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Effect of ketoprofen, lidocaine local anesthesia, and combined xylazine and lidocaine caudal epidural anesthesia during castration of beef cattle on stress responses, immunity, growth, and behavior¹

S. T. L. Ting^*,, B. Earley^*, J. M. L. Hughes and M. A. Crowe^,,2

^* Teagasc, Grange Research Centre, Dunsany, Co. Meath, Ireland, and and Faculty of Veterinary Medicine, and and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland

² Correspondence:
Dept. of Anim. Husbandry and Production, Faculty of Veterinary Medicine, University College Dublin (phone: +353-1-7166255; fax: +353-1-7166253; E-mail:
mcrowe{at}ucd.ie).

	Abstract

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To determine the effects of burdizzo castration alone or in combination with ketoprofen (K), local anesthesia (LA), or caudal epidural anesthesia (EPI) on plasma cortisol, acute-phase proteins, interferon- production, growth, and behavior of beef cattle, 50 Holstein x Friesian bulls (13 mo old, 307 ± 5.3 kg) were assigned to (n = 10/treatment): 1) control (handled; C); 2) burdizzo castration (B); 3) B following K (3 mg/kg of BW i.v.; BK); 4) B following LA (8 mL into each testis and 3 mL s.c. along the line where the jaws of the burdizzo were applied with 2% lidocaine HCl; BLA); and 5) B following EPI (0.05 mg/kg of BW of xylazine HCl and 0.4 mg/kg of BW of lidocaine HCl as caudal epidural; BEPI). The area under the cortisol curve against time was lower (P < 0.05) in BK than in B, BLA, or BEPI animals. On d 1 after treatment, plasma haptoglobin concentrations were higher (P < 0.05) in B, BLA, and BEPI than in BK animals. On d 3, haptoglobin and plasma fibrinogen concentrations were higher (P < 0.05) in all castration groups than in C. On d 7, haptoglobin and fibrinogen concentrations remained higher (P < 0.05) in BLA than in B and C animals. On d 1, concanavalin A-induced interferon- production was lower (P < 0.05) in B, BLA, and BEPI than in C, but there was no difference between BK and C animals. From d -1 to 35, ADG was lower (P < 0.05) in B, BLA, and BEPI animals, but not in BK compared with C animals. Overall, there was a higher (P < 0.05) incidence of combined abnormal postures in B than in C, BK and BEPI animals. Although the use of K and EPI decreased (P < 0.05) these postures compared with B alone or B with LA, there was no difference between the K and EPI treatment. In conclusion, burdizzo castration increased plasma cortisol and acute-phase proteins, and suppressed immune function and growth rates. Local anesthesia prolonged the increase in acute-phase proteins. Ketoprofen was more effective than LA or EPI in decreasing cortisol and partially reversed the reduction in ADG following castration. The use of K or EPI was more effective than LA in decreasing pain-associated behavioral responses observed during the first 6 h after treatment. Systemic analgesia with ketoprofen, a nonsteroidal antiinflammatory drug, was more effective in reducing inflammatory responses associated with castration than LA or EPI.

Key Words: Bulls • Castration • Epidural Anesthesia • Interferon- • Ketoprofen • Stress

	Introduction

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The castration of postpubertal male cattle intended for beef production is a routine practice in many countries. There is a legal requirement in Ireland to provide anesthesia for the surgical/burdizzo castration of cattle older than 6 mo (Protection of Animals [Amendment] Act, 1965). The administration of lidocaine local anesthesia (LA) for castration (Jones, 1997) is a standard procedure employed by veterinary practitioners. However, LA is not effective in reducing the overall stress (cortisol) response associated with castration (Fisher et al., 1996). In contrast, ketoprofen (K), a nonsteroidal antiinflammatory drug (NSAID), was found to be more effective than LA in reducing the stress of castration in calves (Earley and Crowe, 2002). The use of caudal epidural (i.e., intercoccygeal administration of xylazine) anesthesia (EPI) has been described by Caulkett et al. (1993) as a suitable method for inducing analgesia for the castration of mature bulls. They reported that adequate sedation was achieved in 97.4% of animals, and good surgical analgesia was achieved in 80.5% of animals, with no animals displaying a poor level of analgesia. However, their assessment was limited to the behavioral reactivity of animals to the castration procedure. Scientific data are lacking on the effect of caudal epidural anesthesia in modulating the stress and immune response associated with castration in cattle. There is a need to compare this method with other analgesic options in a controlled study.

The objectives of this study were to compare the efficacy of EPI against LA and K in modulating the cortisol response, acute-phase proteins, immune function, hematological variables, total antioxidant status, feed intake, growth, and behavior of 13-mo-old bulls to castration.

	Materials and Methods

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Treatments
Fifty 13-mo-old Holstein x Friesian bulls (mean BW = 307 ± 5.3 kg) were blocked by weight and randomly assigned to one of five treatments (n = 10/treatment): 1) untreated control (C); 2) burdizzo castration alone (B); 3) burdizzo castration following ketoprofen administration (BK); 4) burdizzo castration following lidocaine HCl local anesthesia (BLA); and 5) burdizzo castration following combined xylazine HCl and lidocaine HCl caudal epidural anesthesia (BEPI).

