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J. Anim. Sci. 2003. 81:1253-1264
© 2003 American Society of Animal Science

Effect of repeated ketoprofen administration during surgical castration of bulls on cortisol, immunological function, feed intake, growth, and behavior1

S. T. L. Ting*,{dagger}, B. Earley* and M. A. Crowe{dagger},{ddagger},2

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

2 Correspondence:
Dept. of Animal 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
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Implications
 Literature Cited
 
To determine the effect of repeated ketoprofen (K) administration to surgically castrated bulls on cortisol, acute-phase proteins, immune function, feed intake, growth and behavior, 50 Holstein x Friesian bulls (11 mo old; 300 ± 3.3 kg) were assigned to one of five treatments: 1) untreated control (C); 2) surgical castration at 0 min (S); 3) S following an i.v. injection of 3 mg/kg of BW of K at -20 min (SK1); 4) S following 1.5 mg/kg of BW of K at -20 and 0 min (SK2); or 5) S following 1.5 mg/kg of BW of K at -20 and 0 min and 3 mg/kg of BW of K at 24 h (SK3). Castration acutely increased plasma cortisol concentrations in S- and K-treated animals compared with C, with no differences in peak and interval to peak cortisol responses among the castration groups. Overall, the integrated cortisol response was greater (P < 0.05) in the castrates than in C, whereas K treatments decreased (P < 0.05) this response compared with S alone, with no differences between K treatments. Plasma haptoglobin and fibrinogen concentrations were increased (P < 0.05) on d 3 in the castration groups compared with C as the result of tissue trauma induced by castration, whereas SK1 and SK2 had lower (P < 0.05) haptoglobin concentrations than S animals. On d 1, concanavalin A-induced interferon-{gamma} production was suppressed (P < 0.05) in S and SK3 compared with C, SK1, and SK2 animals. Overall from d 1 to 33, DMI were lower (P < 0.05) in S, SK1, and SK3 than in C animals. From d -1 to 35, ADG were lower (P < 0.05) in S, SK2, and SK3 compared with C animals. A higher (P < 0.05) incidence of standing postures and lower incidence of lying postures was observed in S compared with C during the first 6 h after treatment. However, the higher (P = 0.02) incidence of abnormal standing activities observed for S was reversed (P < 0.05) by the K treatments. In conclusion, surgical castration increased plasma cortisol and acute-phase proteins and decreased immune function, feed intake, and growth rate. Ketoprofen effectively reduced the cortisol response to castration, but there was no advantage in treating with two split doses of K (1.5 mg/kg of BW per dose). A repeated K dose 24 h after treatment (3 mg/kg of BW) had no influence on changes in acute-phase proteins and immune response. Systemic analgesia with K is an effective method for alleviating acute inflammatory stress associated with castration.

Key Words: Behavior • Bulls • Castration • Interferon-{gamma} • Ketoprofen • Stress


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Implications
 Literature Cited
 
Castration of male cattle has been shown to elicit physiological stress, inflammatory reactions, pain-associated behavior, suppression of immune function, and a reduction in performance (Molony et al., 1995; Fisher et al., 1996;1997b). Attempts to alleviate the undesirable effects of castration with analgesia have been achieved with varying degrees of success. Faulkner et al. (1992) reported that the use of butorphanol and xylazine failed to alter the blood cortisol response and reduction in performance of calves following castration. Fisher et al. (1996) found the provision of local anesthesia to be ineffective in diminishing cortisol response beyond the initial 1.5 h after castration of calves. Earley and Crowe (2002) demonstrated that ketoprofen (K), a nonsteroidal, anti-inflammatory drug (NSAID), was superior to lidocaine local anesthesia or combined local anesthesia and K in suppressing the overall plasma cortisol elevation associated with castration. They used a single preemptive treatment of K and suggested that repeated administration of K could further modulate the inflammatory responses (acute-phase proteins) associated with castration.

The objectives of this study were to compare the effect of surgical castration alone or in combination with K on plasma cortisol, acute-phase proteins, in vitro interferon-{gamma} production from cultured leukocytes, total antioxidant status, feed intake, growth, and behavior of beef bulls. The hypotheses were that: 1) K would be effective for the alleviation of postsurgical acute cortisol response, mitigate the suppression of immune function as previously reported (Earley and Crowe, 2002), and diminish the display of abnormal behaviors; and 2) repeated administrations of K would further enhance its efficacy in modulating the cortisol response and acute-phase proteins associated with castration.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Implications
 Literature Cited
 
Treatments
Fifty 11-mo old Holstein x Friesian bulls (mean BW = 300 ± 3.3 kg) were blocked by weight and randomly assigned to one of five treatments (n = 10 per treatment): 1) untreated control (C); 2) surgical castration at 0 min (S); 3) surgical castration following K administration with 3 mg/kg of BW at -20 min (SK1); 4) surgical castration following K administration with 1.5 mg/kg of BW at -20 min and 0 min (SK2); 5) surgical castration following K administration with 1.5 mg/kg of BW at -20 min and 0 min, and 3 mg/kg of BW at 24 h (SK3).

