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Introduced in the late 1950s, halothane became the anesthetic of choice for inhalational induction of children for over 40 years. Halothane enjoyed a generally favorable safety record during its time, but its cardiac contractility depressant effect-well tolerated by most age groups-was profoundly heightened in neonates and infants, leading to increased incidences of hypotension and cardiac arrest. The neonatal myocardium is immature and is characterized by poor ventricular compliance, poor contractility due to fewer contractile elements, immature sympathetic innervation with decreased norepinephrine stores, and immature mechanisms for storage and exchange of calcium in the sarcoplasmic reticulum. In vitro studies of myocardial contractility of mammalian fetal and adult myocardium demonstrated that the fetal heart was twice as sensitive to halothane as the adult. Clinical studies demonstrated that most neonates and infants less than 6 months of age experienced hypotension during halothane induction of anesthesia and significantly (p < .01) greater decreases in blood pressure than older children at equipotent concentrations of halothane. Intraoperative cardiac arrest during the halothane era occurred over twice as frequently in neonates aged less than 1 month than in infants aged 1-12 months and nearly 10 times more frequently than children 1-5 years of age. Halothane was associated with 66% of intraoperative drug-related cardiac arrests in children. The halothane era began to close in the late 1990s with the introduction of sevoflurane, which had a more favorable hemodynamic profile. Shortly thereafter, halothane was completely displaced from pediatric anesthesia practice in North America., (© 2024 John Wiley & Sons Ltd.)

Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through I Kr inhibition in vivo, but its potential to develop torsade de pointes will be small.

Fast gamma oscillations, generated within the retina, and transmitted to the cortex via the lateral geniculate nucleus (LGN), are thought to carry information about stimulus size and continuity. This hypothesis relies mainly on studies conducted under anesthesia and the extent to which it holds under more naturalistic conditions remains unclear. Using multielectrode recordings of spiking activity in the retina and the LGN of both male and female cats, we show that visually driven gamma oscillations are absent for awake states and are highly dependent on halothane (or isoflurane). Under ketamine, responses were nonoscillatory, as in the awake condition. Response entrainment to the monitor refresh was commonly observed up to 120 Hz and was superseded by the gamma oscillatory responses induced by halothane. Given that retinal gamma oscillations are contingent on halothane anesthesia and absent in the awake cat, such oscillations should be considered artifactual, thus playing no functional role in vision. SIGNIFICANCE STATEMENT Gamma rhythms have been proposed to be a robust encoding mechanism critical for visual processing. In the retinogeniculate system of the cat, many studies have shown gamma oscillations associated with responses to static stimuli. Here, we extend these observations to dynamic stimuli. An unexpected finding was that retinal gamma responses strongly depend on halothane concentration levels and are absent in the awake cat. These results weaken the notion that gamma in the retina is relevant for vision. Notably, retinal gamma shares many of the properties of cortical gamma. In this respect, oscillations induced by halothane in the retina may serve as a valuable preparation, although artificial, for studying oscillatory dynamics., (Copyright © 2023 the authors.)

The objective of this study was to determine if ractopamine (RAC) impacts postmortem muscle metabolism and subsequent pork quality in Halothane (HAL) and Rendement Napole (RN) mutant pigs. All RAC fed pigs had increased (P < 0.04) L* values. HAL and RN mutants muscle had lower (P < 0.01) pH values but RAC feeding had no effect. RN mutants had higher and lower (P < 0.05) muscle pH and temperatures, respectfully at 15 min and RN mutant pigs had greater (P < 0.0001) glycogen initially but lactate levels similar to wild type (WT) pigs at 24 h. RAC lowered (P < 0.05) glycogen in RN mutants but not in HAL mutated or WT pig muscle. These data show RAC feeding changes postmortem energy metabolism but does not change pH and pork quality hallmark of two major pig gene mutations and supports our contention that ultimate meat quality traits and their biochemical drivers may be more complex than originally reasoned., (Published by Elsevier Ltd.)

Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic doses (0.05, 0.5 and 5 mg/kg/10 min) of typical PPIs omeprazole, lansoprazole and rabeprazole, using halothane-anesthetized dogs (n = 6 for each drug). The low and middle doses of omeprazole and lansoprazole increased or tended to increase the heart rate, cardiac output and ventricular contraction, whereas the high dose plateaued and decreased them. Meanwhile, the low and middle doses of omeprazole and lansoprazole decreased the total peripheral vascular resistance, whereas the high dose plateaued and increased it. Rabeprazole decreased the mean blood pressure in a dose-related manner; moreover, its high dose decreased the heart rate and tended to reduce the ventricular contractility. On the other hand, omeprazole prolonged the QRS width. Omeprazole and lansoprazole tended to prolong the QT interval and QTcV, and rabeprazole mildly but significantly prolonged them in a dose-related manner. High dose of each PPI prolonged the ventricular effective refractory period. Omeprazole shortened the terminal repolarization period, whereas lansoprazole and rabeprazole hardly altered it. In effects, PPIs can exert multifarious cardiohemodynamic and electrophysiological actions in vivo, including mild QT-interval prolongation; thus, PPIs should be given with caution to patients with reduced ventricular repolarization reserve.

Purpose: Malignant hyperthermia (MH) is a potentially fatal hypermetabolic condition triggered by certain anesthetics and caused by defective calcium homeostasis in skeletal muscle cells. Recent evidence has revealed impairment of various biochemical pathways in MH-susceptible patients in the absence of anesthetics. We hypothesized that clinical differences between MH-susceptible and control individuals are reflected in measurable differences in myoplasmic metabolites., Methods: We performed metabolomic profiling of skeletal muscle samples from MH-negative (control) individuals and MH-susceptible patients undergoing muscle biopsy for diagnosis of MH susceptibility. Cellular metabolites were extracted from 33 fresh and 87 frozen human muscle samples using solid phase microextraction and Metabolon® untargeted biochemical profiling platforms, respectively. Ultra-performance liquid chromatography-high resolution mass spectrometry was used for metabolite identification and validation, followed by analysis of differences in metabolites between the MH-susceptible and MH-negative groups., Results: Significant fold-change differences between the MH-susceptible and control groups in metabolites from various pathways were found (P value range: 0.009 to < 0.001). These included accumulation of long chain acylcarnitines, diacylglycerols, phosphoenolpyruvate, histidine pathway metabolites, lysophosphatidylcholine, oxidative stress markers, and phosphoinositols, as well as decreased levels of monoacylglycerols. The results from both analytical platforms were in agreement., Conclusion: This metabolomics study indicates a shift from utilization of carbohydrates towards lipids for energy production in MH-susceptible individuals. This shift may result in inefficiency of beta-oxidation, and increased muscle protein turnover, oxidative stress, and/or lysophosphatidylcholine levels.

