in LLCRI (at 10 and 50 minutes) and in LHCRI (at 30 minutes) than in the control treatment. The combination of CRIs of lidocaine with xylazine produced greater increases in nociceptive threshold compared with xylazine alone. The effects of xylazine on sedation and cardiorespiratory variables were not enhanced by the coadministration of lidocaine. The potential to increase ataxia may contraindicate the clinical use of LHCRI, in combination with xylazine, in standing horses. Ó 2012 Elsevier Inc. All rights reserved.
Keywords: a2-Adrenoceptor Agonists Equine Analgesia Sedative Effects Antinociception
1. Introduction Several complications, such as hypotension, hypoxemia, myositis, and nerve paralysis, may arise in horses as a result of the effects of general anesthetics on the cardiovascular
Corresponding author at: Eduardo Raposo Monteiro, MV, PhD, School of Veterinary Medicine, Universidade Vila Velha, Vila Velha, Espírito Santo, Brazil. Rua Comissário José Dantas de Melo, 21, Boa Vista, Espírito Santo, Brazil. E-mail address: [email protected] (E. Raposo Monteiro). 0737-0806/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jevs.2011.11.010
and respiratory system and also because of recumbency and positioning [1]. To avoid such complications, many surgical and diagnostic procedures can be performed in the standing horse under sedation and local anesthesia [2]. The a2-adrenoceptor agonists comprise the class of drugs most frequently used to facilitate standing medical procedures in horses. This class of drugs is known to produce sedation, analgesia, and muscle relaxation [2]. However, monotherapy with a2-adrenoceptor agonists may result in insufficient analgesia for some surgical procedures; in such circumstances, the a2-adrenoceptor
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agonists are administered in combination with opioids or local anesthetics to improve analgesia. Systemic administration of opioids was shown to produce short-term antinociception in horses [3], but its use was associated with decreased gastrointestinal motility [4]. Although administration of opioids has also been shown to cause excitement and increased locomotor activity in horses [3], there is evidence that these effects can be prevented if these drugs are administered in combination with sedatives such as a2-adrenoceptor agonists [5]. Lidocaine has been used as a constant rate infusion (CRI), with the aim to provide intraoperative analgesia during surgery [6-8] and to reduce the requirement of inhalational anesthetics for maintenance of anesthesia in horses [6,9]. Administration of lidocaine CRI has also been reported in conscious horses and was associated with thermal antinociception [10]. To the authors’ knowledge, the use of lidocaine CRI in combination with a2-adrenoceptor agonists has not been reported in conscious horses. The study reported here aimed to evaluate the effects of CRIs of xylazine alone or in combination with lidocaine on nociception, sedation, and physiologic values in standing horses. We hypothesized that the combination of xylazine with lidocaine would result in greater antinociception than xylazine alone. 2. Materials and Methods 2.1. Animals The study was approved by the Institutional Animal Care and Use Committee (protocol 103/2010). Five mixed breed mares and one stallion (Mangalarga Marchador), weighing 307 49 kg (mean SD), were used in this study. Horses were judged to be in good health on the basis of results of physical examination, complete blood count (CBC), and serum biochemistry analyses. Horses with preexisting lameness were excluded from the study. Food, but not water, was withheld from horses for 12 hours before each experiment. 2.2. Instrumentation During the study, the horses were restrained in stocks by a loose lead rope attached to their halter. Horses were instrumented with a 14-gauge jugular venous catheter for subsequent drug administration. The catheter was connected to a three-way stopcock and was secured in place with suture. The horses were allowed to acclimate for 30 minutes before each experiment was started. Thereafter, heart rate (HR), respiratory rate (fR), end-tidal carbon dioxide concentration (ETCO2), head height, and nociceptive threshold were determined for use as baseline values. HR was measured by auscultation with a stethoscope, whereas fR and ETCO2 were monitored by a side-stream capnograph (M2000, J.G. Moriya, São Paulo, Brazil) whose sampling tube was positioned inside the horse’s nostrils. Head height was considered the distance from the ground to the lowest point of the lower lip and was determined using a tape measure attached to the stocks. Degree of sedation was assessed by using a subjective scale ranging from 0 to 3, with 0: no sedation; 1: mild sedation with head only slightly lowered; 2: moderate sedation with the head