Animal Housing and Management
Bulls were housed in individual tiestalls from d -22 (day of treatment = d 0) to acclimatize them to handling and their housing environment. Animals had ad libitum access to water and grass silage (mean of nine weekly samples; DM content = 188.3 ± 4.77 g/kg, in vitro DM digestibility = 734.3 ± 11.02 g/kg of DM; pH = 3.9 ± 0.09) supplemented with 2.5 kg of barley/soybean mix concentrates (mean on DM basis of nine weekly samples; CP = 127.0 ± 4.94 g/kg, crude fiber = 33.8 ± 1.10 g/kg, acid hydrolyzable oil = 25.9 ± 0.55 g/kg, ash = 34.9 ± 1.99 g/kg) per animal daily. Individual silage intakes were recorded daily from d -9 to 33 to determine the DMI. Animals were weighed on d -22 before assignment to treatment and on d -1, 7, 14, 21, 28 and 35 to determine ADG.

Experimental Procedures
On d -21, bulls were immunized against keyhole limpet hemocyanin (KLH) by s.c. injection of 1 mg of KLH (Calbiochem, La Jolla, CA; catalog No. 374805) precipitated on potassium aluminum sulfate (Pollock et al., 1992) to determine the cell-mediated immune response to a recall antigen (i.e., KLH). Castration (time of treatment = 0 min) was performed in the B, BK, BLA, and BEPI bulls following the procedure of Fisher et al. (1996). As part of the castration procedure, gentle manual restraint of the bulls was used to facilitate the operator. Ketoprofen, a NSAID, was administered in BK bulls i.v. 20 min before treatment at the rate of 3 mg of ketoprofen/kg of BW (10% Ketofen; Merial Animal Health Ltd., Harlow, Essex, U.K.) via an indwelling jugular catheter followed by 2 mL of 0.9% sterile saline to flush the catheter. Local anesthesia in BLA bulls was provided with 2% lidocaine hydrochloride without adrenaline (Lignavet Injection; C-Vet Ltd., Leyland, Lancashire, U.K.), administered 20 min before treatment following the procedure of Skarda (1986). Caudal epidural anesthesia was administered 10 min before treatment using the anesthetic dosage and methods described by Skarda (1986) and Lewis et al. (1999). Briefly, a mixture of 2% xylazine hydrochloride (Chanazine; Chanelle Pharmaceuticals Manufacturing Ltd., Loughrea, Ireland) at 0.05 mg/kg of BW and 2% lidocaine hydrochloride (Lignavet Injection) at 0.4 mg/kg of BW was slowly injected into the center of the first intercoccygeal (C1 to C2) joint space following the removal of hair and surgical scrubbing of the skin above the space. The injection site was located by elevating and lowering the tail, palpating the depression, and movement between the respective vertebrae. Proper placement of the injection needle in the epidural space was verified by the loss of resistance method. Successful induction of EPI was confirmed when the tail tone was lost shortly following induction of the caudal epidural. Control animals received sham handling for an equivalent period to the time taken to conduct the castration procedure in the remaining groups. Precise dose rates for K and EPI were determined based on the BW of each animal obtained from d -1 before treatments. Animals not receiving K were given an equivalent volume of sterile 0.9% saline solution via their jugular catheter. Rectal temperatures of each bull were monitored twice daily (morning and evening) using an electronic digital thermometer (Jørgen Kruuse A/S model VT-801 BWC, Marslev, Denmark; catalog No. 0701) from d -1 to 5.

To facilitate intensive blood sampling with minimal animal handling, indwelling catheters were fitted into the left jugular vein on d -1, after which animals were returned to their individual tie-stalls. On d 0, blood samples (heparinized plasma) were collected at -2, -1.5, -1, -0.5, -0.25, 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 10, 12, 24, 72 h relative to the time of treatment for each bull for subsequent cortisol assay. Heparinized blood samples for haptoglobin, total anti-oxidant status and stimulated leukocyte production of interferon- (IFN-), citrated blood samples for fibrinogen, EDTA blood samples for routine hematology were collected before treatment on d 0 and on d 1 and 3. Further blood samples for haptoglobin and fibrinogen were collected on d 7, 14, 21, 28, and 35, and for hematology on d 7, 21, 28, and 35. All procedures were conducted under experimental license from the Irish Department of Health in accordance with the Cruelty to Animals Act 1876 and the European Communities (Amendment of Cruelty to Animals Act 1876) Regulations, 1994.

Assay Procedures
Plasma cortisol concentrations were determined using a commercially available RIA kit (Corti-cote, ICN Pharmaceuticals, Orangeburg, NY; catalog No. 06B-256440) previously validated for bovine plasma (Fisher et al., 1996). The intraassay CV (n = three to six per assay) for samples containing 12.8, 40.6, and 111.7 nmol of cortisol/L were 9.6, 5.7, and 6.4%, respectively, and the interassay CV (n = 15 total assays) for the same samples were 15.3, 5.3, and 8.4%. For each bull, the mean cortisol concentration was calculated for the periods - 2 to 0, 0.25 to 1.5, 2 to 6, and 6.5 to 12 h relative to the time of treatment. The peak post-treatment cortisol concentration was recorded, and the area (nmol•L^-1•h) under the cortisol vs. time curve was calculated above the pretreatment baseline from 0 to 12 h using the linear trapezoidal rule (Friend et al., 1977).

