Praca oryginalna Original paper
Use of pigs as an animal model in biomedical research has been increasingly widespread because of their anatomic and physiological similarities to human beings (when compared to non-human primates). Small, immature pigs are preferred to miniature pigs because of their lower cost (21, 34). However, anaesthesia in swine is challenging; the temperament of pigs makes handling difficult and securing venous access problematic (22). As intravenous (IV) injection is difficult in unsedated pigs, the availability of an effective anaesthetic regimen that can be administered intramuscularly (IM) is desirable (1). In spite of these difficulties, there are circumstances which warrant the need for anaesthesia in pigs.
Many anaesthetic protocols, including barbiturate combinations, dissociatives, opioids, alpha-2 adreno-receptor agonists, tiletamine/zolazepam, propofol, and various drug combinations, have been used in domesticated and non-domesticated swine (11, 14, 24). Ketamine (K), a dissociative anaesthetic of the phen-cyclidine group, produces a shorter duration of analgesia with catalepsy on systemic administration when used alone (12). It has been combined with several other pharmacological agents to provide
che-mical restraint, induce anaesthesia, or as a total anaes-thetic protocol for short duration surgery in both wild and domesticated pigs (1, 25).
Recent advances in alpha-2 adrenoceptor pharma-cology suggest that agents acting on this receptor population may possess a strong therapeutic potential in the development of anaesthesia. Several alpha-2 adrenoceptor agonists have therefore been manufac-tured for human or animal use (24). Medetomidine is one such agonist that is more potent than the older, and widely used, alpha-2 adrenoceptor agonist xylazine (33).
Tramadol (T) is a centrally acting analgesic, struc-turally related to codeine and morphine (29). It acts as a weak µ-opioid agonist and inhibits the synaptic re-uptake of serotonin and norepinephrine, achieving a spinal modulation of pain and preventing impulses from reaching the brain (15). It has been used in seve-ral species (5, 6, 15, 29, 31), including pigs (1, 20). Several pharmacokinetic and metabolic studies sug-gest that T cannot be effective as a painkiller because plasma concentrations of its active metabolite are negligible (7-10, 19). Other, more complete, studies (PK/PD) have confirmed previous speculations (3, 13)
Tramadol effect on the ketamine-medetomidine
combination in immature Bamei pigs
DE-ZHANG LU, SHU-HONG QIN, XIN-WU MA, HUA-YAN WANG, BAO-HUA MA
Department of Veterinary Surgery, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi Province 712100, P.R. China
Lu D.-Z., Qin S.-H., Ma X.-W., Wang H.-Y., Ma B.-H.
Tramadol effect on the ketamine-medetomidine combination in immature Bamei pigs
Summary
This experiment was carried out to investigate the effect of the ketamine-medetomidine-tramadol combi-nation (KMT) on pigs and to compare its efficacy as an anaesthetic, with that of ketamine-medetomidine (KM). Eight healthy eight-week-old Bamei pigs of both sexes were immobilized with KMT and KM on two different occasions. The pigs immobilization and analgesia scores and baseline physiological parameters (heart rate, respiratory rate, non-invasive systolic, diastolic and mean arterial blood pressures, arterial hemoglobin oxygen saturation and rectal temperature) were determined before the administration of KMT or KM and 5, 10, 30, 45, 60, 90 and 120 min thereafter. Pigs in both groups became recumbent within 5 min. Some physiological parameters changed after the drug combinations had been administrated, but they remained within biologically acceptable limits and did not differ significantly between the two treatments. Induction and recovery quality in pigs was better with KMT than with KM. Sedation, analgesia, muscle relaxation, posture and auditory response scores were higher in the KMT group. The animals in the KMT group were also much calmer during recovery.
and reports that T may be effective only if administe-red in high doses (27). However, it has also been reported that when T is administered in combination with other analgesic/anaestetic drugs, the final thera-peutic effect is improved (2, 32). Hence, the therathera-peutic profile of this drug is still obscure. To the best of the authors knowledge, there is no available data about the use of T in combination with KM in pigs.
It has been speculated that T, in combination with KM, might produce a deeper and longer analgesia than KM. This study was therefore undertaken to evaluate the anaesthetic and analgesic effects of ketamine in combination with medetomidine and tramadol (KMT) in pigs and to determine the magnitude of changes in some basic physiological variables.
