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    Novel collagen-based wafers as a drug delivery method for local analgesia in deer antlers : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Sciences at Massey University, Manawatu, New Zealand
    (Massey University, 2021) Sahebjam, Farzin
    Introduction This study provided a practical and novel solution for post-operative pain mitigation and wound management after velvet antler removal in red deer (Cervus elaphus). Currently, there are no topical methods to mitigate pain for an extended period of time in deer following surgical removal of antlers. The current methods licensed in New Zealand provide only peri-operative analgesia with short-term effects and raise animal welfare concerns about whether animals are still in pain when the effect has worn off, especially in the deer industry in which a large number of animals are being managed. Materials and methods In vitro study: In vitro drug release test (IVDRT) was conducted using the Franz diffusion cell to assess the drug release rates of lidocaine and bupivacaine in two different phases of the pilot and main studies. The pilot in vitro study contained 9 treatment groups and 3 control groups (n=3), which were classified based on collagen extraction technique, whether modified with zinc oxide-polyvinylpyrrolidone (ZnO-PVP) nanoparticles and the difference in the order of adding local anaesthetics and ZnO-PVP nanoparticles. The main in vitro study was comprised of 4 treatment groups of 5%, 10%, and 25% ZnO-PVP nanoparticles (n=6) proportional to dry collagen weight and a control group. In both pilot and main in vitro studies, the samples were taken every 15 minutes in the first hour and every 2 hours up to 12 hours. LC-MS and HPLC were used for the quantification of the samples in the pilot and main in vitro studies, respectively. MNT validation study: Forty male deer (stags) were assigned for the MNT validation study on three alternative days. A handheld algometer (Wagner FPX50) was used for mechanical nociceptive threshold (MNT) assessment of four antler sites (cranial, medial, caudal, lateral) in both right and left antlers. Animal body weight (kg) and antler length (cm) were recorded to investigate the correlation with MNT. The MNT readings from three days were compared with each other. In addition, the MNT reading from all four antler sites and the right and left antlers were compared with each other. In vivo study: Eighteen stags sorted into three groups of 6 animals in each (2 treatment groups and 1 control group) for the pilot in vivo study, and forty yearling age stags assorted into four groups of 10 animals (three treatments and one control), were used in the main in vivo study. All animals had both antlers removed after administration of local anaesthesia. The control group in both pilot and main in vivo studies received a ring block of 4% articaine hydrochloride only, whilst the treatment groups received modified (with ZnO-PVP) or non-modified collagen composite wafers to the wound sites. The modified collagen composite wafers had 50% ZnO-PVP for the pilot in vivo study and had 0%, 5% or 25% ZnO-PVP proportional to dry collagen weight for the main in vivo study. A handheld algometer (Wagner FPX50), was used for mechanical nociceptive threshold (MNT) assessment at different time points (0, 4, 24, 72 hrs, 7 days and 14 days). Thermal imaging with a forward-looking infrared (FLIR) camera was performed for the detection of temperature differences between the groups. Digital photography of the wounds was performed for further quantitative wound healing analysis. Pharmacokinetic study: Blood samples were drawn from deer after the application of collagen composite wafers at time points t0, t1, t2, t4, t6, t8, t12, and t24 hours for the pilot study and at time points t0, t1, t2, t4, t6, t8, and t24 hours for the main in vivo study. The plasma was iv analysed with LC-MS to calculate pharmacokinetic parameters with the non-compartmental method such as Cmax, Tmax, AUC, AUMC, half-life, the volume of distribution and clearance. Statistical analysis: Higuchi model was mainly incorporated to calculate drug release rates for the in vitro studies. For in vivo studies, the statistical analyses were performed with a linear model for repeated measurements that accounted for the fixed effects of day, antler, location within antler or antler sites, antler length and weight of deer as covariates, and the random effect of animals. Results IVDRT did not show any statistically significant difference between the treatment groups; however, the treatment groups had significantly slower release compared to the control group in the pilot in vitro study. IVDRT in the main in vitro study showed the slowest release rate in the treatment group with 25% ZnO-PVP compared to the other groups for both lidocaine and bupivacaine. The control group had the most rapid drug release rates compared to the treatment groups, particularly for lidocaine. Furthermore, lidocaine showed a considerably slower release compared to bupivacaine