We assessed concentration-dependent effects of halothane or isoflurane inhalation on the electrocardiographic and hemodynamic variables using a cross-over design in intact beagle dogs (n = 4). Elevation of inhaled halothane from 1.0% to 2.0% or isoflurane from 1.5% to 2.5% decreased the mean blood pressure and prolonged the QRS width without significantly altering the heart rate, PR interval or QT interval. However, the observed changes disappeared after regressions of both anesthetic conditions to their initial settings. These results indicate that hypotension-induced, reflex-mediated increase of sympathetic tone may have counterbalanced the direct negative chronotropic, dromotropic and repolarization slowing effects of the anesthetics., Competing Interests: Declaration of competing interest The authors declared no potential conflict of interest except for H.S., K.H. and Y.A., who were employees of CMIC Pharma Science Co., Ltd., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

We compared dl-sotalol-induced electrocardiographic responses in intact dogs using a repeated-measures design among 1% halothane anesthesia, 1.5% isoflurane anesthesia with nitrous oxide (N 2 O), and conscious state to clarify influences of the anesthetics (n = 4). Basal PR interval was longer in halothane than either in isoflurane with N 2 O or in conscious state, reflecting sympathetic nerve suppression for the atrioventricular node by halothane. Both anesthetics exhibited longer basal QRS width than conscious state, suggesting their ventricular I Na inhibition. Also, both anesthetics showed longer basal QT interval, QTcF and T peak -T end than conscious state, indicating their ventricular I Kr inhibition. Meanwhile, dl-sotalol prolonged PR interval similarly in isoflurane with N 2 O and in conscious state, which was less great in halothane, suggesting further sympathetic nerve suppression for the atrioventricular node might be limited in halothane. dl-Sotalol prolonged QT interval and QTcF >3 times greater in either of the anesthetics than in conscious state; moreover, dl-sotalol prolonged T peak -T end similarly in both anesthetics, but hardly altered it in conscious state; indicating isoflurane with N 2 O as well as halothane may have reduced the repolarization reserve to increase the sensitivity of ventricle toward I Kr suppression. Thus, isoflurane with nitrous oxide could be useful for in vivo I Kr assay like halothane., Competing Interests: Declaration of competing interest The authors declared no potential conflict of interest except for H.S., K.H. and Y.A., who were employees of CMIC Pharma Science Co., Ltd., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Drug-induced liver injury (DILI) is a major safety concern in drug development. Halothane (HAL), an inhaled anesthetic, induces severe and idiosyncratic liver injury. Ryanodine receptors (RyR) are major intracellular calcium release channels found on the plasma membrane of the endoplasmic reticulum (ER). It has been reported that disordered hepatic calcium homeostasis is a feature of HAL-induced liver injury (HILI) in guinea pigs. However, there are no reports on whether RyR could mediate the pathogenesis of HILI. The aim of the present study was to investigate the effect of RyR on HILI. Ryanodine (RYA, RyR agonist, 50 μg/kg, i.p.) was administered to BALB/c female mice 1 h before HAL administration (15 mmol/kg, i.p.), which significantly elevated plasma transaminase levels and induced severe hepatic inflammation and necrosis. In contrast, dantrolene sodium (DAN, RyR antagonist) treatment significantly suppressed HILI in a dose- and time-dependent manner and alleviated liver damage. The number of infiltrated neutrophils in the liver were higher in the group treated with HAL + RYA than in the group treated with HAL alone, while DAN treatment decreased neutrophil infiltration in HILI. The hepatic mRNA levels of proinflammatory cytokines; chemokines; and factors related to danger signals, neutrophils, oxidative and ER stress, pro-apoptosis, and RyR were significantly increased with RYA pretreatment, whereas these levels were decreased with DAN treatment. These results suggest that RYA exacerbates HILI, and DAN exerts a protective effect against HILI. Hence, our study provides a novel insight regarding the effect of RyR in the mechanism underlying HILI., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The purpose of this study was to evaluate the pharmacokinetics of morphine in combination with dexmedetomidine and maropitant injected intramuscularly in dogs under general anaesthesia. Eight healthy dogs weighing 25.76 ± 3.16 kg and 3.87 ± 1.64 years of age were used in a crossover study. Dogs were randomly allocated to four groups: (1) morphine 0.6 mg/kg; (2) morphine 0.3 mg/kg + dexmedetomidine 5 μg/kg; (3) morphine 0.3 mg/kg + maropitant 1 mg/kg; (4) morphine 0.2 mg/kg + dexmedetomidine 3 μg/kg + maropitant 0.7 mg/kg. Blood samples were collected before, 15 and 30 min, and 1, 2, 3 4, 6 and 8 hr after injection of the test drugs. Plasma concentration of the drugs was determined by liquid chromatography-mass spectrometry. The elimination half-life (T 1/2 ) of morphine was higher and the clearance rate (CL) was lower when combined with dexmedetomidine (T 1/2  = 77.72 ± 20.27 min, CL = 119.41 ± 23.34 ml kg -1  min -1 ) compared to maropitant (T 1/2  = 52.73 min ± 13.823 ml kg -1  min -1 , CL = 178.57 ± 70.55) or morphine alone at higher doses (T 1/2  = 50.53 ± 12.55 min, CL = 187.24 ± 34.45 ml kg -1  min -1 ). Combining morphine with dexmedetomidine may increase the dosing interval of morphine and may have a clinical advantage., (© 2019 John Wiley & Sons Ltd.)

Although instrumental for optimizing their pharmacological activity, a molecular understanding of the preferential interactions given by volatile anesthetics is quite poor. This paper confirms the ability of halothane to work as a hydrogen-bond (HB) donor and gives the first experimental proof that halothane also works as a halogen-bond (HaB) donor in the solid state and in solution. A halothane/hexamethylphosphortriamide co-crystal is described and its single-crystal X-ray structure shows short HaBs between bromine, or chlorine, and the phosphoryl oxygen. New UV/Vis absorption bands appear upon addition of diazabicyclooctane and tetra(n-butyl)ammonium iodide to halothane solutions, indicating that nitrogen atoms and anions may mediate the HaB-driven binding processes involving halothane as well. The ability of halothane to work as a bidentate/tridentate tecton by acting as a HaB and HB donor gives an atomic rationale for the eudismic ratio shown by this agent., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pigs with the Halothane (HAL) or Rendement Napole (RN) gene mutations demonstrate abnormal muscle energy metabolism patterns and produce meat with poor quality, classified as pale, soft, and exudative (PSE) meat, but it is not well understood how HAL and RN mutations regulate glucose and energy metabolism in porcine muscle. To investigate the potential signaling pathways and phosphorylation events related to these mutations, muscle samples were collected from four genotypes of pigs, wild type, RN, HAL, and RN-HAL double mutations, and subjected to quantitative proteomic and phosphoproteomic analysis using the TiO 2 enrichment strategy. The study led to the identification of 932 proteins from the nonmodified peptide fractions and 1885 phosphoproteins with 9619 phosphorylation sites from the enriched fractions. Among them, 128 proteins at total protein level and 323 phosphosites from 91 phosphoproteins were significantly regulated in mutant genotypes. The quantitative analysis revealed that the RN mutation mainly affected the protein expression abundance in muscle. Specifically, high expression was observed for proteins related to mitochondrial respiratory chain and energy metabolism, thereby enhancing the muscle oxidative capacity. The high content of UDP-glucose pyrophosphorylase 2 (UGP2) in RN mutant animals may contribute to high glycogen storage. However, the HAL mutation mainly contributes to the up-regulation of phosphorylation in proteins related to calcium signaling, muscle contraction, glycogen, glucose, and energy metabolism, and cellular stress. The increased phosphorylation of Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) in HAL mutation may act as a key regulator in these processes of muscle. Our findings indicate the different regulatory mechanisms of RN and HAL mutations in relation to porcine muscle energy metabolism and meat quality.

Background: The volatile anesthetic isoflurane may exert a rapid and long-lasting antidepressant effect in patients with medication-resistant depression. The mechanism underlying the putative therapeutic actions of the anesthetic have been attributed to its ability to elicit cortical burst suppression, a distinct EEG pattern with features resembling the characteristic changes that occur following electroconvulsive therapy. It is currently unknown whether the antidepressant actions of isoflurane are shared by anesthetics that do not elicit cortical burst suppression., Methods: In vivo electrophysiological techniques were used to determine the effects of isoflurane and halothane, 2 structurally unrelated volatile anesthetics, on cortical EEG. The effects of anesthesia with either halothane or isoflurane were also compared on stress-induced learned helplessness behavior in rats and mice., Results: Isoflurane, but not halothane, anesthesia elicited a dose-dependent cortical burst suppression EEG in rats and mice. Two hours of isoflurane, but not halothane, anesthesia reduced the incidence of learned helplessness in rats evaluated 2 weeks following exposure. In mice exhibiting a learned helplessness phenotype, a 1-hour exposure to isoflurane, but not halothane, reversed escape failures 24 hours following burst suppression anesthesia., Conclusions: These results are consistent with a role for cortical burst suppression in mediating the antidepressant effects of isoflurane. They provide rationale for additional mechanistic studies in relevant animal models as well as a properly controlled clinical evaluation of the therapeutic benefits associated with isoflurane anesthesia in major depressive disorder., (© The Author(s) 2018. Published by Oxford University Press on behalf of CINP.)

