On the Functional Role of Gamma Synchronization in the Retinogeniculate System of the Cat.

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 Response entrainment to the monitor refresh was commonly observed up to 120 Hz and was superseded by the gamma oscillatory responses induced by halothane.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.

The halothane era in pediatric anesthesia: The convergence of a cardiac depressant anesthetic with the immature myocardium of infancy.

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.

Reactions Using Freons and Halothane as Halofluoroalkyl/Halofluoroalkenyl Building Blocks.

In recent years, hydrofluorocarbon compounds such as chlorofluorocarbons, hydrochlorofluorocarbons, and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) have been used as fluorine-containing building blocks to construct functional fluorine-containing compounds, e. g., polymers, liquid crystals, and medicines. Hydrofluorocarbons promote the formation of reactive fluoroalkyl or fluoroalkenyl species via anionic or radical processes, and these species can act as nucleophiles or electrophiles depending on the reaction conditions. Progress in fluorine chemistry using hydrofluorocarbons in the last 30 years is described in this review and diverse reactions are discussed, including the fluoroalkyl/alkenyl products and proposed mechanisms involved.

Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (Drosophila melanogaster) to Ether and Non-Ether Volatile Anesthetics.

The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. The ND-2360114 and mt:ND2del1 lines of fruit flies (Drosophila melanogaster) that carry mutations in core subunits of Complex I of the mETC replicate numerous characteristics of Leigh syndrome (LS) caused by orthologous mutations in mammals and serve as models of LS. ND-2360114 flies are behaviorally hypersensitive to volatile anesthetic ethers and develop an age- and oxygen-dependent anesthetic-induced neurotoxicity (AiN) phenotype after exposure to isoflurane but not to the related anesthetic sevoflurane. The goal of this paper was to investigate whether the alkane volatile anesthetic halothane and other mutations in Complex I and in Complexes II-V of the mETC cause AiN. We found that (i) ND-2360114 and mt:ND2del1 were susceptible to toxicity from halothane; (ii) in wild-type flies, halothane was toxic under anoxic conditions; (iii) alleles of accessory subunits of Complex I predisposed to AiN; and (iv) mutations in Complexes II-V did not result in an AiN phenotype. We conclude that AiN is neither limited to ether anesthetics nor exclusive to mutations in core subunits of Complex I.

Silylated-Acetylated Cyclodextrins as Chiral Sensors for the Enantiodiscrimination of Fluorinated Anesthetics.

Silylated-acetylated cyclodextrin (CD) derivatives have recently been investigated, via nuclear magnetic resonance (NMR) spectroscopy, as chiral sensors for substrates that are endowed and devoid of fluorine atoms, and the importance of Si-F interaction in the discrimination phenomena has been assessed. Here, the contributions of both superficial interactions and inclusion processes were further evaluated by extending the records to other chiral fluorinated substrates of interest for pharmaceutical applications. Non-equivalences were measured for both the 1H and 19F resonances in equimolar mixtures with the CDs; the promising results also supported the use of chiral sensors in sub-stoichiometric amounts. Finally, the occurrence of inclusion processes was evaluated by analyzing the intermolecular dipolar interactions by means of ROESY (Rotating-frame Overhauser Enhancement Spectroscopy) experiments. The study confirmed that the γCD derivative is the best chiral solvating agent for the fluorinated substrates investigated, likely due to the higher number of silyl moieties that can be involved in Si-F interactions. The contribution of inclusion processes to the enantiodiscrimination was also confirmed by comparison with the α- and ß-analogues. Overall, the CD derivatives proved to be able to discriminate fluorinated substrates even when used in sub-stoichiometric amounts.

Anesthetics and Cell-Cell Communication: Potential Ca2+-Calmodulin Role in Gap Junction Channel Gating by Heptanol, Halothane and Isoflurane.

Cell-cell communication via gap junction channels is known to be inhibited by the anesthetics heptanol, halothane and isoflurane; however, despite numerous studies, the mechanism of gap junction channel gating by anesthetics is still poorly understood. In the early nineties, we reported that gating by anesthetics is strongly potentiated by caffeine and theophylline and inhibited by 4-Aminopyridine. Neither Ca2+ channel blockers nor 3-isobutyl-1-methylxanthine (IBMX), forskolin, CPT-cAMP, 8Br-cGMP, adenosine, phorbol ester or H7 had significant effects on gating by anesthetics. In our publication, we concluded that neither cytosolic Ca2+i nor pHi were involved, and suggested a direct effect of anesthetics on gap junction channel proteins. However, while a direct effect cannot be excluded, based on the potentiating effect of caffeine and theophylline added to anesthetics and data published over the past three decades, we are now reconsidering our earlier interpretation and propose an alternative hypothesis that uncoupling by heptanol, halothane and isoflurane may actually result from a rise in cytosolic Ca2+ concentration ([Ca2+]i) and consequential activation of calmodulin linked to gap junction proteins.