when zinc oxide nanoparticles were incorporated, and the results significantly differed. MNT validation results showed that antler length (cm) and animal body weight (kg) are directly and positively correlated with the baseline MNT readings. The MNT readings from four sites of antlers, including cranial, medial, caudal and lateral aspects, did not have any significant difference from each other. In addition, the MNT readings from the right and left antlers did not show any significant difference from each other. In vivo results in the pilot study showed a lack of collagen composite wafer adherence for the non-modified wafers (PT2) and 50% adherence for the modified wafers (PT1) in the pilot study. As a result of the main in vivo study, 90%, 70%, and 45% were in group 25%NP (T1), 5%NP (T2), and 0%NP (T3) to the wounds, respectively. A significant difference was observed in the recovery rates of PT1 compared to the control group (P<0.0001) for the pilot study. For the main in vivo study, all three treatment groups also showed a significant difference compared to each other: T1 vs. T2 (P<0.01), T1 vs. T3 (P<0.05), and T2 vs. T3 (P<0.0001). In addition, the treatment groups showed a significantly slower recovery rate from analgesia compared to the control group (P<0.0001 for all). All the treatment groups in the main study demonstrated analgesia beyond 6 hrs and up to 10 hrs. The pharmacokinetics study showed significantly smaller Cmax for T1 and T2 compared to T3 only for bupivacaine. Tmax showed significantly smaller values for T1 compared to T2 for only bupivacaine. Both AUC (0-24), AUC (0-∞), and AUMC (0-∞) showed smaller values for T1 and T2 compared to T3. Conclusion The physically modified collagen composite wafer with zinc oxide-PVP nanoparticles, containing a short-acting (lidocaine) and a long-acting (bupivacaine) local anaesthetic, is a novel method to sustain drug delivery of local anaesthetics after the surgical removal of velvet antlers. Our suggested treatment can deliver analgesia to the wounded antler for up to 10 hours and is a safe and convenient method to use by farmers in the deer industry. Furthermore, the collagen wafer is very adhesive to the wound and can help facilitate wound healing of deer antlers.
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    Effects of general anaesthesia and intravenous fluid therapy on renal biomarkers in cats undergoing ovariohysterectomy : a thesis presented in partial fulfilment of the requirements for the degree of Master of Veterinary Science at Massey University, Manawatu, New Zealand
    (Massey University, 2022) Valsan, Sruthi
    Traditional screening tests used to evaluate renal function have been demonstrated to be insensitive in detecting early kidney damage, such as subclinical acute kidney injury. It is probable that general anaesthesia and routinely performed surgical procedures could cause subclinical changes in the renal structure, predisposing the animal to subsequent functional impairment. However, these active changes might go undetected while screening using traditional renal markers, such as serum creatinine (SCr) and blood urea nitrogen (BUN). Novel urinary biomarkers, that indicate renal injury earlier than conventional markers, have been extensively studied in humans during the perioperative period. A feline model of mild acute kidney injury, potentially induced through general anaesthesia during routine surgeries, may prove useful in testing novel renal biomarkers and providing insight into the effects of anaesthesia on kidneys. A randomised controlled trial was performed using 60 healthy cats presented to the Massey University Veterinary Teaching Hospital for routine ovariohysterectomy. Blood and urine samples were collected immediately before (0 h), and after (24 and 48 h) anaesthesia and spay surgery. Traditional renal marker levels (SCr, BUN) were measured from the serum samples. Commercial assays were used to detect the levels of novel markers, such as N-acetyl-β-D glucosaminidase (NAG) enzyme, Neutrophil Gelatinase-associated Lipocalin (NGAL), Retinol Binding Protein (RBP) and Kidney Injury Molecule-1 (KIM-1), in the urine samples. This study aimed to use these urinary markers to investigate the effects of general anaesthesia and intraoperative fluid therapy on feline renal structure. Statistical tests such as t-test and ANOVA were conducted to establish differences in renal marker values between the time points and between treatment groups. Upon comparing the changes in renal marker concentrations, the study found no measurable evidence of structural or functional kidney damage in the cats. This is plausible since the vital parameters, such as arterial blood pressure and oxygenation levels, of the study cats were maintained within or near the borderline physiological range throughout the surgical procedure, resulting in the apparent absence of assessable kidney damage postoperatively. It is inferred that a more severe form of renal injury would be required to test the sensitivity of these novel renal markers in cats.