lowered below the manubrium but with the horse responsive to an audible stimulus (by clapping hands behind the animal); and 3: intense sedation with the head lowered below the manubrium and no response to an audible stimulus. Degree of ataxia was also evaluated by using a subjective scale with 0: no ataxia; 1: the horse was stable but slightly swaying; 2: the horse was swaying and leaning against the stock; and 3: the horse was leaning against the stock and swaying with its hind limbs crossed and its forelimbs buckling at the carpal joints. To evaluate nociceptive threshold, an electrical stimulus (50 Hz and 0.3 ms) was applied to the horse by the use of two electrodes connected to a transcutaneous electrical nerve stimulation (TENS) device (Physiotonus Four, Bioset, Rio Claro, São Paulo, Brazil). Electrodes were placed on the clipped skin over the lateral palmar nerve of the right forelimb after previous local application of conductive gel. The positive electrode was placed on the abaxial surface of the right proximal sesamoid, and the negative electrode was placed 3 cm proximal to the positive electrode. Electrodes were kept in place by an adhesive wrap around the limb. During testing, the electrical current was gradually increased until a clear avoidance response (lifting of the leg) was apparent. At that moment, the stimulus was stopped, and the corresponding intensity of the stimulus provided by the TENS device was recorded. At least two measurements of nociceptive threshold were obtained at each time point. If a different value was obtained during the first and second measurements, a third measurement was obtained, and all values were averaged for the analysis. Although the TENS unit allows the gradual increase of the electrical stimulus, the display of the device provides arbitrary units and not the output current. To determine the current intensity delivered in each level, the electrodes of the TENS unit were connected to a two-channel digital storage oscilloscope (DS5062MA, Rigol, Oakwood Village, OH). The level of stimulus was progressively increased, and the corresponding current intensity (in mA) registered by the oscilloscope was recorded. Four sets of measurements were performed, and percentage variations among the four measurements, obtained for each level of stimulus, were calculated. These procedures did not use animals and were performed after all the experiments with horses were concluded. Values of nociceptive threshold determined in the horses (in arbitrary units), before (baseline) and after administration of each of the three treatments, were converted to the corresponding current intensity (in mA) determined with the oscilloscope. 2.3. Study Design and Treatments The study was designed as a randomized, placebocontrolled, and blinded crossover study. Horses received a loading dose (LD) of xylazine (0.55 mg/kg, IV; Sedazine, Fortdodge, Campinas, São Paulo, Brazil), administered over 1 minute, followed by a CRI of xylazine (1.1 mg/kg/hr) using a syringe pump (ST 670, Samtronic, São Paulo, Brazil). Ten minutes after the beginning of the xylazine CRI, each horse was randomly assigned to receive one of three treatments IV as an LD (administered over 5 minutes), followed by a CRI: control treatment, physiologic saline (LD: 0.125 mL/kg, CRI 1 mL/kg/hr); lidocaine low CRI (LLCRI), lidocaine (LD: 1.3
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Fig. 1. Mean SD values of heart rate (HR), head height, respiratory rate (fR), and end-tidal carbon dioxide concentration (ETCO2) in six horses before (baselineeBL) and after administration of xylazine (0.55 mg/kg LD followed by 1.1 mg/kg/hr constant rate infusion [CRI]) in combination with physiologic saline (control treatment) or lidocaine. In LLCRI and LHCRI treatments, horses received an LD of lidocaine (1.3 mg/kg administered over 5 minutes) followed by a CRI of 0.025 and 0.05 mg/kg/min, respectively. Measurements at time point XYL were performed within 10 minutes after the beginning of the xylazine CRI. Measurements at time points 10, 20, 30, 40, and 50 minutes were performed during CRIs of xylazine and lidocaine. At time points 65, 80, and 110 minutes, measurements were performed within 15, 30, and 60 minutes after discontinuation of CRIs, respectively. Within each treatment group: brackets that follow the symbol (*) indicate the time points that are significantly different from BL (P < .05). Among treatment groups, y indicate significant difference between LHCRI and the control treatment (P < .05).
