How to Personalize General Anesthesia-A Prospective Theoretical Approach to Conformational Changes of Halogenated Anesthetics in Fire Smoke Poisoning.

Smoke intoxication is a central event in mass burn incidents, and toxic smoke acts at different levels of the body, blocking breathing and oxygenation. The majority of these patients require early induction of anesthesia to preserve vital functions. We studied the influence of hemoglobin (HMG) and myoglobin (MGB) blockade by hydrochloric acid (HCl) in an interaction model with gaseous anesthetics using molecular docking techniques. In the next part of the study, molecular dynamics (MD) simulations were performed on the top-scoring ligand-receptor complexes to investigate the stability of the ligand-receptor complexes and the interactions between ligands and receptors in more detail. Through docking analysis, we observed that hemoglobin creates more stable complexes with anesthetic gases than myoglobin. Intoxication with gaseous hydrochloric acid produces conformational and binding energy changes of anesthetic gases to the substrate (both the pathway and the binding site), the most significant being recorded in the case of desflurane and sevoflurane, while for halothane and isoflurane, they remain unchanged. According to our theoretical model, the selection of anesthetic agents for patients affected by fire smoke containing hydrochloric acid is critical to ensure optimal anesthetic effects. In this regard, our model suggests that halothane and isoflurane are the most suitable choices for predicting the anesthetic effects in such patients when compared to sevoflurane and desflurane.

The Triple Bottom Line and Stabilization Wedges: A Framework for Perioperative Sustainability.

We present a narrative review of environmental sustainability aimed at perioperative clinicians. The review will familiarize readers with the triple bottom line framework, which aims to align the goals of delivering high-quality patient care, promoting environmental sustainability, and improving the financial position of health care organizations. We introduce the stabilization wedges model for climate change action adopted for the perioperative setting and discuss areas in which perioperative leaders can make sustainable choices. The goal of this review is to increase awareness among perioperative physicians of the environmental impacts of surgical and anesthetic care, promote engagement with sustainability efforts as a topic of professional concern for our specialty, and inspire new research in perioperative environmental sustainability.

Anesthetics isoflurane and sevoflurane attenuate flagellin-mediated inflammation in the lung.

Isoflurane and sevoflurane are volatile anesthetics (VA) widely used in clinical practice to provide general anesthesia. We and others have previously shown that VAs have immunomodulatory effects and may have a significant impact on the progression of disease states. Flagellin is a component of Gram negative bacteria and plays a significant role in the pathophysiology of bacterial pneumonia through its binding to Toll-like Receptor 5 (TLR5). Our results showed that VAs, not an intravenous anesthetic, significantly attenuated the activation of TLR5 and the release of the neutrophil chemoattractant IL-8 from lung epithelial cells. Furthermore, flagellin-induced lung injury was significantly attenuated by VAs by inhibiting neutrophil migration to the bronchoalveolar space. The lungs of cystic fibrosis (CF) patients are highly colonized by Pseudomonas aeruginosa, which causes inflammation. The retrospective study of oxygenation in patients with CF who had received VA versus intravenous anesthesia suggested that VAs might have the protective effect for gas exchange. To understand the interaction between VAs and TLR5, a docking simulation was performed, which indicated that isoflurane and sevoflurane docked into the binding interphase between TLR5 and flagellin.

The effect of anesthetics on toll like receptor 9.

Toll like receptors (TLRs) are critical receptors to respond to danger signals, and their functions are relevant in the perioperative period. We previously reported that volatile anesthetics directly bound to TLR2 and TLR4 and attenuated their functions. Given that TLR9 can respond to mitochondrial DNA, a danger signal that is released upon tissue injury, we examined the role of anesthetics on TLR9 function. Our reporter assay showed that volatile anesthetics isoflurane and sevoflurane increased the activation of TLR9, while propofol attenuated it. TLR9 activation occurs via its dimerization. The dimerization is facilitated by unmethylated cytosine-phosphate-guanine (CpG) DNA as well as DNA containing cytosine at the second position from 5'-end (5'-xCx DNA). Our structural analysis using photoactivable anesthetics and rigid docking simulation showed that isoflurane and sevoflurane bound to both TLR9 dimer interface and 5'-xCx DNA binding site. Propofol bound to the TLR9 antagonist binding site. This is the first illustration that anesthetics can affect the binding of nucleic acids to their receptor. This study sets the foundation for the effect of anesthetics on TLR9 and will pave the way for future studies to determine the significance of such interactions in the clinical setting.

Scientific Accuracy Matters.