Little is known about the effects of inhalant anaesthetics on the avian electroencephalogram (EEG). The effects of halothane on the avian EEG are of interest, as this agent has been widely used to study nociception and analgesia in mammals. The objective of this study was to characterize the effects of halothane anaesthesia on the EEG of the chicken. Twelve female Hyline Brown chickens aged 8-10 weeks were anaesthetized with halothane in oxygen. For each bird, anaesthesia was progressively increased from 1-1.5 to 2 times the Minimum Anesthetic Concentration (MAC), then progressively decreased again. At each concentration, a sample of EEG was recorded after a 10-min stabilization period. The mean Total Power (P TOT ), Median Frequency (F50) and 95% Spectral Edge Frequency (F95) were calculated at each halothane MAC, along with the Burst Suppression Ratio (BSR). Burst suppression was rare and BSR did not differ between halothane concentrations. Increasing halothane concentration from 1 to 2 MAC resulted in a decrease in F50 and increase in P TOT , while F95 increased when MAC was reduced from 1.5 to 1. The results indicate dose-dependent spectral EEG changes consistent with deepening anaesthesia in response to increasing halothane MAC. As burst suppression was rare, even at 1.5 or 2 times MAC, halothane may be a suitable anaesthetic agent for use in future studies exploring EEG activity in anaesthetized birds., (© 2018 The Authors. Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

In order to better understand the variability of pharmacodynamic and pharmacokinetic profiles of terfenadine between the previous studies as well as to qualitatively and quantitatively examine the proarrhythmic potential of its major active metabolite fexofenadine in comparison with that of terfenadine, we directly compared their electropharmacological effects with halothane-anesthetized dogs (n = 3). For this purpose, we adopted a cross-over design, which can directly compare the effects of terfenadine and fexofenadine under the identical metabolic condition. Terfenadine in doses of 0.03 and 0.3 mg/kg increased the mean blood pressure, but that of 3 mg/kg decreased it. Terfenadine also increased the heart rate and ventricular contractility in a dose-related manner; but delayed the atrioventricular nodal and intraventricular conductions as well as repolarization suggesting its proarrhythmic potential. Meanwhile, fexofenadine in the same dose increased the mean blood pressure in a dose-related manner without affecting any of the electrophysiological variables in the same animals that proarrhythmic risk of terfenadine was confirmed, indicating its lack of proarrhythmic risk. Peak plasma concentrations for fexofenadine were 3.7, 8.1 and 11.2 times greater than for terfenadine at each matching dose, indicating terfenadine may be metabolized much faster than fexofenadine. Taken together, after the low and middle doses of terfenadine, vasopressor effect of a metabolite fexofenadine could be greater than the depressor effect of parent compound terfenadine, but its reverse would be correct after the high dose. Thus, the cross-over analysis can be an effective way to better understand drug-induced cardiovascular responses.

Background: Occupational exposure to halogenated hydrocarbons has been associated with halothane hepatitis, an increase of liver enzymes, and congenital malformations. The objectives of this study were to investigate whether bromide, a urinary metabolite of halothane, could be used as a biological marker of exposure to this anesthetic gas and assessment of associated exposure to halothane with any significant changes in conventional parameters of liver function (serum aminotransferase activities)., Study Design: A cross-sectional study., Methods: Seventy-five anesthesiologists, anesthesia nurses, operating room nurses, and surgeons (exposed group) and 75 matched unexposed individuals (reference group) were selected randomly from two public hospitals in Hamadan City, western Iran.  Atmospheric concentrations of halothane in the breathing zone of the exposed subjects and urinary bromide levels were measured by headspace gas chromatography. Similarly, serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by the enzymatic method using an automatic Prestige instrument., Results: Mean atmospheric concentrations of halothane and urinary bromide levels for exposed subjects were 1.49 ±1.36 ppm and 0.83 ±0.29 mM, respectively. A relatively good correlation was found between exposure to halothane and urinary bromide levels (r=0.38). The chi-squared test results showed that the proportions of the subjects with abnormal ALT and AST among the women exposed were significantly higher than those of reference individuals (P<0.05)., Conclusions: Urinary bromide can be used as a potential biomarker of exposure to halothane, although additional studies are necessary to further validate these initial findings.

Fatal cases with the use of atypical antipsychotic drug paliperidone have been reported; however, there was no clinical report describing paliperidone-induced torsade de pointes. In this study we assessed its electropharmacological effects together with its proarrhythmic potential in intravenous doses of 0.03, 0.3 and 3 mg/kg using the halothane-anesthetized dogs (n = 5), which could provide approximately 2, 20 and 200 times higher peak plasma drug concentrations than its therapeutic level, respectively. Paliperidone exerted potent vasodilator effect resulting in hypotension, which may be largely explained by its α 1 -adrenoceptor blocking action. In vivo electrophysiological results suggest that paliperidone may inhibit human ether-à-go-go-related gene K + channel in a dose-related manner and modestly suppress Na + channel in the in situ heart. The high dose of paliperidone may have some potential to induce early afterdepolarization that can trigger lethal ventricular arrhythmias, whereas the low and middle doses lack such proarrhythmic possibility, indicating that at least 20 times higher plasma concentration may be considered to be safe., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: The use of equipment powered by electricity in the operating room increased the risk of fires in the presence of flammable agents such as ether and cyclopropane. Chloroform was associated with cardiac arrhythmias and liver damage. The introduction of halothane in the late 1950s was heralded as a solution to many problems facing the specialty of anesthesia. We explore whether the manufacturer promptly reported halothane's adverse effects to regulatory agencies and practitioners., Sources: We consulted documents submitted by Ayerst Laboratories to federal authorities through the Freedom of Information Act, promotional advertisements, package inserts, published articles, and textbooks., Results: Two major complications associated with the use of halothane, cardiac arrhythmias and the risk of hepatotoxicity, were disclosed by the manufacturer when the drug was first introduced to the US market. Reports appeared timely and complete; there was no apparent attempt to conceal or otherwise downplay these risks., Conclusion: The process of drug discovery and approval for clinical use has always been a lengthy, complex, and extremely expensive undertaking, with only a small minority of compounds receiving approval. The risk of adverse effects or drug interaction directly impacts commercial viability. In the case of halothane, the manufacturer disclosed major adverse effects, and the drug enjoyed decades of popularity until it was replaced by agents with a better drug profile., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Our asphyxia cardiac arrest (ACA) rat model is well established. The original model was designed in the 1990th using halothane and nitrous oxide for pre-insult anesthesia. Because of its hepato-toxicity and its potential to induce severe liver failures, halothane is no longer used in clinical anesthesia for several years. In order to minimize the health risk for our laboratory staff as well as to keep the experimental settings of our model on a clinically oriented basis we decided to replace halothane by sevoflurane. In this study we intended to determine if the change of the narcotic gas regiment causes changes in the neurological damage and how far our model had to be adjusted., Methods: Adult rats were subjected to 5min of ACA followed by resuscitation. There were four treatment groups: ACA - halothane, ACA - sevoflurane and with halothane or sevoflurane sham operated animals. Vital and blood parameters were monitored during the 45min post-resuscitation intensive care phase. After a survival time of 7 days histological evaluation of the hippocampus was performed., Results: We observed that resuscitated rats anesthetized prior by sevoflurane (i) have had a lower heart rate and a higher MAP compared to halothane anesthetized animals; (ii) The neurological damaged were significantly reduced in the hippocampal CA1 region in sevoflurane treated rats., Conclusion: Using sevoflurane instead of halothane for anesthesia requires some physiological and experimental changes. However the model keeps its validity. Sevoflurane caused less pronounced neurodegeneration in the CA1 region of the hippocampus. This had to be considered in further resuscitation-studies containing sevoflurane as anesthetic. Institutional protocol number for animal studies: 42502-2-2-947 Uni MD., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In order to bridge the gap of action of dl-sotalol between the human ether-a-go-go-related gene (hERG) K(+) channel inhibition in vitro and QT-interval prolongation in vivo, its electropharmacological effect and pharmacokinetic property were simultaneously studied in comparison with those of 10 drugs having potential to prolong the QT interval (positive drugs: bepridil, haloperidol, dl-sotalol, terfenadine, thioridazine, moxifloxacin, pimozide, sparfloxacin, diphenhydramine, imipramine and ketoconazole) and four drugs lacking such property (negative drugs: enalapril, phenytoin, propranolol or verapamil) with the halothane-anesthetized guinea pig model. A dose of each drug that caused 10 % prolongation of Fridericia-corrected QT interval (QTcF) was calculated, which was compared with respective known hERG K(+) IC50 value and currently obtained heart/plasma concentration ratio. Each positive drug prolonged the QTcF in a dose-related manner, whereas such effect was not observed by the negative drugs. Drugs with more potent hERG K(+) channel inhibition showed higher heart/plasma concentration ratio, resulting in more potent QTcF prolongation in vivo. The potency of dl-sotalol for QTcF prolongation was flat middle, although its hERG K(+) channel inhibitory property as well as heart/plasma concentration ratio was the smallest among the positive drugs, which may be partly explained by its lack of binding to plasma protein.