Material and methods
Eight healthy eight-month-old Bamei pigs of both sexes were used on two occasions during the study. The animals received two different treatments at a rate of one treatment per week in a randomized crossover study design. The mean ± SD age of the pigs at the beginning of the study was 8 ± 1 weeks, and their weight was 15.7 ± 4.1 kg. The use of the animals was approved by the Animal Care and Use Committee of the Northwest A&F University. All pigs were found to be in good physical condition on the basis of physical examination and a complete blood count.
Food, but not water, was withheld for 12 hours prior to the experiment. The animals were allowed to acclimate to a room with a temperature of 25°C for at least 30 min before each experiment was started. Subsequently, the animals were caught in a net and weighed in a calm state. Baseline physiological parameters, systolic arterial blood pressure (SAP), diastolic arterial blood pressure (DAP), mean arte-rial blood pressure (MAP), artearte-rial hemoglobin oxygen saturation (SpO2) and rectal temperature (RT), were measured with a noninvasive monitor (G3F, General Medi-tech Inc, Shen Zhen, China) before drug administration. Blood pressure was monitored with a cuff placed circum-ferentially around the left antebrachium of the animals, the cuff width being approximately 40% of the total circum-ference of the limb. The heart rate (HR) was determined by counting heart beats for 1 minute with a stethoscope placed at the lower left lateral thoracic wall, and the respi-ratory rate (RR) was counted from thoracic excursions for 1 minute. A dose of 15 mg kg1 ketamine (200 mg L1, Shen
Yang Animal pharmaceutical factory, Shen Yang, China) and 60 µg kg1 medetomidine (Domitor, Pfizer Animal
Health, Exton, PA, USA), with or without 2 mg kg1
trama-dol (Tramal® 100; Grunenthal GmbH, Aachen, Germany),
was administered with a hand-held syringe into the muscles of the caudal thigh region in either the KMT or the KM group of animals. After the baseline values (time 0) of physiological parameters had been collected, the pigs were immediately given an intramuscular injection of the drug combination. Physiological parameters were then recorded at 5, 10, 30, 45, 60, 90 and 120 min. Once sedated, the pigs were placed in a canvas sling in lateral recumbency. An ophthalmic ointment was placed in their eyes to prevent corneal drying.
Induction time was defined as the time from injection to complete immobilization. Complete immobilization was defined as the absence of response to handling. Anaesthesia time was defined as the time interval between complete immobilization and the animals first attempt to lift its head a few centimeters above the ground. Time to standing was defined as the time interval from the end of anaesthesia until the animal stood without assistance for longer than 10 seconds, whereas time to walking was defined as the time from standing until the animal could walk a short distance (20, 28).
Scores for sedation, analgesia and muscle relaxation were determined at each time point according to the criteria described in Tab. 1. Behavioural changes were evaluated
Tab. 1. Criteria used to score anaesthetic effects of KMT and KM in Bamei pigs a ir e ti r C Score Observaiton e r o c s n o it a d e S 0 Normal 1 Msrtolidnsgepdaalpitoenbrar(elrceumlfebxe,nno,trhmeaadledyoewpno,siiton) 2 Mmooddeerraatteespeadlpaeitbornalr(reeclfuemx,bpeanr,titahleaddown, ) n o it a t o r e y e l a i d e m o rt n e v 3 Pnoropfoaulpnedbsrealdareitolfenx,r(ceocummplbeeten,tvehneartodmdeodwian,l ) n o it a t o r e y e ) s p e c r o f s 'r e h c o K h ti w n o it a u l a v e a i s e g l a n a ( e r o c s a i s e g l a n A 0 Normal(producitvefilghtresponse) 1 Mattelidm(petxsatgoggeerattuepd)movementsof ilmbsand 2 Mattoedmerpatsteto(sgilegthutpm)ovementsofthe ilmbsand 3 Profound l(ackofresponse) e r o c s n o it a x a l e r e l c s u M 0 Normaljawandlegtone 1 Mlidrelaxaitonofjawandlegtone 2 Moderaterelaxaitonofjawandlegtone 3 Profoundrelaxaitonofjawandlegtone e r o c s e r u t s o P 0 Standing 1 Stiitngorataxic,butabletowalk 2 Statelironarlarepcauwmbency,butabletomovethe 3 Lateralrecumbencywtihoutmovement e r o c s e s n o p s e r y r o ti d u A ) s r a e s 'l a m i n a e h t o t e s o l c p a l c d n a h a y b d e t a e r c e s i o n o t e s n o p s e r( 0 Normalresponse 1 M(eyliedmdeocvreeamseentinwretihspboondsyemovemen)t 2 M(eoydeemraotevedmeecnretawsetihionurtebsopdoynsmeovemen)t 3 P(nroofmouonvdemdeecnre)taseinresponse