Animal Housing and Management
Bulls were housed in individual tie-stalls from d -22 (day of treatment = d 0) to acclimate them to handling, restraint, and their novel environment. Animals had ad libitum access to water and grass silage (mean of eight weekly samples; DM content = 183.6 ± 3.21 g/kg, in vitro DM digestibility = 733.9 ± 8.41 g/kg of DM; pH = 4.4 ± 0.12) supplemented with 2.5 kg of barley/soybean concentrates (mean on DM basis of eight weekly samples; CP = 128.5 ± 7.15 g/kg, crude fiber = 34.4 ± 0.80 g/kg, acid-hydrolyzable oil = 24.3 ± 0.29 g/kg, ash = 40.3 ± 9.48 g/kg) per animal daily. Individual silage intakes were recorded daily from d -9 to 33 to determine 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; catalogue No. 374805) precipitated on potassium aluminium sulphate (Pollock et al., 1992) to determine the cell-mediated immune response to a recall (KLH) antigen. Castration (time of treatment = 0 min) was performed on S, SK1, SK2, and SK3 bulls using an open method according to the procedure of Jennings (1984). As part of the castration procedure, gentle manual restraint of the bulls was used to facilitate the operator. Castration was performed between 0900 and 1127 GMT. The K (10% Ketofen, Merial Animal Health Ltd., Harlow, Essex, U.K.) was administered to SK1, SK2, and SK3 animals by slow infusion through an indwelling jugular catheter followed by 2 mL of 0.9% sterile saline to flush the catheter. Animals in the control group were sham handled for a period equivalent to the time required to perform the castration procedure in the remaining treatment groups. Precise dose rates for K were determined based on the BW of each animal obtained on d -1 before treatments. Animals not receiving K in the S group were given an equivalent volume of sterile 0.9% saline solution via their jugular catheter.

To facilitate intensive blood sampling, indwelling jugular catheters were fitted aseptically on d -1 with a 12-gauge Anes spinal needle (Popper and Sons, Inc., New Hyde Park, NY) and vinyl tubing (approximately 1.47 mm o.d.; Ico-Rally Corp., Palo Alto, CA; catalogue No. SVL 105-18CLR). All catheters were exteriorized on the neck of the animals, filled with sterile 3.5% sodium citrate solution, and plugged with a stopper. Catheters were secured in place in resealable patches with the aid of an adhesive cement (Big Bull Hip Tag Cement; Biguel Supply Co., Elysian, MN), Velcro, and zinc oxide wrapping bandages. After catheterization, 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 antioxidant status, and stimulated leukocyte production of interferon-{gamma} (IFN-{gamma}), citrated blood samples for fibrinogen, and 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, 28, and 35. Plasma samples were separated by centrifugation at 1,600 x g at 8°C for 15 min and subsequently stored at -20°C until assayed. Rectal temperatures of each bull were monitored twice daily (morning and evening) with a digital electronic thermometer (Jørgen Kruuse A/S model VT-801 BWC, Marslev, Denmark; catalogue No. 0701) from d -1 to 4. 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; catalogue No. 06B-256440) adapted and validated for bovine plasma (Fisher et al., 1996). The intraassay CV (n = three to four per assay) for samples containing 12.9 and 119.1 nmol of cortisol/L were 14.3 and 6.0%, respectively, and the interassay CV (n = 15 total assays) for the same samples were 19.0 and 6.2%. For each calf, 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 (AUC) was calculated for the pretreatment period from -2 to 0 h, and for above the pretreatment baseline from 0 to 12 h using the linear trapezoidal rule:


where Ct is the concentration of a plasma cortisol sample in nmol/L of an animal at time t, and for the next sample Ct+1 with a time interval of {delta}I in hours between them, and {Sigma} is the sum of the responses from Ct to n-1 total number of concentration time points (Friend et al., 1977). The stimulated lymphocyte production of IFN-{gamma} was determined from harvested heparinized plasma following a whole-blood culture (Wood et al., 1990). Duplicate 1.48-mL aliquots of blood were cultured in sterile 24-well flat culture plates (Sarstedt Ltd., Drinagh, Wexford, Ireland) with 20 µL of PBS (GibcoBRL, Life Technologies Ltd., Paisley, Scotland; catalogue No. 14190-094) containing either 1 mg/mL of KLH (Calbiochem) or 0.5 mg/mL of Concanavalin A (Con A; Sigma-Aldrich, Inc., St. Louis, MO; product No. C 5275) or no additive for 24 h at 37°C and in an atmosphere of 5% CO2. Aseptic techniques were practiced during this procedure under laminar flow conditions. The culture plates were then centrifuged and the supernatant harvested and frozen at -20°C until it was assayed for IFN-{gamma} using an ELISA procedure specific for bovine plasma (Rothel et al., 1990; Bovigam, CSL Biosciences, Parkville, Victoria, Australia; catalogue No. 03000201). The in vitro KLH- and Con A-stimulated IFN-{gamma} production was calculated by subtracting the absorbance at 450 nm of wells that received PBS alone from the absorbance of wells that received either KLH or Con A.