Vidarabine has been used for the treatment of patients with local and systemic herpes virus infection; moreover, it was recently reported that it inhibits cardiac type 5 adenylyl cyclase. Furthermore, vidarabine has been shown to suppress atrial fibrillation and improve congestive heart failure in experimental models of mice induced by the isoproterenol infusion. Since information that can explain its experimentally demonstrated efficacy against congestive heart failure and atrial fibrillation remains limited, in this study we precisely assessed cardio-electropharmacological effect using the halothane-anesthetized canine model. Vidarabine was intravenously administrated in three escalating doses of 1, 10, 100 mg/kg over 10 min with a pause between the doses (n = 4). Meanwhile, the vehicle dimethyl sulfoxide in volumes of 0.033, 0.033 and 0.33 mL/kg was intravenously administrated in the same manner as was vidarabine (n = 4). No significant difference was detected in any cardiohemodynamic or electrophysiological variables between the vehicle- and vidarabine-treated groups, which indicates that effective doses of vidarabine adequately inhibiting type 5 adenylyl cyclase did not affect the cardiovascular variables in vivo at all, showing its cardiac safety profile under physiological condition. Thus, the clinical utility of vidarabine might be limited to the pathological situation including congestive heart failure with increased adrenergic tone and/or sympathetic nerve-dependent atrial fibrillation.

Background: The effects of anesthesia on the equine electroencephalogram (EEG) after administration of various drugs for sedation, induction, and maintenance are known, but not that the effect of inhaled anesthetics alone for EEG recording., Objective: To determine the effects of isoflurane and halothane, administered as single agents at multiple levels, on the EEG and quantitative EEG (qEEG) of normal horses., Animals: Six healthy horses., Methods: Prospective study. Digital EEG with video and quantitative EEG (qEEG) were recorded after the administration of one of the 2 anesthetics, isoflurane or halothane, at 3 alveolar doses (1.2, 1.4 and 1.6 MAC). Segments of EEG during controlled ventilation (CV), spontaneous ventilation (SV), and with peroneal nerve stimulation (ST) at each MAC multiple for each anesthetic were selected, analyzed, and compared. Multiple non-EEG measurements were also recorded., Results: Specific raw EEG findings were indicative of changes in the depth of anesthesia. However, there was considerable variability in EEG between horses at identical MAC multiples/conditions and within individual horses over segments of a given epoch. Statistical significance for qEEG variables differed between anesthetics with bispectral index (BIS) CV MAC and 95% spectral edge frequency (SEF95) SV MAC differences in isoflurane only and median frequency (MED) differences in SV MAC with halothane only., Conclusions and Clinical Importance: Unprocessed EEG features (background and transients) appear to be beneficial for monitoring the depth of a particular anesthetic, but offer little advantage over the use of changes in mean arterial pressure for this purpose., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Since amantadine-induced long QT syndrome has been clinically reported, we investigated its electropharmacological effects to estimate the extent of proarrhythmic risk by using the halothane-anesthetized beagle dogs (n = 4). Amantadine in doses of 0.1, 1 and 10 mg/kg was infused over 10 min with a pause of 20 min under the monitoring of multiple cardiovascular variables. J-Tpeak and Tpeak-Tend were separately measured on the lead II electrocardiogram to precisely analyze the net balance between inward and outward current modifications by amantadine. The low dose increased the ventricular contractile force, but suppressed the intraventricular conduction. The middle dose prolonged the QT interval besides enhancing the changes induced by the low dose. The high dose increased the mean blood pressure, left ventricular end-diastolic pressure and total peripheral resistance, and accelerated the atrioventricular nodal conduction, but decreased the cardiac output besides enhancing the changes induced by the middle dose. A reverse use-dependence was confirmed in the repolarization delay. Amantadine hardly affected the J-Tpeak, but prolonged the Tpeak-Tend. Amantadine can be considered to stimulate Ca(2+) channel but inhibit Na(+) and K(+) channels in the in situ heart. J-Tpeak and Tpeak-Tend analysis suggests that amantadine may possess modest risk for arrhythmia.

