Comparison of the analgesic, clinicophysiological andhematobiochemical effects of epidural bupivacaine
in healthy and uremic goats
K. Singh, P. Kinjavdekar ∗, Amarpal, H.P. Aithal, A. Gopinathan,G.R. Singh, A.M. Pawde, K. Pratap
Division of Surgery, Indian Veterinary Research Institute, Izatnagar 243122, Uttar Pradesh, India
Received 18 January 2006; accepted 27 February 2006Available online 4 April 2006
bstract
The analgesic effect of bupivacaine (0.5 mg/kg) was evaluated in the uremic (n = 6) and healthy goats (n = 6) after its lumbosacralpidural administration by clinicophysiological and hematobiochemical parameters. The onset of analgesia was delayed in uremicnimals than in healthy animals. Bupivacaine produced complete analgesia of tail, perineum, inguinal and thigh regions in bothroups. However, in healthy animals it produced a longer duration of complete analgesia than in uremic animals. Greater ataxia wasroduced in healthy animals than in uremic animals. The heart rate, respiratory rate, rectal temperature, hemoglobin, packed cellolume and differential leukocyte count did not show any significant changes in both healthy and uremic animals. However, totaleukocyte count, urea nitrogen and creatinine showed significantly higher values in uremic animals. The blood electrolytes, bloodases and acid base parameters did not show any significant changes in any group. However, base excess was significantly higher
n uremic animals. The changes in these parameters were however, minimal and transient and became normal as the effect of therug was over. Therefore, bupivacaine (0.5% solution at 0.5 mg/kg) may be used in clinical situations in uremic caprines and in thenimals which are under a similar type of physiological stress.
The incidence of urolithiasis has been reported to be
igher in goats as compared to other species (Sharma,001). Uremia invariably succeeds urolithiasis obstruct-ng urine flow and causing rupture of urinary bladder.
Uremic patients are considered as poor surgical riskpatients and hence great care is needed during inductionand maintenance of anesthesia. Systemic use of generalanesthetics may affect cardiovascular and neural func-tions. Hence, anesthetic agents with minimal effects onthese systems should be selected. Alternatively, epiduraluse of drugs eliminates these side effects and increasesthe margin of safety (Pascoe, 1992). Conventionally, lig-
nocaine has been used as epidural analgesic in manyspecies of animals (Hall et al., 2001). Bupivacaine, along acting anilide local analgesic agent has been usedas epidural or spinal analgesic in healthy sheep (Lebeaux,
1975), cattle (Gill et al., 1984; Mishra et al., 1993) andgoat (Trim, 1989; Pathak, 1999; Singh, 2000). It is fourtimes more potent and twice more analgesic as com-pared to lignocaine but has a delayed onset of action(Hall et al., 2001). It has been reported that the effectof epidural bupivacaine was meager on mean arterialpressure (MAP) with no alteration in central venous pres-sure (CVP), blood gas and clinical parameters (Bonathand Gerlach, 1983). It was hypothesized that poor riskpatients weakened by disease may safely be adminis-tered with epidural bupivacaine. But, its use as epiduralanalgesic in uremic caprine has not been investigated orreported so far. To the authors knowledge there is noreport on the effect of the drug on physiological andhematobiochemical parameters studied in the presentinvestigation. The present study was therefore, designedto evaluate and compare the analgesic potency, clini-cophysiological and hematological effects of epidurallyadministered bupivacaine (0.5 mg/kg) in uremic as wellas in healthy goats.
