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      Effects of Methadone on the Minimum Anesthetic Concentration of Isoflurane, and Its Effects on Heart Rate, Blood Pressure and Ventilation during Isoflurane Anesthesia in Hens ( Gallus gallus domesticus)

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          Abstract

          The aim of this study was to measure the temporal effects of intramuscular methadone administration on the minimum anesthetic concentration (MAC) of isoflurane in hens, and to evaluate the effects of the isoflurane-methadone combination on heart rate and rhythm, blood pressure and ventilation. Thirteen healthy adult hens weighing 1.7 ± 0.2 kg were used. The MAC of isoflurane was determined in each individual using the bracketing method. Subsequently, the reduction in isoflurane MAC produced by methadone (3 or 6 mg kg -1, IM) was determined by the up-and-down method. Stimulation was applied at 15 and 30 minutes, and at 45 minutes if the bird had not moved at 30 minutes. Isoflurane MAC reduction was calculated at each time point using logistic regression. After a washout period, birds were anesthetized with isoflurane and methadone, 6 mg kg -1 IM was administered. Heart rate and rhythm, respiratory rate, blood gas values and invasive blood pressure were measured at 1.0 and 0.7 isoflurane MAC, and during 45 minutes after administration of methadone once birds were anesthetized with 0.7 isoflurane MAC. Fifteen minutes after administration of 3 mg kg -1 of methadone, isoflurane MAC was reduced by 2 (-9 to 13)% [logistic regression estimate (95% Wald confidence interval)]. Administration of 6 mg kg -1 of methadone decreased isoflurane MAC by 29 (11 to 46)%, 27 (-3 to 56)% and 10 (-8 to 28)% after 15, 30 and 45 minutes, respectively. Methadone (6 mg kg -1) induced atrioventricular block in three animals and ventricular premature contractions in two. Methadone caused an increase in arterial blood pressure and arterial partial pressure of carbon dioxide, while heart rate and pH decreased. Methadone, 6 mg kg -1 IM significantly reduced isoflurane MAC by 30% in hens 15 minutes after administration. At this dose, methadone caused mild respiratory acidosis and increase in systemic blood pressure.

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          Inhaled anesthetics and immobility: mechanisms, mysteries, and minimum alveolar anesthetic concentration.

          Studies using molecular modeling, genetic engineering, neurophysiology/pharmacology, and whole animals have advanced our understanding of where and how inhaled anesthetics act to produce immobility (minimum alveolar anesthetic concentration; MAC) by actions on the spinal cord. Numerous ligand- and voltage-gated channels might plausibly mediate MAC, and specific amino acid sites in certain receptors present likely candidates for mediation. However, in vivo studies to date suggest that several channels or receptors may not be mediators (e.g., gamma-aminobutyric acid A, acetylcholine, potassium, 5-hydroxytryptamine-3, opioids, and alpha(2)-adrenergic), whereas other receptors/channels (e.g., glycine, N-methyl-D-aspartate, and sodium) remain credible candidates.
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            Effects of remifentanil on measures of anesthetic immobility and analgesia in cats.

            To evaluate effects of various doses of remifentanil on measures of analgesia in anesthetized cats. 6 healthy adult cats. Minimum alveolar concentration (MAC) for isoflurane and thermal threshold responses were evaluated in anesthetized cats. Remifentanil infusions of 0 (baseline), 0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8, and 16 microg/kg/min were administered; after a 45-minute equilibration period, isoflurane MAC and responses were determined. Isoflurane MAC was determined in anesthetized cats once for each remifentanil infusion rate by use of a standard tail clamp technique. Thermal threshold was measured in awake cats by use of a commercially available analgesiometric probe placed on the lateral portion of the thorax; remifentanil infusions were administered in randomized order to anesthetized cats, and thermal threshold determinations were made by an investigator who was unaware of the infusion rate. Mean +/- SEM median effective concentration (EC(50)) for remifentanil and its active metabolite, GR90291, for the thermal threshold test was 1.00 +/- 0.35 ng/mL and 307 +/- 28 ng/mL of blood, respectively. Dysphoria was detected in all awake cats at the 2 highest remifentanil infusion rates. However, isoflurane MAC during remifentanil infusions was unchanged from baseline values, even at blood opioid concentrations approximately 75 times the analgesic EC(50). Immobility and analgesia as reflected by thermal threshold testing were independent anesthetic end points in the cats. Results of MAC-sparing evaluations should not be used to infer analgesic potency without prior validation of an MAC-analgesia relationship for specific drugs and species.
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              Issues in the design and interpretation of minimum alveolar anesthetic concentration (MAC) studies.

              The two experimental designs (quantal and bracketing) used for population minimum alveolar anesthetic concentration studies give equivalent results. An expression relating variability in terms of Hill coefficients and SD is presented. Evolutionary implications of low population variability in anesthetic phenotypes is discussed.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 March 2016
                2016
                : 11
                : 3
                : e0152546
                Affiliations
                [1 ]Department of Veterinary Clinics and Surgery, School of Agricultural and Veterinarian Sciences, Sao Paulo State University, Jaboticabal, SP, Brazil
                [2 ]Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America
                University of Bari, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AE RWR. Performed the experiments: AE RWR DZF SSS CAAV. Analyzed the data: AE BHP RWR. Contributed reagents/materials/analysis tools: AE CAAV. Wrote the paper: AE RWR BHP DZF SSS CAAV. Obtained the animals: AE RWR. Obtained permission to use the laboratory: AE CAAV. Donated the animals after the experiments: RWR.

                ‡ These authors also contributed equally to this work.

                Article
                PONE-D-15-34031
                10.1371/journal.pone.0152546
                4809615
                27018890
                5ead0645-de0f-4843-8197-e5a09311d304
                © 2016 Escobar et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 August 2015
                : 16 March 2016
                Page count
                Figures: 1, Tables: 2, Pages: 12
                Funding
                This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico - 475127/2012-9 CNPq - Brazil. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Pró-reitoria de Pesquisa UNESP - 1769/009/13 PROPe/CDC. "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Animals
                Vertebrates
                Amniotes
                Birds
                Fowl
                Gamefowl
                Chickens
                Biology and Life Sciences
                Organisms
                Animals
                Vertebrates
                Amniotes
                Birds
                Poultry
                Chickens
                Biology and Life Sciences
                Agriculture
                Livestock
                Poultry
                Chickens
                Biology and Life Sciences
                Organisms
                Animals
                Vertebrates
                Amniotes
                Birds
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Medicine and Health Sciences
                Cardiology
                Heart Rate
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Anesthetics
                Medicine and Health Sciences
                Pain Management
                Anesthetics
                Medicine and Health Sciences
                Anesthesiology
                Anesthesia
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Anesthesia
                Physical Sciences
                Chemistry
                Chemical Elements
                Oxygen
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Functional Electrical Stimulation
                Custom metadata
                All relevant data are within the paper.

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