Background: Previous study of the diagnostic validity of electroencephalography (EEG) to detect abnormalities in equine cerebral cortical function relied on the administration of various drugs for sedation, induction, and maintenance of general anesthesia but used identical criteria to interpret recordings., Objectives: To determine the effects of 2 inhalation anesthetics on the EEG of healthy horses., Animals: Six healthy horses., Methods: Prospective study. After the sole administration of one of either isoflurane or halothane at 1.2, 1.4, and 1.6 times the minimum alveolar concentration, EEG was recorded during controlled ventilation, spontaneous ventilation, and nerve stimulation., Results: Burst suppression was observed with isoflurane, along with EEG events that resembled epileptiform discharges. Halothane results were variable between horses, with epileptiform-like discharges and bursts of theta, alpha, and beta recorded intermittently. One horse died and 2 were euthanized as the result of anesthesia-related complications., Conclusions and Clinical Importance: The results of this study indicate that the effects of halothane and isoflurane on EEG activity in the normal horse can be quite variable, even when used in the absence of other drugs. It is recommended that equine EEG be performed without the use of these inhalation anesthetics and that general anesthesia be induced and maintained by other contemporary means., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Cardiovascular effects of a highly selective prostaglandin E2 type 4 (EP4) receptor agonist ONO-AE1-329 were assessed with the halothane-anesthetized dogs (n=6). ONO-AE1-329 was intravenously infused in three escalating doses of 0.3, 1 and 3ng/kg/min for 10min with a pause of 20min between the doses. The low dose of 0.3ng/kg/min significantly increased maximum upstroke velocity of left ventricular pressure by 18% at 20min, indicating increase of ventricular contractility. The middle dose of 1ng/kg/min significantly decreased total peripheral resistance by 24% and left ventricular end-diastolic pressure by 32% at 10min, indicating dilation of arteriolar resistance vessels and venous capacitance ones, respectively; and increased cardiac output by 25% at 10min in addition to the change induced by the low dose. The high dose of 3ng/kg/min increased heart rate by 34% at 10min; decreased mean blood pressure by 14% at 10min and atrioventricular nodal conduction time by 13% at 5min; and shortened left ventricular systolic period by 8% at 10min and electromechanical coupling defined as an interval from completion of repolarization to the start of ventricular diastole by 39% at 10min in addition to the changes induced by the middle dose. No significant change was detected in a ventricular repolarization period. These results indicate that ONO-AE1-329 may possess a similar cardiovascular profile to typical phosphodiesterase 3 inhibitors as an inodilator, and suggest that EP4 receptor stimulation can become an alternative strategy for the treatment of congestive heart failure., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Malignant hyperthermia is a well-known rare life-threatening autosomal-dominant pharmacogenetic disease, The arti- cle deals with a halothane-caffeine contracture test. The test is a model of muscle reaction to triggers in-vitro and it is the "golden standard" for malignant hyperthermia susceptibility (MHS) diagnosis. Genetic analysis is less invasive, but its sensitivity is significantly lower. The review discusses both the methods which are essential to be completely reproduced in Russia, and their role in modern approach to MHS diagnosis.

MicroRNAs (miRNA) form a class of small non-coding RNA molecules that negatively regulate gene expression. Most cellular pathways are modulated by miRNAs. However, the pathophysiological role of miRNAs during drug-induced liver injury (DILI) remains largely unknown. In this study, the possible involvement of miRNAs in DILI caused by the hepatotoxic drug halothane (HAL) was investigated. Toward this purpose, miRNA microarray studies of HAL-induced liver injury were performed in mice at five different time points up to 24h after dosing. To exclude any pharmacological effects on miRNA expression, isoflurane was used as a low hepatotoxic drug because it is structurally similar to HAL. Approximately 30-50% of the miRNA expression levels changed more than two-fold at every time point. In silico biological pathway analysis was performed to predict the targeted genes. Consequently, the miRNA gene down-regulation that occurred 1h after HAL administration was primarily related to inflammation, immune systems and liver injury. Based on additional in silico analyses, we identified miR-106b. Subsequently target of miR-106b was investigated using liver samples from mice with HAL-induced liver injury. Among the predicted targets, we discovered that a signal transducer and activator of transcription 3 (STAT3) was particularly up-regulated beginning during the early phase of HAL-induced liver injury. Collectively, the suppressed miR-106b expression, as well as the subsequent up-regulation of STAT3, was critical for the pathogenesis of HAL-induced liver injury., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Sevoflurane is a known triggering agent of malignant hyperthermia (MH). The present study analyzed different effects of sevoflurane on skeletal muscle of MH susceptible and nonsusceptible individuals in vitro and compared the results to the standardized test protocol with halothane and caffeine. A potential influence of a present ryanodine receptor type 1 (RyR1) mutation was investigated., Methods: Muscle bundles of 24 MH-susceptible patients with or without an RyR1 mutation, 35 MH-nonsusceptible and 10 MH-equivocal patients were exposed either to sevoflurane 8 vol% bolus or increasing doses of 2, 4, 6, and 8 vol%. In MH-positive patients, a screening for mutations in the RyR1 gene was performed., Results: The in vitro parameters initial length, weight, predrug resting tension, and predrug twitch height did not differ between the groups. Sevoflurane caused significant contractures in MH-susceptible but not in MH-nonsusceptible muscle after increasing doses [1.4 (0.3-6.0) vs. 0 (0-0) mN] and after bolus application [6.9 (2.4-21.4) vs. 0 (0-0) mN]. However, only 50% of the susceptible patients developed contractures ≥ 2 mN after increasing concentrations while 83% did so after rapid bolus administration. Presence of an RyR1 mutation was detected in 36% of the examined MH-positive patients but had no influence on developing contractures., Conclusion: Sevoflurane-induced contractures do not reliably detect MH susceptibility on an individual level. Therefore, sevoflurane is no suitable alternative for diagnostic use. Mutation-specific effects regarding contracture sizes after incubation with sevoflurane, halothane, or caffeine were not found., (© 2013 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Malignant hyperthermia (MH) is a potentially lethal disorder of skeletal muscle triggered by anesthetic agents. A histomorphological examination of diseased muscle may provide insight into MH pathophysiology, but it is not a routine part of standard-of-care practice for the identification of MH-susceptibility. In this study, we investigated muscle histomorphology in a large cohort of MH-susceptible (MHS) patients and examined its relationship to genotype and phenotype., Methods: All consenting patients who were identified as MHS based on a caffeine-halothane contracture test (CHCT) performed during 1992-2011 were retrospectively identified and recruited for this study. Results of the histomorphological examination, which is a routine part of our centre-specific practice, were reviewed. Patient demographics, MH proband status, histological features, CHCTs, and genetic results for MH-causative mutations were summarized., Results: Seven of the 399 patients classified as MHS had histological characteristics consistent with central core disease, and one patient was a carrier of Duchenne's muscular dystrophy. Eighty-six (22%) patients had histological abnormalities, and five (6%) of these had evidence of "frank" myopathy. No histologic abnormalities were consistent among the MHS patients; however, a higher proportion of MH probands had abnormal histomorphology compared with the general MHS population, and patients with evidence of "frank" myopathy showed similarities in clinical history, biochemistry, CHCT, and genetic testing., Conclusion: Despite the inability of the histomorphological examination to identify consistent features in MHS patients, histology may serve as a potential adjunct to CHCT and aid in the identification of other myopathies. Nevertheless, the specifics of its utility ought to be assessed in other studies and by way of formal cost-effectiveness analysis.

The fluoroquinolone antibiotic ciprofloxacin has been reported to block delayed rectifier K(+) channels at much higher concentrations than those at which it exerts its bactericidal activity. In this study using the halothane-anesthetized guinea pig, we assessed whether ciprofloxacin has a proarrhythmic activity. Ciprofloxacin at a clinically relevant dose of 3 mg/kg, i.v. did not affect any electrocardiographic parameters. At 10 mg/kg, it prolonged the QT interval and the duration of the monophasic action potential of the ventricle under sinus rhythm and constant ventricular pacing (n = 6). The extents of its effects on the ventricular repolarization phase were comparable to those of another fluoroquinolone antibiotic moxifloxacin at a clinically relevant dose of 3 mg/kg (n = 6). Meanwhile, the PR interval and QRS width were also increased by ciprofloxacin at 10 mg/kg, suggesting that the drug inhibited cardiac K(+) channels as well as Na(+) and Ca(2+) channels in vivo. These results suggest that ciprofloxacin exerted a multi-ion channel-blocking action in the heart within the supra-therapeutic dose range. Therefore, careful observation may be necessary for patients with heart disease receiving a higher dose of ciprofloxacin in order to prevent the emergence of resistance.