2. Materials and methods
The study was conducted on 12 nondescript malegoats, of 6–9 month of age in two groups (A and B). Ingroup A, clinically healthy animals (n = 6) were main-tained under uniform feeding and management condi-tions. Animals were dewormed one month before thecommencement of the experiment and were vaccinatedagainst Rinderpest (1 ml s/c). During this period theywere acclimatized to approaching and handling. Duecare was taken from the view of animal welfare and thestudy was approved by the Committee for the Purposeof Control and Supervision on Experimental Animals(CPCSEA), Ministry of Social Justice and Empower-ment, Government of India, New Delhi. Group B com-prised of animals (n = 6) presented to the polyclinicwhich were suffering from urethral obstruction for 2–3days. These animals were considered as uraemic as theblood urea nitrogen and creatinine levels on the day ofpresentation were above the normal range for the species(in this case, goat). The animals of both groups were sub-jected to pre or post scrotal urethrotomy. In group A, ure-throtomy was performed for evaluation of a few suturematerials/techniques in another study. While in group B,urethrotomy was performed for removal of urethral cal-culi in clinical cases. Surgical procedure and the extent ofsurgical trauma inflicted on all the animals of both groups
were similar and uniform. The animals of group A werekept off feed for 24 h and water was withheld for 12 hbefore the start of the experiment. However, the animalsof group B were operated immediately for relieving ure-
esearch 71 (2007) 13–20
thral obstruction, after thorough clinical investigation,on the same day as soon as they were brought to theclinic. The anesthetic trials and surgery was conductedin the morning hours of the day. Bupivacaine (0.5%) atthe dose rate of 0.5 mg/kg body weight was adminis-tered to all the animals of both groups. The dose rate forbupivacaine was determined on clinically healthy exper-imental animals after conducting pilot trials before itsactual use in clinical cases. For determination of doserates of bupivacaine, three dose rates (0.25 mg, 0.5 mgand 1 mg/kg) of bupivacaine were used randomly afterconducting a few trials in four healthy goats. The doserate of 0.5 mg/kg was found sufficient enough and suit-able for performing urethrotomy in these animals.
The animals were restrained in the standing positionand the lumbosacral region was aseptically prepared forepidural injection. A 20 gauge, 4 cm long hypodermicneedle was inserted along the midline, perpendicularto the skin, at the lumbosacral region. Gentle pressurewas applied on the needle to pass through the skin andsupraspinous ligament. The needle was advanced at anangle of 70◦ to the skin surface, with the direction anteri-orly and vertically, up to 2–3 cm in depth. Resistance wasfelt as the needle punctured the interarcuate ligament,which lies over the epidural space. Correct position ofthe needle was ascertained by observing air bubbles inthe syringe mounted on the needle. The drug was theninjected. The baseline value (time = 0) for physiologicaland clinical parameters was recorded before the injec-tion of the drug. Under surgical analgesia, pre or postscrotal urethrotomy was performed uniformly.
The effect of bupivacaine in healthy and uremic ani-mals was compared on the basis of clinical, physiolog-ical, hematological and biochemical parameters. Sub-jective scores for depth and extent of analgesia, motorincoordination and sedation were recorded by the sameperson blinded to the treatment throughout the periodof the experiment in each trial. Onset of analgesia (ins/min) was recorded by pinprick method at the perinealregion at every 10 s interval till the onset of analge-sia was achieved (Aithal et al., 1996; Amarpal et al.,1997, 1999). The extent of analgesia was recorded attail, perineum, inguinal region, thigh, digits, flank, tho-rax and ventral abdomen at 5, 10, 15, 20, 30, 45, 60,75, 90, 105 and 120 min after administration of thedrug. Depth of analgesia was graded on a 0–3 scale,where 0: no analgesia—strong reaction of pinpricks,1: mild analgesia—weak response to pinpricks (mild
response shown by the animal to the pinprick on a par-ticular region), 2: moderate analgesia—occasional mod-erate response to pinpricks, 3: complete analgesia—noresponse to pinpricks. Motor incoordination of hind
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sia of the flank (Fig. 4) and thorax (Fig. 5) was recordedat different intervals in healthy goats as compared to ure-mic goats.