mg/kg, CRI 0.025 mg/kg/min); or lidocaine high CRI (LHCRI), lidocaine (LD: 1.3 mg/kg, CRI 0.05 mg/kg/min). In all cases, the volume of the LD was 0.125 mL/kg. Saline solution was used as vehicle where applicable. Each horse was tested with each of the three treatments in a 7-day interval. The lidocaine solutions were prepared by injecting 750 mg (LLCRI) or 1,500 mg (LHCRI) of 2% lidocaine hydrochloride (Hipolabor, Sabará, Minas Gerais, Brazil) into a 500-mL bag of physiologic saline (NaCl 0.9%). In all treatments, the solutions were administered at a rate of 1 mL/kg/hr using a peristaltic infusion pump (Nutrimat II, B-Braun, São Gonçalo, Rio de Janeiro, Brazil). 2.4. Assessments Measurements were performed before drug administration (baseline values), within 10 minutes after initiation of the xylazine CRI (time point XYL) and every 10 minutes after initiation of the CRI of the experimental treatment (time points 10, 20, 30, 40, and 50). When data collection was completed at 50 minutes, the infusions of xylazine and the experimental treatment were discontinued, and measurements were performed again within 15, 30, and 60 minutes after discontinuing the infusions (time points 65, 80, and 110). A single blinded assessor was responsible for assessing objective and subjective data throughout the study. 2.5. Statistical Analysis Normal distribution of data was checked with a KolgomoroveSmirnov test. For each horse, head heights
after treatment administration were converted to percentages of the baseline heights. Comparisons among treatments in cardiorespiratory variables and head height were performed by using a 2-way repeated-measures analysis of variance with time (baseline, XYL, 10, 20, 30, 40, 50, 65, 80, and 110) and treatment (control, LLCRI, and LHCRI) as main factors. When a significant treatment effect was detected, treatment comparison was performed by using a Bonferroni correction for multiple pairwise comparisons to identify the time points at which the treatments differed. To evaluate the time-related effects, a 1-way repeated-measures analysis of variance was performed within each treatment. When a significant effect was detected, values at each time point (XYL through 110) were compared with baseline values by use of a Dunnett test. Comparisons among treatments and over time in sedation, ataxia, and nociceptive threshold were analyzed by use of Friedman and Dunn’s multiple comparison test. For all analysis, differences were considered significant at values of P < .05. 3. Results There was no significant difference among treatments in baseline values of HR, fR, ETCO2, head height, and nociceptive threshold. In all cases, the horses were assigned sedation and ataxia scores of 0 at baseline (Figs. 1 and 2, Table 1). HR decreased in all treatments after administration of xylazine (time point XYL). HR values were also lower than baseline from 10 to 50 minutes in the control treatment, from 20 to 30 minutes in the LLCRI treatment, and only at
In treatments LLCRI and LHCRI, horses received an LD of lidocaine (1.3 mg/kg administered over 5 minutes) followed by a CRI of 0.025 and 0.05 mg/kg/min, respectively. See Figure 1 for remainder of key. a Significant difference compared with value for the baseline. b Significant difference compared with value for the control treatment (P < .05).