Although suppression of thermoregulatory mechanisms by anesthetics is generally assumed, the extent to which thermoregulation is active during general anesthesia is not known. The only thermoregulatory responses available to anesthetized, hypothermic patients are vasoconstriction and nonshivering thermogenesis. To test anesthetic effects on thermoregulation, the authors measured skin-surface temperature gradients (forearm temperature - fingertip temperature) as an index of cutaneous vasoconstriction in unpremedicated patients anesthetized with 1% halothane and paralyzed with vecuronium during elective, donor nephrectomy. Patients were randomly assigned to undergo maximal warming (warm room, humidified respiratory gases, and warm intravenous fluids; n = 5) or standard temperature management (no special warming measures; n = 5). Skin-surface temperature gradients of 4°C or more were prospectively defined as significant vasoconstriction. Normothermic patients (average minimum esophageal temperature = 36.4° ± 0.3°C [SD]) did not demonstrate significant vasoconstriction. However, each hypothermic patient displayed significant vasoconstriction at esophageal temperatures ranging from 34.0 to 34.8°C (average temperature = 34.4° ± 0.2°C). These data indicate that active thermoregulation occurs during halothane anesthesia, but that it does not occur until core temperature is approximately 2.5°C lower than normal. In two additional hypothermic patients, increased skin-temperature gradients correlated with decreased perfusion as measured by a laser Doppler technique. Measuring skin-surface temperature gradients is a simple, noninvasive, and quantitative method of determining the thermoregulatory threshold during anesthesia.

Objective: To assess the effect of halothane (H), isoflurane (I) or sevoflurane (S) on the bispectral index (BIS), and the effect of the addition of meperidine in dogs subjected to ovariohysterectomy., Study Design: Prospective, randomized, blinded, clinical trial., Animals: Forty-eight female mixed-breed dogs, with weights varying from 10 to 25 kg., Methods: All dogs were premedicated with acepromazine (A) (0.1 mg kg(-1) IM) or A and meperidine (M) (3 mg kg(-1) IM) and they were divided into six groups of eight animals (AH, AMH, AI, AMI, AS, and AMS). Fifteen minutes after premedication they were anesthetized with propofol (5 mg kg(-1) IV) and then orotracheally intubated. Anesthesia was maintained with halothane, isoflurane or sevoflurane, respectively. The BIS, variables were recorded at 15 minutes after administering pre-anesthetic medication (T0); 10 minutes of anesthesia maintenance (T1); right ovarian pedicle ligation (T2); muscle suturing (T3); skin suture (T4) and 10 minutes after terminating the inhalant anesthetic (T5), respectively., Results: BIS values were decreased at all times when compared to the baseline values in all groups (p<0.05). In the comparative assessment between groups, the values obtained at T0 and T1 were similar for all groups. At T2, the values in AMH were lower than those obtained in AI, AMI and AS (p<0.05). At the same time significantly higher values were found for AI when compared to AMS (p<0.01). There was a correlation between the bispectral index and the expired anesthetic fraction in all groups., Conclusions and Clinical Relevance: Within groups given the same inhalant anesthetic the bispectral index was a good indicator for the degree of hypnosis in dogs, indicating a good correlation with the amount of anesthetic and the nociceptive stimulation. BIS was a less reliable indicator of relative anesthetic depth when comparing equipotent end-tidal concentrations between the three inhalants., (© 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)

Background: To diagnose malignant hyperthermia (MH) susceptibility, muscle bundles are exposed to halothane and caffeine. We investigated whether sevoflurane, which is more clinically relevant but less potent of an anesthetic, could replace halothane in diagnostic MH testing., Methods: With prior written consent, muscle bundles from 6 malignant hyperthermia susceptible (MHS) and 5 non-susceptible (MHN) individuals were exposed to increasing concentrations of sevoflurane (1.3; 2.6; 5.2 vol%). In addition, muscles from 9 MHS and 8 MHN were tested with a rapid exposure to 8 vol% of sevoflurane. Maximal contractures were measured and statistically analyzed (Mann-Whitney-U-test; P<0.05)., Results: There were no differences in weight, length or pre-drug tension of the muscle bundles. Incremental sevoflurane concentrations induced no differences in contracture between susceptible and non-susceptible muscles. The rapid application of sevoflurane induced significant contractures in all malignant hyperthermia susceptible compared with non-susceptible individuals., Conclusion: The rapid application of a high sevoflurane concentration but not an increasing stepwise application allowed for the diagnostic discrimination of susceptible individuals.

Objective: To assess the accuracy of isoflurane, halothane, and sevoflurane vaporizers during high oxygen flow and at maximum dial settings at room temperature and to test sevoflurane vaporizers similarly during heating and at low-fill states., Sample: 5 isoflurane, 5 halothane, and 5 sevoflurane vaporizers., Procedures: Vaporizers were tested at an oxygen flow of 10 L/min and maximum dial settings for 15 minutes under various conditions. All 3 vaporizer types were filled and tested at room temperature (21° to 23°C). Filled sevoflurane vaporizers were wrapped with circulating hot water (42°C) blankets for 2 hours and tested similarly, and near-empty sevoflurane vaporizers were tested similarly at room temperature. During each 15-minute test period, anesthetic agent concentration was measured at the common gas outlet with a portable refractometer and temperature of the vaporizer wall was measured with a thermistor., Results: For each vaporizer type, anesthetic agent concentrations and vaporizer wall temperatures decreased during the 15-minute test period. Accuracy of isoflurane and halothane vaporizers remained within the recommended 20% (plus or minus) deviation from dial settings. Heated and room-temperature sevoflurane vaporizers were accurate to within 23% and 11.7% (plus or minus) of dial settings, respectively. Sevoflurane vaporizers at low-fill states performed similarly to vaporizers at full-fill states., Conclusions and Clinical Relevance: Under these study conditions, the isoflurane and halothane vaporizer models tested were accurate but the sevoflurane vaporizers were not. Sevoflurane vaporizer accuracy was not affected by fill state but may be improved with vaporizer heating; measurements of inspired anesthetic agent concentrations should be obtained during the use of heated vaporizers.

Background: Malignant hyperthermia is a potentially lethal inherited hypermetabolic syndrome that develops in susceptible individuals following administration of depolarising neuromuscular relaxants or volatile anaesthetics. Genetic analysis can only confirm a diagnosis of malignant hyperthermia in about 70%, and in the remainder an in-vitro contracture test, with halothane and caffeine, on muscle obtained from open muscle biopsy is required to establish the diagnosis. As the licence for clinical use of halothane expired in 2005, its continuing availability is in doubt. More modern volatile anaesthetics such as enflurane, isoflurane, desflurane and sevoflurane are less potent triggers of malignant hyperthermia in humans and pigs. The aim of this study was to investigate whether these agents can be considered possible substitutes for halothane in a modified in-vitro contracture test., Method: With institutional review board approval and prior written consent, muscle bundles of 30 patients with a personal or family history of malignant hyperthermia were investigated. Of these, 13 were diagnosed malignant hyperthermia susceptible and 17 nonsusceptible. Surplus muscle was tested with increasing concentrations of enflurane, isoflurane, desflurane and sevoflurane., Results: There were no differences in weight, length or predrug tension of the muscle bundles. At increasing concentration, all volatile anaesthetics except sevoflurane induced significantly greater contractures in malignant hyperthermia susceptible compared to malignant hyperthermia nonsusceptible muscle. In malignant hyperthermia susceptible muscle bundles, halothane led to significantly higher contractures compared to the other investigated substances., Conclusion: Halothane was the strongest discriminator for malignant hyperthermia in the in-vitro contracture tests. It remains the ideal substance for diagnostic testing and cannot simply be replaced by other agents in this test.

