A dose characterization study evaluating the pharmacodynamics and safety of a concentrated alfaxalone solution (4%) as an intramuscular sedative in dogs.

Alfaxalone is a commonly employed veterinary anaesthetic induction and sedation agent. A 4% w/v preserved, aqueous formulation of alfaxalone 'RD0387' (A4%) has recently been developed. To evaluate the sedative effects of A4%, three doses, 5 mg kg-1 (A5); 7.5 mg kg-1 (A7.5) and 10 mg kg-1 (A10) were administered intramuscularly into the epaxial musculature of six healthy adult mixed-breed dogs in an experimental, randomized, blinded, crossover study. Sedation time variables, quality of sedation (including onset of sedation and recovery), physiological variables, response to cephalic vein catheterization and frequency of undesirable events were recorded. Continuous variables were analysed between treatments (one-way ANOVA or restricted maximum likelihood modelling) and within treatments compared with baseline (Tukey's test). Categorical data were analysed between treatments (Kruskal-Wallis' test) and within treatments from baseline (Dunn's test). Significance was set at p < .05. All dogs became sedated (laterally recumbent) and sedation onset was significantly faster in groups A7.5 (9.8 ± 5.3 min) and A10 (9.1 ± 5.6 min) compared to A5 (25.6 ± 16.1 min) (p = .033, p = .027, respectively). Duration of sedation was significantly longer in A10 (168.5 ± 70.6 min) and A7.5 (143.8 ± 58 min) compared to A5 (63.8 ± 28.2 min) (p = .005 and p = .003, respectively). Dogs in A10 had a superior quality of onset of sedation compared to A5 (p = .028). Sedation scores and quality of recovery from sedation were not significantly different between doses. Two dogs (2/6) in A5 were insufficiently sedated for cephalic catheterization. Ataxia was the most frequently observed undesirable event with an overall frequency of 78% (14/18) and 89% (16/18) during sedation onset and recovery, respectively. Overall, A4% administered IM in dogs at 7.5 and 10 mg kg-1 resulted in sufficient sedation for IV catheterization in dogs. To improve the speed and quality of the sedation, it is recommended that future research focuses on combining A4% with other sedative or analgesic drugs.

Comparison of sublingual microcirculatory parameters measured by sidestream darkfield videomicroscopy in anesthetized pigs and adult humans.

BACKGROUND: This study aimed to compare sublingual microcirculatory parameters between anesthetized pigs and conscious adult humans using sidestream darkfield videomicroscopy. The overarching aim of the work was to validate the pig as an experimental model of changes in microcirculatory function following traumatic haemorrhagic shock and resuscitation. METHODS: Fourteen large white pigs and 14 humans were recruited for the study. Sublingual sidestream darkfield videomicroscopy clips were captured in anesthetized pigs and conscious humans. Clips underwent manual analysis in Automated Vascular Analysis 3.2 software. The total vessel density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPVs) and microvascular flow index (MFI) were quantified. An independent samples t test was used for between species comparison of microcirculatory parameters. RESULTS AND CONCLUSIONS: Conscious humans had a significantly lower TVD, PVD and MFI than anesthetized pigs. No significant difference in PPVs was observed between the species. Perfusion of the microcirculation is a critical determinant of tissue metabolic function and viability. Whilst it may not be surprising that some interspecies differences in the sublingual microcirculatory anatomy were identified between pig and human subjects, it is interesting to report the insignificant difference in PPVs. This direct microcirculatory measure represents a relative change which should hold translatable value across species. We therefore conclude the pig is a suitable model for microcirculatory research and may be a suitable species to investigate changes in microcirculatory perfusion following perturbations in cardiovascular homeostasis, for example during traumatic haemorrhagic shock and resuscitation.

Pre-hospital emergency cricothyrotomy in dogs part 2: Airway sealing and ventilation using cricothyrotomy tubes.