The Solubility of Halothane in Blood and Tissue Homogenates. By Larson CP, Eger EI, Severinghaus JW. Anesthesiology 1962; 23:349-55. Measured samples of human and bovine blood, human hemoglobin, and tissue homogenates from human fat and both human and bovine liver, kidney, muscle, whole brain, and separated gray and white cortex were added to stoppered 2,000-ml Erlenmeyer flasks. To each flask, 0.1 ml of liquid halothane was added under negative pressure using a calibrated micropipette. After the flask was agitated for 2 to 4 h to achieve equilibrium between the gas and blood or tissue contents, a calibrated infrared halothane analyzer was used to measure the concentration of halothane vapor. Calculated partition coefficients ranged from 0.7 for water to 2.3 for blood and from 3.5 for human or bovine kidney to 6 for human whole brain or liver and 8 for human muscle. Human peritoneal fat had a value of 138. The human blood-gas partition coefficient of 2.3 as determined by this equilibration method was well below the previously published value of 3.6.

Environmental and economic impact of using increased fresh gas flow to reduce carbon dioxide absorbent consumption in the absence of inhalational anaesthetics.

BACKGROUND: Increasing fresh gas flow (FGF) to a circle breathing system reduces carbon dioxide (CO2) absorbent consumption. We assessed the environmental and economic impacts of this trade-off between gas flow and absorbent consumption when no inhalational anaesthetic agent is used. METHODS: A test lung with fixed CO2 inflow was ventilated via a circle breathing system of an anaesthetic machine (Dräger Primus or GE Aisys CS2) using an FGF of 1, 2, 4, or 6 L min-1. We recorded the time to exhaustion of the CO2 absorbent canister, defined as when inspired partial pressure of CO2 exceeded 0.3 kPa. For each FGF, we calculated the economic costs and the environmental impact associated with the manufacture of the CO2 absorbent canister and the supply of medical air and oxygen. Environmental impact was measured in 100 yr global-warming potential, analysed using a life cycle assessment 'cradle to grave' approach. RESULTS: Increasing FGF from 1 to 6 L min-1 was associated with up to 93% reduction in the combined running cost with minimal net change to the 100 yr global-warming potential. Most of the reduction in cost occurred between 4 and 6 L min-1. Removing the CO2 absorbent from the circle system, and further increasing FGF to control CO2 rebreathing, afforded minimal further economic benefit, but more than doubled the global-warming potential. CONCLUSIONS: In the absence of inhalational anaesthetic agents, increasing FGF to 6 L min-1 reduces running cost compared with lower FGFs, with minimal impact to the environment.

New Method of Destroying Waste Anesthetic Gases Using Gas-Phase Photochemistry.

BACKGROUND: The inhalation anesthetics are potent greenhouse gases. To reduce the global environmental impact of the health care sector, technologies are sought to limit the release of waste anesthetic gas into the atmosphere. METHODS: Using a photochemical exhaust gas destruction system, removal efficiencies for nitrous oxide, desflurane, and sevoflurane were measured at various inlet concentrations (25% and 50%; 1.5%, 3.0%, and 6.0%; and 0.5%, 1.0%, and 2.0%, respectively) with flow rates ranging from 0.25 to 2.0 L/min. To evaluate the economic competitiveness of the anesthetic waste gas destruction system, its price per ton of carbon dioxide equivalent was calculated and compared to other greenhouse gas abatement technologies and current market prices. RESULTS: All inhaled anesthetics evaluated demonstrate enhanced removal efficiencies with decreasing flow rates (P < .0001). Depending on the anesthetic and its concentration, the photochemical exhaust gas destruction system exhibits a constant first-order removal rate, k. However, there was not a simple relation between the removal rate k and the species concentration. The costs for removing a ton of carbon dioxide equivalents are <$0.005 for desflurane, <$0.114 for sevoflurane, and <$49 for nitrous oxide. CONCLUSIONS: Based on this prototype study, destroying sevoflurane and desflurane with this photochemical anesthetic waste gas destruction system design is efficient and cost-effective. This is likely also true for other halogenated inhalational anesthetics such as isoflurane. Due to differing chemistry of nitrous oxide, modifications of this prototype photochemical reactor system are necessary to improve its removal efficiency for this gas.

Preparation of anaesthesia workstation for trigger-free anaesthesia: An observational laboratory study.

