Visual and quantitative electroencephalographic analysis of healthy young and adult cats under medetomidine sedation

A study was designed to investigate the effect of medetomidine sedation on quantitative electroencephalography (q-EEG) in healthy young and adult cats to determine objective guidelines for diagnostic EEG recordings and interpretation. Preliminary visual examination of EEG recordings revealed high-voltage low-frequency background activity. Spindles, k-complexes and vertex sharp transients characteristic of sleep or sedation were superimposed on a low background activity. Neither paroxysmal activity nor EEG burst-suppression were observed. The spectral analysis of q-EEG included four parameters, namely, relative power (%), and mean, median and peak frequency (Hz) of all four frequency bands (delta, theta, alpha and beta). The findings showed a prevalence of slow delta and theta rhythms as opposed to fast alpha and beta rhythms in both young (group A) and adult (group B) cats. A posterior gradient was reported for the theta band and an anterior gradient for the alpha and beta bands in both groups, respectively. The relative power value in group B compared to group A was significantly higher for theta, alpha and beta bands, and lower for the delta band. The mean and median frequency values in group B was significantly higher for delta, theta and beta bands and lower for the alpha band. The study has shown that a medetomidine sedation protocol for feline EEG may offer a method for investigating bio-electrical cortical activity. The use of q-EEG analysis showed a decrease in high frequency bands and increased activity of the low frequency band in healthy cats under medetomidine sedation.

Influence of the magnesium aspartate hydrochloride administration to the maternal circuit on the aspartate concentration of the fetal circuit under in vitro perfusion of human placenta

OBJECTIVES: Magnesium aspartate hydrochloride (Magnesiocard, Mg-Asp-HCl) is proposed as a substitute of magnesium sulfate for the treatment of preeclampsia and premature labor. After an i.v. administration of a dose equivalent to that used in the treatment of preeclampsia to nonpregnant volunteers, a 10-fold increase of aspartic acid (Asp) over the physiological level was observed. Animal experiments have demonstrated that highly increased fetal levels of acidic amino acids such as Asp could be associated with neurotoxic damage in the fetal brain. The influence of such an elevation of Asp concentration in the maternal circuit on the fetal level, using the in vitro perfusion model of human placenta, was investigated. STUDY DESIGN: After a control phase (2h), a therapeutic dose of Mg combined with Asp (Magnesiocard, Mg-Asp-HCl) was applied to the maternal circuit approaching 10 times the physiological level of Asp. The administration was performed in two different phases simulating either a peak of maximum concentration (bolus application, 2h) or a steady state level (initially added, 4h). RESULTS: In four experiments, during experimental phases (6h) a slow increase in concentration in the fetal circuit was seen for Mg, AIB (alpha-aminoisobutyric acid, artificial amino acid) and creatinine confirming previous observations. In contrast, no net transfer of Asp across the placenta was seen. A continuous decrease in the concentration of Asp on both maternal and fetal side suggests active uptake and metabolization by the placenta. Viability control parameters remained stable indicating the absence of an effect on placental metabolism, permeability and morphology. CONCLUSION: Elevation of Asp concentration up to 10 times the physiological level by the administration of Mg-Asp-HCl to the maternal circuit under in vitro perfusion conditions of human placenta has no influence on the fetal level of Asp suggesting no transfer of Asp from the maternal to fetal compartment. Therefore, the administration of Mg-Asp-HCl to preeclamptic patients would be beneficial for the patients without any impact on placental or fetal physiology.