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    Perioperative fluid administration to optimise haemodynamics without fluid overload in anaesthetised dogs : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Science at Massey University, Manawatu, New Zealand
    (Massey University, 2021) Sano, Hiroki
    Perioperative fluid therapy is the mainstay of anaesthetic management. Fluid administration improves haemodynamics during anaesthesia as it increases preload and thus cardiac output and blood pressure. However, excessive fluid administration can cause detrimental adverse effects, such as haemodulution and oedema, resulting in prolonged hospital stay and increased morbidity and mortality in people. Therefore, fluid administration should be restricted to those who are able to increase stroke volume or cardiac output in response to the fluid administration (responders) and should not be given to those who are unable to do so (non-responders) based on the famous “Frank–Starling law of the heart” Previously static parameters such as central venous pressure were believed to be a clinical gold standard to estimate preload and fluid responsiveness. Over the last decade, dynamic parameters such as pulse pressure variation and pleth variability index have been shown to be reliable predictors for fluid responsiveness in people. This study found that pulse pressure variation and pleth variability index were more accurate than central venous pressure for predicting fluid responsiveness in dogs. Mini-fluid challenge is another technique that is currently available and can be reliably used to determine fluid responsiveness in human medicine. Mini-fluid challenge is an administration of a small amount of fluid to increase preload. Thus, fluid responsiveness can be assessed based on whether stroke volume increases following mini-fluid challenge according to the Frank-Starling curve. The change in stroke volume of a heart at the steep portion of the Frank-Starling curve will be greater than at the plateau portion after mini-fluid challenge. The studies revealed a percentage change in pulse wave transit time (a surrogate parameter of stroke volume, which was also one of results in this thesis) following mini-fluid challenge could predict fluid responsiveness in mechanically ventilated anaesthetised dogs under an experimental condition, and spontaneously breathing anaesthetised dogs undergoing stifle surgery in clinical setting. Lastly, these methods are still of limited use in veterinary clinical practice because of availability of equipment, difficulty of their interpretation and a cumbersome process. The main purpose of this thesis was to obtain evidence on how to optimise haemodynamics in anaesthetised dogs and prevent excessive fluid administration. The time when most practitioners administer a bolus of fluid during anaesthesia is when hypotension is encountered because of anaesthesia. Thus, prevention of hypotension could avoid excessive fluid administration. Therefore, the study found that prophylactic noradrenaline administration, which counteracts some of the cardiovascular adverse effects of anaesthesia, was able to prevent hypotension, and thus minimise fluid administration in anaesthetised dogs. Although all of these methods tested in this thesis have pros and cons in clinical veterinary practice, they were shown to be able to optimise haemodynamics without fluid overload in anaesthetised dogs.
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    The minimal anaesthesia model : development and refinement of the concept and subsequent practical applications : a collection of papers and a monograph presented in application for the degree of Doctor of Science at Massey University, Manawatu
    (Massey University, 2020) Johnson, Craig
    The research presented in this thesis represents both my development of the minimal anaesthesia model and its application in a number of theoretical and applied areas of animal welfare science. The use of this methodology, especially when combined with other techniques such as behavioural analysis, has proven to be a very powerful way to investigate the perception of noxious stimuli. In particular it enables clear links between physical responses and the underlying affective state of the animal to be made. These links have both expanded our understanding of the development and mechanisms of pain perception in the central nervous system of mammals and also enabled the extent to which animal husbandry procedures such as castration, tail docking and killing are painful to be measured. These latter applied studies have been used as the basis for significant changes to the ways in which painful procedures are carried out. They have contributed to new ways of providing pain relief in a variety of contexts and to changing legislation to ensure that pain relief is used in practice.
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    Comparative assessment of physiological homeostasis in zoo mammals under general anaesthesia : a thesis presented in partial fulfilment of the requirements for the degree of Master of Veterinary Science in Wildlife Health at Massey University, Palmerston North, Manawatū, New Zealand
    (Massey University, 2020) Dougherty, Nigel
    During the anaesthesia of dangerous zoo animals, additional anaesthetic risks to patients arise from precautions required to assure human safety. Evaluating the safety of anaesthetic approaches for these animals is not straightforward, with challenges associated with identifying disturbances to physiological homeostasis, attributing these disturbances to particular interventions and relating them to morbidity endpoints. In zoo animal anaesthesia, more reliance is necessarily placed on observational studies to quantify risks related to immobilisation regimens and to refine and improve the ways anaesthesia is subsequently delivered. This study applied an opportunistic approach, using readily accessible monitoring methods to investigate general changes to physiological homeostasis occurring under zoo anaesthesia in twenty-six individuals. This included comparative analysis of nine large mammal species, of diverse phylogeny and dietary ecology. In eleven large felids representing