by recording the pigs posture. The pigs responses to noci-ceptive and other stimuli were evaluated by recording their reaction to a handclap close to the animals ears (auditory response), and to direct stimulation by touching and, if possible, rocking the animals body (11, 28). Kochers forceps (closed to the third ratchet) were used to assess analgesia. A withdrawal reflex to the clamping of the tail and the skin in the inguinal area for 3 seconds with Kochers forceps was assessed. The tail was clamped, and the response was defined as the movement of the tail. The skin of body surface in the inguinal area was clamped in the same way, and the response was defined as the twit-ching of the abdomen. Any major purposeful movement of a limb or the body in reaction to clamping was interpreted as the absence of analgesia, and the corresponding analgesia scores were determined and recorded. Analgesia evaluation occurred immediately after cardiorespiratory evaluation. All analgesia evaluations occurred in the same order at each time point.
Induction, anaesthesia, standing and walking times were compared between the two groups by the use of Students t-test. Physiological parameters were analyzed by means of ANOVA for repeated measurements to evaluate changes within each group and between two different treatments.
The scores for immobilization and analgesia (sedation, anal-gesia, muscle relaxation, posture, and auditory response) were compared with Mann-Whitneys test. All statistical analyses were performed with SPSS 13.0 (SPSS Statistical Product and Service Solutions 13.0, SPSS Incorporation, Chicago, Illinois). A probability level of 5% (p < 0.05) was considered significant. All values are reported as the mean ± standard deviation.
Results and discussion
After drug administration, all animals showed signs of dissociative anaesthesia characterized by mydriasis and nose licking. The pigs in both groups became laterally recumbent within 5 min. The duration of induction was not significantly different between the KMT treatment (3.28 ± 1.26 min) and the KM treat-ment (3.41 ± 1.16 min). Uncoordinated head and leg movements were observed in the KM group during the induction period. These were less intense and of shorter duration after KMT administration. Recovery was characterized by slow movements of the eyes, the twitching of the ears and attempts to lift the head. In a similar manner, the animals were more agitated during recovery from KM: they were extremely ataxic and would fall and roll on the ground or suddenly run in an uncontrolled manner. Most of the animals in the KMT group made a few attempts before they could walk for a short distance without ataxia seen in the KM group. With the KMT treatment, the animals were much calmer during recovery, and the behaviour described
s p u o r G Induciton itme Anaesthesia itme Standing itme Walking itme T M K 3.28±1.26 83.37±13.06a 25.35±12.41a 31.23±11.31a M K 3.41±1.16 70.28±16.24b 17.23±8.42b 20.51±8.33b
Tab. 2. Mean (± SD) values (min) for induction, anaesthesia, standing and walking times in Chinese experimental miniature pigs
Explanations: a, b significant differences between groups at P £ 0.05; KM ketamine--medetomidine; KMT KM plus tramadol
Tab. 3. Physiological parameters evaluated in miniature pigs anaesthetized with KMT or KM (x ± SD)
s r e t e m a r a P Groups Time(min). 0 5 10 30 45 60 90 120 s t a e b ( R H ) e t u n i m r e p T M K 110±5 117±7 125±6* 103±5 97±6* 90±6* 95±5* 104±7 M K 114±7 120±8 127±9* 111±7 103±6 93±6* 98±6* 113±6 s h t a e r b ( R R ) e t u n i m r e p T M K 34±2 42±3* 49±2* 33±2 32±2 30±3 34±2 36±1 M K 38±4 47±5* 52±4* 42±5 40±4 38±2 41±3 44±3 O p S 2 ) % ( T M K 98.0±1.1 95.1±3.7 94.6±2.2 95.7±2.0 96.7±3.1 96.6±2.1 97.3±2.4 98.8±1.0 M K 98.3±1.5 95.5±4.1 95.1±2.1 95.8±3.1 96.2±3.2 96.5±2.7 97.1±1.1 98.5±1.2 T R (° )C T M K 38.9±0.2 38.8±0.1 38.5±0.1* 37.8±0.2* 37.4±0.1* 37.2±0.1* 37.2±0.1* 37.1±0.1* M K 39.0±0.2 38.8±0.1 38.6±0.2* 38.0±0.2* 37.8±0.3* 37.6±0.1* 37.3±0.2* 37.2±0.2* P A S ) g H m m ( T M K 136±9 140±13 145±11 126±11 114±11* 100±14* 110±7* 129±12 M K 133±12 144±12 146±15 128±12 113±9* 98±12* 112±11* 127±15 P A D ) g H m m ( T M K 93±8 99±11 105±12 85±7 76±8* 70±6* 81±6* 89±7 M K 95±8 101±9 110±11 90±6 79±7* 72±8* 83±5* 92±8 P A M ) g H m m ( T M K 106±11 113±10 120±13 95±9 85±9* 77±7* 83±8* 98±9 M K 108±9 116±11 123±9* 101±10 92±7* 83±9* 91±8* 102±9