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane).

A series of aryl fluoroalkenyl ethers that contain chlorine and bromine as well as fluorine atoms were prepared in moderate to good yields via the reactions of phenols and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) in the presence of KOH. This simple reaction enabled the construction of highly halogenated compounds with the potential for further functionalization. The reaction involved a highly reactive difluoroethylene intermediate, which was produced by the reaction between halothane and KOH.

In vivo analysis of concentration-dependent effects of halothane or isoflurane inhalation on the electrocardiographic and hemodynamic variables in dogs.

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.

In vivo comparison of dl-sotalol-induced electrocardiographic responses among halothane anesthesia, isoflurane anesthesia with nitrous oxide, and conscious state.

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 (N2O), and conscious state to clarify influences of the anesthetics (n = 4). Basal PR interval was longer in halothane than either in isoflurane with N2O 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 INa inhibition. Also, both anesthetics showed longer basal QT interval, QTcF and Tpeak-Tend than conscious state, indicating their ventricular IKr inhibition. Meanwhile, dl-sotalol prolonged PR interval similarly in isoflurane with N2O 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 Tpeak-Tend similarly in both anesthetics, but hardly altered it in conscious state; indicating isoflurane with N2O as well as halothane may have reduced the repolarization reserve to increase the sensitivity of ventricle toward IKr suppression. Thus, isoflurane with nitrous oxide could be useful for in vivo IKr assay like halothane.

Synthesis of aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers through the base-mediated reaction between phenols and halothane.

An efficient and convenient method for the synthesis of structurally unique and highly functionalized aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers has been developed. This approach exhibits a broad reaction scope, a simple operation and without the need of any expensive transition-metal catalyst, highly toxic or corrosive reagents. Notably, we demonstrate the potential utility of halothane for the synthesis of aryl gem-difluoroalkyl ethers containing the bromochloromethyl group.

Sensitivity of inhalation anesthetics isoflurane and sevoflurane for the drug-induced QT-interval prolongation in guinea pigs.

We investigated effects of isoflurane and sevoflurane on sparfloxacin-induced QT-interval prolongation in guinea pigs under the monitoring of electrocardiogram and monophasic action potential (MAP), which was compared with those of halothane or non-inhaled anesthetics ketamine/xylazine. Intravenous administration of sparfloxacin at 3 and 10 mg/kg prolonged the QT interval and MAP duration together with bradycardic action under 4 different anesthetic conditions. The order of extent of prolongation of corrected QT interval after the administration of sparfloxacin was isoflurane ≈ sevoflurane ≈ halothane >> ketamine/xylazine, whereas that of the MAP90 at a pacing cycle length of 300 ms was halothane ≥ isoflurane ≈ sevoflurane >> ketamine/xylazine. These results suggest that isoflurane and sevoflurane as well as halothane could sensitize the heart to sparfloxacin-induced QT interval prolongation in guinea pigs.

Pharmacokinetics of morphine in combination with dexmedetomidine and maropitant following intramuscular injection in dogs anaesthetized with halothane.

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 (T1/2 ) of morphine was higher and the clearance rate (CL) was lower when combined with dexmedetomidine (T1/2  = 77.72 ± 20.27 min, CL = 119.41 ± 23.34 ml kg-1  min-1 ) compared to maropitant (T1/2  = 52.73 min ± 13.823 ml kg-1  min-1 , CL = 178.57 ± 70.55) or morphine alone at higher doses (T1/2  = 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.

Molecular Bases for Anesthetic Agents: Halothane as a Halogen- and Hydrogen-Bond Donor.

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.

Life-threatening Episodes of Malignant Hyperthermia Following Halothane Anesthesia in Three Children: A Case Series and Review of Literature.

Malignant hyperthermia (MH) is an inherited, pharmacogenetic disorder of the skeletal muscle, characterized by dangerous hypermetabolic state after anesthesia with succinylcholine and/ or volatile halogenated anesthetic agents, clinically manifested as hyperpyrexia and related complications like tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, rigid muscles, rhabdomyolysis and disseminated intravascular coagulation (DIC). Here we present a series of three cases of MH, admitted in our hospital in a span of 8 months for three different operative procedures to be done under general anesthesia (cleft lip repair, Duhamel's operation for Hirschsprung's disease and surgical repair of development dysplasia of hip), who developed probable hyperthermia owing to Halothane being used as an anesthetic agent. HOW TO CITE THIS ARTICLE: Laha S, Giri PP, Saha A, Gupta PP, De A. Life-threatening Episodes of Malignant Hyperthermia Following Halothane Anesthesia in Three Children: A Case Series and Review of Literature. Indian Journal of Critical Care Medicine, January 2019;23(1):47-50.