Cricothyrotomy (CTT) has been recommended for use in the pre-hospital setting for military working dogs and Operational K9s during airway emergencies. Although the CTT can establish a patent airway for spontaneous ventilation, the ability to seal the airway and provide positive pressure ventilation (PPV) using tubes designed for humans has not been determined. Using various CTT tubes placed in cadaver dog airways, this study aimed to determine: (1) Whether the tube cuff could create a functional airway seal with safe intra-cuff pressures; (2) The magnitude of delivered tidal volume (TV) loss during a standard breath to assess the possibility of delivering an adequate tidal volume with a bag-valve device (BVM); (3) The best performing tubes for either test; (4) The reasons behind the findings using observations from upper airway endoscopy, dissection, and measurements. Cadaver dogs of similar weights to MWD and Operational K9 breeds had various CTT tubes placed including three from commercial kits, a standard endotracheal tube, and a tracheostomy tube. The minimum occlusive volume technique was used to inflate the tube cuff and a pressure ≤ 48 cm H2O with an adequate seal was considered successful. Individual TVs were calculated for each dog and added to the volume lost during delivery of a standard breath from an ICU ventilator. Endoscopy and airway dissection were performed to assess the relationship between tubes cuffs and the airway. The tubes from the CTT kits performed poorly with regards to producing an airway seal with the H&H tube failing to seal the airway all tests. Tracheal dimensions were significantly associated with successful airway sealing (P = 0.0004). Tidal volume loss could be compensated using a BVM in 34/35 tests with the H&H tube in cadaver 8 the only to fail. Tracheal airway sealing is influenced by airway anatomy when tube cuffs are inflated to a target pressure and larger tubes do not always provide a better seal. The CTT tubes tested have the potential to facilitate ventilation with a BVM under the conditions set in this study. The 8.0 mm endotracheal tube performed the best and the H&H the worst in both tests.

Adverse Reaction Following the Subarachnoid Injection of Xylazine in a Sheep.

Alpha2 receptor agonists are frequently used to provide sedation and analgesia in sheep. There are numerous reports of adverse pulmonary effects following intravenous (IV) injection; however, adverse effects following subarachnoid injection (SAI) are underreported. An adult Merino wether was one of eighteen animals anaesthetised during an experimental trial modelling intervertebral disc injury. The animal was premedicated with methadone 0.1 mg/kg and midazolam 0.3 mg/kg IV. Anaesthesia was induced using alfaxalone IV and it was maintained using isoflurane, delivered in 100% oxygen by controlled mechanical ventilation. An SAI of xylazine 0.05 mg/kg diluted to 1 mL with 0.9% saline was performed at the lumbosacral site prior to recovery. This resulted in rapid narcosis, oxygen dependency and ventilatory compromise. Treatment with frusemide 1 mg/kg IV and salbutamol 0.2 mg inhaled did not attenuate the adverse cardiopulmonary effects. A rapid improvement in all physiological variables was seen following high dose atipamezole 0.05 mg/kg IV. This case report adds to the current knowledge regarding the risk for potential side effects when using alpha2 receptor agonists, such as xylazine, for the sedation or regional analgesia in sheep.

Long duration anaesthesia in pigs with an infusion of alfaxalone and dexmedetomidine.

Pigs are commonly maintained on total intravenous anaesthesia when used in comparative medical research to study controlled manual ventilation of the lung. In this case study, four pigs were anaesthetised with a total intravenous anaesthetic infusion of alfaxalone and dexmedetomidine for up to 24 h whilst being mechanically ventilated. Cardiovascular parameters, blood gas values and body temperature were minimally affected throughout the anaesthetic period. Additional analgesia is recommended when utilising this drug combination for procedures that involve noxious stimuli.

Comparison of two formulations of alfaxalone for immersion anaesthesia in laboratory zebrafish (Daniorerio).