The KLH- and concanavalin A (Con A)-stimulated leukocyte production of IFN- was determined following whole-blood culture of heparinized samples using a method described by Fisher et al. (1997a), except that 1.48 mL of the blood sample volume plus 20 µL of PBS with or without additive (i.e., KLH or Con A) were used in the assay. The plasma supernatants were harvested and kept at -20°C until assayed for IFN- using an ELISA procedure specific for bovine plasma (Rothel et al., 1990; Bovigam, CSL Biosciences, Parkville, Victoria, Australia; catalog No. 03000201).

Plasma haptoglobin concentrations were measured using an assay kit (Tridelta Development Ltd., Bray, Wicklow, Ireland; catalog No. TP801) on an automated analyzer (Ciba Corning 550 Express; Ciba Diagnostics Corp., Oberlin, OH) previously validated for bovine plasma (Eckersall et al., 1999). The intraassay CV (n = three to five per assay) for samples containing 1.32 g/L was 5.7%, and the interassay CV (n = three total assays) for the same samples was 11.1%. Plasma fibrinogen concentrations were measured using a commercial kit (Roche Diagnostics GmbH, Mannheim, Germany; catalog No. 524484) adopted for bovine plasma (Earley and Crowe, 2002) on an automated clinical analyzer (spACE, Alfa Wassermann, Inc., West Caldwell, NJ) according to the manufacturer’s procedure. The intraassay CV (n = three to four per assay) for samples containing 0.79 and 2.81 g/L were 7.2 and 3%, respectively, and the interassay CV (n = two total assays) for the same samples were 5.1 and 0.4%. A number of samples (n = 11) collected for the fibrinogen assay were hemolyzed and/or clotted; these samples were excluded from the analyses due to interference with the assay.

Total antioxidant status in the plasma samples were assayed using a commercial kit (Randox Laboratories Ltd., Crumlin, N. Ireland; catalog No. NX2332) on an automated analyzer (Ciba Corning 550 Express) according to the manufacturer’s procedure.

Red blood cell (RBC) number, white blood cell (WBC) number, differential WBC (as percentages of granulocytes, monocytes, and lymphocytes), packed cell volume (PCV), hemoglobin concentrations, mean corpuscular volume, and platelet numbers were determined for unclotted (EDTA) whole-blood samples using an automated cell counter (Celltac MEK-6108K; Nihon-Kohdon, Tokyo, Japan) within 2 h of blood sampling.

Behavioral Assessment
Behavioral observations were conducted on d 0 for each animal 3 min immediately following treatment, once every 6 min for 114 min, followed by every 30 min for 180 min, and again at 354 min after treatment (27 total time points per animal) on an instantaneous scan sampling basis (Martin and Bateson, 1986) with direct observation by a single observer to avoid inter-observer variation. Behavioral categories recorded were standing, lying, feeding, and ruminating. These categories were further classified into a range of normal and abnormal behaviors as described by Molony et al. (1995) with slight modification as follows.

Standing.
This posture was defined as the sum of standing normally and standing abnormally. Standing normally was further classified as standing passively with no obvious abnormality or standing actively feeding, ruminating, and grooming. Standing abnormally was further classified as standing stationary with no movement of legs or body, sometimes with a hunched back or trembling, and standing actively with persistent kicking, foot stamping, or lifting of hind legs, tail swishing, or pacing forwards and backwards.

Lying.
This posture was defined as the sum of lying normally and lying abnormally. Lying normally was further classified as lying actively ruminating and lying passively in the ventral position with head up or down. Lying abnormally was the same as passive ventral lying with full or partial extension of hind legs, or lying in the lateral position.

Each observed action was recorded either as "1" for a single posture, or "0" for no observation. Data from each animal were amalgamated across the observation periods for each behavioral category. The sum of all normal behaviors and abnormal behaviors were calculated for each animal.

The duration and degree of sedation/ataxia in the BEPI animals were recorded as described by Caulkett et al. (1993) with slight modification. No to slight ataxia was present if the animal remained standing following the castration procedure without swaying and did not attempt to lie down. With moderate ataxia, the animal continuously swayed while standing and sometimes leaned against the partition bar to remain standing or attempted to lie down. Severe ataxia occurred if the animal could not remain standing or lay down immediately after the procedure and remained lying down for an extended period (>1 h) of time.