Plasma haptoglobin concentrations were measured with a commercial multispecies assay kit (Tridelta Development Ltd., Bray, Wicklow, Ireland; catalogue No. TP801) adopted for an automated analyzer (Ciba Corning 550 Express; Ciba Corning Diagnostics Corp., Oberlin, OH). The analysis was based on the hemoglobin-binding capacity of haptoglobin, and the method has been validated for bovine plasma (Eckersall et al., 1999). The intraassay CV (n = 4 to 7/assay) for samples containing 1.4 g/L was 3.8%, and the interassay CV (n = four total assays) for the same samples was 5.7%. Fibrinogen concentrations were measured with a commercial kit (Roche Diagnostics GmbH, Mannheim, Germany; catalogue No. 524484) on an automated clinical analyzer (spACE, Alfa Wassermann, Inc., West Caldwell, NJ) according to the manufacturer’s procedure. The method was based on a turbidimetric measurement of the thrombin-induced rate of plasma clotting previously adapted for bovine plasma in our laboratory (Fisher et al., 1996;Earley and Crowe, 2002). The intraassay CV (n = 5 to 6/assay) for samples containing 2.59 g/L was 6.3%, and the interassay CV (n = three total assays) for the same samples was 4.5%. A number of samples (n = 27) collected for the fibrinogen assay were hemolyzed and/or clotted and were excluded from the analysis due to interference with the assay.

Total antioxidant status was assayed with a commercial kit (Randox Laboratories Ltd., Crumlin, Antrim, N. Ireland; catalogue No. NX2332) on an automated analyzer (Ciba Corning 550 Express) according to the manufacturer’s procedure. The assay was based on the capacity of all the antioxidants present in the plasma sample to inhibit the formation of a color complex by a free radical cation (2,2'-azinobis-[3-ethylbenzthiazoline-6-sulphonate]) that is generated by a pseudoperoxidase (metmyoglobin) and hydrogen peroxide.

Red blood cell (RBC) number, white blood cell (WBC) number, differential WBC (percentage granulocyte, percentage monocyte, and percentage lymphocyte), packed cell volume (PCV), hemoglobin concentration, mean corpuscular volume (MCV), and platelet numbers were determined for unclotted (EDTA) whole-blood samples with an automated cell counter (Celltac MEK-6108K; Nihon-Kohdon, Tokyo, Japan) within 1 to 2 h of blood sampling.

Behavioral Assessment
Behavioral observations were conducted on a scan-sampling basis (Martin and Bateson, 1986) on d 0 starting at 3 min after treatment by direct observation using a single observer to avoid interobserver variation. Behavioral activities were recorded once every 15 min for 60 min, followed by once every 60 min for 180 min, and a further observation at 6 h after treatment (total time points = nine per animal). 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 described below.

Standing.
This posture was defined as the sum of standing normally and standing abnormally. Standing normally was further divided into standing passively with no obvious abnormality and standing actively feeding, ruminating, drinking, or grooming. Standing abnormal 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 head turned backwards to examine the hind quarters.

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

Each observed action was recorded either as "1" for the presence of a single posture or "0" for no observation. The total number of postures recorded for each behavioral category was amalgamated across time, and the sum of all standing and lying postures and feeding and ruminating activities was calculated.

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.). Data that departed from the assumptions of normality and/or homogeneity of variance were subjected to suitable transformations before ANOVA. Data relating to the log10 of mean plasma cortisol by period, peak cortisol, interval to peak cortisol, plasma haptoglobin and fibrinogen, hematological variables (RBC number, log10 of WBC number, angular transformed {x = (180/{pi}) x arcsin[{surd}(p/100)], where p is a percentage [0 < p < 100; {pi} = 3.1416]} differential WBC subpopulations, PCV, hemoglobin concentration, MCV, and platelet number), and ADG were analyzed by ANOVA using a randomized complete-block design for the main effect of treatments at each individual time point (Steel and Torrie, 1960). The AUC for cortisol from 0 to 12 h, log10 (x + 1) of IFN-{gamma} production, total antioxidant status, rectal temperature, and DMI data were similarly analyzed by ANOVA with the pretreatment values (from -2 to 0 h of the AUC for cortisol, d 0 for INF-{gamma} and total antioxidant status, d -1 for rectal temperature and d -9 to -4 for DMI) included as significant covariates. Following an F-test, Fisher’s least significant difference test was applied to determine statistical differences between treatments (Steel and Torrie, 1960). Data on behavior showed a lack of normality and was heterogeneous, which led to nonparametric analysis using Kruskall-Wallis ANOVA with Conover’s multiple comparisons procedure based on ranks (Conover, 1980). The standing stationary, kicking, foot stamping, tail swishing, and head turning behaviors were combined to form a single group for all abnormal standing behaviors to stabilize the low frequencies recorded before analysis. A probability of P < 0.05 was chosen as the level of significance for the statistical tests. Three animals from the S group, and one animal from the SK1 group suffered excessive hemorrhage after castration that required interventions; data from these animals were excluded from all statistical analyses to avoid the confounded effects of the additional surgical manipulation required to prevent the hemorrhage. One animal from the S group developed severe lameness, and showed a dramatic reduction in growth with highly elevated acute-phase proteins from d 21; this animal was removed from the experiment and provided with appropriate care and treatments. The data from this animal were excluded from the analysis from d 14 onward to exclude any lameness-associated effects.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Implications
 Literature Cited
 