OBJECTIVE: To compare two commercial formulations of alfaxalone for immersion anaesthesia in laboratory zebrafish. STUDY DESIGN: Prospective, blinded, randomized study. ANIMALS: A total of 20 adult Danio rerio (Tuebingen strain). METHODS: Zebrafish were divided into two groups of 10 (five female, five male) and placed in individual immersion baths containing 10 mg L-1 of unpreserved alfaxalone (group 1) or preserved alfaxalone (group 2). Anaesthetists blinded to treatment used a composite score scale (CSS) (range 0-12) to assess fish every 30 seconds until induction of anaesthesia. Anaesthetic induction occurred when equilibrium and response to stimulus were lost. Fish were then placed in a clean water bath and scored every 60 seconds. Recovery from anaesthesia was defined as a CSS of ≤ 1. Time variables recorded were anaesthetic induction time (AIT), anaesthetic recovery time (ART) and total procedure time (TPT). Fish were observed for evidence of roupgross external pathology during the procedure. Following anaesthesia, four fish from each group were randomly chosen and euthanized for gill histopathology analysis immediately after recovery criteria were met. Data are presented as mean ± standard deviation. An independent t test was used to compare the difference in average anaesthetic time variables between groups (α = 0.05). RESULTS: There were no statistical differences between groups in reported variables. TPT, AIT and ART were 10.2 ± 1.2, 1.9 ± 0.9 and 8.3 ± 1.2 minutes for group 1 and 10.8 ± 2.9, 2.4 ± 1.2 and 8.4 ± 2.7 minutes for group 2. No gross external pathology was evident, and no fish died during the experimental period. Histopathology showed normal gill pathology and no difference between the groups. CONCLUSIONS AND CLINICAL RELEVANCE: Immersion anaesthesia using 10 mg L-1 of either formulation of alfaxalone resulted in anaesthesia of similar quality and duration.

A Proposed Guideline for Performance of Emergency Surgical Airways in Small Animals: Analysis of Five Unsuccessfully Managed Cannot Intubate, Cannot Oxygenate Cases.

Objective-To describe three dogs and two cats diagnosed with a cannot intubate, cannot oxygenate (CICO) condition, and discuss the appropriateness and timing of emergency front-of-neck airway access (eFONA). The authors aim to increase awareness of CICO events and effective management strategies, which may result in faster airway access and improve patient outcomes. Case series summary-Three dogs and two cats could not be easily intubated resulting in the inability to deliver oxygen and contributing to their death. Emergency front-of-neck airway access was attempted in three cases, it could not be performed in one when indicated, and it was not considered in managing another. Conclusions-This is the first report of small animals suffering CICO emergencies and tracheostomy attempts without a concurrently secured airway. Cannot intubate, cannot oxygenate events and eFONA attempts were managed sub-optimally in all cases, which likely contributed to the poor outcomes. Rapid diagnosis of CICO and early eFONA using appropriate techniques has the potential to improve the management of difficult airways in small animals.

Bias Associated with Peripheral Non-Invasive Compared to Invasive Arterial Blood Pressure Monitoring in Healthy Anaesthetised and Standing Horses Using the Bionet BM7Vet.