Medetomidine continuous rate intravenous infusion in horses in which surgical anaesthesia is maintained with isoflurane and intravenous infusions of lidocaine and ketamine

OBJECTIVE: To evaluate medetomidine as a continuous rate infusion (CRI) in horses in which anaesthesia is maintained with isoflurane and CRIs of ketamine and lidocaine. STUDY DESIGN: Prospective, randomized, blinded clinical trial. ANIMALS: Forty horses undergoing elective surgery. METHODS: After sedation and induction, anaesthesia was maintained with isoflurane. Mechanical ventilation was employed. All horses received lidocaine (1.5 mg kg(-1) initially, then 2 mg kg(-1) hour(-1)) and ketamine (2 mg kg(-1) hour(-1)), both CRIs reducing to 1.5 mg kg(-1) hour(-1) after 50 minutes. Horses in group MILK received a medetomidine CRI of 3.6 mug kg(-1) hour(-1), reducing after 50 minutes to 2.75 mug kg(-1) hour(-1), and horses in group ILK an equal volume of saline. Mean arterial pressure (MAP) was maintained above 70 mmHg using dobutamine. End-tidal concentration of isoflurane (FE'ISO) was adjusted as necessary to maintain surgical anaesthesia. Group ILK received medetomidine (3 mug kg(-1) ) at the end of the procedure. Recovery was evaluated. Differences between groups were analysed using Mann-Whitney, Chi-Square and anova tests as relevant. Significance was taken as p < 0.05. RESULTS: FE'ISO required to maintain surgical anaesthesia in group MILK decreased with time, becoming significantly less than that in group ILK by 45 minutes. After 60 minutes, median (IQR) FE'ISO in MILK was 0.65 (0.4-1.0) %, and in ILK was 1 (0.62-1.2) %. Physiological parameters did not differ between groups, but group MILK required less dobutamine to support MAP. Total recovery times were similar and recovery quality good in both groups. CONCLUSION AND CLINICAL RELEVANCE: A CRI of medetomidine given to horses which were also receiving CRIs of lidocaine and ketamine reduced the concentration of isoflurane necessary to maintain satisfactory anaesthesia for surgery, and reduced the dobutamine required to maintain MAP. No further sedation was required to provide a calm recovery.

Anaesthesia with medetomidine-ketamine-isoflurane with and without midazolam, in eight captive Chimpanzees (Pan troglodytes) premedicated with oral zuclopenthixol

In 8 captive adult chimpanzees of various ages premedicated with oral zuclopenthixol anaesthesia was induced intramuscularly with a combination of medetomidine and ketamine (40 or 50 µg/kg and 5 mg/kg, IM, respectively), with and without midazolam (0.05 mg/kg), and maintained with isoflurane in oxygen. At the end of the procedure, sedation was reversed with atipamezole (0.25 mg/kg, IM) and sarmazenil (0.005 mg/kg, IM) when midazolam had been administered. Oral zuclopenthixol resulted in tranquillization of the whole group and only one animal required a second dart injection to achieve adequately deep anaesthesia. Effective and reliable anaesthesia was achieved in all apes; the depth of hypnosis was stable and sudden arousal did not occur. Physiological parameters remained within normal ranges in the majority of the animals; however, manageable anaesthesia-related complications, namely apnoea after darting, hypotension, hypoventilation, hypoxemia and prolonged recovery, occurred in 6 out of 8 animals. The use of monitoring devices was essential to guarantee adequate management of these complications.

Anaesthesia with medetomidine, midazolam and ketamine in six gorillas after premedication with oral zuclopenthixol dihydrochloride