Statistical Analyses
All statistical analyses were performed using GENSTAT (5th ed., release 4.2 for Windows, Lawes Agricultural Trust, Rothamsted Exp. Stn., Harpenden, Hertfordshire, U.K.). To ensure that the assumptions of parametric ANOVA were met, a probability plot of the residuals was used to determine the normality of the data, and a plot of residuals against fitted values was used to determine the homogeneity of variance. Data that deviated from these assumptions were subjected to suitable transformations before the ANOVA. Data relating to the area under the cortisol curve, peak cortisol, interval to peak cortisol, hematological variables (RBC, WBC, PCV, hemoglobin concentrations, mean corpuscular volume, and platelet numbers), rectal temperature, and DMI were analyzed by ANOVA using a randomized complete block design for the main effect of treatments at each separate time point (Steel and Torrie, 1960). The x^0.5 of plasma haptoglobin data, log₁₀ of mean plasma cortisol by period, log₁₀ of plasma fibrinogen, and the angular transformed (x = [180/] x arcsin {square root [p/100]}, where p is a percentage (0 < p < 100); = 3.1416) percentage differential WBC subpopulations data were analyzed by ANOVA as before. The x^0.5 of IFN- production, total antioxidant status, and ADG data were similarly analyzed by ANOVA with the pretreatment values (from d 0 for IFN- and total antioxidant status and from d -22 to -1 for ADG) included as significant covariates. Following a significant F-test, Fisher’s least significant difference test was applied to determine statistical differences between treatments (Steel and Torrie, 1960). Data on behaviors showed a lack of normality and were heterogeneous, which led to nonparametric analysis using Kruskall-Wallis ANOVA with Conover’s multiple comparisons procedure based on ranks (Conover, 1980). One animal from the control group accidentally received lidocaine i.v. instead of saline following collection of a blood sample on d 0; therefore, the data from this animal was excluded from all statistical analyses.

	Results

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Plasma Cortisol
Mean plasma cortisol concentrations in the control animals were less than 10.0 nmol/L from -2 to 12 h, and there were no differences (P = 0.75) among treatments during the pretreatment time period from -2 to 0 h (Table 1). Following castration from 0.25 to 1.5 h, mean cortisol concentration (on a log₁₀ transformed scale) in the B animals increased acutely (Figure 1), and was greater (P < 0.05) than in C animals, whereas the administration of K, LA, or EPI reduced (P < 0.05) the cortisol concentrations compared with B alone, but the concentrations were still higher (P < 0.05) than in C animals. Peak cortisol concentrations were higher (P < 0.05) in all castration groups than in C, and the administration of K, LA, or EPI reduced (P < 0.05) the peak cortisol concentrations compared with B alone (Table 1). Within the castration groups, the interval to peak cortisol was greater (P < 0.05) in BEPI than in B and BK and was greater (P < 0.05) in BLA than in BK animals, but it was not different from B or BEPI animals. From 2 to 6 h, mean cortisol concentrations were higher (P < 0.05) in the B animals compared with C, and the concentrations in BLA and BEPI animals were higher (P < 0.05) than in C, B, and BK animals. By contrast, BK animals had a lower (P < 0.05) cortisol concentration compared with C and the other castration groups during the same period. From 6.5 to 12 h, mean cortisol concentration in BK animals remained low and was not different from C. Whereas there were no differences among B, BLA, and BEPI animals, the concentrations were higher (P < 0.05) in these groups than in C and BK animals. On d 1, BK and BLA animals had higher (P < 0.05) plasma cortisol concentrations than in C animals, with intermediate concentrations in the B and BEPI animals that were not different from C or the other castration groups. There were no differences (P = 0.27) among treatments on d 3.

View larger version (28K): [in this window] [in a new window]   Figure 1. Mean ± SE plasma cortisol concentrations for bulls left untreated (), burdizzo castration (), burdizzo castration following ketoprofen administration (•), burdizzo castration following lidocaine local anesthesia (), or burdizzo castration following combined xylazine and lidocaine caudal epidural anesthesia (); n = 9 for group C, and n = 10 for the remaining treatment groups. The integrated plasma cortisol responses (area under the curve) were greater (P < 0.05) in all castrated animals than in control bulls. The administration of either ketoprofen, local or caudal epidural anesthesia reduced (P < 0.05) the peak cortisol response to castration, but only ketoprofen decreased (P < 0.05) the integrated cortisol response compared with castration alone or castration with local or caudal epidural anesthesia.

Acute-Phase Proteins
On d 0, pretreatment plasma haptoglobin and fibrinogen concentrations were not different (P > 0.10) among treatment groups, and the concentrations in the control group remained within baseline concentrations throughout the study. Following castration on d 1, haptoglobin concentrations were elevated (P < 0.05) in the B, BLA, BEPI animals compared with BK animals, and there was no difference between BK and C animals on d 1 (Figure 2). On d 3, haptoglobin concentrations were higher (P < 0.05) in all castration groups than in C. On d 7, haptoglobin concentrations were not different between B and C animals, and there was no difference in haptoglobin concentrations between either BK or BEPI animals compared with B and C animals. By contrast, haptoglobin concentrations in BLA were higher (P < 0.05) than in C, B, BK, and BEPI animals. From d 14 onwards, haptoglobin concentrations in the castration treatments returned to normal baseline levels.