Plasma Cortisol
Mean plasma cortisol concentrations in the control animals from -2 to 12 h were less than 8.7 nmol/L, and there were no differences (P = 0.20) among treatment groups in plasma cortisol concentrations from -2 to 0 h before treatment. From 0.25 to 1.5 h following castration, plasma cortisol concentrations in the S animals increased acutely (Table 1Go; Figure 1Go) and were greater (P < 0.05) than in C. The administration of K in the SK1, SK2, and SK3 animals during the same time period failed to prevent the elevation of cortisol. Peak cortisol concentrations were greater (P < 0.05) in all castration treatments than in C, and the intervals to peak cortisol concentrations were not different (P =0.45) among the castration groups. Mean cortisol concentrations from 2 to 6 h after surgery remained high (P < 0.05) in the S animals compared with C; in contrast, K-treated animals had reduced (P < 0.05) cortisol concentrations compared with S, with no difference between the K treatment regimes (Table 1Go). From 6.5 to 12 h, mean cortisol concentrations were greater (P < 0.05) in the castration groups with or without K treatments compared with C. There were no differences (P > 0.20) among treatments in cortisol concentrations on d 1 and 3 following castration.


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  		Table 1. The effect of treatment on mean plasma cortisol by period, peak cortisol, interval to peak cortisol, and area under the cortisol vs. time curve from 0 to 12 h in beef cattle
 


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  		Figure 1. Mean ± SE plasma cortisol concentrations for bulls left untreated (C), surgically castrated (S), surgically castrated following i.v. administration of 3 mg of ketoprofen/kg of BW at -20 min (SK1), surgical castration following administration of 1.5 mg of ketoprofen/kg of BW at -20 min and 0 min (SK2), or surgical castration following administration of 1.5 mg of ketoprofen/kg of BW at -20 min and 0 min, and 3 mg of ketoprofen/kg of BW at 24 h after treatment (SK3; n = 10, 7, 9, and 10/treatment, respectively). Surgical castration acutely increased (P < 0.05) peak plasma cortisol concentrations in all castration treatment groups compared with C. However, the sustained increase in the cortisol response observed in S animals following the initial peak response was reduced (P < 0.05) with ketoprofen treatments, but there were no differences between the ketoprofen treatments. Overall, the integrated cortisol responses were lower (P < 0.05) in the ketoprofen-treated animals than in S animals.

 
Overall, the integrated cortisol response (i.e., AUC) was greater (P < 0.05) in all surgically castrated animals with or without K treatments compared with C animals. In contrast, the provision of K reduced (P < 0.05) the integrated cortisol response in SK1, SK2, and SK3 animals compared with S animals with no differences between the K treatments (Table 1Go).

Acute-Phase Proteins
On d 0, all pretreatment plasma haptoglobin and fibrinogen concentrations were within the normal physiological ranges (i.e., <0.5 g/L, and 3 to 7 g/L, respectively) based on data from Kaneko (1989) and Fisher et al. (1997a), and there were no differences (P > 0.30) among treatment groups on d 0. Values in C animals remained within the physiological range throughout the study (Figure 2Go).



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  		Figure 2. Effect of no treatment (—{diamondsuit}—), surgical castration (—{square}—), surgical castration following i.v. administration of 3 mg of ketoprofen/kg of BW at -20 min (—{circ}—), surgical castration following administration of 1.5 mg of ketoprofen/kg of BW at -20 min and 0 min (—*—), or surgical castration following administration of 1.5 mg of ketoprofen/kg of BW at -20 min and 0 min, and 3 mg of ketoprofen/kg of BW at 24 h after treatment (—{triangleup}—) on (upper panel) plasma haptoglobin and (lower panel) plasma fibrinogen concentrations of beef bulls. a,b,cWithin day, means that do not have common superscripts differ (P < 0.05).

 
On d 1 and 3 following castration, mean plasma haptoglobin concentrations were elevated (P < 0.05) in all castration treatments compared with C animals (Figure 2Go). The administration of K in the SK1 and SK2 animals reduced (P < 0.05) the haptoglobin concentrations compared with S animals on d 3, with intermediate concentrations in SK3 animals. On d 7, haptoglobin concentrations in S, SK2, and SK3 animals continued to be greater (P < 0.05) than in C animals, whereas the SK1 animals had a haptoglobin concentration that was between C and the other castration groups. Following this period, haptoglobin concentrations returned to baseline, with no further differences (P > 0.10) detected among treatment groups.