K. Singh et al. / Small Rum
imbs was evaluated before restraining the animal forurgery, at every 5 min post injection and after comple-ion of surgery up to 2 h. It was graded on a 0–4 scale,here 0, animal walks without staggering; 1, animalalks with a stagger; 2, animal walks with extreme inco-rdination; 3, sternal recumbency and 4, lateral recum-ency. Sedation was evaluated at the same time intervalss the motor incoordination and was graded on a 0–4cale, where 0, standing alert; 1, standing but tired withlight ptosis of eyelids; 2, standing with wide stance andxtreme lowering of head; 3, animal attained recum-ency but could sit without support; 4, lateral recum-ency. Time (in min) from loss of sensation to return ofensation at perineal region was considered as durationf analgesia. Recovery time (in min) was noted whenhe animal started walking without support. During theeriod of analgesia, animals were also observed for thextent of salivation, and the frequency of urination. Phys-ological parameters like heart rate (HR), respiratory rateRR) and rectal temperature (RT) were also recorded athe same time intervals after injection of the drug. Bloodamples were collected in clean dry heparinised vialssodium fluoride for glucose estimation) before and at0, 60, 120 min after administration of the drug for esti-ation of hemoglobin (Hb), packed cell volume (PCV),
otal leukocyte count (TLC) and differential leukocyteount (DLC) using standard procedures. Plasma ureaitrogen (PUN), creatinine, total protein and glucoseere estimated at the same intervals using Span Diag-ostic Kits. The fresh heparinised blood was also utilizedor estimation of pH, pCO2 , BE, pO2 , SO2, HCO3
−, Na+,+, Cl−, Ca2+ using blood gas analyzer (Stat Profile M,ova Biomedicals, USA).
. Statistical analysis
The data of physiological, hematological and bio-hemical parameters was analyzed using one way anal-sis of variance (ANOVA) for comparison of meansetween the groups at different intervals. The objectivearameters were analyzed using Signed Rank Test dueo Wilcoxon. Paired t-test was used for comparison of
eans at different intervals with their respective basealue (Snedecor and Cochran, 1967).
. Result
Absence of response to pin pricks at the perineal
egion provided satisfactory indication for the onset ofnalgesia with bupivacaine, which ranged between 94nd 226 s in uremic goats. However, in healthy goats thenset was faster (17–44 s).
Fig. 1. Analgesia at tail (mean ± S.E.) after subarachnoid adminis-tration of bupivacaine in healthy (n = 6) and uremic goats (n = 6)(*p < 0.05).
Analgesia at tail (Fig. 1) was moderate at 10 minwhich became complete thereafter, until 45 min anddeclined gradually up to 120 min in uremic goats. Inhealthy goats complete analgesia was recorded from 5 to75 min, which was significantly (p < 0.05) higher at mostof the intervals than uremic goats. Analgesia of perineum(Fig. 2) was complete from 10 min till 45 min in group Band 75 min in group A. Thereafter, it receded to moderateand later on became mild at 120 min. Similarly, analgesiaof the inguinal region in healthy goats was significantly(p < 0.05) deeper at most of the intervals than in uremicgoats. Moderate analgesia at 10 min and complete anal-gesia from 15 to 30 min of the thigh region was recordedin uremic goats. Whereas in healthy goats, moderateanalgesia was attained earlier (5 min) and complete anal-gesia was recorded from 10 to 60 min. Analgesia of digits(Fig. 3) in uremic goats was significantly (p < 0.05) lesserat 5, 10, 60 and 75 min intervals than that recorded inhealthy goats. A significantly (p < 0.05) higher analge-
Fig. 2. Analgesia at perineum (mean ± S.E.) after subarachnoidadministration of bupivacaine in healthy (n = 6) and uremic goats(n = 6) (*p < 0.05).
16 K. Singh et al. / Small Ruminant Research 71 (2007) 13–20
Fig. 3. Analgesia at digit (mean ± S.E.) after subarachnoid admin-istration of bupivacaine in healthy (n = 6) and uremic goats (n = 6)(*p < 0.05).
Fig. 4. Analgesia at flank (mean ± S.E.) after subarachnoid admin-istration of bupivacaine in healthy (n = 6) and uremic goats (n = 6)(*p < 0.05).
