The potential of midazolam for use as a sedative for blesbok (Damaliscus pygargus phillipsi)

Du Plessis, Dianca (2018-03)

Thesis (MScAgric)--Stellenbosch University, 2018.

Thesis

ENGLISH ABSTRACT: Wildlife translocation results in stress in the animals, which impacts negatively on their welfare. Midazolam is used as a sedative in domestic species, with minimal cardiopulmonary side effects. Midazolam’s effects in wildlife has not yet been determined. This study aimed to evaluate midazolam as a sedative in blesbok. The first phase of the overall study entailed a pilot study using indigenous goats to determine the pharmacokinetic behavior of midazolam. Blood samples were collected at set time intervals following intramuscular (IM) midazolam administration in the goats. Resulting serum samples were analysed by means of gas chromatography-mass spectrophotometry, and a concentration-time profile of IM midazolam was compiled. Calculation of the pharmacokinetic parameters of midazolam indicated that it took approximately 36 min to reach a maximum serum concentration of 127.3 ng/L. Midazolam had a poor bioavailability and a relatively short elimination half-life. In the second part of the study, the EquivitalTM EQ02 biotelemetry system was validated for use in blesbok. On the first day of the validation study, two blesbok were immobilised, fitted with a biotelemetry belt, and translocated to a laboratory. The heart and respiration rate of each animal were individually recorded for 20 min using the EquivitalTM system, a Cardell® monitor and a manual recording method. The accuracy of the EquivitalTM system in detecting changes in heart and respiration rate caused by adrenaline and Dopram® administration respectively, was also assessed. After 20 min of recording, the animals were returned to the enclosure and the anaesthetic was reversed. The EquivitalTM system remained on the animals for an additional 24 hrs to determine its accuracy in measuring physiological parameters and motion changes of conscious blesbok in captivity. After this 24 hr period, the experimental procedure was repeated. The agreement of the EquivitalTM system with the Cardell® and the manual method for heart rate was moderate to excellent, while the agreement for respiration rate was poor to moderate. The EquivitalTM system was accurate in measuring heart rate and detecting increases in heart rate resulting from adrenaline administration, but failed to accurately measure respiration rate and detect changes caused by Dopram®. The EquivitalTM system successfully measured heart rate and motion changes of conscious blesbok in captivity. In the third part of the study, the effect of three midazolam doses on behaviour, feed intake, heart rate, respiration rate, motion, and level of sedation in blesbok were studied. Four trials were conducted to establish the effect of four different dosages, i.e. a placebo, 0.6 mg midazolam/kg body weight (BWt), 0.4 mg midazolam/kg BWt or 0.2 mg midazolam/kg BWt. After immobilisation, the animals were fitted with the EquivitalTM biotelemetry belts. After reversal of the anaesthetic, the specific dose was administered intramuscularly. Blesbok behaviour was recorded for 12 hrs using a CCTV system. The animals were stimulated and scored for sedation and response to stimulus for the first six hours after midazolam administration. After an observation period of 24 hours, the animals were immobilised, the belts removed and the anaesthetic reversed. To determine the effects of midazolam on feed intake, the feed was weighed at the start of each trial and the end of each trial. Midazolam suppressed vigilance in blesbok. The lowest dose of midazolam decreased walking in blesbok, and increased standing and ruminating behaviour. Heart rate and respiration were decreased by the low dose when the animals were showing vigilance and trotting in alarm. The low dose did not affect heart rate and respiration when the animals were stimulated, but decreased both these parameters when the animals were not stimulated. The medium dose increased standing and ruminating behaviour, while it caused slower heart rate when the animals showed vigilance, trotting in alarm and avoidance. The high dose reduced grooming and agitation, increased walking and reduced standing and ruminating behaviour in blesbok. The high dose elevated the respiration rate of blesbok. Midazolam increased fast motion in stimulated blesbok. The low dose decreased motion in unstimulated blesbok. Midazolam treated via the IM route caused moderate sedation in blesbok. Midazolam decreased the response to stimulus of blesbok. The medium dose caused the least responsiveness to stimulation. Midazolam caused an increase in feed intake in blesbok. In conclusion, a dose of 0.2 mg midazolam/kg BWt was most effective in sedating blesbok without side effects and doses of 0.6 mg midazolam/kg BWt and higher should not be used on its own in blesbok to prevent the occurrence of extrapyramidal effects and severe ataxia. Higher doses of midazolam should rather be used in as adjuvants to anaesthetic immobilisation protocols in wild ungulates, but requires further research.