7.4 (5.9-9.2) 7.6 (7.4-14.0) 9.7 (7.2-11.3) 11.3 (8.3-13.2)a 10.3 (9.6-13.3)a 10.1 (9.0-13.1)a 9.9 (8.7-10.9) 8.6 (7.2-11.3) 7.9 (6.1-9.7) 11.0 (8.4-12.2)a 18.2 (11.5-22.5)a 19.2 (11.3-25.6)a 21.2 (10.3-26.4)a,b 11.1 (8.7-21.2) 7.6 (7.6-18.1) 17.8 (9.4-25.6)a,b 18.7 (9.3-24.5)a a a a,b a a b 17.7 (12.2-25.5) 19.1 (14.7-25.9) 11.8 (9.4-15.4) 11.6 (8.3-13.8) 17.0 (11.3-22.0) 19.1 (12.3-23.0) 16.2 (13.2-23.8) (7.6-14) (8.5-14.8) (8.9-13.0)
0.0 (0.0-0.0) 0.0 (0.0-0.0) 0.0 (0.0-0.25) 0.0 (0.0-0.25) 0.0 (0.0-0.25) 0.5 (0.0-1.0) 0.5 (0.0-1.0) 0.5 (0.0-1.0) 1.0 (1.0-1.25) 1.0 (0.75-1.0) 1.5 (1.0-2.0)a 2.0 (1.75-2.0)a 1.0 (0.75-1.0) 1.0 (1.0-1.25) 2.0 (1.75-2.0)a 1.0 (0.0-1.0) 2.0 (1.0-2.0)a 2.0 (1.0-2.25)a 1.0 (1.0-1.25)a 2.0 (1.0-2.25)a 2.5 (1.75-3.0)a (1.0-1.25)a (1.0-1.0) (1.0-2.0)
1.0 (1.0-1.0) 2.0 (1.0-2.25)a 2.0 (2.0-2.25)a,b
1.0 (0.75-1.0) 0.0 (0.0-0.25) 1.0 (0.0-2.0) 0.0 (0.0-0.3) 1.0 (0.75-1.25) 0.0 (0.0-0.25) 1.5 (0.75-2.0) 2.0 (1.0-2.0) 2.0 (2.0-2.0) 2.0 (1.75-3.0)a 2.0 (2.0-3.0)a 2.0 (2.0-2.25)a 2.0 (1.75-3.0)a 2.0 (2.0-2.3)a 2.0 (2.0-2.0) 2.0 (1.75-3.0)a 2.0 (2.0-2.3)a 2.5 (2.0-3.0)a 1.75 (2.0-3.0)a 2.0 (2.0-3.0)a 2.0 (2.0-3.0)a 2.0 (2.0-3.0)a 2.0 (2.0-2.25)a 2.0 (2.0-2.25)a
20 10
(1.75-2.25)a (2.0-2.0) (2.0-3.0)a
Sedation Control 0.0 (0.0-0.0) 2.0 LLCRI 0.0 (0.0-0.0) 2.0 LHCRI 0.0 (0.0-0.0) 2.0 Ataxia Control 0.0 (0.0-0.0) 1.0 LLCRI 0.0 (0.0-0.0) 1.0 LHCRI 0.0 (0.0-0.0) 1.5 Nociceptive threshold (mA) Control 6.3 (5.7-8.2) 9.3 LLCRI 7.3 (5.7-10.8) 11.0 LHCRI 7.4 (5.9-9.3) 12.2
BL
XYL
Time Points (Minutes)
30
40
50
65
80
110
J.F. Fernandes de Souza et al. / Journal of Equine Veterinary Science 32 (2012) 339-345 Table 1 Medians (interquartile range) sedation scores, ataxia scores, and nociceptive threshold in six horses before (baselineeBL) and after administration of xylazine (0.55 mg/kg LD followed by 1.1 mg/kg/hr CRI) in combination with physiologic saline (control treatment) or lidocaine
342
10 minutes in LHCRI. There was no significant difference among treatments in HR during the infusions. Thirty minutes after discontinuation of the CRIs (time point 80), HR was lower in LHCRI than in the control treatment (Fig. 1). Compared with baseline values, there was a significant decrease in fR in all treatments at time point XYL. Respiratory rate remained significantly lower than baseline in all treatments until completion of the study (time point 110). At time point XYL, values of ETCO2 increased compared with the value for the baseline only in the control treatment, but from 10 to 110 minutes, values of ETCO2 were higher in all treatments than the values for the baseline. There was no significant difference among treatments at any time point in fR and ETCO2 values (Fig. 1). Head height decreased in all treatments after administration of xylazine and remained lower than baseline until 80 minutes. At 110 minutes, head height returned to baseline values in all treatments. No significant difference among treatments was observed in head height throughout the study (Fig. 1). Administration of xylazine caused moderate to intense sedation in most horses. Although median sedation scores were the same in all treatments at time point XYL (median ¼ 2.0), sedation scores were higher than baseline in the control and LHCRI treatments but not in LLCRI. Sedation scores were significantly higher than baseline values in all treatments during most of the infusion period. Compared with baseline, there was no significant difference in sedation scores in any treatment after discontinuation of the infusions (time points 65, 80, and 110). However, some horses still presented mild to moderate sedation until 30 minutes after the CRIs were stopped. Sedation scores did not differ among treatments at any time point (Table 1). During the study, mild ataxia was observed in most horses in the control treatment group. The highest ataxia scores observed in these horses were (at least in one time point during the study) as follows: 1 in five of six horses and 2 in one of six horses. Moderate to intense ataxia was observed in LLCRI and LHCRI treatments. In LLCRI, the highest ataxia scores were as follows: 1 in one of six horses, 2 in four of six horses, and 3 in one of six horses. The highest ataxia scores recorded in LHCRI were as follows: 2 in three of six horses and 3 in three of six