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Effects of Isoflurane, Sevoflurane, Propofol and Alfaxalone on Brain

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Effects of Isoflurane, Sevoflurane, Propofol and Alfaxalone on Brain Söbbeler et al. BMC Veterinary Research (2018) 14:69 https://doi.org/10.1186/s12917-018-1396-1 RESEARCH ARTICLE Open Access Effects of isoflurane, sevoflurane, propofol and alfaxalone on brain metabolism in dogs assessed by proton magnetic resonance spectroscopy (1H MRS) Franz Josef Söbbeler1*, Inés Carrera2, Kirby Pasloske3, Millagahamada Gedara Ranasinghe3, Patrick Kircher2 and Sabine Beate Rita Kästner1 Abstract Background: The purpose of this study was to determine the effects of isoflurane, sevoflurane, propofol and alfaxalone on the canine brain metabolite bioprofile, measured with single voxel short echo time proton magnetic resonance spectroscopy at 3 Tesla. Ten adult healthy Beagle dogs were assigned to receive isoflurane, sevoflurane, propofol and alfaxalone at 3 different dose rates each in a randomized cross-over study design. Doses for isoflurane, sevoflurane, propofol and alfaxalone were FE’Iso 1.7 vol%, 2.1 vol%, 2.8 vol%, FE’Sevo 2.8 vol%, 3.5 vol% and 4. 7 vol%, 30, 45 and 60 mg kg− 1 h− 1 and 10, 15 and 20 mg kg− 1 h− 1 respectively. A single voxel Point Resolved Spectroscopy Sequence was performed on a 3 T MRI scanner in three brain regions (basal ganglia, parietal and occipital lobes). Spectral data were analyzed with LCModel. Concentration of total N-acetylaspartate (tNAA), choline, creatine, inositol and glutamine and glutamate complex (Glx) relative to water content was obtained. Plasma concentration of lactate, glucose, triglycerides, propofol and alfaxalone were determined. Statistics were performed using repeated measures ANOVA or Wilcoxon Sign Rank test with alpha = 5%. Results: Plasma glucose increased with isoflurane, sevoflurane and alfaxalone but decreased with propofol. Plasma lactate increased with all anesthetics (isoflurane > sevoflurane > propofol > alfaxalone). Cerebral lactate could not be detected. Only minor changes in cerebral metabolite concentrations of tNAA, choline, inositol, creatine and Glx occurred with anesthetic dose changes. Conclusion: The metabolomic profile detected with proton magnetic resonance spectroscopy at 3 Tesla of canine brain showed only minor differences between doses and anesthetics related to tNAA, choline, creatine, inositol and Glx. Keywords: Anesthesia, Lactate, Glucose, MRI, Cerebral, PRESS, Plasma, LcModel, Canine Background found a consistent suppression of CMRglu under isoflur- Injectable as well as volatile anesthetics influence cerebral ane, sevoflurane and propofol with varying impact on dif- metabolism. The classic paradigm that neuronal activity ≈ ferent brain regions in man [2–6]. Cerebral metabolic rate metabolism ≈ blood flow has been used to study the effect of oxygen is also reduced by sevoflurane, propofol, isoflur- − of anesthetics on brain metabolism. Positron Emission ane and also Althesin® (a combination of 9 mg mL 1 − Tomography studies with 2-deoxy-2(18F)fluoro-D-glucose alfaxalone- and 3 mg mL 1 alfadolone acetate) [7–9]. In to determine the cerebral metabolic rate of glucose microdialysis studies in rodents [10, 11] volatile anes- (CMRglu) as an indirect measure of neuronal activity [1] thetics led to a rapid and dose-dependent increase in cere- bral lactate levels without changes in cerebral glucose levels. Ketamine/xylazine, and chloral hydrate moderately * Correspondence: [email protected] 1Small Animal Clinic (Söbbeler, Kästner), University of Veterinary Medicine increased cerebral lactate, but cerebral glucose levels rose Hanover Foundation, Bünteweg 9, 30559 Hannover, Germany markedly. Both propofol and pentobarbital did not affect Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Söbbeler et al. BMC Veterinary Research (2018) 14:69 Page 2 of 15 cerebral lactate levels and only propofol led to a minor in- Methods crease in cerebral glucose. All animal procedures were performed according to the Brain metabolism can also be investigated by magnetic German animal protection law after review and approval resonancespectroscopy(MRS),whichisanon-invasive by the ethical committee for animal experimentation of magnetic resonance imaging technique that allows the de- the Federal State Office for Consumer Protection and termination of the biochemical composition of the brain in Food Safety of Lower Saxony, Germany (3392 42,502– vivo for accurate identification and quantification of metab- 04-13/1252). olites in