Explanations: *significantly (P < 0.05) different from values at 0 min within each group; HR heart rate; RR respiratory rate; SpO2
arterial oxyhemoglobin saturation; RT rectal temperature; SAP systolic arterial blood pressure; DAP diastolic arterial blood pressure; MAP mean arterial blood pressure; KM ketamine-medetomidine; KMT KM plus tramadol
in the KM treatment was rarely observed. Standing time for KMT was 25.35 ± 12.41 min, and for KM it was 17.23 ± 8.42 min, after which the animals were able to walk. Walking time for KMT was 31.23 ± 11.31 min, and for KM it was 20.51 ± 8.43 min. Anaesthesia, standing and walking times were significantly longer for KMT than for KM. Induction, anaesthesia, stand-ing and walkstand-ing times are reported in Tab. 2.
The changes in the HR and RR, SpO2, RT and
blood pressure for the KMT treatment and for the KM treatment are shown in Tab. 3. There was no signifi-cant difference in these parameters between the two treatments.
The administration of KMT or KM to conscious Bamei pigs caused changes in the HR, RR, RT, SpO2, SAP, DAP and MAP. The mean HR ranged from 90 to 125 bpm in the KMT treatment, and from 93 to 127 bpm in the KM treatment. No episodes of severe bra-dycardia or tachycardia were observed. The HR was significantly increased at 10 min after administration and decreased gradually to baseline values at 30 min, then decreased significantly below baseline at 45, 60 and 90 min, finally returning to near-normal rates by the end of the monitoring period. The RR increased significantly during the first 5 min, reached the highest value at 10 min, and then decreased to the lowest value at 60 min. The RR increased from 60 to 120 min after the administration of the combinations, but did not diverge significantly from baseline values. By contrast, SPO2 decreased during the period of anaesthesia, compared with the first value measured, and returned to baseline values at the end of the study. In this study, RT decreased significantly after the administration of KMT or KM throughout this study. SAP, DAP and MAP increased at 10 min after drugs administration, and they reached the lowest levels at 60 min. Blood pressure decreased significantly from 45 to 90 min and then returned to baseline values, but no statistically
significant results were observed at the end of the study.
Sedation scores for KMT were significantly higher than those in the KM group at both 90 and 120 min after drug administration. The response to clamping with Kochers forceps can provide a satisfactory indi-cation regarding the depth of analgesia during the post--injection period. Analgesia scores in the KMT group were higher than those in the KM group at 5, 90 and 120 min. The scores for muscle relaxation and posture were significantly lower at 90 and 120 min in the KM group compared with the KMT group. The degree of auditory response was significantly higher at 5 min in the KMT group, but the scores were significantly lower at 90 and 120 min after KM administration (Tab. 4).
Ketamine (K) has been used as a major component of most regimens used to induce chemical restraint or anaesthesia in pigs because it can be given IM and has a rapid onset of action (25). However, when used alone, it has some undesirable effects on muscle tonus and emergence delirium. These disadvantages can be offset if K is used in combination with sedatives, such as alpha-2 adrenoceptor agonists (1, 25). To date, medetomidine is the newest commercially available alpha-2 adrenoceptor agonist drug. It is the most potent, selective, and specific agonist in both the peripheral and central nervous systems, and as such, it may offer some advantages over xylazine (23). In this study, KM provided good induction and anaesthesia, and this state is well maintained with K. The admini-stration of sedative-hypnotics with muscle relaxant properties, such as M, may improve conditions for sedation and muscle relaxation with K.