three different Felidae species included in the study, assessment was then undertaken of changes in metabolic acid-base status, the contribution of anions that are not normally measured to these changes and their possible association with mean arterial blood pressure preceding blood sampling episodes. Strong evidence was found for time effects during anaesthesia on a variety of the measures of homeostasis that were monitored. Within the broad species ranges that were apparent in the homeostatic parameters measured, many unexpected findings were manifest in the way that different species and/or different conspecific individuals responded to anaesthesia. Within a species, differences were sometimes apparent in spite of relatively minor variations in the immobilisation protocols used, as was evident within the Panthera genus. Clinically significant alterations noted included blood pressure changes, changes to ventilation, possible ventilation-perfusion mismatches, alterations in acid-base status and occasional but concerning instances of acidaemia, hypoglycaemia, hypoxaemia and hyperkalaemia. All animals survived anaesthesia and did not show any apparent morbidity, limiting our ability to determine the pathological effects, if any, of the changes seen. Based on extrapolations from other mammals, some disturbances may have caused pathology or mortality if they had become more sustained or progressive. Extracellular (blood) base deficits exceeding -7mmol/L were common in the anaesthetised large felids, suggesting that these animals commonly displayed a state of metabolic acidosis under anaesthesia based on proposed definitions from domestic felids. However, there were marked species differences in acid-base status under anaesthesia, and further analysis showed that the drivers of the changes also varied between species. Although strong cautionary caveats are associated with the low power of the analysis, the findings suggest that inter-species extrapolations of acid-base physiology will be flawed, indicating a strong need for readily accessible species-specific reference ranges. There was no evidence for an association between strong ion gap and mean arterial pressure, but blood pressure was actively managed in most of the anaesthetics which may have confounded these results. Further study of tissue perfusion states than those provided by mean arterial blood pressure will be required to evaluate if a relationship exists between strong ion gap levels and corresponding states of blood flow in zoo animal anaesthesia. Nevertheless, this study has demonstrated that strategic point of care clinical pathology tests and blood gas analysis provide practical opportunities to minimise and even prevent many physiological changes, with the potential to diminish risk to patients without placing human safety at additional risk.
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    Analgesic efficacy and pharmacokinetics of combinations of morphine, dexmedetomidine and maropitant in dogs : a thesis presented in partial fulfilment of the requirement for the degree of Doctor of Philosophy at Massey University, Palmerston North, New Zealand
    (Massey University, 2020) Karna, Sandeep Raj
    Multimodal analgesia is gaining popularity in veterinary medicine. It is an approach that involves the administration of two or three classes of analgesic drugs with different modes of actions to enhance the analgesic effects and lower the adverse effects associated with high dose of a single drug. In a series of experiments conducted in this thesis, the combinations of morphine, dexmedetomidine and maropitant were evaluated using different pain models with the aim of using them in a multimodal strategy in dogs undergoing ovariohysterectomy or other surgical procedures. Firstly, a pilot study evaluating the efficacy of combinations of the test drugs was performed using a hot-plate test and tail-flick test in rats. The combination of morphine and maropitant showed a significantly higher (p < 0.0001) tail-flick latency compared to all other treatment groups indicating a supra-additive effect of spinal analgesia between morphine and maropitant. A pharmacokinetic study to investigate the disposition of the test drug combinations after intramuscular (IM) administration in dogs under anaesthesia was conducted. The results showed that the elimination half-life of morphine was higher and the clearance rate was lower when combined with dexmedetomidine compared to morphine and maropitant combination or morphine alone at higher doses. This effect may have a clinical advantage of prolonging the dosing interval of morphine. A study to evaluate and compare the analgesic efficacy of the combination of morphine, dexmedetomidine and maropitant in dogs undergoing ovariohysterectomy was conducted. The study showed that dogs receiving the combination of morphine and dexmedetomidine had significantly lower (p < 0.05) pain scores, obtained by the short form of the Glasgow composite measure pain scale and visual analogue pain scale, in the postoperative period. All dogs that received dexmedetomidine showed arrhythmia and second-degree heart block immediately after IM administration. Finally, the efficacy of the test drug combinations was evaluated using changes in electroencephalographic indices of nociception (median frequency, spectral edge frequency and total power) in anaesthetised dogs subjected to a noxious electrical stimulus. The combination of morphine and dexmedetomidine showed a significantly lower change in the post stimulation median and spectral edge frequencies compared to all other treatment groups. The dogs receiving dexmedetomidine also demonstrated arrhythmia and second-degree heart block. In conclusion, the combination of morphine and dexmedetomidine showed a superior analgesic effect compared to morphine alone at higher dose and appeared to be the most effective combination among other combinations of morphine, dexmedetomidine and maropitant. The cardiovascular changes produced by the test drugs may be clinically insignificant in fit and healthy dogs. In future, the efficacy of the combination of morphine, dexmedetomidine and maropitant at other different doses rates and ratios should also be evaluated.