View larger version (28K): [in this window] [in a new window]   Figure 2. Effect of no treatment (C; ), burdizzo castration (B; ), burdizzo castration following ketoprofen administration (BK; ), burdizzo castration following lidocaine local anesthesia (BLA; *), or burdizzo castration following xylazine and lidocaine caudal epidural anesthesia (BEPI; ) on plasma haptoglobin (upper panel) and plasma fibrinogen (lower panel) concentrations of bulls. Data are presented on the square root and log10-transformed scale, respectively. Pooled SE is across treatment within day. a,b,cWithin day, means that do not have common superscripts differ (P < 0.05). *BK differs from B, BLA, and BEPI on d 1 for plasma haptoglobin.

Interferon-
There were no differences among treatments in IFN- production from the blood samples collected before treatment on d 0 (P = 0.30) and following castration on d 1 (P = 0.32), and on d 3 (P = 0.53) in response to KLH (Figure 3). On d 0, Con A-induced IFN- production was not different (P = 0.08) among treatments. On d 1, Con A-induced IFN- production was lower (P < 0.05) in B, BLA, and BEPI animals compared with C animals, whereas there were no differences among animals castrated following K treatment compared with either C, B alone, or animals castrated following LA or EPI administration (Figure 3). On d 3, Con A-induced IFN- production continued to be suppressed (P < 0.05) in BLA and BEPI animals compared with C, with intermediate IFN- production in the samples from B animals that was not different from either C or the other castration treatments. By contrast, the Con A-induced IFN- level in the BK animals was suppressed (P < 0.05) on d 3 compared with C animals.

View larger version (32K): [in this window] [in a new window]   Figure 3. Effect of no treatment (C), burdizzo castration (B), burdizzo castration following ketoprofen administration (BK), burdizzo castration following lidocaine local anesthesia (BLA), or burdizzo castration following xylazine and lidocaine caudal epidural anesthesia (BEPI) on keyhole limpet hemocyanin- (KLH; upper panel) and concanavalin A- (Con A; lower panel) induced in vitro interferon- (IFN-) production from cultured whole blood of bulls on d 1 and 3 after treatment. Data are presented on the square root scale. The pooled SE is across treatment within day. a,bWithin day, bars that do not have common superscripts differ (P < 0.05).

Total Antioxidant Status
There were no differences among treatments in total antioxidant status on d 1 (mean concentrations for C, B, BK, BLA, and BEPI = 0.71, 0.73, 0.70, 0.76, and 0.71 mM, respectively; pooled SE = 0.015 mM; P = 0.08), d 3 (mean concentrations for C, B, BK, BLA, and BEPI = 0.79, 0.76, 0.81, 0.80, and 0.82 mM, respectively; pooled SE = 0.028 mM; P = 0.61), and d 7 (mean concentrations for C, B, BK, BLA, and BEPI = 0.89, 0.89, 0.91, 0.90, and 0.87 mM, respectively; pooled SE = 0.017 mM; P = 0.51).

Rectal Temperatures
On d -1 before treatment, there were no differences (P = 0.80) in the mean daily rectal temperatures among treatment groups. Rectal temperatures were different among treatments on d 0 (mean values for C, B, BK, BLA, and BEPI = 38.3, 38.2, 38.1, 38.5, and 38.5°C, respectively; pooled SE = 0.11°C; P = 0.02), d 2 (mean values for C, B, BK, BLA, and BEPI = 38.1, 38.5, 38.4, 38.7, and 38.7°C, respectively; pooled SE = 0.11°C; P = 0.009), and on d 4 (mean values for C, B, BK, BLA, and BEPI = 38.1, 38.3, 38.3, 38.6 and 38.3°C, respectively; pooled SE = 0.11°C; P = 0.02). However, the temperatures remained within the normal physiological range of 38 to 39°C for cattle. Only three animals from the S, BK, and BEPI groups on d 1, one animal from the BEPI group on d 2, and one animal from the BK group on d 3 had rectal temperatures ranging from 39.9 to 40.3°C.

Average Feed Intake and Daily Gain
There were no effects of treatments on DMI (P 0.20) during the course of the study (Table 2). Growth rates did not differ (P = 0.36) among treatments during the pretreatment period from d -22 to -1. From d -1 to 7, the ADG were reduced (P < 0.05) in all castration treatments compared with intact bulls, and the administration of K, LA, or EPI failed to prevent the suppression of growth rates. Furthermore, BLA animals had the greatest reduction (P < 0.05) in ADG compared with C animals and animals in the other castration treatments. Following this period, the ADG did not differ (P > 0.20) among treatments. Overall, the ADG from d -1 to 35 was higher (P < 0.05) in C than in B, BLA, and BEPI animals, and the provision of K resulted in intermediate growth rates that were not different from C, B, BLA, or BEPI animals (Table 2).