BACKGROUND: Trigger-free anaesthesia is required for patients who are susceptible to malignant hyperthermia. Therefore, all trace of volatile anaesthetics should be removed from anaesthetic machines before induction of anaesthesia. Because the washout procedure is time consuming, activated charcoal filters have been introduced, but never tested under minimal flow conditions. OBJECTIVE: To investigate performance of activated charcoal filters during long duration (24 h) simulated ventilation. DESIGN: A bench study. SETTING: A Primus anaesthesia machine (Dräger) was contaminated with either 4% sevoflurane or 8% desflurane by ventilating a test lung for 90 min. The machine was briefly flushed according to manufacturer instructions, activated charcoal filters were inserted and a test lung was ventilated in a 24 h test. Trace gas concentrations were measured using a closed gas loop high-resolution ion mobility spectrometer with gas chromatographic preseparation. During the experiment reduced fresh gas flows were tested. At the end of each experiment the activated charcoal filters were removed and the machine was set to standby for 10 min to test for residual contamination within the circuit. The activated charcoal filters were reconnected into the circuit to test their ability to continue removing volatile anaesthetics (functional test) from the gas. Control experiments were conducted without activated charcoal filters. MAIN OUTCOME MEASURES: Absolute concentrations of desflurane and sevoflurane. RESULTS: The concentration of volatile anaesthetics dropped to less than 5 ppm (parts per million) following insertion of activated charcoal filters. In the desflurane experiments at least 1 l min FGF was needed to keep the concentration below an acceptable level (<5 ppm): 0.5 l min fresh gas flow was required in sevoflurane experiments. While activated charcoal filters in the sevoflurane tests passed the functional test after 24 h, activated charcoal filters in the desflurane tests failed. CONCLUSION: Activated charcoal filters meet the requirements for trigger-free low flow (1 l min) ventilation over 24 h. Minimal flow (0.5 l min) ventilation may be possible for sevoflurane contaminated machines.

Kinetics of isoflurane and sevoflurane in a unidirectional displacement flow and the relevance to anesthetic gas exposure by operating room personnel.

International guidelines recommend the use of ventilation systems in operating rooms to reduce the concentration of potentially hazardous substances such as anesthetic gases. The exhaust air grilles of these systems are typically located in the lower corners of the operating room and pick up two-thirds of the air volume, whereas the final third is taken from near the ceiling, which guarantees an optimal perfusion of the operating room with a sterile filtered air supply. However, this setup is also employed because anesthetic gases have a higher molecular weight than the components of air and should pool on the floor if movement is kept to a minimum and if a ventilation system with a unidirectional displacement flow is employed. However, this anticipated pooling of volatile anesthetics at the floor level has never been proven. Thus, we herein investigated the flow behaviors of isoflurane, sevoflurane, and carbon dioxide (for comparison) in a measuring chamber sized 2.46 × 1.85 × 5.40 m with a velocity of 0.3 m/sec and a degree of turbulence <20%. Gas concentrations were measured at 1,728 measuring positions throughout the measuring chamber, and the flow behaviors of isoflurane and sevoflurane were found to be similar, with an overlap of 90%. The largest spread of both gases was 55 cm at 5.4 m from the emission source. Interestingly, neither isoflurane nor sevoflurane was detected at floor level, but a continuous cone-like spreading was observed due to gravity. In contrast, carbon dioxide accumulated at floor level in the form of a gas cloud. Thus, floor level exhaust ventilation systems are likely unsuitable for the collection and removal of anesthetic gases from operating rooms.

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.

A membrane-embedded pathway delivers general anesthetics to two interacting binding sites in the Gloeobacter violaceus ion channel.

General anesthetics exert their effects on the central nervous system by acting on ion channels, most notably pentameric ligand-gated ion channels. Although numerous studies have focused on pentameric ligand-gated ion channels, the details of anesthetic binding and channel modulation are still debated. A better understanding of the anesthetic mechanism of action is necessary for the development of safer and more efficacious drugs. Herein, we present a computational study identifying two anesthetic binding sites in the transmembrane domain of the Gloeobacter violaceus ligand-gated ion channel (GLIC) channel, characterize the putative binding pathway, and observe structural changes associated with channel function. Molecular simulations of desflurane reveal a binding pathway to GLIC via a membrane-embedded tunnel using an intrasubunit protein lumen as the conduit, an observation that explains the Meyer-Overton hypothesis, or why the lipophilicity of an anesthetic and its potency are generally proportional. Moreover, employing high concentrations of ligand led to the identification of a second transmembrane site (TM2) that inhibits dissociation of anesthetic from the TM1 site and is consistent with the high concentrations of anesthetics required to achieve clinical effects. Finally, asymmetric binding patterns of anesthetic to the channel were found to promote an iris-like conformational change that constricts and dehydrates the ion pore, creating a 13.5 kcal/mol barrier to ion translocation. Together with previous studies, the simulations presented herein demonstrate a novel anesthetic binding site in GLIC that is accessed through a membrane-embedded tunnel and interacts with a previously known site, resulting in conformational changes that produce a non-conductive state of the channel.

The Un(f)told Story of General Anesthesia.