AFRIKAANSE OPSOMMING: Die verskuiwing en aanhouding van wild belemmer dierewelsyn omdat dit stres veroorsaak. Midazolam is 'n doeltreffende kalmeermiddel vir plaasdiere, met minimale newe-effekte op die kardiopulmonêre stelsel, maar die effek daarvan in wild is nog nie bepaal nie. Hierdie studie het gepoog om midazolam te evalueer as 'n kalmeermiddel in blesbokke. ‘n Loodsstudie is eerstens in inheemse bokke gedoen om midazolam se farmakokinetiese gedrag te bepaal. Bloedmonsters is per tydsinterval versamel na intramuskulêre behandeling van die bokke met midazolam en gesentrifugeer. Die serum vanaf die bloedmonsters is geanaliseer met gas kromatografie massa spektrometrie en ‘n konsentrasie-tyd grafiek is getrek. Berekening van midazolam se farmakokinetiese parameters het getoon dat dit ongeveer 36 min geneem het om ‘n maksimum serum konsentrasie van 127.3 ng/L te bereik. Midazolam se biobeskikbaarheid was laag en die eliminasie halfleeftyd was relatief kort. In die tweede deel van die studie is die EquivitalTM EQ02 biotelemetrie stelsel gevalideer vir gebruik in blesbokke. Op die eerste dag is twee blesbokke onder narkose geplaas, toegerus met 'n biotelemetrie belt en na 'n laboratorium gedra. Hartklop en asemhalings tempo van altwee diere is afsonderlik vir 20 min gemeet met die EquivitalTM stelsel, 'n Cardell® monitor en per hand. Die akkuraatheid van die EquivitalTM sisteem om veranderinge in hartklop en asemhaling tempo op te tel wat veroorsaak is deur adrenalien en Dopram® onderskeidelik, is ook bepaal. Na 20 min se data per dier versamel is, is hul terug geneem na die boma en die narkose is omgekeer. Die biotelemetrie belde is op die diere gelos vir nog 24 uur om die akkuraatheid daarvan in die meet van hart en asemhalings tempo veranderings, asook veranderinge in die beweging van die diere by hul volle bewussyn in aanhouding te bepaal. Na hierdie 24 uur is die eksperimentele prosedure herhaal. Die verwantskap van die EquivitalTM sisteem met die Cardell® en die per hand metode was middelmatig tot uitstekend vir hart tempo, maar die verwantskap vir asemhalings tempo was swak tot middelmatig. Die EquivitalTM stelsel was akkuraat in die meet van hartklop en hartklop stygings veroorsaak deur adrenalien behandeling, maar was onsuksesvol daarin om asemhalingstempo en veranderinge aangebring deur Dopram® akkuraat te meet. Die EquivitalTM sisteem was suksesvol in die meet van hartklop en veranderinge in beweging van blesbokke by hul volle bewussyn in aanhouding. In die derde deel van die studie is die effek van drie midazolam dosisse op die gedrag, voerinname, hartklop, asemhalings tempo en beweging, asook die vlak van verdowing in blesbokke bepaal. Vier proewe is gedoen om die effek van vier verskillende behandelings, naamlik 'n plasebo, 0.6 mg midazolam/kg liggaamsmassa, 0.4 mg midazolam/kg liggaamsmassa en 0.2 mg midazolam/kg liggaamsmassa, te bepaal. Nadat hulle onder narkose geplaas is, is elke dier toegerus met 'n EquivitalTM biotelemetrie belt. Nadat die narkose omgekeer is, is die spesifieke behandeling binnespiers toegedien. Die gedrag van die diere is opgeneem met CCTV vir 12 ure. Die diere is gestimuleer en tellings vir verdowingsvlak en reaksie tot stimulasie is toegeken vir die eerste ses ure. Die diere is 24 uur na behandeling weer onder narkose geplaas, die belde is verwyder en die narkose omgekeer. Om midazolam se effek op voerinname te bepaal is die voer aan die begin van elke proef en die voer aan die einde van elke proef geweeg. Midazolam het waaksaamheid in die blesbokke laat afneem. Die laagste dosis het veroorsaak dat die blesbokke minder rondloop en meer staan en herkou. Hartklop en asemhalings tempo is deur die lae dosis verlaag gedurende die toon van waaksaamheid en vlug gedrag in die belsbokke. Die lae dosis het geen effek gehad op die diere se hart en asemhalings tempo tydens stimulasies nie, maar het beide hierdie parameters verlaag toe die diere nie gestimuleer is nie. Die medium dosis het staan en herkou gedrag verhoog en hart tempo gedurende waaksaamheid, vlug gedrag en vermyding verlaag. Die hoë dosis het “grooming” en “agitation” verminder, loop gedrag verhoog en staan en herkou gedrag in blesbokke verminder. Die asemhalings tempo van blesbokke is deur die hoë dosis verhoog. Midazolam het vinnige beweging in blesbokke tydens stimulasies verhoog. Die lae dosis het beweging in blesbokke tydens tye van geen stimulasie verminder. ’n Midazolam dosis van 0.2 mg/kg liggaamsmassa was dus mees suksesvol daarin om blesbokke te verdoof sonder om ongewenste newe effekte te veroorsaak. Binnespierse midazolam het matige verdowing in blesbokke veroorsaak. Midazolam het die intensiteit van blesbokke se reaksie op stimulasie verminder. Die medium dosis het die reaksie tot stimulus die meeste verlaag. Midazolam het voerinname in blesbokke laat toeneem. Ten slotte, ’n dosis van 0.2 mg midazolam/kg liggaamsmassa was mees suksesvol daarin om blesbokke te verdoof sonder om ongewenste newe effekte te veroorsaak. Die gebruik van 0.6 mg midazolam/kg liggaamsmaasa dosisse en hoër word nie aanbeveel in blesbokke nie, om die voorkoms van ekstrapyramidale simptome en erge ataksie te verhoed. Hoë dosisse van midazolam moet eerder saam met narkose middels gebruik word as deel van immobiliserings protokolle in wilde boksoorte, maar dit verg verdere navorsing.

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