Following castration, the incidence of combined standing postures was greater (P < 0.05) in B and BK animals than in C, with an intermediate level in BLA that was not different from C, B, and BK animals. In contrast, BEPI animals had a lower (P < 0.05) incidence of combined standing postures compared with B, BK, and BLA, but was not different from C animals (Table 3). The incidence of combined abnormal standing activities was greater (P < 0.05) in B animals than in C, BK, BLA, and BEPI animals. The use of LA failed to reduce (P < 0.05) the incidence of abnormal standing behaviors compared with C and BEPI animals. However, BLA animals had a reduced (P < 0.05) display of abnormal standing behaviors compared with B alone. In contrast, the provision of K resulted in an intermediate level of abnormal standing behaviors that was not different from C, BLA, or BEPI animals, but was less (P < 0.05) than in B animals. Within the standing abnormal behavioral category, the incidence of tail swishing was greater (P < 0.05) in B and BLA than in C animals, with an intermediate level in BK animals. Whereas BEPI animals showed less (P < 0.05) tail swishing than B, BK, and BLA but was not different from C animals. There was a tendency for incidence of hind leg lifting to differ (P = 0.06), with greater incidences observed in BLA and BEPI than in BK animals. There were no differences among treatments in the incidences of abnormal standing stationary (P = 0.17), kicking (P = 0.19), pacing (P = 0.94), and lying with legs extended (i.e., abnormal lying; P = 0.15) among the treatment groups. The incidences of feeding and combined incidence of ruminating activities (at the standing + lying postures) were reduced (P < 0.05) in B compared with C animals. The incidence of feeding in BLA animals was not different from B, but was lower (P < 0.05) than in C bulls, with intermediate levels in BEPI animals. The incidences of total rumination in BEPI and BLA animals were not different from B animals, and this activity was lower (P < 0.05) compared with C and BK animals. By contrast, BK animals had an increased (P < 0.05) incidence of feeding and ruminating activities compared with B and BLA, and the activities were not different from C animals.

	Discussion

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Activation of the neuroendocrine-immune axis is a hallmark of stress, tissue injury, and infection, and glucocorticoids secretion plays a major role in the stress-induced suppression of the immune-inflammatory reactions (Breazile, 1988; Chrousos, 1995; Webster et al., 2002). In the present study, the stress induced by burdizzo castration increased the integrated cortisol response (i.e., AUC) in excess of 100% compared with control animals. Whereas the provision of LA or EPI failed to reduce the integrated cortisol response compared with burdizzo castration alone, K effectively reduced the integrated cortisol response to castration. The integrated cortisol response in BK animals was approximately 52% lower than that in B and BLA animals, and was 58% lower than that in BEPI animals.

Excessive or prolonged circulation of glucocorticoids in vivo due to stress may compromise the "fitness" and welfare of animals (Barnett and Hemsworth, 1990). Evidence supporting this postulate include: 1) the immunosuppressive effects of glucocorticoids on the traffic and distribution of leukocyte subpopulations (Anderson et al., 1999; Kehrli et al., 1999); 2) the inhibitory effects of glucocorticoids on the functions of leukocytes and immune accessory cells and molecules (Nonnecke et al., 1997), for example, through the reduced production of interleukin 2, interleukin 6, and IFN- (see reviews by Sapolsky et al., 2000; Webster et al., 2002), which are essential for maintaining an effective immune response to antigens; and 3) the inhibitory effects of glucocorticoids on lymphocyte proliferation (Murata and Hirose, 1991; Blecha and Baker, 1986). These processes can increase the susceptibility of the host to disease processes (Ben-Nathan, 1994; de Groot et al., 2001).

In the present study, the peak cortisol responses were attenuated (approximately 30% mean reduction) with the provision of K, LA, or EPI. However, the failure of LA to maintain effective cortisol suppression beyond the initial peak cortisol reduction was in accordance with the reported short 1.5- to 2-h duration of action for a regional infiltration of lidocaine local anesthesia without a vasoconstrictive agent (Jones, 1997), and was in agreement with previous castration studies (Fisher et al., 1996; Earley and Crowe, 2002). The suppression of cortisol with the EPI treatment was also not sustained beyond 1 h after treatment. It has been reported in calves that epidural xylazine injected at the first intercoccygeal space using a dose of 0.05 mg/kg had an effective antinociceptive action on the dermatome at the caudal scrotum from 1 to 5 h, and the onset of cutaneous analgesia was attained by 15 min following administration (McCormick, 2001). A combined xylazine and lidocaine epidural treatment was selected in the current study since ₂-adrenergic agonists are known to operate synergistically with spinal local anesthetics (McQuay and Moore, 1999). This combined treatment was reported to prolong the analgesic effects in horses (Grubb et al., 1992) and in sheep undergoing surgery (Scott and Gessert, 1996; 1997). However, it is possible that the EPI administration at the first intercoccygeal space may have been insufficient to completely block the nociceptive (i.e., visceral pain) response to the crushing of the spermatic cords during castration. Brook (1935) remarked that caudal epidural blockage would not anesthetize the testicles and penis, and only extensive anterior anesthesia will desensitize the testicle. However, it would be impractical to provide extensive anterior epidural anesthesia for conducting the castration procedure in cattle, as this procedure involves severe interference with the motor function of the limbs, with resultant locomotory incoordination or recumbency (Caulkett et al., 1993). The epidural anesthetic doses used, and the site of drug administration chosen in the current study, were sufficient to induce an acceptable degree of analgesia (as determined by the reduced peak cortisol response compared with B alone) without immediate ataxia for castration.