Duration of analgesia, recovery time and loss of motorcontrol was significantly (p < 0.05) prolonged in healthygoats with a faster recovery in uremic goats. Epidu-ral bupivacaine failed to induce sedation, salivation orurination in either healthy or uremic goats at any inter-vals. Absence of response to the perineal incision, while
performing urethrotomy, was indicative of the adequatedepth of analgesia (complete analgesia).
Fig. 5. Analgesia at thorax (mean ± S.E.) after subarachnoid admin-istration of bupivacaine in healthy (n = 6) and uremic goats (n = 6)(*p < 0.05).
Fig. 6. PUNmmol/L (mean ± S.E.) after subarachnoid administrationof bupivacaine in healthy (n = 6) and uremic goats (n = 6) (*p < 0.05).
In uremic goats a significant (p < 0.05) decrease in HRwas observed up to 20 min from base value, but no signif-icant difference in HR was noticed between healthy anduremic goats. There was no significant difference in RRfrom base value in uremic and healthy goats at differentintervals. Uraemic goats showed a significantly (p < 0.05) lower RT than healthy goats at all intervals exceptat 15 and 20 min. Hemoglobin (Table 2) and PCV val-ues decreased, but remained within normal physiologicalrange, throughout the observation period in both groups.Total leukocyte count decreased gradually in both groupsat different intervals (Table 1). Significantly (p < 0.05)higher TLC was recorded in uremic goats at all inter-vals. The neutrophil count was more or less near the baseline value at all intervals but a significantly (p < 0.05)higher percentage neutrophils was recorded in uremicgoats than in healthy goats at all intervals. A similarpattern was also observed in monocyte percent betweenthe two groups. Lymphocyte and eosinophil values alsofluctuated near the base value.
There was no significant increase in the PUN (Fig. 6)
and creatinine (Fig. 7) values at different intervals inboth groups. However, the PUN values showed a non-significant decrease at different intervals in the uremicgoats. Comparison between the two groups revealed that
Fig. 7. Creatinine �mol/L (mean ± S.E.) after subarachnoid adminis-tration of bupivacaine in healthy (n = 6) and uremic goats (n = 6).
K. Singh et al. / Small Ruminant Research 71 (2007) 13–20 17
Table 1Significant effect of epidural bupivacaine in healthy (group A) and uremic (group B) goats on hematological and biochemical parameters(mean ± S.E.)
S. no. Parameters Groups Baseline 30 min 60 min 120 min
alues with different superscript alphabets (a and b) differ significantl* Differ significantly (p < 0.05) from pre-induction values.
** Differ significantly (p < 0.01) from pre-induction values.
ignificantly (p < 0.05) higher values of PUN and creati-ine were recorded in uremic goats than in healthy goats.he glucose (Table 2) and total protein (Table 1) valuesid not show any significant change at different inter-
able 2on-significant effect of epidural bupivacaine in healthy (group A) and ure
mean ± S.E.)
. no. Parameters Groups Baseline
1 Hb (g/L) A 85.25 ± 4.08B 83.16 ± 2.50
2 PCV (%) A 26.96 ± 1.00B 25.11 ± 0.73
3 Neutrophil (%) A 37.00 ± 1.00B 38.60 ± 0.71
4 Lymphocyte (%) A 56.75 ± 1.30B 54.80 ± 0.87
5 Glucose (mmol/L) A 27.30 ± 0.18B 25.40 ± 0.18
6 Sodium (mmol/L) A 144.50 ± 0.86B 142.60 ± 2.40
7 Potassium (mmol/L) A 4.50 ± 0.13B 4.10 ± 0.17
8 pCO2 (mmHg) A 47.10 ± 1.60B 41.80 ± 1.3
9 pO2 (mmHg) A 26.90 ± 1.4B 30.50 ± 1.3
0 SO2 (%) A 43.80 ± 5.4B 52.36 ± 3.03
.05) at corresponding intervals.