To compare arterial blood pressure (ABP) measured invasively (IBP) to ABP measured non-invasively (NIBP) via oscillometry in healthy anaesthetised and standing horses using the Bionet BM7Vet. Fourteen horses were anaesthetised for elective procedures (anaesthetised group) and 10 horses were enrolled for standing blood pressure manipulation (standing group). In both groups, IBP and NIBP-corrected to heart level were measured every 3 min using the Bionet BM7Vet. The overall mean difference (bias), standard deviation and limits of agreement (LOA) were calculated for paired IBP and NIBP systolic (SAP), mean (MAP) and diastolic (DAP) blood pressure measurements. In anaesthetised horses, the NIBP cuff was placed at either the proximal tail base or the metacarpus. Invasive MAP was used to retrospectively characterise measurements into hypotensive (≤70 mm Hg), normotensive (71-110 mm Hg) or hypertensive (≥111 mm Hg) subgroups. In standing horses, the NIBP cuff was placed at the tail base only and invasive MAP was manipulated to achieve hypertension (≥126 mm Hg) and hypotension (≤90 mm Hg) using phenylephrine and acepromazine, respectively. When measuring NIBP at the tail in anaesthetised horses, the Bionet BM7Vet failed on 8/185 occasions and overestimated SAP, MAP and DAP during hypotension and normotension. The biases (lower, upper LOA) for MAP were -11.4 (-33.3, 10.5) and -6.0 (-25.8, 13.8) mm Hg, respectively. Hypertension could not be evaluated. When measuring NIBP at the metacarpus in anaesthetised horses, the Bionet BM7Vet failed on 24/65 occasions and underestimated SAP, MAP and DAP when all ABP subgroups were combined. The bias (lower, upper LOA) for pooled MAP was 3.6 (-44.3, 51.6) mm Hg. When measuring NIBP at the tail in standing horses, the Bionet BM7Vet failed on 64/268 occasions and underestimated SAP, MAP and DAP during hypotension, normotension and hypertension. The biases (lower, upper LOA) for MAP were 16.3 (-10.5, 43.1), 16.6 (-19.5, 52.7) and 30.0 (-8.1, 68.0) mm Hg, respectively. Monitoring NIBP on the Bionet BM7Vet in anaesthetised horses overestimated ABP at the tail and underestimated ABP at the metacarpus. The device inaccurately detected hypotension and should be used cautiously. In standing horses, the Bionet BM7Vet underestimated ABP at the tail, especially during pharmacologically induced hypertension.

Measurement of Tissue Oximetry in Standing Unsedated and Sedated Horses.

Near infrared spectroscopy (NIRS) noninvasively measures peripheral tissue oxygen saturation (StO2) and may be useful to detect early changes in StO2 in anaesthetized and critically ill horses. This study aimed to identify the muscle belly that provided the highest percentage of successful StO2 readings and the highest mean StO2 value. Fifty adult horses were enrolled in a prospective controlled study. StO2 was measured at six different muscles in each horse, for each intervention: hair overlying the muscle was clipped (post clipping: PC), clipped skin was cleaned with chlorhexidine (post-surgical prepping: PP) and medetomidine was administered intravenously (post medetomidine: PM). Mean StO2 values were calculated for each muscle, and a linear effects model was used to assess the effect of muscle group and intervention on StO2. The sartorius muscle gave the highest percentage of successful StO2 values (p < 0.001) and the highest mean (90% CI) StO2 values for the PC, PP and PM interventions. Surgical prepping of the skin increased the success for measurement of StO2 values. For all muscles, administration of medetomidine was associated with lower StO2 values (p < 0.001). In conclusion, of the muscles examined, the sartorius muscle may be the preferred muscle to measure StO2 in horses, and clipping and cleaning of the probe placement site is recommended.

Total Intravenous Anaesthesia with Ketamine, Medetomidine and Midazolam as Part of a Balanced Anaesthesia Technique in Horses Undergoing Castration.

To evaluate the use of ketamine-medetomidine-midazolam total intravenous infusion as part of a balanced anaesthetic technique for surgical castration in horses. Five healthy Standardbred cross colts were premedicated with IV acepromazine (0.01-0.02 mg/kg), medetomidine (7 µg/kg) and methadone (0.1 mg/kg) and anaesthesia induced with IV ketamine (2.2 mg/kg) and midazolam (0.06 mg/kg). Horses were anaesthetised for 40 min with an IV infusion of ketamine (3 mg/kg/h), medetomidine (5 µg/kg/h) and midazolam (0.1 mg/kg/h) while routine surgical castration was performed. Cardiorespiratory variables, arterial blood gases, and anaesthetic depth were assessed at 5 to 10 min intervals. Post-anaesthesia recovery times were recorded, and the quality of the recovery period was assessed. The anaesthetic period and surgical conditions were acceptable with good muscle relaxation and no additional anaesthetic required. The median (range) time from cessation of the infusion to endotracheal tube extubation, head lift and sternal recumbency were 17.2 (7-35) min, 25 (18.9-53) min and 28.1 (23-54) min, respectively. The quality of anaesthetic recovery was good, with horses standing 31.9 (28-61) min after the infusion was ceased. During anaesthesia, physiological variables, presented as a range of median values for each time point were: heart rate 37-44 beats/min, mean arterial pressure 107-119 mmHg, respiratory rate 6-13 breaths/min, arterial partial pressure of oxygen 88-126 mmHg, arterial partial pressure of carbon dioxide 52-57 mmHg and pH 7.36-7.39. In conclusion, the co-administration of midazolam, ketamine and medetomidine as in IV infusion, when used as part of a balanced anaesthetic technique, was suitable for short term anaesthesia in horses undergoing castration.