horses. Ataxia scores were higher in the control treatment than the value for the baseline at XYL and 10 minutes. In LLCRI and LHCRI treatments, ataxia was higher than at baseline during most time points from 10 to 50 minutes. At 20 minutes, ataxia score was higher in LHCRI than in the control treatment. In all treatments, ataxia scores did not differ compared with baseline values from 65 to 110 minutes, and most horses did not show apparent signs of ataxia within 30 minutes after discontinuation of the infusions (time point 80, Table 1). Connection of the TENS unit to an oscilloscope revealed that the increase in output current varied from 0.5 to 1.5 mA between two consecutive levels of stimulus. The use of the oscilloscope also demonstrated that an identical current intensity is expected to be delivered when the same level of stimulus is selected on the same TENS unit. Deviations among measurements for each level of stimulus performed on four different occasions ranged from 3% to þ3%.
J.F. Fernandes de Souza et al. / Journal of Equine Veterinary Science 32 (2012) 339-345
Baseline values of nociceptive threshold did not differ among treatments. In the control treatment, nociceptive threshold was increased compared with the baseline value from 10 to 40 minutes, whereas in LLCRI and LHCRI treatments, nociceptive threshold was increased from 10 to 50 minutes. Maximum percentage increases above baseline in median values were 79% in control (at 20 minutes), 190% in LLCRI (at 50 minutes), and 158% in LHCRI (at 20 and 50 minutes). Compared with values for the control treatment, nociceptive threshold was significantly higher in LLCRI at 10 and 50 minutes and higher in LHCRI at 30 minutes. Fifteen minutes after discontinuation of the infusions, nociceptive threshold was higher in LHCRI than at baseline. In the remaining treatments, nociceptive threshold did not differ significantly from baseline after discontinuation of the infusions (Table 1). 4. Discussion Under the conditions of this study, the administration of xylazine as a CRI produced moderate to intense sedation and increased the nociceptive threshold in response to electrical stimulation (up to 79% increase in median) in horses; these effects were accompanied by mild ataxia, decreased HR and fR, and increased ETCO2. The combination of lidocaine with xylazine resulted in greater increases in nociceptive threshold (up to 190% increase in median), but this effect was not influenced by the infusion rate of lidocaine. The effects of xylazine on HR, fR and ETCO2 were not enhanced by the coadministration of lidocaine, but the degree of ataxia appeared to be increased, especially in the LHCRI treatment. In the present study, horses were not assigned to a lidocaine-only group. The inclusion of this additional experimental treatment would have provided useful information. However, only treatments that might be used in clinical practice were included in this study. Although lidocaine CRI has been shown to provide analgesia in horses [10], it does not induce adequate sedation for most procedures in standing horses. One limitation of the study reported here was the fact that serum lidocaine and xylazine concentrations were not determined. To evaluate the effect of a given drug administered as a CRI on nociception, it is important that plasma/ serum concentrations of the drug or drugs being tested have achieved a steady state. It has been reported that in awake and in sevoflurane-anesthetized horses, steady lidocaine serum concentrations are achieved within 30 minutes after LD (1.3 mg/kg) followed by a CRI of 0.05 mg/kg/min [11,12]. This infusion regimen is similar to that administered in the LHCRI treatment. Therefore, it is likely that steady state lidocaine concentrations were achieved in the LHCRI treatment in this study. Conversely, there is no evidence to support that a steady state was reached in the LLCRI treatment, and this shortcoming may be a reason why no major differences were observed between the two lidocaine dose groups. The a2-adrenoceptor agonists produce sedation by activation of presynaptic a2 receptors within the central nervous system, which inhibits neurotransmitter release and decreases the discharge rate of central and peripheral neurons [2]. In the present study, administration of a LD of