OBJECTIVE To evaluate the effects of medetomidine, midazolam and ketamine (MMK) in captive gorillas after premedication with oral zuclopenthixol. STUDY DESIGN Case series. ANIMALS Six gorillas, two males and four females, aged 9-52 years and weighing 63-155 kg. METHODS The gorillas were given zuclopenthixol dihydrochloride 0.2 ± 0.05 mg kg(-1) per os twice daily for 3 days for premedication. On the day of anaesthesia the dose of zuclopenthixol was increased to 0.27 mg kg(-1) and given once early in the morning. Anaesthesia was induced with medetomidine 0.04 ± 0.004 mg kg(-1) , midazolam 0.048 ± 0.003 mg kg(-1) and ketamine 4.9 ± 0.4 mg kg(-1) intramuscularly (IM). Upon recumbency, the trachea was intubated and anaesthesia was maintained on 1-2% isoflurane in oxygen. Physiological parameters were monitored every 10 minutes and arterial blood gas analysis was performed once 30-50 minutes after initial darting. At the end of the procedure, 42-115 minutes after initial darting, immobilisation was antagonized with atipamezole 0.21 ± 0.03 mg kg(-1) and sarmazenil 5 ± 0.4 μg kg(-1) IM. RESULTS Recumbency was reached within 10 minutes in five out of six animals. One animal required two additional darts before intubation was feasible. Heart rate ranged from 60 to 85 beats minute(-1) , respiratory rate from 17 to 46 breaths minute(-1) and temperature from 36.9 to 38.3 °C. No spontaneous recoveries were observed and anaesthetic level was stable. Blood gas analyses revealed mild respiratory acidosis, and mean PaO(2) was 24.87 ± 17.16 kPa (187 ± 129 mmHg) with all values being above 13.4 kPa (101 mmHg). Recovery was smooth and gorillas were sitting within 25 minutes. CONCLUSION AND CLINICAL RELEVANCE The drug combination proved to be effective in anaesthetizing captive gorillas of various ages and both sexes, with minimal cardio-respiratory changes.

Effects of medetomidine and its active enantiomer dexmedetomidine on N-demethylation of ketamine in canines determined in vitro using enantioselective capillary electrophoresis.

Cytochrome P450 (CYP) enzymes catalyze the metabolism of both, the analgesic and anesthetic drug ketamine and the α2 -adrenergic receptor-agonist medetomidine that is used for sedation and analgesia. As racemic medetomidine or its active enantiomer dexmedetomidine are often coadministered with racemic or S-ketamine in animals and dexmedetomidine together with S- or racemic ketamine in humans, drug-drug interactions are likely to occur and have to be characterized. Enantioselective CE with highly sulfated γ-cyclodextrin as chiral selector was employed for analyzing in vitro (i) the kinetics of the N-demethylation of ketamine mediated by canine CYP3A12 and (ii) interactions occurring with racemic medetomidine and dexmedetomidine during coincubation with ketamine and canine liver microsomes (CLM), canine CYP3A12, human liver microsomes (HLM), and human CYP3A4. For CYP3A12 without an inhibitor, Michaelis-Menten kinetics was determined for the single enantiomers of ketamine and substrate inhibition kinetics for racemic ketamine. Racemic medetomidine and dexmedetomidine showed an inhibition of the N-demethylation reaction in the studied canine enzyme systems. Racemic medetomidine is the stronger inhibitor for CLM, whereas there is no difference for CYP3A12. For CLM and CYP3A12, the inhibition of dexmedetomidine is stronger for the R- compared to the S-enantiomer of ketamine, a stereoselectivity that is not observed for CYP3A4. Induction is observed at a low dexmedetomidine concentration with CYP3A4 but not with CYP3A12, CLM, and HLM. Based on these results, S-ketamine combined with dexmedetomidine should be the best option for canines. The enantioselective CE assay with highly sulfated γ-cyclodextrin as chiral selector is an effective tool for determining kinetic and inhibition parameters of metabolic pathways.

The choice of anesthesia influences oxidative energy metabolism and tissue survival in critically ischemic murine skin

In surgical animal studies anesthesia is used regularly. Several reports in the literature demonstrate respiratory and cardiovascular side effects of anesthesiologic agents. The aim of this study was to compare two frequently used anesthesia cocktails (ketamine/xylazine [KX] versus medetomidine/climazolam/fentanyl [MCF]) in skin flap mouse models. Systemic blood values, local metabolic parameters, and surgical outcome should be analyzed in critical ischemic skin flap models. Systemic hypoxia was found in the animals undergoing KX anesthesia compared with normoxia in the MCF group (sO(2): 89.2% +/- 2.4% versus 98.5% +/- 1.2%, P < 0.01). Analysis of tissue metabolism revealed impaired anaerobic oxygen metabolism and increased cellular damage in critical ischemic flap tissue under KX anesthesia (lactate/pyruvate ratio: KX 349.86 +/- 282.38 versus MCF 64.53 +/- 18.63; P < 0.01 and glycerol: KX 333.50 +/- 83.91 micromol/L versus MCF 195.83 +/- 29.49 micromol/L; P < 0.01). After 6 d, different rates of flap tissue necrosis could be detected (MCF 57% +/- 6% versus KX 68% +/- 6%, P < 0.01). In summary we want to point out that the type of anesthesia, the animal model and the goal of the study have to be well correlated. Comparing the effects of KX and MCF anesthesia in mice on surgical outcome was a novel aspect of our study.

Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency

INTRODUCTION: N-Acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder, which may present in the neonatal period with severe hyperammonemia and marked neurological impairment. CASE REPORT: We report on a Turkish family with a patient who died due to hyperammonemia in the neonatal period. Reduced activity of NAGS and carbamyl phosphate synthetase were found at autopsy. A second child who developed hyperammonemia on the second day of life was immediately treated with arginine hydrochloride, sodium benzoate and protein restriction. After NAGS deficiency was suspected by enzyme analysis, sodium benzoate was replaced by N-carbamylglutamate (NCG). A third child who developed slight hyperammonemia on the third day of life was treated with NCG before enzyme analysis confirmed reduced NAGS activity. Neither of the patients developed hyperammonemia in the following years. After the human NAGS gene was identified, mutation analysis revealed that the older sibling on NCG therapy was homozygous for a 971G>A (W324X) mutation. The parents and the younger sibling were heterozygous. Therapy was continued in the older sibling until now without any adverse effects and favourable neurodevelopment outcome. In the younger sibling, therapy was stopped without any deterioration of urea cycle function. CONCLUSION: NAGS deficiency can be successfully treated with NCG and arginine hydrochloride with favourable outcome. Molecular diagnostic rather than enzyme analysis should be used in patients with suspected NAGS deficiency.

Comparison of the effects of racemic ketamine and S-ketamine for anesthesia in Rheem gazelles (Gazella subgutturosa marica) and Subgutturosa gazelles (Gazella subgutturosa subgutturosa)

OBJECTIVE: To evaluate effects of racemic ketamine and S-ketamine in gazelles. ANIMALS: 21 male gazelles (10 Rheem gazelles [Gazella subgutturosa marica] and 11 Subgutturosa gazelles [Gazella subgutturosa subgutturosa]), 6 to 67 months old and weighing (mean+/-SD) 19 +/- 3 kg. PROCEDURES: In a randomized, blinded crossover study, a combination of medetomidine (80 mug/kg) with racemic ketamine (5 mg/kg) or S-ketamine (3 mg/kg) was administered i.m.. Heart rate, blood pressure, respiratory rate, rectal temperature, and oxygen saturation (determined by means of pulse oximetry) were measured. An evaluator timed and scored induction of, maintenance of, and recovery from anesthesia. Medetomidine was reversed with atipamezole. The alternate combination was used after a 4-day interval. Comparisons between groups were performed with Wilcoxon signed rank and paired t tests. RESULTS: Anesthesia induction was poor in 2 gazelles receiving S-ketamine, but other phases of anesthesia were uneventful. A dominant male required an additional dose of S-ketamine (0.75 mg/kg, i.m.). After administration of atipamezole, gazelles were uncoordinated for a significantly shorter period with S-ketamine than with racemic ketamine. Recovery quality was poor in 3 gazelles with racemic ketamine. No significant differences between treatments were found for any other variables. Time from drug administration to antagonism was similar between racemic ketamine (44.5 to 53.0 minutes) and S-ketamine (44.0 to 50.0 minutes). CONCLUSIONS AND CLINICAL RELEVANCE: Administration of S-ketamine at a dose 60% that of racemic ketamine resulted in poorer induction of anesthesia, an analogous degree of sedation, and better recovery from anesthesia in gazelles with unremarkable alterations in physiologic variables, compared with racemic ketamine.

Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs

Seventy-six dogs with clinical acquired atrioventricular valvular disease were evaluated to determine the efficacy of pimobendan (n=41) versus benazepril hydrochloride (n=35) in a randomized, positive-controlled, multicenter study. The study was divided into 56-day and long-term evaluation periods. In a subgroup of dogs with concurrent furosemide treatment (pimobendan [n=31], benazepril [n=25]), the Heart Insufficiency Score improved in favor of pimobendan (P=0.0011), equating to a superior overall efficacy rating (P<0.0001) at day 56. Long-term median survival (i.e., death or treatment failure) for dogs receiving pimobendan was 415 days versus 128 days for dogs not on pimobendan (P=0.0022).

Antimicrobial therapy using a local drug delivery system (Arestin) in the treatment of peri-implantitis. I: Microbiological outcomes

OBJECTIVES: To assess the microbiological outcome of local administration of minocycline hydrochloride microspheres 1 mg (Arestin) in cases with peri-implantitis and with a follow-up period of 12 months. MATERIAL AND METHODS: After debridement, and local administration of chlorhexidine gel, peri-implantitis cases were treated with local administration of minocycline microspheres (Arestin). The DNA-DNA checkerboard hybridization method was used to detect bacterial presence during the first 360 days of therapy. RESULTS: At Day 10, lower bacterial loads for 6/40 individual bacteria including Actinomyces gerensceriae (P<0.1), Actinomyces israelii (P<0.01), Actinomyces naeslundi type 1 (P<0.01) and type 2 (P<0.03), Actinomyces odontolyticus (P<0.01), Porphyromonas gingivalis (P<0.01) and Treponema socranskii (P<0.01) were found. At Day 360 only the levels of Actinobacillus actinomycetemcomitans were lower than at baseline (mean difference: 1x10(5); SE difference: 0.34x10(5), 95% CI: 0.2x10(5) to 1.2x10(5); P<0.03). Six implants were lost between Days 90 and 270. The microbiota was successfully controlled in 48%, and with definitive failures (implant loss and major increase in bacterial levels) in 32% of subjects. CONCLUSIONS: At study endpoint, the impact of Arestin on A. actinomycetemcomitans was greater than the impact on other pathogens. Up to Day 180 reductions in levels of Tannerella forsythia, P. gingivalis, and Treponema denticola were also found. Failures in treatment could not be associated with the presence of specific pathogens or by the total bacterial load at baseline. Statistical power analysis suggested that a case control study would require approximately 200 subjects.

Endoscopic scoring of the tracheal septum in horses and its clinical relevance for the evaluation of lower airway health in horses

REASONS FOR PERFORMING STUDY: Although endoscopic scoring of the tracheal septum thickness is used as a diagnostic tool for evaluation of lower airway disease, its clinical relevance and reliability have never been critically assessed in the horse. OBJECTIVES: To investigate if septum thickness scores (STS) are reliable and serve as a clinically useful indicator of lower airway disease status and/or inflammation. METHODS: The variance of STS attributable to the horse, observer and changes over time was determined. The distribution of STS in a population of clinically normal horses and correlations of STS with age, gender, as well as mucus accumulation and cell differentials of tracheobronchial secretions and bronchoalveolar lavage fluid were investigated. Effects of altered pulmonary ventilation, induced by different drugs, on STS were assessed. Finally, STS of horses affected with recurrent airway obstruction (RAO) were compared to those of clinically normal horses. RESULTS: Recorded STS showed excellent intra- and satisfactory interobserver agreement Established clinical, endoscopic and cytological measures of lower airway inflammation, i.e. mucus accumulation scores and airway neutrophilia, did not correlate with STS. In horses age > or = 10 years, septum scores were significantly higher (P = 0.022) than in younger horses. Septum thickness scores did not differ significantly between clinically normal and RAO-affected horses both in exacerbation and in remission. Horses with markedly increased breathing effort (i.e. with metacholine- or lobeline hydrochloride-challenge), often differed markedly (up to 1.9 scores), but the average of end-inspiratory and end-expiratory STS did not differ from baseline STS. CONCLUSIONS AND CLINICAL RELEVANCE: Endoscopic STS are a reproducible measure, but STS did not correlate with clinical, endoscopic and cytological findings indicative of RAO or inflammatory airway disease.