This study showed that in Bamei pigs, T combined with the KM combination improved the quality of anaesthetic induction, as well as increased the duration of analgesia, without adversely affecting the cardio-pulmonary parameters measured in this study or reco-very characteristics. Compared with KM, KMT obtained significantly higher scores not only for anaesthesia time, but also for the duration of sedation, muscle relaxation, posture and audi-tory response. In this study, the values for sedation, analgesia, muscle relaxa-tion, posture and auditory response were good in both treatments, but appeared to be better in the treatment including T. Tramadol is a centrally acting analgesic with weak opioid agonist properties and effects on nor-adrenergic and serotonergic neuro-transmission (18). It has proven effec-tive in both experimental and clinical pain suppression without causing se-rious adverse cardiovascular or respi-ratory effects (22). Although T has been widely used in cats, dogs, goats, Explanations: a, b means with different superscripts within each effect are significantly
different (P £ 0.05); KM ketamine-medetomidine; KMT KM plus tramadol Tab. 4. Mean values for sedation, analgesia, muscle relaxation, posture and auditory response in Bamei pigs anaesthetized with KMT or KM
t c e ff E Groups Time(min). 0 5 10 30 45 60 90 120 n o it a d e S KMT 0 1.7 2.9 3.0 3.0 3.0 2.8a 1.6a M K 0 1.6 2.7 3.0 3.0 3.0 2.4b 1.2b a i s e g l a n A KMT 0 2.5a 3.0 3.0 3.0 3.0 2.7a 1.7a M K 0 2.1b 2.9 3.0 3.0 3.0 2.1b 1.1b e l c s u M n o it a x a l e r T M K 0 2.4 2.9 3.0 3.0 3.0 2.7a 1.8a M K 0 2.3 2.8 3.0 3.0 3.0 1.9b 1.2b e r u t s o P KMT 0 2.6 3.0 3.0 3.0 3.0 2.4a 1.6a M K 0 2.7 3.0 3.0 3.0 3.0 1.8b 1.1b y r o ti d u A e s n o p s e r T M K 0 2.4 2.8 3.0 3.0 3.0 2.6a 1.8a M K 0 2.2 2.7 3.0 3.0 3.0 2.1b 1.2b
horses and other animals (5, 6, 8, 9, 15, 19, 29, 31), there is little information about the use of T in pigs (1, 20). This study showed that in Baimei pigs, the addition of T to KM improved the quality of anaes-thetic induction and increased the analgesia effect, without adversely affecting the cardiopulmonary para-meters measured in this study.
In this study both KMT and KM completely immo-bilized Bamei pigs without any major adverse effects (28). The doses of K used were lower than those reported with other pigs (1). In Niger hybrid pigs, the use of K (25 mg kg1) and xylazine (2.5 mg kg1)
resulted in 32.0 ± 13.3 min of anaesthesia with a great number of adverse effects, such as transient apnoea and cardiac dysrhythmias (1). The effective M dose used in the KM treatment was much lower than those reported by Sakaguchi (25) with other pig species.
The quality of induction was better in the KMT group than in the KM group because fewer agitation signs were observed in the KMT group during the induction period. However, the standing time and the walking time for the KMT combination were longer than for KM in this study; induction was quicker and recovery calmer. Compared with KM, KMT has the ability to increase the anaesthetic time and prolong the sedative effect, which, in turn, results in longer stan-ding and walking times. In this study the addition of T increased significantly the duration of antinociception, which suggests that the KMT combination will be useful not only for the induction of anaesthesia but also for surgeries of short duration. Bamei pigs receiving KMT made very few attempts to stand up, whereas animals receiving KM tried to stand up several times before they could remain standing. Better recovery characte-ristics are an advantage of the tramadol combination compared with KM alone.