There was no difference (P = 0.86) among treatments in plasma fibrinogen concentrations on d 1. However, on d 3, fibrinogen concentrations were elevated (P < 0.05) in all castration treatments compared with C animals. On d 7, fibrinogen concentrations remained higher (P < 0.05) in the K treatment groups compared with C, with intermediate concentrations in S animals. From d 14 onward, fibrinogen concentrations within the castration groups returned to baseline and were lower (P < 0.05) than in C animals by d 28 and 35 (Figure 2Go).

Interferon-{gamma}
There were no differences among treatments in IFN-{gamma} production from leukocytes cultured in whole-blood samples collected on either d 0 (P = 0.30), d 1 (P = 0.86), or d 3 (P = 0.49) in response to a recall antigen KLH (Figure 3Go). On d 0 and 3, the IFN-{gamma} production in response to a novel mitogen Con A were not different (P = 0.99, and 0.26, respectively) among treatments. However on d 1 following castration, Con A-induced IFN-{gamma} production was lower (P < 0.05) in S animals compared with C (Figure 3Go). The administration of K in SK1, and SK2 animals prevented (P < 0.05) the suppression of Con A-induced IFN-{gamma} production compared with S, and the IFN-{gamma} levels in these animals were not different from C. This beneficial effect was not consistent across the K treatments since the Con A-induced IFN-{gamma} production was lower (P < 0.05) in SK3 compared with C animals and not different from S animals.



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  		Figure 3. Effect of no treatment (C), surgical castration (S), surgical castration following i.v. administration of 3 mg of ketoprofen/kg of BW at -20 min (SK1), surgical castration following administration of 1.5 mg of ketoprofen/kg of BW at -20 min and 0 min (SK2), or surgical castration following administration of 1.5 mg of ketoprofen/kg of BW at -20 min and 0 min, and 3 mg of ketoprofen/kg of BW at 24 h after treatment (SK3) on (upper panel) keyhole limpet hemocyanin (KLH)- and (lower panel) concanavalin A (Con A)-induced in vitro interferon-{gamma} production from cultured leukocytes in whole-blood samples of bulls on d 0 before castration, and on d 1 and 3 after treatment. Data are presented on the log10 (x + 1) scale. The pooled SE is across treatment within day. a,bWithin day, bars that do not have common superscripts differ (P < 0.05).

 
Hematological Variables
There were no differences (P > 0.50) among treatments in the hematological variables measured from the blood samples collected on d 0 (Figure 4Go). Generally, there were no differences (P > 0.10) among treatments on the changes in total WBC numbers following castration, except that on d 35, the S animals had greater (P = 0.05) WBC numbers compared with C, SK2, and SK3 animals, but was not different from SK1 animals (Figure 4aGo). However, the S animals had a greater (P < 0.05) percentage of granulocyte WBC subpopulations compared with C and the K-treated animals on d 1, 7, 28, and 35 (Figure 4bGo). Proportionately, the percentage of lymphocyte subpopulations was reduced (P < 0.05) in the S animals compared with C on d 1, 7, and 28. In contrast, the percentage of lymphocytes in the K-treated animals remained higher (P < 0.05) compared with S, and the levels were not different from C animals on d 7, 28, and 35 (Figure 4dGo). Generally, there were no differences (P > 0.10) among treatments in the percentage of monocyte subpopulations. On d 35, the S animals tended (P = 0.065) to have a higher percentage of monocytes than the K-treated animals (Figure 4cGo). The RBC numbers in S, SK2, and SK3 animals were reduced (P < 0.05) compared with C animals on d 1, with intermediate numbers in the SK1 animals (Figure 4eGo). The PCV were lower (P < 0.05) in all castration groups than in controls on d 1, 3, and 7; and were lower (P < 0.05) in the SK2 and SK3 animals compared with C animals on d 28 (data not shown). There were no differences (P > 0.40) among treatments on MCV (data not shown). On d 7, platelet numbers were increased (P < 0.05) in S, SK1, and SK3 animals compared with C, with intermediate numbers in SK2 animals (Figure 4fGo).



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  		Figure 4. Effect of no treatment (—{triangleup}—), surgical castration (—{square}—), surgical castration following i.v. administration of 3 mg of ketoprofen/kg of BW at -20 min (—{circ}—), surgical castration following administration of 1.5 mg of ketoprofen/kg of BW at -20 min and 0 min (—{diamondsuit}—), or surgical castration following administration of 1.5 mg of ketoprofen/kg of BW at -20 min and 0 min and 3 mg of ketoprofen/kg of BW at 24 h after treatment (—*—) on a) white blood cell (WBC) count; b) percentage of granulocytes, c) percentage of monocytes, d) percentage of lymphocytes WBC subpopulations (note the transformations); e) red blood cell (RCB) number; and f) platelet number. x,y,zWithin day, means that do not have common superscripts differ (P < 0.05).