localized brain regions [12–14]. With proton mag- netic resonance spectroscopy (1HMRS)at3Teslaseveral Animals metabolites can be identified in the normal brain, such as Ten purpose-bred (purpose bred at our own institution) N-acetylaspartate (NAA), choline, creatine, myo-inositol, adult Beagle dogs (8 neutered males and 2 spayed females) and sum of glutamate and glutamine (Glx) [15–18]. At > 7 were included in the study. Age ranged from 32 to Tesla, the spectral differentiation between the glutamine 91 month (mean ± SD, 50.7 ± 22.2 months) and the weight and glutamate is complete, and other smaller metabolites ranged from 11 to 21.8 kg (mean ± SD, 16.5 kg ± 3.2). like glucose and GABA are well depicted [19, 20]. The dogs were housed in groups of 5 to 6 dogs per group Several 1H MRS studies have been performed to inves- with daily periods in enriched outside runs and regular tigate metabolism within the brain under general walking by veterinary students. Ambient temperature is anesthesia in rodents [21, 22], monkeys [23], humans regulated to 18–21 °C. The dogs received commercial dog [24] and dogs [25]. The main findings of these studies food (Hills VetEssentials Canine adult) according to body [21–24] were the increase in cerebral lactate under the weight, twice daily except on study days. dose-dependent influence of volatile anesthetics inde- Health status of the dogs was confirmed by a clinical pendent of plasma lactate [21–23]. They also found in- and neurological examination and complete blood count creases in other cerebral metabolites, especially and blood chemistry. Physical status was classified ac- glutamate, alanine and creatine. These changes have cording to the American Society of Anesthesiologists been shown to be fully reversible within minutes after (ASA) physical status classification system as ASA I. completion of the anesthesia [21]. On the other hand, the injectable anesthetics and premedication drugs keta- Study design mine/medetomidine, medetomidine, pentobarbital, fen- The study was performed as a randomized, experimental tanyl, diazepam and propofol did not influence cerebral trial in a complete cross-over design with four treat- lactate concentration [21, 22]. ments [isoflurane (I), sevoflurane (S), propofol (P), alfax- In veterinary medicine, clinical MRI can only be per- alone (A)] and a wash out period of at least 14 days formed under general anesthesia. Recently, relative metab- between treatments. olite concentrations and their ratios in the brain of healthy beagle dogs under general anesthesia have been Instrumentation published [15–17], as well as a few clinical studies [26, 27] All dogs were fasted overnight, water was available until using different anesthetic protocols. Since the influence of the trial started. Blood was drawn from the jugular vein anesthetics on the canine brain bioprofile at 3 Tesla is ac- for analysis of blood gases, electrolytes, plasma lactate, tually not known, the purpose of the study reported here plasma glucose and plasma triglycerides. A peripheral ven- was to determine the possible effects of the commonly ous catheter was placed into the cephalic or lateral saphe- used anesthetics isoflurane, sevoflurane, propofol and nous vein for induction and maintenance of anesthesia alfaxalone on canine brain bioprofile assessed with single (treatment P and A) and cardiovascular support (treat- voxel short echo time proton magnetic resonance spec- ment I, S, P, A). A central venous catheter was placed into troscopy at a field strength of 3.0 Tesla. Secondary aim of the right or left jugular vein for blood sampling. All dogs this study was to evaluate the possible effects of the anes- were wrapped in self-made bubble wrap vests equipped thetics on plasma levels of lactate and glucose. with 41 °C warm gel heat pads for temperature manage- Our hypothesis was that volatile anesthetics isoflurane ment. Earplugs were used for noise protection. and sevoflurane, but not the injectable anesthetics propo- fol and alfaxalone, cause a dose-dependent increase in Anesthetic protocol cerebral lactate. Furthermore, we hypothesized an increase In treatment I and S dogs were induced by mask with in cerebral levels of creatine and glutamate under influ- 5% isoflurane (Isofluran CP®, CP-Pharma) or 6% sevo- ence of volatile anesthetics compared to the injectable an- flurane (SevoFlo®, EcuPhar GmbH) in 100% oxygen with − esthetics propofol and alfaxalone. Regional differences in a flow of 8 L min 1. In treatment P and A, induction − cerebral metabolites were
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