Increasing ventilator surge capacity in COVID 19 pandemic: design, manufacture and in vitro-in vivo testing in anaesthetized healthy pigs of a rapid prototyped mechanical ventilator.

OBJECTIVE: The advent of new technologies has made it possible to explore alternative ventilator manufacturing to meet the worldwide shortfall for mechanical ventilators especially in pandemics. We describe a method using rapid prototyping technologies to create an electro-mechanical ventilator in a cost effective, timely manner and provide results of testing using an in vitro-in vivo testing model. RESULTS: Rapid prototyping technologies (3D printing and 2D cutting) were used to create a modular ventilator. The artificial manual breathing unit (AMBU) bag connected to wall oxygen source using a flow meter was used as air reservoir. Controlled variables include respiratory rate, tidal volume and inspiratory: expiratory (I:E) ratio. In vitro testing and In vivo testing in the pig model demonstrated comparable mechanical efficiency of the test ventilator to that of standard ventilator but showed the material limits of 3D printed gears. Improved gear design resulted in better ventilator durability whilst reducing manufacturing time (< 2-h). The entire cost of manufacture of ventilator was estimated at 300 Australian dollars. A cost-effective novel rapid prototyped ventilator for use in patients with respiratory failure was developed in < 2-h and was effective in anesthetized, healthy pig model.

Clinical evaluation of arterial blood pressure in anesthetized dogs by use of a veterinary-specific multiparameter monitor.

OBJECTIVE: To compare noninvasive blood pressure (NIBP) measurements with invasive blood pressure (IBP) measurements of arterial blood pressure (ABP) in anesthetized dogs as obtained with a veterinary-specific multiparameter monitor. ANIMALS: 21 client-owned healthy female dogs anesthetized for routine ovariohysterectomy. PROCEDURES: ABP measurements were obtained with a single veterinary-specific multiparameter monitor via a pneumatic cuff placed over the medial dorsal metatarsal artery (NIBP) and a transducer connected to a catheter placed in the contralateral artery (IBP). The 224 paired ABP measurements (complete data set) were categorized into 3 subsets-hypotension, normotension, and hypertension-on the basis of invasive measurements of mean arterial blood pressure (MAP). The NIBP and IBP measurements of systolic and diastolic arterial blood pressure (SAP and DAP, respectively) and MAP were compared. RESULTS: NIBP measurements were frequently lower than IBP measurements. The greatest underestimation was for the hypertension subset of NIBP measurements, with biases for SAP of 15.7 mm Hg, DAP of 14.1 mm Hg, and MAP of 12.0 mm Hg. Considering the complete data set, precision was acceptable (SD of the differences between paired measurements ≤ 15 mm Hg for DAP [9.0 mm Hg] and MAP [12.1 mm Hg]); however, precision was not acceptable for SAP (SD, 18.6 mm Hg). CONCLUSIONS AND CLINICAL RELEVANCE: NIBP measurements with the studied veterinary-specific multiparameter monitor generally agreed with IBP measurements during hypotensive and normotensive periods for anesthetized healthy female dogs undergoing routine ovariohysterectomy. However, inaccuracies, frequently underestimations, were observed during periods of hypertension, and therefore, NIBP measurements should be interpreted cautiously.

Alfaxalone for total intravenous anaesthesia in horses.