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xylazine (0.55 mg/kg) resulted in moderate to intense sedation, which had a rapid onset, as judged by our subjective scale. Sedation scores were consistently stable throughout the xylazine CRI (1.1 mg/kg/hr) and returned to near baseline values within 60 minutes after discontinuing the CRI. These results suggest that the xylazine LD and CRI used in this study can be administered to produce stable and predictable sedation in standing horses, with fast recovery without the use of antagonists. To the authors’ knowledge, there are no studies reporting pharmacokinetic data about xylazine CRI. In a recently published study, it was reported that xylazine 0.5 mg/kg (LD) followed by 0.40 mg/kg/hr CRI, in combination with either butorphanol or morphine and ketamine, was enough to maintain a sufficient level of sedation to perform common carotid translocation in standing horses [13]. The LD used in the present study and the study by Benredouane et al. [13] was similar, but the xylazine CRI used in our study was much higher (1.1 mg/kg/hr vs. 0.40 mg/kg/hr). When a2-adrenoceptor agonists are administered in combination with drugs that possess analgesic and/or sedating properties, such as opioids, the dose of the a2-adrenoceptor agonist can be reduced. A ceiling effect appears to exist after which, further increases in the dose of the a2-adrenoceptor agonist increase the duration but not the depth of sedation [5,14]. In the present study, the LD and CRI administered to horses in the control treatment was the same for treatments LLCRI and LHCRI. The findings that sedation did not differ among treatments and that ataxia was increased in treatment LHCRI suggest that, for the use in clinical practice, a reduction in the dose of xylazine CRI is necessary when administered in combination with a CRI of lidocaine. Administration of a CRI of lidocaine in isofluraneanesthetized dogs resulted in smooth recovery from anesthesia [15]. Similarly, in horses anesthetized with isoflurane and a CRI of lidocaine, recoveries were incident-free, whereas in horses anesthetized with isoflurane alone, some horses showed excitement during recovery [6]. In a previous study by Meyer et al. [16], the authors reported that conscious horses given a CRI of lidocaine appeared mildly sedated. The results of previous studies suggest that lidocaine administered as a CRI possesses sedating properties. Conversely, in the study reported here, sedation scores did not differ between horses in the control treatment and horses given lidocaine. It is possible that, at the doses used in this study, no additive or synergistic effect is obtained by the combination of lidocaine with xylazine or the subjective scale used to assess the degree of sedation was not sufficiently sensitive to detect differences among treatments. Lidocaine CRI administered IV has been associated with the occurrence of muscle tremors in conscious horses [17-19], and this effect was considered as a sign of drug toxicity [16-19]. Serum concentrations that resulted in muscle fasciculations ranged from 1.85 to 4.53 ng/mL [16]. Lidocaine serum concentrations in the range of 2 ng/mL are expected in awake horses given an LD of 1.3 mg/kg (0.087 mg/ kg/min for 15 minutes) followed by a CRI of 0.05 mg/kg/min [11,12,17]. It has been reported that serum lidocaine concentrations were even higher in sevoflurane-anesthetized horses than awake horses given the same infusion regimen,
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because of decreased clearance of lidocaine secondary to decreased cardiac output and hepatic blood flow [11]. Clinical signs of lidocaine toxicosis were not reported in this latter study, but the authors suggested that general anesthesia may have masked neurologic signs of toxicosis. Although lidocaine serum concentrations of lidocane were not measured in the present study, it is likely that lidocaine toxic levels have been achieved because a fast infusion rate (0.30 mg/kg/min) was administered during 5 minutes as an LD. Xylazine is known to decrease cardiac output [20-22]; therefore, administration of xylazine in combination with lidocaine may decrease the clearance of lidocaine and increase serum concentrations of this drug. Although clinical signs of toxicity were not observed in this