We evaluated the effect of the halothane (HAL) gene on the quality of pork in domestic pigs. Half-carcasses from two different commercial pig (Sus domestica) crossbreeds were analyzed, 46 of which were homozygous dominant (HAL(NN)) and 69 of which were heterozygous (HAL(Nn)) for the halothane gene. The measures included backfat thickness, lean meat percentage, carcass weight, pH 24 h after slaughtering, color, and drip loss; DNA was extracted from the haunch muscle. Swine with the HAL(Nn) genotype had less backfat thickness and higher lean meat percentages than swine with the HAL(NN) genotype. Yet, swine with the HAL(Nn) genotype had lower quality meat than those with the HAL(NN) swine. The pH at 24 h was lower in HAL(Nn) swine. The meat color was paler in HAL(Nn) animals, the drip loss was greater in those animals bearing the n allele, and the amount of intramuscular fat was not related to the halothane genotype. We conclude that bearers of the recessive allele of the halothane gene produce more meat, but with quality parameters that are inferior to those sought by consumers and industry.

Malignant hyperthermia (MH) is a pharmacogenetic disease triggered by volatile anesthetics and succinylcholine. Deaths due to MH have been reported in Brazil. The first Malignant Hyperthermia Diagnostic and Research Center in Latin America was inaugurated in 1993 at the Federal University of Rio de Janeiro, Brazil. The center followed the diagnostic protocols of the North America MH Group, in which the contractures of biopsies from the vastus lateralis muscle are analyzed after exposure to caffeine and halothane (CHCT). CHCT was performed in individuals who survived, their relatives and those with signs/symptoms somewhat related to MH susceptibility (MHS). Here, we report data from 194 patients collected over 16 years. The Southeast (N = 110) and South (N = 71) represented the majority of patients. Median age was 25 (4-70) years, with similar numbers of males (104) and females (90). MHS was found in 90 patients and 104 patients were normal. Abnormal responses to both caffeine and halothane were observed in 59 patients and to caffeine or halothane in 20 and 11 patients, respectively. The contracture of biopsies from MHS exposed to caffeine and halothane was 1.027 +/- 0.075 g (N = 285) and 4.021 +/- 0.255 g (N = 226), respectively. MHS was found in patients with either low or high blood creatine kinase and also, with a low score on the clinical grading scale. Thus, these parameters cannot be used with certainty to predict MHS. We conclude that the CHCT protocol described by the North America MH Group contributed to identification of MHS in suspected individuals at an MH center in Brazil with 100% sensitivity and 65.7% specificity.

Objective: To record the bispectral index (BIS) when horses moved during either halothane or sevoflurane anaesthesia and when they made volitional movements during recovery from these anaesthetics., Study Design: Randomized prospective clinical study., Animals: Twenty-five client-owned horses undergoing surgery aged 8.8 (+/- 5.3; 1-19) years (mean +/- SD; range)., Methods: Baseline BIS values were recorded before pre-anaesthetic medication (BIS(B)) and during anaesthesia (BIS(A)) maintained with halothane (group H; n = 12) or sevoflurane (group S; n =13) at approximately 0.8-0.9 x minimum alveolar concentrations (MAC). Bispectral indices were recorded during the surgery when unexpected movement occurred (BIS(MA)), during recovery when the first movement convincingly associated with consciousness was observed (BIS(M1)) and once sternal recumbency was achieved (BIS(ST))., Results: No significant difference in BIS(M1) was found between halothane- (85 +/- 7; 75-93) and sevoflurane- (87 +/- 10; 70-98) anaesthetized horses although BIS(A) was significantly (p = 0.0002) lower in group S (62 +/- 7; 53-72) than group H (74 +/- 7; 60-84). Differences between BIS(M1) and BIS(A) were significant in sevoflurane (p = 0.00001) and halothane recipients (p = 0.002) but were greater in group S (25 +/- 9; 4-38) compared with group H (12 +/- 10; -9-25). In six of eight horses, BIS(MA) values ranged between those recorded during anaesthesia and at first movement., Conclusions and Clinical Relevance: Bispectral indices appear to approximate levels of unconsciousness, suggesting that monitoring the BIS may assist equine anaesthesia. However, it does not predict intra-operative movement.

Objective: To evaluate electroencephalographic (EEG) changes during ovariohysterectomy (OVH) in rats anaesthetized with halothane, and modification of the EEG changes by the co-administration of fentanyl, ketamine or thiopental., Study Design: Prospective, randomized, blinded controlled study., Animals: Sixty adult female Sprague-Dawley rats., Methods: Anaesthesia was induced and maintained with halothane [Fe'HAL 0.95 +/- 0.05%]. The electroencephalogram was recorded continuously from the left and right primary somatosensory cortices. Rats were randomly divided into four groups and a rapid IV infusion of physiological saline, thiopental, ketamine or fentanyl was administered. OVH started 10 minutes after drug administration. Blood samples, for assay of plasma drug concentrations, were collected 5 minutes after administration and at the end of surgery. Electroencephalograph descriptors median frequency (F50), spectral edge frequency 95% (F95) and total power (P(tot)), recorded during non-surgical baseline periods, were compared with those recorded during defined surgical periods; skin incision, right and left ovarian pedicle ligation; cervical ligation. Plasma drug concentrations were measured using high performance lipid chromatography., Results: Although a large number of statistical differences in EEG data were observed, these generally represented a reduction in F50 or F95 throughout the experimental recording period and were similar between groups. A significant reduction in P(tot) occurred during ligation of the ovaries and cervix in the control group compared with other recording periods. The co-administration of ketamine, fentanyl and thiopental obtunded the reduction in P(tot)., Conclusions and Clinical Relevance: Electroencephalographic changes, in the control group, mimicked changes reported in other studies using the minimal anaesthesia model. However, the stability in F50 during the surgical period compared with the baseline period indicated that OVH is an unsuitable surgical stimulus to investigate EEG changes with noxious stimulation. This may be attributed to the relatively prolonged duration of this surgical procedure and the primarily visceral afferent sensory innervation of the genital tract.

The objective of this study was to estimate the effects of breed, sex, and halothane (HAL-1843) genotype on fatty acid composition of triacylglycerols (TAG) and phospholipids (PL) extracted from porcine longissimus muscle (LM). Purebred Yorkshire (n = 131), Duroc (n = 136), Hampshire (n = 49), Spotted (n = 35), Chester White (n = 74), Poland China (n = 51), Berkshire (n = 169) and Landrace (n = 82) pigs (n = 727; 427 barrows and 300 gilts) from the 1994 and 2001 National Barrow Show Sire Progeny Tests were used. For statistical analyses, a mixed model was used that included fixed effects of breed, sex, HAL-1843(TM) genotype, year, slaughter date within each year, interaction of breed x sex and random effects of sire and dam within breed. Breeds and sex were significantly associated with the percentages of the majority fatty acids in TAG. Duroc pigs had greater total saturated fatty acids (SFA) and lower total monounsaturated fatty acids (MUFA) (p < 0.05) contents than did pigs of all other breeds except Berkshire (p > 0.05). The concentration of total polyunsaturated fatty acids (PUFA) was the greatest in Hampshire pigs (p < 0.05). The content of total SFA was greater (p < 0.01), whereas the concentrations of total MUFA and PUFA were lower (p < 0.01) in barrows than those in gilts. The contents of major SFA in PL did not differ significantly among pigs from different breeds and sex groups. However, breed and sex significantly affected the concentrations of major MUFA and PUFA in PL and strong negative correlation between the total contents of MUFA and PUFA in PL was observed in the current study. Chester White pigs had greater total MUFA and lower total PUFA contents (p < 0.05) in PL than did pigs of all other breeds except Spotted (p > 0.05). In contrast to breed and sex effects, the concentrations of fatty acids in PL were more affected by HAL-1843 genotype than those in TAG. The content of C16:0, a major SFA in PL, differed significantly in pigs with different HAL-1843 genotypes. In conclusion, these results suggest that breed and sex are important sources of the variations for fatty acid composition of TAG and PL in LM.