In Bamei pigs anaesthetized with KMT or KM combinations, the HR changed immediately after drug administration, and an anticholinergic agent was not used, but there was no significant difference between the KMT treatment and the KM treatment. The results of this study indicate that T produces a less pronoun-ced cardiovascular depression effects (16). The results also suggest that the MK combination has a slightly stimulating effect on the cardiovascular system (26). Similar findings have been reported for tramadol administered to pigs in combination with xylazine--ketamine (1).
Sakaguchi (26) reported that the MK combination caused scarcely any changes in respiratory parameters, so this limited effect on the cardiopulmonary system was an advantage of the MK combination for chemical restraint in pigs. Lehmann (16) reported that clinically relevant respiratory depression was rarely observed in humans after T administration. In this study, a similar RR was observed in both groups. The results of this study also suggest that T causes no significant addi-tional depressive respiratory effect in pigs.
In this study, there was no significant difference in SpO2 between Bamei pigs anaesthetized with the KMT treatment and those anaesthetized with the KM treat-ment. The reduction of SpO2 in the treated animals may partially be due to the depressive effects of alpha-2 adrenoreceptor agonists (4, 18). A major advantage of T is that, unlike other opioids, it has no depressive cardiopulmonary effects, so animals medicated with tramadol are likely to maintain a better cardiopulmo-nary function (1). Although there was no significant difference in respiratory rates or in SpO2 between KMT- and KM-anaesthetized pigs in this study, blood gas analysis and end-tidal carbon dioxide would be needed to further evaluate the respiratory function following KMT or KM administration.
In this study, RT in both groups decreased imme-diately after the injection of KMT or KM, possibly owing to the loss of thermoregulatory control following the administration of alpha-2 adrenoreceptor agonists (4, 28). Further, the decrease in RT may be due to generalized sedation, a decrease in metabolic rate, muscle relaxation, and central nervous system depres-sion produced by alpha-2 adrenoreceptor agonists (4). In the current study, there was a transient increase in SAP, DAP and MAP after drug administration, but they reached their lowest values 60 min later. The changes in blood pressure were possibly due to anti-hypertensive properties of the alpha-2 adrenoreceptor agonist metomidine. Alpha-2 adrenoreceptor agonists elicit a dual response: the first phase is characterized by transient hypertension (caused by peripheral vaso-constriction) followed by hypotension in the second phase (caused by central vasodilation) (30). However, there were no significant differences between the trends of blood pressure in the two groups. The results of this study suggest that T used in combination with KM has little effect on Bamei pigs blood pressure. This is agreement with Lehmanns findings (17) with regard to humans.
At 5 min, we observed similar sedation, muscle relaxation, and posture scores for the two treatments, but analgesia and auditory response scores were diffe-rent. Thereafter, the KMT group had higher scores for immobilization, analgesia, degree of sedation, muscle relaxation, posture and auditory response. The scores for the degree of sedation, analgesia, muscle relaxa-tion, posture and auditory response were higher in the KMT group. This could be attributed to the effect of T (2 mg kg1), which, when combined with KM, extends
the anaesthetic time compared with KM alone. The absence of response to a noxious stimulus and the depth of anaesthesia were assessed on the basis of reflex withdrawal from Kochers forceps applied to the inguinal area (28). In this study, repeated stimu-lation was applied to the tail and the inguinal area at each testing time point. The first stimulus seemed to arouse the animal to a state in which a repeated stimu-lus evoked a response. As most surgical procedures
include repetitive nociceptive stimulation, it seemed logical to repeat the stimulus when assessing analgesia by the withdrawal reflex. In this study, the addition of T significantly increased the duration of antinocicep-tion, which suggests that the KMT combination can provide a satisfactory anaesthesia effect for nearly 80 min.
Conclusion
This study showed that KM combined with T caused an adequate immobilization of pigs that was charac-terized by rapid induction, adequate analgesia and muscle relaxation with no complications. In conclu-sion, the results of this study support the use of KMT as an immobilization technique for pigs.
Acknowledgments
We are grateful to all those who helped with this study, especially to Professor Hua-yan Wang for assi-sting us with the animals. This study was supported by the Foundation for Talent of Northwest A&F Uni-versity (Grant No. Z109021110).
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Corresponding author: Bao-hua Ma, PhD; Department of Veterinary Surgery, College of Veterinary Medicine, Northwest A&F University; No. 3 Taicheng Road, Yangling, Shaanxi Province 712100, P.R. China; e-mail: mabh@nwsuaf.edu.cn