 
Total Antioxidant Status
There were no differences (P = 0.28) in total antioxidant status among treatment groups on d 0 (mean concentrations for C, S, SK1, SK2, and SK3 = 0.80, 0.77, 0.78, 0.79, and 0.77, respectively; pooled SE = 0.010 mM). The mean total antioxidant status in S animals was lower (P < 0.05) compared with C animals on d 1 (0.68 vs. 0.74, respectively; pooled SE = 0.013 mM). In contrast, SK1, SK2, and SK3 animals had total antioxidant statuses (mean concentrations = 0.72, 0.72, and 0.71, respectively; pooled SE = 0.013 mM) that were not different from either C or S animals on d 1. There were no differences among treatment groups on d 3 (mean concentrations for C, S, SK1, SK2, and SK3 = 0.71, 0.70, 0.72, 0.71, and 0.70, respectively; pooled SE = 0.014 mM; P = 0.94) and d 7 (mean concentrations for C, S, SK1, SK2, and SK3 = 0.68, 0.65, 0.66, 0.66, and 0.68, respectively; pooled SE = 0.010 mM; P = 0.08).

Rectal Temperatures
There were no differences in mean daily rectal temperatures among treatment groups on d 0 (P = 0.07) before treatment and on d 3 (P = 0.27) and 4 (P = 0.65) after treatment. On d 2, rectal temperatures were different (P = 0.03) among treatments (daily mean values for C, S, SK1, SK2, and SK3 = 38.4, 38.1, 38.6, 38.3, and 38.7, respectively; pooled SE = 0.03°C); however, the values remained within the normal physiological range of 38 to 39°C. Only three castrated animals (one animal in SK1 treatment on d 1 and two animals in SK3 treatment on d 3) had rectal temperatures in the range of 39.9 to 40.2°C.

Average Feed Intake and Daily Gain
There was no difference (P = 0.81) in DMI among treatment groups from d -9 to -4 before treatment. Differences in DMI among treatments did not appear until d 20 to 26 when all the castrated animals had a lower (P < 0.05) DMI compared with C animals (Table 2Go). From d 27 to 33, DMI were not different (P = 0.09) among treatments. Overall from d 1 to 33, DMI were lower (P < 0.05) in S, SK1, and SK3 compared with C, with intermediate values in SK2 that were not different from C, S, SK1, and SK3 animals.


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  		Table 2. The effect of treatment on DM intake and ADG in beef cattle during a 35-d period
 
From d -22 to -1 before treatment, the ADG were not different (P = 0.19) among treatment groups (Table 2Go). From d -1 to 7, ADG were immediately suppressed (P < 0.05) in all castrated animals compared with C (Table 2Go). Reductions in ADG within the castration treatments began to recover following this period. Overall, from d -1 to 35, ADG was lower (P < 0.05) in S, SK2, and SK3 compared with C animals, and values in SK1 were in between that of C and the other castration groups.

Behaviors
During the 6-h postcastration period, the incidence of combined lying postures was lower (P < 0.05) in S than in C animals, and these behaviors were not modified by K treatments (Table 3Go). In contrast, the higher (P < 0.05) combined abnormal standing activities observed in S compared with C animals were reversed by the K treatments. Lower (P < 0.05) incidences of abnormal standing activities were observed in the SK2 and SK3 compared with S animals, with intermediate levels in SK1 animals that were not different from either S or the other K treatments (Table 3Go). Overall, the incidence of feeding activities did not differ (P = 0.25) among treatments. The incidence of total rumination activities was almost absent (P < 0.05) in S compared with C animals, whereas the administration of ketoprofen in all K treatment groups increased (P < 0.05) the incidence of total rumination compared with S, and the levels were not different from C animals (Table 3Go).


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  		Table 3. The effect treatment on the behavior of beef cattle during the first 6 h after treatment
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Implications
 Literature Cited
 
Tissue injury leads to the activation of nociceptive and inflammatory responses that are often associated with pain and hyperalgesia (Dahl and Kehlet, 1991;Tracey and Walker, 1995), and the secretion of glucocorticoids limits the inflammatory stress (Weissman, 1990; Morand and Leech, 1999). In the present study, the pattern and duration of castration-induced plasma cortisol elevation measured in the S animals were in accord with previous experiments (Fisher et al., 1996;1997a; Earley and Crowe, 2002). However, failure of the K treatments to reduce peak plasma cortisol response to castration was in contrast to the results reported by Earley and Crowe (2002). The animals used in the present study were 5.5-mo older than those used in the previous study, and it is possible that there was an effect of age at castration on plasma cortisol response. Robertson et al. (1994) found that calves castrated at 6, 21, or 42 d of age had increasing cortisol responses to castration with increasing age. A similar observation was made by King et al. (1991) in the castration of calves at 78 or 167 d of age. It has also been reported that increased cortisol concentrations are correlated with the degree of surgical trauma in humans (Weissman, 1990) and farm animals (Fisher et al., 1996; HREF="#MELLOR-ETAL-2000">Mellor et al., 2000). Earley and Crowe (2002) proposed that a NSAID treatment with K would be beneficial for the alleviation of postsurgical acute stress (cortisol) response. Therefore, the reduction in the integrated plasma cortisol response found in the present study lends further support to their hypothesis.