Isoflurane but Not Halothane Prevents and Reverses Helpless Behavior: A Role for EEG Burst Suppression?

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.

[Selection of optimal method of general anesthesia for intubation of nasolacrimal duct in young children]. / Vybor optimal'nogo metoda obshchei anestezii pri zondirovanii sleznogo kanala u detei mladshego vozrasta.

PURPOSE: comparative assessment of safety and clinical efficacy of Sevoflurane and Halothane in general anesthesia for nasolacrimal duct intubation in children. MATERIAL AND METHODS: Clinical results of nasolacrimal duct intubation in 288 children with persistent obstruction of tear duct were analyzed. A newly developed method of general anesthesia in the supine position was used for all cases. General anesthetic Phthorothanum was used in 146 children; general anesthesia with Sevoflurane - in 142 children. RESULTS AND DISCUSSION: A new safe and efficient method of general anesthesia for nasolacrimal duct intubation was developed. In the first group, aspiration complications (coughing) occurred in 7 patients under the age of 1 year and short apnea - in 2 children. In the second group, depression of respiration was seen in a three-year-old child caused by the action of the anesthetic, and coughing - in one patient under the age of 1 year during the final phase of intubation. CONCLUSIONS: The newly developed method of general anesthesia in the supine position with oropharyngeal aspiration for nasolacrimal duct intubation in children was effective because it helped avoid aspiration complications at a more physiological position (on the back) in children of both groups. Comparative analysis of safety and efficacy of mask anesthesia with Sevoflurane and Halothane for nasolacrimal duct intubation in children in the supine position showed Sevoflurane to be more preferable. The advantages of Sevoflurane anesthesia for nasolacrimal duct intubation in children in the supine position are higher anesthesia induction speed, absence of respiratory tract irritation, cardiodepressive effects or suppression of laryngeal reflexes, and minimum time between the end of anesthesia and awakening.

Fifty years of the American Academy of Pediatrics Section on Anesthesiology: a history of our specialty.

The American Academy of Pediatrics Section on Anesthesiology and Pain Medicine celebrated its 50th Anniversary in 2015. The Section was one of the first and only subspecialty organizations in anesthesiology at the time. This special article will focus on the contributions of the Section to the practice of pediatric anesthesiology in the areas of advocacy, education and member contributions. In 1986, the Section created the Robert M. Smith Award to honor those members who had made significant advances in the practice of pediatric anesthesiology. It is named after one of the Section founders, an influential educator, inventor, and researcher in our field. We will focus the latter part of the article on the Robert M. Smith award winners to illustrate the contributions of the Section and its members to the development of the field of pediatric anesthesiology.

Outstanding contribution to pediatric anesthesiology: An interview with Dr. Robert H. Friesen.

Dr. Robert H. Friesen, (1946-) Professor of Anesthesiology, Children's Hospital Colorado, University of Colorado, Anschutz Medical Campus, has played a pivotal and pioneering role in the development of pediatric and congenital cardiac anesthesiology. His transformative research included the study of the hemodynamic effects of inhalational and intravenous anesthetic agents in the newborn and the effects of anesthetic agents on pulmonary vascular resistance in patients with pulmonary hypertension. As a model clinician-scientist, educator, and administrator, he changed the practice of pediatric anesthesia and shaped the careers of hundreds of physicians-in-training, imbuing them with his core values of honesty, integrity, and responsibility. Based on a series of interviews with Dr. Friesen, this article reviews a career that advanced pediatric and congenital cardiac anesthesia during the formative years of the specialties.

Genetic Factors Affecting Pork Quality: Halothane and Rendement Napole Genes.

The most common pork quality problems are pale, soft, and exudative (PSE) and acid pork (AP). PSE is associated with the expression of recessive halothane (Hal) allele Haln. Recessive Hal pigs (Halnn) have defective Ca2+ release channels (CRC) or Ryanodine Receptors (RYR1) within the sarcoplasmic reticulum that allow uncontrolled release of Ca2+ in response to stress. Abnormal lactic acid metabolism caused by stress prior to slaughter leads to the sudden drop in postmortem muscle pH producing the PSE pork. Conversely, AP is caused by the dominant RN- allele of the Rendement Napole gene. RN- pigs have high glycolytic potential that causes the lower ultimate pHu due to excessive lactic acid production postmortem. Poor water holding capacity of muscle cells in PSE and AP causes excessive drip loss leading to low cooking and processing yields. The conventional methods to evaluate Hal and RN genotypes are less effective compared to the more accurate gene marker tests. Selection against the Haln and RN- alleles by genomic selection can potentially reduce the frequencies of the defective genes with high accuracy in less time. As more quantitative trait loci (QTL) are identified, pig breeders are able to select traits more effectively to increase efficiency of pig production and enhance pork quality.