OBJECTIVE: To determine the suitability of alfaxalone total intravenous (IV) anaesthesia in horses and concurrently evaluate infusion rates, cardiovascular effects, pharmacokinetics and the quality of the anaesthetic recovery period. STUDY DESIGN: Prospective, experimental study. ANIMALS: Eight Standardbred horses. METHODS: Horses were premedicated with IV acepromazine (0.03 mg kg-1) and xylazine (1 mg kg-1) and anaesthesia was induced with guaifenesin (35 mg kg-1) and alfaxalone (1 mg kg-1). Anaesthesia was maintained for 180 minutes using an IV infusion of alfaxalone at a rate determined by a horse's response to a supramaximal electrical noxious stimulus. Venous blood samples were regularly collected to determine alfaxalone plasma concentrations and for pharmacokinetic analysis. Cardiopulmonary variables were monitored and the quality of the anaesthetic recovery period scored. RESULTS: The median (range) alfaxalone infusion rate was 3.1 (2.4-4.3) mg kg-1 hour-1. The mean ± standard deviation plasma elimination half-life, plasma clearance and volume of distribution for alfaxalone were 41 minutes, 25 ± 6.3 mL minute-1 kg-1 and 1.6 ± 0.5 L kg-1, respectively. During anaesthesia, mean arterial blood pressure was maintained above 70 mmHg in all horses. Cardiac index reached a minimum value (68% of baseline values) immediately after induction of anaesthesia and was maintained between 74% and 90% of baseline values for the remainder of the anaesthetic protocol. Following the cessation of the alfaxalone infusion, six of eight horses exhibited muscle tremors and paddling. All horses stood without incident on the first or second attempt with a median recovery score of 4.5 (good to excellent). CONCLUSIONS AND CLINICAL RELEVANCE: Anaesthesia in horses can be maintained with an infusion of alfaxalone at approximately 3 mg kg-1 hour-1. The alfaxalone infusion rates used resulted in minimal haemodynamic changes and good recovery quality. Mean alfaxalone plasma concentration was stable over the infusion period and clearance rates were similar to previously published single-dose alfaxalone studies in horses.

Effective Implementation of Peri-operative Local Guidelines for Metabolic Surgery in Patients with Diabetes Mellitus in a Tier 4 Setting Demonstrate Improved Work Efficiency and Resource Allocation.

BACKGROUND: Dynamic changes in glycaemia predominate peri-operatively in patients with type 2 diabetes mellitus (T2DM) undergoing metabolic surgery. There is a lack of consensus and clear guidance on effective glycaemic management of such patients. The aim of this study was to design, pilot, and implement a proforma to improve consistency of glycaemic management and clarity of communication with healthcare professionals following metabolic surgery in patients with T2DM, thereby reducing unnecessary diabetes specialist nurse (DSN) referrals. METHODS: A proforma was designed and piloted for 12 months to guide healthcare professionals on managing glycaemic therapies for T2DM patients undergoing metabolic surgery. Glycaemic control (HbA1c) and glycaemic therapies were reviewed 3 weeks pre-operatively and a proforma was completed accordingly. RESULTS: Of the patients with T2DM (n = 34) who underwent metabolic surgery prior to the new proforma being implemented, 71% (n = 24) had a DSN referral. Half of these referrals were deemed unnecessary by the DSNs. Of the patients with T2DM (n = 33) who underwent metabolic surgery following implementation of the proforma, 21% (n = 7) had a DSN referral. Only 10% of these were deemed unnecessary. Despite the reduced DSN input, no diabetes-related complications were reported. CONCLUSION: Implementation of our proforma effectively halved the proportion of patients with T2DM requiring a DSN referral. Additionally, there was a 40% absolute reduction in the proportion of unnecessary DSN referrals. The proforma improved clarity of communication and guidance for healthcare professionals in the glycaemic management of patients. This also facilitated improved work efficiency and resource allocation.

The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles.

Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects' genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional--and possibly phenotypic--consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci.