The elevated production of acute-phase proteins (plasma haptoglobin and fibrinogen) recorded in the S animals on d 1, 3, and 7 was the result of tissue trauma associated with surgical castration (Faulkner et al., 1992;Fisher et al., 2001;Earley and Crowe, 2002). However, there were no reductions in plasma haptoglobin concentrations on d 1 following the administration of K compared with surgery alone; this was contrary to previous findings (Earley and Crowe, 2002). The delayed reductions in the haptoglobin concentrations on d 3 in SK1 and SK2 animals compared with S in the present study supported the data from Earley and Crowe (2002), who reported that a K treatment would continue to maintain a lower haptoglobin concentration up to 3 d following surgical castration in calves. Surprisingly, a repeated treatment of K 24 h after castration in the SK3 animals failed to influence the haptoglobin production on d 3 compared with surgery alone. Conflicting results on the efficacy of NSAID in reducing acute-phase proteins have been documented in human surgery (Kehlet, 2000). Therefore, the benefit of a repeated K treatment at 24 h after surgery in reducing acute-phase proteins associated with castration was not supported by the present study.

Immunological assessment is a useful indicator of cattle welfare (Amadori et al., 1997), and the establishment of protective immunity depends critically on IFN-{gamma} (Arad et al., 1995). In the present study, there were no detectable differences in KLH-induced IFN-{gamma} production in all the castration treatments compared with controls on d 0, 1, and 3. This conflicted with previous findings that consistently showed castration to be suppressive on the memory T-lymphocyte response to KLH (Fisher et al., 1997a,b;Earley and Crowe, 2002). There was a wide dispersion of data among individual animals in this component of immunity (CV of 75 to 228% within treatments from d 0 to 3) in their responses to the KLH primary immunization procedure, and this may have accounted for the loss of power to detect any statistical difference among treatments. The suppression of Con A-induced IFN-{gamma} production in the S animals on d 1 compared with controls supports the previous findings that castration reduces IFN-{gamma} production from cultured lymphocytes and lymphocyte blastogenesis in response to Con A (Fisher et al., 1997b;Murata, 1997;Earley and Crowe, 2002). The provision of K in the SK1 and SK2 animals prevented the suppression of IFN-{gamma} production in response to Con A compared with surgery alone on d 1. A similar beneficial effect of K on IFN-{gamma} production was observed by Earley and Crowe (2002) on d 3 in response to KLH but not Con A. However, the SK3 animals had a reduced IFN-{gamma} level that was not prevented by the K treatment; the reason for this observation was unclear. Immune suppression in calves has been associated with increased plasma cortisol and haptoglobin production (Blecha and Baker, 1986;Murata and Miyamoto, 1993). Haptoglobin production by calf liver parenchymal cells is inducible with glucocorticoids in vitro (Higuchi et al., 1994). However, the function of endogenous cortisol secretion is more heterogeneous than is generally appreciated (Sapolsky et al., 2000). (Fisher et al., 1997a,b;) found that cortisol elevation per se may not result in castration-induced immune suppression, and suggested that other inflammation related processes were responsible for modulating immune function.

The increased total WBC numbers, increased percentage of granulocytes, the tendency for increased percentage of monocytes, and reduced percentage of lymphocytes observed in the S animals following castration was in agreement with the results of Murata (1997), who reported that castration in calves induced leukocytosis with neutrophilia; and Fisher et al. (1997b), who showed that the increase in WBC numbers in surgically castrated calves was largely due to increased neutrophil numbers. This event coincided with increasing plasma fibrinogen concentrations in the castrated animals in the present study. Fibrinogen has been implicated to have a regulatory role on the resolution of inflammation by binding with specific surface receptors on human neutrophils in vitro and promoting their functional capacity and survival (Rubel et al., 2001). Surgical sepsis has been correlated with monocytosis, suppressed leukocyte antigen receptor (HLA-DR), expression, and suppressed IFN-{gamma} production that potentially increases host susceptibility to opportunistic infections (Schinkel et al., 1998). The provision of K prevented the development of leukocytosis and the changes in WBC subpopulations (i.e., granulocytosis, monocytosis, and lymphopenia) observed with surgery alone, but there was no difference between the K treatments. The NSAID have specific action on leukocyte adhesion molecules (e.g., L-selectin) that impairs the recruitment of neutrophils during inflammation (Gómez-Gaviro et al., 2000). The changes in other hematological variables (reduced RBC numbers, PCV, and hemoglobin concentrations; and increased platelet numbers) recorded in all castrated animals with or without K were a reflection of ongoing hematopoiesis following surgery and acute blood loss (Dorr et al., 1986).

Oxygen-derived free radicals have been implicated as important mediators of inflammation, shock, and ischemia/reperfusion injury (Cuzzocrea et al., 2001). The production of reactive oxygen species is in part due to activated neutrophils following inflammation (Brigham, 1991). Castration resulted in reduced total antioxidant status of 8.1% on d 1 in S animals compared with controls. In contrast, the administration of K in the SK1, SK2, and SK3 animals mitigated the reduction of total antioxidant status. Ketoprofen has been shown to reduce the generation of superoxide (O2-) anions by neutrophils in vitro (Landoni et al., 1995). Although the differences in total antioxidant status among treatments were statistically significant, the low numerical difference would indicate that other oxidative stress indicators (e.g., glutathione peroxidase) would need to be investigated.