The current study has demonstrated that the degree of analgesia (as defined by the suppressive effect on integrated cortisol response) induced by the EPI treatment was no better than LA for castration. Caulkett et al. (1993) reported (based on behavioral reactivity) that a good degree of surgical analgesia was evident in 80.5% of the bulls castrated following EPI. Interestingly, Caulkett et al. (1993) also reported that a number of animals (19.5% of the total being assessed) showed minimal response to the incision, but they reacted to the traction on the spermatic cords during surgical castration. Caulkett et al. (1993) remarked that in these animals, excellent somatic analgesia was evident, but visceral analgesia appeared to be less adequate. In contrast, the effective cortisol suppression maintained in the K treatment can be explained by the mechanisms in which NSAID act to potently inhibit the cyclooxygenase production of eicosanoids involved in pain transmission and the promotion of inflammation (Breazile, 1988; Dahl and Kehlet, 1991; Nolan, 2000) and their suppressive effect on ACTH secretion during inflammation (Turnbull and Rivier, 1996). Thus, the current study has demonstrated that ketoprofen is more effective than either LA or EPI in minimizing cortisol secretion in response to castration stress.

Tissue damage, inflammation, or invasion of pathogenic organisms induces systemic changes collectively known as the acute phase response (Alsemgeest et al., 1994; van Miert, 1995). The castration-induced increase in acute-phase proteins (plasma haptoglobin and fibrinogen) on d 1 and 3 were consistent with previously reported findings (Faulkner et al., 1992; Fisher et al., 1997b; Earley and Crowe, 2002). The reduced haptoglobin concentrations in the castrated animals with K treatment on d 1 are in agreement with Earley and Crowe (2002). A sustained elevation of haptoglobin and fibrinogen concentrations on d 7 in the BLA animals compared with C or B treatments indicates that LA administration further exacerbates inflammatory reactions associated with castration. Fisher et al. (1996) showed that burdizzo castration induced scrotal swelling on d 7 that persisted up to d 35 in the castrated animals administered lidocaine LA compared with control animals. A similar effect of castration-induced swelling was reported by other workers (Chase et al., 1995; Murata, 1997; Keane, 1999). Morris and Tracey (1977) reported that the infiltration of lidocaine (2 mL of 1 to 2% solution) in the skin of rats impaired wound healing (tensile strength). Since haptoglobin production can be related to the magnitude of an inflammatory stimulus (Conner and Eckersall, 1988), the reduced plasma haptoglobin concentrations in the BEPI animals compared with BLA on d 7 may indicate that the EPI caused a less traumatic effect compared with the direct infiltration of LA into the scrotal tissues, possibly predisposing the underlying tissues to injury and delayed healing.

Interferon- is a cytokine produced by activated T-lymphocytes and natural killer cells that helps to regulate immune responses (Clough and Roth, 1998) to antigens. An increase in in vitro IFN- production correlates well with lymphocyte proliferation (d’Andrea et al., 1986), and this has been used as a measure of immune responsiveness in calf castration studies (Fisher et al., 1997a, b; Earley and Crowe, 2002). The current study failed to demonstrate the immunosuppressive effect of castration on in vitro IFN- production following exposure to a recall antigen, KLH. There was a wide variation in individual animal responses (CV of 82.9 to 177.3% between d 0 and 3 for the IFN- production) to the primary KLH immunization procedure that warrants further investigation. Fisher et al., 1997a,breported that in surgically castrated cattle preimmunized against KLH, the in vitro IFN- production in response to KLH was reduced from d 1 up to d 3 following castration. By contrast, the current study showed that the in vitro IFN- production in response to a novel mitogen, Con A, was suppressed on d 1 in B animals compared with controls in agreement with previous experiments (Fisher et al., 1997a,b; Earley and Crowe, 2002). Murata (1997) found that Con A-induced blastogenesis was impaired 2 d after burdizzo castration, and remarked that the delayed response could be attributed to the inflammation around the testis rather than a direct reaction induced by the cortisol rise. The provision of either LA or EPI failed to prevent the suppression of Con A-induced IFN- production on d 1 and 3. By contrast, the provision of K tended to ameliorate the reduced Con A-stimulated IFN- production on d 1, but the level became suppressed by d 3. Earley and Crowe (2002) reported that in surgically castrated bull calves, the Con A-induced IFN- production was suppressed on d 3 with or without K, LA, or LA + K treatments. However, these workers showed that the reduced IFN- production on d 3 in response to a recall antigen, KLH, could be partially reversed by the administration of either K, LA or LA + K treatments.

There were no significant differences in WBC number between B and C animals. However, increased WBC numbers in the BLA and BEPI animals on d 1 compared with controls would suggest that leukocytosis was increased by the administration of anesthetic agents. Macaulay (1989) reported higher total WBC counts for surgically or burdizzo-castrated calves than for sham-operated calves. A similar observation was reported by Chase et al. (1995). Eicher et al. (2000) showed that tail docking following a s.c. injection of LA induced a greater increase in CD4⁺:CD8⁺ T-cell phenotype ratio compared with docking alone and controls, which suggests that the inflammatory response was increased by the LA. The provision of K before castration resulted in a lower WBC number on d 1 compared with EPI, and the WBC numbers were not different compared with C or the other castrated groups.