Plasma pharmacokinetics and pharmacodynamics of alfaxalone in neonatal foals after an intravenous bolus of alfaxalone following premedication with butorphanol tartrate.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of the neurosteroid anaesthetic, alfaxalone, in neonatal foals after a single intravenous (IV) injection of alfaxalone following premedication with butorphanol tartrate. STUDY DESIGN: Prospective experimental study. ANIMALS: Five clinically healthy Australian Stock Horse foals of mean ± SD age of 12 ± 3 days and weighing 67.3 ± 12.4 kg. METHODS: Foals were premedicated with butorphanol (0.05 mg kg(-1) IV) and anaesthesia was induced 10 minutes later by IV injection with alfaxalone 3 mg kg(-1) . Cardiorespiratory variables (pulse rate, respiratory rate, direct arterial blood pressure, arterial blood gases) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Venous blood samples were collected at strategic time points and alfaxalone plasma concentrations were assayed using liquid chromatography-mass spectrometry (LC/MS) and analysed by noncompartmental pharmacokinetic analysis. RESULTS: The harmonic, mean ± SD plasma elimination half life (t½) for alfaxalone was 22.8 ± 5.2 minutes. The observed mean plasma clearance (Cl(p) ) and volume of distribution (Vd) were 19.9 ± 5.9 mL minute kg(-1) and 0.6 ± 0.2 L kg(-1) , respectively. Overall, the quality of the anaesthetic inductions and recoveries was good and most monitored physiological variables were clinically acceptable in all foals, although some foals became hypoxaemic for a short period following recumbency. The mean durations of anaesthesia from induction to first movement and from induction to standing were 18.7 ± 7 and 37.2 ± 4.7 minutes, respectively. CONCLUSIONS: The anaesthetic protocol used provided a predictable and consistent plane of anaesthesia in the five foals studied, with minimal cardiovascular depression. In foals, as in the adult horse, alfaxalone has a short elimination half life. CLINICAL RELEVANCE: Alfaxalone appears to be an adequate anaesthetic induction agent in foals and the pharmacokinetics suggest that, with continuous infusion, it might be suitable to provide more prolonged anaesthesia. Oxygen supplementation is recommended.

Diabetes care during Hajj.

Keeping well during Hajj is a challenge for people with diabetes. However, with proactive planning and education, it may prove to be an excellent opportunity for reviewing management and enhancing diabetes education to reduce diabetes-related short- and long-term problems. People with diabetes should have enough time to consider a management plan. It is important that healthcare professionals are well informed regarding the effects of Hajj on diabetes and are able to offer advice, guidance and change of medications as required during pre-Hajj counselling to enable patients to stay healthy.

The pharmacokinetics and pharmacodynamics of the injectable anaesthetic alfaxalone in the horse.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of the neurosteroidal anaesthetic, alfaxalone, in horses after a single intravenous (IV) injection of alfaxalone, following premedication with acepromazine, xylazine and guaiphenesin. STUDY DESIGN: Prospective experimental study. ANIMALS: Ten (five male and five female), adult, healthy, Standardbred horses. METHODS: Horses were premedicated with acepromazine (0.03 mg kg(-1) IV). Twenty minutes later they received xylazine (1 mg kg(-1) IV), then after 5 minutes, guaiphenesin (35 mg kg(-1) IV) followed immediately by IV induction of anaesthesia with alfaxalone (1 mg kg(-1) ). Cardiorespiratory variables (pulse rate, respiratory rate, pulse oximetry) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Venous blood samples were collected at strategic time points and plasma concentrations of alfaxalone were assayed using liquid chromatography-mass spectrometry (LC/MS) and analysed by noncompartmental pharmacokinetic analysis. The quality of anaesthetic induction and recovery was scored on a scale of 1-5 (1 very poor, 5 excellent). RESULTS: The median (range) induction and recovery scores were 4 (3-5) (good: horse slowly and moderately gently attained recumbency with minimal or no rigidity or paddling) and 4 (1-5) (good: horse stood on first attempt with some knuckling and ataxia) respectively. The monitored cardiopulmonary variables were within the range expected for clinical equine anaesthesia. The mean ± SD durations of anaesthesia from induction to sternal recumbency and from induction to standing were 42.7 ± 8.4 and 47 ± 9.6 minutes, respectively. The mean ± SD plasma elimination half life (t(1/2) ), plasma clearance (Clp) and volume of distribution (V(d) ) for alfaxalone were 33.4 minutes, 37.1 ± 11.1 mL minute(-1) kg(-1) and 1.6 ± 0.4 L kg(-1) , respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone, in a 2-hydroxypropyl-beta-cyclodextrin formulation, provides anaesthesia with a short duration of recumbency that is characterised by a smooth induction and satisfactory recovery in the horse. As in other species, alfaxalone is rapidly cleared from the plasma in the horse.