Oxidation of 3-hydroxyanthranilic acid to the phenoxazinone cinnabarinic acid by peroxyl radicals and by compound I of peroxidases or catalase

Since 3-hydroxyanthranilic acid (3HAA), an oxidation product of tryptophan metabolism, is a powerful radical scavenger [Christen, S., Peterhans, E., ; Stocker, R. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 2506], its reaction with peroxyl radicals was investigated further. Exposure to aqueous peroxyl radicals generated at constant rate under air from the thermolabile radical initiator 2,2'-azobis[2-amid-inopropane] hydrochloride (AAPH) resulted in rapid consumption of 3HAA with initial accumulation of its cyclic dimer, cinnabarinic acid (CA). The initial rate of formation of the phenoxazinone CA accounted for approximately 75% of the initial rate of oxidation of 3HAA, taking into account that 2 mol of 3HAA are required to form 1 mol of CA. Consumption of 3HAA under anaerobic conditions (where alkyl radicals are produced from AAPH) was considerably slower and did not result in detectable formation of CA. Addition of superoxide dismutase enhanced autoxidation of 3HAA as well as the initial rates of peroxyl radical-induced oxidation of 3HAA and formation of CA by approximately 40-50%, whereas inclusion of xanthine/xanthine oxidase decreased the rate of oxidation of 3HAA by approximately 50% and inhibited formation of CA almost completely, suggesting that superoxide anion radical (O2.-) was formed and reacted with reaction intermediate(s) to curtail formation of CA. Formation of CA was also observed when 3HAA was added to performed compound I of horseradish peroxidase (HRPO) or catalytic amounts of either HRPO, myeloperoxidase, or bovine liver catalase together with glucose/glucose oxidase.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired vascular function in normoglycemic mice prone to autoimmune diabetes: role of nitric oxide

Type 1 diabetes is an immuno-inflammatory condition which increases the risk of cardiovascular disease, particularly in young adults. This study investigated whether vascular function is altered in mice prone to autoimmune diabetes and whether the nitric oxide (NO)-cyclic GMP axis is involved. Aortic rings suspended in organ chambers and precontracted with phenylephrine were exposed to cumulative concentrations of acetylcholine. To investigate the role of NO, some experiments were performed in the presence of either 1400W (N-(3-aminomethyl)benzyl-acetamidine hydrochloride), a selective inhibitor of the iNOS-isoform, L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride), an inhibitor of all three NOS-isoforms, or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), a selective inhibitor of guanylate cyclase. Moreover, contractility to phenylephrine, big endothelin-1, and endothelin-1 was assessed and histological analysis and iNOS immunohistochemistry were performed. Endothelium-dependent relaxation was reduced in prediabetic NOD mice (78+/-4 vs. 88+/-2%, respectively, P<0.05 vs. control) despite normal plasma glucose levels (n.s. vs. control). Preincubation with 1400W further attenuated responses in prediabetic (P<0.05 vs. untreated) but not in diabetic or in control mice. In contrast, basal NO bioactivity remained unaffected until the onset of diabetes in NOD mice. Contractile responses to big endothelin-1 and endothelin-1 were reduced in prediabetic animals (P<0.05 vs. control), whereas in diabetic mice only responses to big endothelin-1 were decreased (P<0.05 vs. control). These data demonstrate that endothelium-dependent and -independent vascular function in NOD mice is abnormal already in prediabetes in the absence of structural injury. Early proinflammatory activation due to iNOS in diabetes-prone NOD mice appears to be one of the mechanisms contributing to impaired vasoreactivity.