Surgical castration acutely reduced the ADG during the period from d -1 to 7, but had no effect on DMI until 20 d after treatment. The reason for this delayed response was unknown; the quality or quantity of feeds offered to the animals remained consistent, the environmental conditions were similar during the entire study, and there was no recorded higher incidence of morbidity in the castrates compared with intact controls. Ketoprofen treatments failed to prevent the acute effects of surgery on the ADG. Overall, surgical castration reduced DMI and live weight gain by 12 and 26%, respectively, compared with intact controls over the 35-d trial period. The loss of growth in the castrates was the result of acute tissue trauma associated with castration and the loss of beneficial testicular function (testosterone) in enhancing growth efficiency (Seideman et al., 1982;Knight et al., 1999). In contrast, the administration of K, irrespective of dose regimes, failed to consistently prevent the suppression of DMI or ADG when compared with surgery alone. Earley and Crowe (2002) showed that surgical castration of 5.5-mo-old calves with K resulted in no difference in ADG when compared with that of intact controls and surgery alone over the same time period.

Surgical castration increased the combined standing postures and reduced the lying postures compared with controls (approximate ratio of percentage of total standing:percentage of lying = 80:20 and 50:50, respectively) during the 6-h observation period. The administration of K failed to influence this overall response; however, K treatment reversed the combined incidence of abnormal behaviors and increased the incidence of rumination compared with surgery alone and controls. Carragher et al. (1997) observed higher rates of rear leg stamping and tail swishing in castrated bulls than in handled control bulls, and the castrates lay down for shorter periods and stood in different postures for up to 21 h after treatment. In lambs, a preemptive i.m. injection of a NSAID, diclofenac, effectively reduced plasma cortisol response to castration and lessened the time spent in abnormal postures compared with controls (Molony et al., 1997). The benefit of NSAID in modulating inflammatory response to other acute stressors, such as dehorning, has also been demonstrated in calves (McMeekan et al., 1999;Faulkner and Weary, 2000); however, these workers showed a multimodal approach (using a NSAID and/or local anesthetic with or without xylazine for sedation) to be more effective than a single treatment of NSAID. Interestingly, Earley and Crowe (2002) found a more diminished integrated plasma cortisol response in 5.5-mo-old castrated calves administered with K or with a combined local anesthetic and K treatment compared with local anesthetic alone. In contrast, Stafford et al. (2002) showed that a combined local anesthetic and K treatment almost completely eliminated the peak and integrated plasma cortisol responses of 2- to 4-mo-old Friesian calves to surgical castration, indicating that it is beneficial to castrate calves at younger ages.

In conclusion, surgical castration acutely increased the secretion of cortisol and acute-phase proteins, suppressed Con A-induced IFN-{gamma} production from leukocytes in whole-blood cultures, and reduced animal feed intakes and growth rates. Ketoprofen treatments effectively mitigated the overall cortisol response to castration, but had no effect on the initial peak response. There was no advantage in treating with two split doses of K (1.5 mg/kg of BW per dose) compared with a single treatment (3 mg/kg of BW) before castration. A repeated treatment of K at 24 h after castration had no effect on the changes in acute-phase proteins and immune response. The benefit of K in alleviating the reduction of feed intake and growth due to castration were not consistently demonstrated across the K treatments. Surgical castration increased the incidence of combined standing postures and reduced the lying postures compared with controls. However, the higher incidence of abnormal standing activities was reversed by the K treatments.


   Implications
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Implications
Literature Cited
 
Systemic analgesia with ketoprofen is an effective method for decreasing the inflammatory (acute-phase proteins) and the stress (integrated cortisol) responses associated with castration. Under the Protection of Animals (Amendment) Act, 1965 (Ireland), the use of anesthesia is required for surgical/burdizzo castration of cattle over 6 mo old. However, the use of analgesics, such as a nonsteroidal, anti-inflammatory drug, should be considered as an alternative therapeutic or an adjunct to local anesthesia to achieve a more balanced analgesia for castration. The practical/optimal age to castrate cattle with and without analgesia requires further investigation.


   Footnotes
 
1 This study was supported by a Teagasc Walsh Fellowship to S. T. L. Ting. The authors acknowledge Merial Animal Health Ltd., Harlow, U.K. for the supply of Ketofen. The authors thank L. Lane, M. Duane, A. Hanlon, G. Claffey, and N. Hynes (Faculty of Veterinary Medicine, University College Dublin [UCD]) for their assistance. The help of graduate students at Teagasc (Grange) and UCD, and the excellent technical support and dedication of the staff at Teagasc (Grange; J. A. Farrell, J. Larkin, M. Munnelly, M. Murray, and D. Prendiville) during the study are gratefully acknowledged. Thanks to P. Reid (Teagasc, Dublin) for her 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 acknowledged. The comments of P. Lees (Royal Veterinary College, U.K.) on ketoprofen are acknowledged. Back

Received for publication September 22, 2002. Accepted for publication January 2, 2003.


   Literature Cited
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Implications
 Literature Cited
 


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