Rotenone prevents impact-induced chondrocyte death.

Mechanical insult to articular cartilage kills chondrocytes, an event that may increase the risk of posttraumatic osteoarthritis. Recent reports indicate that antioxidants decrease impact-induced chondrocyte death, but the source(s) of oxidants, the time course of oxidant release, and the identity of the oxidative species generated in response to injury are unknown. A better understanding of these processes could lead to new treatments of acute joint injuries. To that end, we studied the kinetics and distribution of oxidant production in osteochondral explants subjected to a single, blunt-impact injury. We followed superoxide production by measuring the time-dependent accumulation of chondrocyte nuclei stained with the superoxide-sensitive probe dihydroethidium. The percentage of chondrocytes that were dihydroethidium-positive was 35% above baseline 10 min after impact, and 65% above baseline 60 min after impact. Most positive cells were found within and near areas contacted directly by the impact platen. Rotenone, an electron transport chain inhibitor, was used to test the hypothesis that mitochondria contribute to superoxide release. Rotenone treatment significantly reduced dihydroethidium staining, which remained steady at 15% above baseline for up to 60 min postimpact. Moreover, rotenone reduced chondrocyte death in impact sites by more than 40%, even when administered 2 h after injury (p < 0.001). These data show that much of the acute chondrocyte mortality caused by in vitro impact injuries results from superoxide release from mitochondria, and suggest that brief exposure to free radical scavengers could significantly improve chondrocyte viability following joint injury.

Mechanical stimulation of tendon tissue engineered constructs: effects on construct stiffness, repair biomechanics, and their correlation.

The objective of this study was to determine how in vitro mechanical stimulation of tissue engineered constructs affects their stiffness and modulus in culture and tendon repair biomechanics 12 weeks after surgical implantation. Using six female adult New Zealand White rabbits, autogenous tissue engineered constructs were created by seeding mesenchymal stem cells (0.1 x 10(6) cells/ml) in collagen gel (2.6 mg/ml) and combining both with a collagen sponge. Employing a novel experimental design strategy, four constructs from each animal were mechanically stimulated (one 1 Hz cycle every 5 min to 2.4% peak strain for 8 h/day for 2 weeks) while the other four remained unstretched during the 2 week culture period. At the end of incubation, three of the mechanically stimulated (S) and three of the nonstimulated (NS) constructs from each animal were assigned for in vitro mechanical testing while the other two autogenous constructs were implanted into bilateral full-thickness, full-length defects created in the central third of rabbit patellar tendons (PTs). No significant differences were found in the in vitro linear stiffnesses between the S (0.15+/-0.1 N/mm) and NS constructs (0.08+/-0.02 N/mm; mean+/-SD). However, in vitro mechanical stimulation significantly increased the structural and material properties of the repair tissue, including a 14% increase in maximum force (p=0.01), a 50% increase in linear stiffness (p=0.001), and 23-41% increases in maximum stress and modulus (p=0.01). The S repairs achieved 65%, 80%, 60%, and 40% of normal central PT maximum force, linear stiffness, maximum stress, and linear modulus, respectively. The results for the S constructs exceed values obtained previously by our group using the same animal and defect model, and to our knowledge, this is the first study to show the benefits of in vitro mechanical stimulation on tendon repair biomechanics. In addition, the linear stiffnesses for the construct and repair were positively correlated (r=0.56) as were their linear moduli (r=0.68). Such in vitro predictors of in vivo outcome hold the potential to speed the development of tissue engineered products by reducing the time and costs of in vivo studies.