study, it is possible that neurologic manifestations of toxicosis may have been masked by the sedative effects of xylazine. When administered at recommended doses, ataxia in horses given a2-adrenoceptor agonists is usually not a concern. However, coadministration of drugs that possess analgesic and/or sedating properties, such as opioids, enhance sedation and ataxia and increase the danger for horses to fall over [5,14]. In this study, more horses given lidocaine were assigned ataxia scores of 2 (moderate ataxia) and 3 (intense ataxia) compared with horses in the control treatment. The median ataxia scores were numerically higher in LLCRI and LHCRI than in the control treatment during most of the infusion period, although a significant difference was observed only between LHCRI and the control treatment (time point 20). These results suggest that, as reported with opioids, administration of lidocaine CRI increases the degree of ataxia caused by xylazine. This effect appears to be dose-related. To the authors’ knowledge, the use of a TENS device with the aim of assessing nociception in horses has not been reported previously. In the study reported here, the use of a TENS unit produced avoidance responses in conscious horses, which were consistent with those reported in other studies [23-25]. Moreover, baseline values of nociceptive threshold observed in this study (converted to mA) were very close to those reported in a previous study that used a gold standard electrical stimulus to evaluate nociception in horses [23]. Although in this study, the output current delivered in each level of intensity was not measured at the moment that the stimulus was applied to the horses, the use of a digital oscilloscope revealed that when the same level of stimulus is selected on the same TENS unit, on different occasions, an identical current intensity is expected to be delivered. The use of the TENS merits further investigation, but results of this study suggest that it can be a feasible technique to evaluate nociception in horses. Xylazine, detomidine, and romifidine were shown to cause antinociception in conscious horses [23,25,26]. After administration of a single bolus, the maximum antinociceptive effect of a2-adrenoceptor agonists appeared to occur within 15 minutes after drug administration, and nociceptive thresholds gradually decreased thereafter [23,25]. In the present study, administration of a CRI of xylazine increased the nociceptive threshold to electrical stimulus from 10 to 40 minutes. Unlike the antinociceptive effect of single bolus administration, in our study, the increase in nociceptive threshold remained constant during most of the xylazine infusion (increases of 57%-79% in
medians for the control treatment from 10 to 50 minutes). These results indicate that administration of a CRI of xylazine produces stable analgesic effect compared with the administration of a single bolus of a2-adrenoceptor agonists. The administration of an LD of 2 mg/kg lidocaine followed by 0.05 mg/kg/min CRI produced thermal, but not visceral, antinociception in conscious horses [10]. Results of this latter study suggest that systemic administration of lidocaine may produce somatic analgesia in conscious animals. In the present study, the increase in electrical nociceptive threshold was significantly higher for the combination of the low and high doses of lidocaine with xylazine than for xylazine alone. In addition to the thermal antinociception effect reported by Robertson et al. [10], results of this study indicate that lidocaine CRI also produces antinociception in response to electrical stimulation. Because the effect of lidocaine on nociception in this study was not assessed alone, it was not possible to determine whether the combination of lidocaine with xylazine has additive or synergistic effects. Lidocaine reduces the minimum alveolar concentration of inhalational anesthetics in a dose-dependent manner in dogs [15] and in ponies [9]. However, the effect of the dose of lidocaine on antinociception could not be demonstrated in this study. Nociceptive threshold was significantly higher in LHCRI than in the control treatment at 30 minutes, whereas in LLCRI, a significant difference was observed at 10 and 50 minutes. It is likely that the reason no major differences were