We hypothesized that like bispectral index, entropy may be anesthetic agent specific. We carried out a study to assess the entropy values of different anesthetics at equi-minimal alveolar concentrations (MACs) with air and nitrous oxide as carrier gases. Thirty adult patients undergoing spine surgery were randomized to receive halothane, isoflurane, or sevoflurane, in 2 stages, (a) with air/oxygen mixture (2:1) and (b) in nitrous oxide/oxygen (2:1). Heart rate, mean arterial blood pressure, response entropy (RE), and state entropy (SE) were noted at 1.0 and 1.5 MACs for each agent. Statistical analysis was done using the 2-way analysis of variance followed by Bonferroni correction and Student t test for paired data. P value of less than 0.05 were considered significant. The demographics and baseline values of heart rate, mean arterial blood pressure, RE, and SE were comparable. Changing from air/oxygen as carrier gas to 66% nitrous oxide in oxygen resulted in significant increase in both RE and SE at 1.0 MAC for all the agents (P<0.05). Among the agents, it was found that both RE and SE values were significantly higher during halothane anesthesia as compared with sevoflurane and isoflurane (P<0.05). At 1.5 MAC for all agents, after addition of nitrous oxide, there was an insignificant reduction in both RE and SE (P>0.05). Again the values of RE and SE remained high for halothane as compared with isoflurane and sevoflurane. In conclusion, our data suggest a possibility of misinterpretation of anesthetic hypnosis when entropy values increase with addition of nitrous oxide to 1 MAC isoflurane and sevoflurane.

Objective: To explore the application of caffeine-halothane contracture test (CHCT) in the confirmation of malignant hyperthermia (MH)., Methods: One patient who underwent radical gastrectomy presented with clinical manifestations of MH during routine intravenous-inhalation anesthesia process. Isoflurane inhalation and the operation were ceased immediately and emergency management approaches such as physical cooling therapy were taken. Meanwhile, the levels of serum creatine kinase (CK), serum myoglobin, and urinary myoglobin were examined and rectus abdominis was taken and then CHCT was performed to confirm the clinical diagnosis. Total genome was extracted from the patient and then exons 2-18, 39-46, and 90-104 of ryanodine receptor 1 (RYR1) gene were screened to detect mutations using DNA sequencing technique., Results: The patient was diagnosed as MH episode by clinical characteristics and postoperatively continuous elevation of the levels of CK, serum myoglobin, and urinary myoglobin (30 times higher than normal level). Despite halothane test was negative, the diagnosis of MH was verified by the positive result of caffeine test. DNA sequencing of RYR1 gene of the patient revealed c. 6724C > T (p. T 2 206M)., Conclusion: CHCT can be used to confirm the diagnosis of MH.

Purpose: Circulatory instability is often observed upon emergence from general anesthesia. The increased blood pressure (BP) lability has been associated with poor clinical outcome. However, its underlying mechanisms are not fully understood. Thus, we investigated a possible role of the sympathetic nervous system (SNS) and cardiac baroreflex in the increased pressure lability observed upon emergence from general anesthesia., Methods: Male rats (n = 16) were allocated to two groups, i.e., (1) a control group (n = 8) and (2) an alpha-methylparatyrosine (alpha-MPT; an inhibitor of tyrosine hydroxylase)-treated group (n = 8). In the alpha-MPT-treated group, in order to deplete catecholamines both in the central nervous system and in the SNS, alpha-MPT (300 mg x kg(-1)) was injected intraperitoneally (i.p.), administered twice, 4 and 2 h before halothane discontinuation (total dose, 600 mg x kg(-1) i.p.). In the control group, saline was administered at identical time-points. Systolic BP (SBP) lability was evaluated on a beat-by-beat basis, using the coefficient of variation of SBP, and the occurrence of slow and rapid rises in SBP and their amplitude, while the cardiac baroreflex slope was calculated using the "sequences" method., Results: In the control group, heart rate, SBP, and the three indices of BP lability (i.e., the 3 indices of BP lability are: coefficient of variation of SBP, number of slow and rapid rises in pressure, amplitude of slow and rapid rises in pressure) all increased upon emergence from anesthesia (P < 0.05). Such increases were all blunted in the alpha-MPT-treated group, with the increases in the three indices of BP lability almost entirely suppressed (P < 0.05). The cardiac baroreflex slope was similarly decreased in both groups (P < 0.05)., Conclusion: The postanesthetic increase in pressure lability seems largely a consequence of increased sympathetic activity, irrespective of any change in cardiac baroreflex sensitivity.

Objective: To determine whether hyoscine has a sparing effect on the volume of dobutamine required to maintain mean arterial pressure (MAP) at 70 mmHg in horses anaesthetized with halothane., Study Design: Prospective, randomized, controlled clinical trial., Animals: Twenty adult horses weighing 507 +/- 97 kg (mean +/- SD), aged 10 +/- 5 years., Materials and Methods: Pre-anaesthetic medication in all horses was intramuscular (IM) acepromazine (40 mug kg(-1)) and intravenous (IV) detomidine (0.02 mg kg(-1)). Anaesthesia was induced with ketamine (2.2 mg kg(-1) IV) and diazepam (0.02 mg kg(-1) IV), and maintained with halothane in oxygen. Horses breathed spontaneously. Flunixin (1.1 mg kg(-1) IV) was given to provide analgesia. Heart rate, ECG, invasive arterial pressure, respiratory rate, percentage end-tidal carbon dioxide, percentage end-tidal halothane and partial pressure of oxygen and carbon dioxide in arterial blood and blood pH were monitored. Dobutamine was infused by an infusion pump to maintain MAP at 70 mmHg. Horses were randomly assigned to receive saline or hyoscine (0.1 mg kg(-1)) IV 30 minutes after induction. The heart rate, MAP and volume of dobutamine infused over 30-minute periods were measured and analysed statistically using a one-way anova., Results: After administration of hyoscine, heart rate increased for 10 minutes (p < 0.01) and MAP for 5 minutes (p < 0.01). There was no difference in the volume of dobutamine infused over 30 minutes between horses given hyoscine or saline, although there was a wide individual variation in dobutamine requirements. No side effects of hyoscine were seen., Conclusions: The increase in heart rate and blood pressure that occurs after 0.1 mg kg(-1) hyoscine is given IV in anaesthetized horses, is of short duration and does not significantly alter the amount of dobutamine required to maintain arterial pressure over the next 30 minutes. Clinical relevance The short duration of action of 0.1 mg kg(-1) hyoscine IV may limit its usefulness for correction of hypotension in horses anaesthetized with halothane. Further work is necessary to investigate the effects of higher or repeated doses or constant rate infusions of hyoscine.

Our previous study using the urethane-anesthetized guinea-pig model has shown that an I(Ks) blocker chromanol 293B hardly affects the QT interval itself nor potentiates the I(Kr) blocker-induced QT-interval prolongation. The former is in good accordance with the previous results in the human isolated intact ventricular tissue, but the latter is in sharp contrast with them. In this study, we characterized the ventricular repolarization ability of a newly developed halothane-anesthetized guinea-pig model by using I(Kr) and I(Ks) blockers. Intravenous administration of a selective I(Kr) blocker d-sotalol (3 mg/kg) prolonged the QT interval by +27 ms. On the other hand, intravenous administration of chromanol 293B (1 mg/kg) prolonged the QT interval by +35 ms, and additional administration of the same dose of d-sotalol further prolonged the QT interval by +48 ms. These results suggest that the abundance of the repolarization reserve among the current and previous models may be in the order of the urethane-anesthetized guinea-pig heart>human intact ventricular tissue>halothane-anesthetized guinea-pig heart. Thus, the halothane-anesthetized guinea-pig model may be considered to be more sensitive than the previous models in predicting the QT-interval prolonging effects of new drugs in patients with high risks for the acquired long QT syndrome.