The involvement of activated neutrophils and their generation of reactive oxygen species is a characteristic of inflammation (Brigham, 1991). Murata (1997) reported that burdizzo castration in calves induced leukocytosis with neutrophilia by d 2. There is a well-documented link between compromised antioxidant status and clinical disease (Harper, 2001). However, the total antioxidant status was not affected by the castration treatments in the current study.

Castration treatments resulted in reduced animal growth rates, but not feed intakes in the present study. The administration of K, LA, or EPI did not prevent this reduction in growth rates. The reduction in performance is, in part, due to the immediate tissue trauma, inflammation (Obled, 2002), and probably psychological (pain) stress in response to castration and the loss of anabolic (testosterone) steroid (Knight et al., 1999). Overall, there was a mean reduction in growth rate of 46% in B and BLA animals and a 34% reduction in BEPI animals compared with controls. By contrast, the administration of K partially ameliorated the reduction in ADG of castrated animals (20% reduction) over the 35-d period after castration.

Changes in behavior as a means of quantifying pain-associated with castration have previously been established (Molony et al., 1993 ; 1995; Robertson et al., 1994). In the present study, the incidence of combined abnormal standing behaviors was highest in B compared with control animals and other castration groups, and this was consistent with a previous study (Molony et al., 1995). The incidence of tail swishing was higher in B than in C animals and is in agreement with the findings of Fisher et al. (2001). The provision of K reduced the incidence of combined abnormal standing behaviors when compared with B alone, but it was still greater than in controls. Similarly, LA reduced the incidence of combined abnormal standing behaviors compared with B animals, indicating that the LA provided a degree of pain relief. This was in agreement with Kent et al. (1998), who reported that the use of LA immediately after the rubber ring castration of 1-wk-old lambs was effective in reducing the peak plasma cortisol, the incidence of active behaviors, and the time spent in abnormal postures. By contrast, Molony et al. (1997) reported that the administration of a long-acting local anesthetic, bupivacaine, 2 min before burdizzo castration was less effective than a single dose of a NSAID, diclofenac, given 20 min before castration in reducing plasma cortisol response and the time spent in abnormal postures compared with untreated lambs. The incidence of abnormal standing postures in the BEPI animals was lower than that observed in B and BLA animals and was not different from BK and C animals. The apparent reduction in the incidence of abnormal behaviors, feeding, and ruminating activities in BEPI animals could be partially attributed to the sedative and ataxic effects of the epidural anesthesia. Castration alone resulted in reduced incidence of feeding and rumination activities in B animals compared with controls. By contrast, K treatment before castration significantly improved the observed frequency of feeding and ruminating activities compared with B and BLA, and the levels were not different from C animals.

In conclusion, burdizzo castration increased plasma cortisol and acute-phase proteins, suppressed immune function, and reduced growth rates. Local anesthesia prolonged the increase in acute-phase proteins. Ketoprofen was more effective in reducing the overall cortisol response to castration than local anesthesia or epidural anesthesia and tended to ameliorate the weight loss associated with castration. The use of K or EPI was more effective than local anesthesia in minimizing pain-associated behavioral responses observed during the first 6 h after castration.

	Implications

Top Abstract Introduction Materials and Methods Results Discussion Implications Literature Cited

 
Acute stress response is a normal and essential adaptation process to the challenges imposed by animal husbandry procedures, such as castration in male cattle. Animal health and welfare may be compromised when the adaptive response becomes excessive or is exhausted due to an overt (pain and inflammatory) challenge. Applying the best method for reducing the magnitude of the acute stress response to an injurious procedure will benefit the welfare of animals. The finding that systemic analgesia with ketoprofen, a nonsteroidal antiinflammatory drug, was more effective in minimizing the acute stress (cortisol) response and suppression of immune function associated with castration than local or epidural anesthesia, and that ketoprofen or epidural anesthesia was more effective than local anesthesia in minimizing pain-related behavioral displays, would imply that local anesthesia failed to provide optimal analgesia for alleviating castration-induced stress in 13-mo-old cattle.

	Footnotes

 
¹ This study was supported by a Teagasc Walsh Fellowship Research Fund to S. T. L. Ting. The authors acknowledge Merial Animal Health Ltd., Harlow, U.K., for the supply of Ketofen. The authors thank G. Claffey, V. P. Gath, and N. Hynes (Faculty of Veterinary Medicine, University College Dublin; UCD), graduate students at Teagasc Grange and UCD, for their invaluable help during the study. The authors also acknowledge the skilled technical assistance of the staff at Teagasc Grange: F. Collier, J. A. Farrell, J. Larkin, M. Munnelly, M. Murray, and D. Prendiville. Many thanks to P. Reid (Teagasc, Dublin) and S. Hanrahan (Teagasc, Athenry) for their invaluable advice on statistical analyses. The help of the foreman, G. Santry, and the farm staff, B. Duffy and S. Fagan, for care and management of the animals is gratefully acknowledged.

Received for publication September 23, 2002. Accepted for publication January 16, 2003.

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