vals in both groups. However, the total protein valueswere significantly (p < 0.05) higher at zero and 60 minin healthy goats and significantly (p < 0.05) higher at30 min in uremic goats. There were no significant differ-
mic (group B) goats on hematological and biochemical parameters
ences in Na+ values from baseline at different intervalsin both groups. In uremic goats, there was a gradualdecline in Ca++ value which was significantly (p < 0.05)low at 30 min interval (Table 1). Healthy goats had signif-icantly (p < 0.05) greater values of Ca++ at 0 and 60 minthan in uremic goats. In healthy goats the decline in theK+ value at 30 min was significant (p < 0.05) (Table 2).A significant decline in the Cl− value was observed inhealthy goats at 30 and 120 min intervals. Bicarbonate,pH, BE, pCO2 , pO2 and SO2 values fluctuated near base-line in both groups at different intervals and did notdiffer significantly from baseline at different intervals(Tables 1 and 2). However, uremic goats showed signif-icantly (p < 0.05) higher values of bicarbonates and BEthroughout the post induction period as compared to thehealthy goats.
5. Discussion
Obstructive urolithiasis complicating into uremianeeds immediate surgical intervention. General anes-thesia is generally avoided in these animals with ele-vated blood urea nitrogen and creatinine levels. There-fore, the technique of epidural analgesia may be veryuseful for patients suffering from urinary tract dys-functions (Klide, 1984). Epidural use of different drugseliminates most of the side effects generally seen withsystemically administered drugs and also increases theduration of action (Pascoe, 1992). Conventionally, lig-nocaine has been used epidurally/spinally in differentspecies of healthy animals. However, its use in dis-eased animals has not been documented so far. Bupiva-caine, a long acting anilide local analgesic, is approx-imately four times as potent as lignocaine and pro-vides longer duration of action at least twice as thatof lignocaine (Hall et al., 2001). However, the onsetof analgesia was delayed (20–30 min) as compared tolignocaine. In the present study also the onset of anal-gesia was relatively delayed in uremic goats comparedto healthy goats. It may be attributed to the delayeddrug absorption from the epidural venous sinuses in ure-mic goats as a result of the alkalinity of tissue (Hall etal., 2001). It might be possible that most of the anes-thetic drug (local anesthetics), here bupivacaine, mighthave remained ineffective because of the availability ofthe uncharged or ionized form in an alkaline environ-ment. Hence the drug might have not been sufficiently
absorbed in an alkaline environment through the venoussinuses and resulted in poor conduction blockade anddelayed onset of analgesia. Further, it could also beresponsible for the availability of more drugs in the
esearch 71 (2007) 13–20
free or unionized form which remained ineffective to beabsorbed and produce analgesia, and only lesser ionicconcentration of local anesthetic was available for theaction.
Accurate assessment of the depth of analgesia maysometimes be difficult and variation in results may occurin different species of animals. Response elicited to nox-ious stimuli (pinpricks) has been used for assessmentof analgesia (Amarpal et al., 1999). The method wasfound quite effective and simple in assessing the depthof analgesia at different sites in the present study. Bupi-vacaine produced complete analgesia of tail, perineum,inguinal region and upper hind limbs and mild to moder-ate analgesia of flank, thorax, digits and ventral abdomenin both groups. Local anesthetic agents injected epidu-rally block the spinal nerves distal to the dural sheath,after leaving the intervertebral foramina, and produce amultiple vertebral block (Buchholz and Koener, 1948);dura covered spinal roots within the spinal canal (Saekerand Gaida, 1995); dorsal root ganglia in the spinal canal(Frumin et al., 1953); the neurons (Bromage, 1952) andthe spinal cord after diffusion across the dura matter intothe subarachnoid space and spinal cord itself (Frey andSoehring, 1954). Epidural bupivacaine, in the presentstudy, may have produced analgesia by acting throughone or many of these sites and mechanisms. Prolongedanalgesia with epidural bupivacaine in cattle (Mishra etal., 1993) and complete loss of pain reflexes for variabletime intervals at tail, perineum, inguinal region, thigh anddigits in cattle (Gill et al., 1984) has also been reportedand are in accordance with the findings of the presentstudy.