observed between the two lidocaine dose groups is that plasma concentrations did not differ significantly, given the LD and the short time (50 minutes) over which data were assessed. It is possible that, after only 50 minutes, lidocaine serum concentrations were higher than at a steady state in LLCRI because a high infusion rate was used as an LD (0.30 mg/kg/min for 5 minutes). In the present study, HR decreased by 15%-20% in all treatments after administration of xylazine. It has been reported that administration of a2-adrenoceptor agonists has the potential to produce significant decreases in both HR and cardiac output [20-22]. This class of drugs was also shown to produce a biphasic effect on arterial blood pressure characterized by initial increase followed by a decrease to near baseline values [20-22]. Although significant, the cardiovascular effects caused by administration of a2-adrenoceptor agonists are well tolerated by healthy animals [2]. Blood pressure was not measured in this study, but all horses were considered to be in good health, and cardiovascular complications were not observed during this study or in the short-term follow-up. Lidocaine has been used as a CRI to provide intraoperative analgesia in horses. Lidocaine administered at an LD of 2.0-2.5 mg/kg followed by a CRI of 0.05 mg/kg/min to isoflurane-anesthetized horses did not result in cardiovascular side effects [6-8]. In one study, administration of lidocaine (1.3 mg/kg LD followed by 0.05 mg/kg/min CRI) to sevoflurane-anesthetized horses did not result in deterioration or improvement in cardiac output and arterial blood pressure compared with anesthesia with equipotent concentrations of sevoflurane alone [27]. In another study, the effects of lidocaine on the electrocardiogram (ECG), HR, and blood pressure were studied in conscious horses [16]. The authors did not report significant changes on HR and
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blood pressure at serum lidocaine concentrations below the levels that produce signs of intoxication, defined as the onset of muscle tremors. Although significant changes were observed in ECG parameters, all variables remained within normal limits for horses [16]. During the infusion period in the present study, no significant difference in HR was observed between horses in the control treatment compared with horses given lidocaine (LLCRI and LHCRI treatments). These results suggest that the combination of lidocaine with xylazine, at the doses used, did not enhance the effect of xylazine on HR. After discontinuation of the CRIs, HR appeared to return faster to values for the baseline in control than in LLCRI and LHCRI treatments. Thirty minutes after the CRIs were discontinued, HR was higher in the control treatment than in LHCRI. Although significant, this difference cannot be considered as clinically relevant. Administration of xylazine resulted in significant decreases in fR, which were accompanied by increases in ETCO2 in the control treatment (time point XYL). It has been reported that administration of a2-adrenoceptor agonists to horses causes a reduction in fR [20], tidal volume, and minute volume, which are followed by transient decreases in arterial oxygen tension (PaO2) and increases in arterial carbon dioxide tension (PaCO2) [21,22,28]. The effects of xylazine on the respiratory system were not enhanced by administration of lidocaine CRI, as fR and ETCO2 did not differ among treatments throughout this study. Also, in all treatments, the effects on fR and ETCO2 persisted for 60 minutes after discontinuation of the CRIs, which is different from the effect on HR. Despite causing a significant effect on the respiratory system, respiratory depression observed after administration of xylazine does not seem to be a concern in conscious horses [2]. In conclusion, the combination of CRIs of lidocaine with xylazine produces greater increases in nociceptive threshold in response to electrical stimulation compared with xylazine alone. The effects of xylazine on sedation and cardiorespiratory variables were not enhanced by the coadministration of lidocaine. The potential to increase ataxia may contraindicate the clinical use of LHCRI, in combination with xylazine, in standing horses.
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