Hypothermia recorded in the present study follow-ing epidural bupivacaine has also been reported in goats(Pathak, 1999; Singh, 2000), buffalo (Mishra et al., 1993)and calves (Singh, 1999). Fall in RT might be attributedto depression of the hypothalamic thermoregulatory cen-tre (MacDonald et al., 1988).
The values of Hb, PCV, TLC and different blood cellsfluctuated within normal physiological limits and there-fore, have no clinical significance as far as the effectof the bupivacaine on the hematopoitic system is con-cerned. Similar findings were also reported by Singh(1999) with epidural bupivacaine in goats. The effectof bupivacaine on different electrolytes such as Na+, K+,Cl− and Ca++ in uremic animals has not yet been studied.In the present study the effect of bupivacaine on theseparameters and the disturbance on Na+, K+, Cl− and
Ca++ metabolism were found to be transient in uremicor healthy goats. However, no reason could be ascribedto such changes as the values returned to base line as theeffect of the drugs weaned off.
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There was no significant increase in plasma creati-ine and PUN at different intervals in both groups. Thencrease in plasma creatinine and PUN in healthy goatsould be attributed to a temporary inhibitory effect ofupivacaine on the renal blood flow, which in turn mightave caused a rise in plasma creatinine and PUN. In ure-ic goats it could be due to urinary tract obstruction
eading to increased creatinine and PUN levels. Increasen creatinine and PUN during urethral obstruction haslso been reported in goats (Gera and Nigam, 1981) andlso after epidural administration in goats (Pathak, 1999;ingh, 2000). An increased hepatic urea production frommino acid degradation during anesthesia could accountor the observed increase in PUN values (Eichner et al.,979). However, the decrease in PUN values later on inremic goats could be due to the relieving of the urethralbstruction. The effect of bupivacaine on plasma glucosend total protein levels was temporary and transient. Thelucose and total protein values fluctuated near baselinehroughout the period of observation. The fluctuationsn the glucose and protein may be due to increased sym-athetic activity as a result of stress which may mediaten increased amount of glucose release from alpha cells.elative increase in plasma level of glucagons, as com-ared to insulin, is another factor which is associatedith gluconeogenesis and ureagenesis at the expense ofrotein synthesis leading to fluctuations in these parame-ers (Wilmore et al., 1976). In uremic and healthy goats,he epidural use of bupivacaine did not show any sig-ificant effect on pH, HCO3
−, BE, pCO2 , pO2 and SO2alues during the post injection period. The higher bicar-onate and base excess in uremic animals could be dueo alkalosis arising from urinary tract obstruction. Peshint al. (1993) also reported a higher base excess values inremic ruminants after epidural injection. The variationn acid base and blood gas parameters during the postnjection period was of little clinical significance. Thesehanges were however, transient in nature and becameormal as the effect of the combination weaned off.
. Conclusions
The results of the study suggested that bupivacaineroduced regional analgesia of sufficient depth to con-uct surgery in the perineal region (in this case, ure-hrotomy) in goats suffering from urethral obstruction.owever, bupivacaine produced delayed onset of anal-esia, shorter duration of analgesia and lesser ataxia in
remic animals than in healthy animals. Total leukocyteount, PUN and creatinine values were higher in uremicnimals than in healthy animals. The changes in thesearameters were, however, minimal and transient and
esearch 71 (2007) 13–20 19
became normal as the effect of the drug was over. There-fore, it was concluded that it is safe after its epiduraluse in uremic goats as far as its effects on clinicophysio-logical, hematological, biochemical, acid base and bloodgas parameters are concerned. Hence, bupivacaine (0.5%solution at 0.5 mg/kg) may be used in clinical situationsin uremic caprines and in the animals, which are undera similar type of physiological stress.
Acknowledgements
The authors are grateful to the ICAR and the Director,IVRI, for providing the necessary facilities to carry outthe research work.
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