Inhalational anesthetics are routinely employed in clinical practice to accomplish general anesthesia. Concerns have recently emerged regarding the deleterious impact of these volatile agents on cognitive performance, immune functions, and tumor recurrence and metastasis. These agents have been shown to modify the gene-expression pattern as well as cell signaling in tumor cells, but the underlying molecular mechanisms remain a matter of conjecture. Regulatory/signaling proteins either of cytosolic or membrane origin abundantly contain intrinsically disordered sequences, the conformational pliability of which is pivotal in their biological functions. It is well known that chloroform (an anesthetic itself), trifluoroethanol, hexafluoroisopropanol, and related haloalcohols markedly affect the structure of disordered proteins and protein regions by inducing folding, misfolding, or even aggregation. Taking into consideration the physicochemical similarities and protein interaction modes of these volatile solvents and inhaled anesthetics, it is postulated that administration of these drugs can also modify the secondary structure of disordered protein segments. Accordingly, pharmacological effects of anesthetics may, at least in part, be mediated by conformational perturbations of intrinsic disorder-based regulatory protein networks of cells.

Past, present, and future of nitrous oxide.

Introduction: For a drug that has been omnipresent for nearly 200 years, nitrous oxide's (N2O) future seems less certain than its illustrious past. Environmental concerns are coming to the fore and may yet outweigh important clinical benefits. Sources of data: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. Areas of agreement: The analgesic and anaesthetic advantages of N2O remain despite a plethora of newer agents. Areas of controversy: N2O greenhouse gas effect and its inhibition of key enzymes involved in protein and DNA synthesis have provided further fuel for those intent on eliminating its further clinical use. Growing points: The use of N2O for treatment-resistant depression has gained traction. Areas timely for developing research: Comparative studies for N2O role in combatting the prescription opioid analgesic epidemic may well provide further clinical impetus.

Tunable Porous Coordination Polymers for the Capture, Recovery and Storage of Inhalation Anesthetics.

The uptake of inhalation anesthetics by three topologically identical frameworks is described. The 3D network materials, which possess square channels of different dimensions, are formed from the relatively simple combination of ZnII centres and dianionic ligands that contain a phenolate and a carboxylate group at opposite ends. All three framework materials are able to adsorb N2 O, Xe and isoflurane. Whereas the framework with the widest channels is able to adsorb large quantities of the various guests from the gas phase, the frameworks with the narrower channels have superior binding enthalpies and exhibit higher levels of retention. The use of ligands in which substituents are bound to the aromatic rings of the bridging ligands offers great scope for tuning the adsorption properties of the framework materials.

Molecular mechanism of anesthetic-induced depression of myocardial contraction.

Isoflurane and propofol are known to depress cardiac contraction, but the molecular mechanisms involved are not known. In this study, we determined whether decreasing myofilament Ca(2+) responsiveness underlies anesthesia-induced depression of contraction and uncovered the molecular targets of isoflurane and propofol. Force and intracellular Ca(2+) ([Ca(2+)]i) were measured in rat trabeculae superfused with Krebs-Henseleit solution, with or without propofol or isoflurane. Photoaffinity labeling of myofilament proteins with meta-Azi-propofol (AziPm) and Azi-isoflurane (Azi-iso) and molecular docking were also used. Both propofol and isoflurane dose dependently depressed force from low doses (propofol, 27 ± 6 µM; isoflurane, 1.0 ± 0.1%) to moderate doses (propofol, 87 ± 4 µM; isoflurane, 3.0 ± 0.25%), without significant alteration [Ca(2+)]i During steady-state activations in both intact and skinned preparations, propofol and isoflurane depressed maximum Ca(2+)-activated force and increased the [Ca(2+)]i required for 50% of activation. Myofibrils photolabeled with AziPm and Azi-iso identified myosin, actin, and myosin light chain as targets of the anesthetics. Several adducted residues in those proteins were located in conformationally sensitive regions that underlie contractile function. Thus, propofol and isoflurane decrease force development by directly depressing myofilament Ca(2+) responsiveness and have binding sites in key regions for contraction in both actin and myosin.-Meng, T., Bu, W., Ren, X., Chen, X., Yu, J., Eckenhoff, R. G., Gao, W. D. Molecular mechanism of anesthetic-induced depression of myocardial contraction.

Vapor Pressures of Anesthetic Agents at Temperatures Below 0°C and a Novel Anesthetic Delivery Device.

At room temperature, the vapor pressures of desflurane, isoflurane, and sevoflurane are well above the clinically useful range. We hypothesized that therapeutic concentrations of these agents could be achieved at temperatures below 0°C, but the vapor pressure-temperature relationship is unknown below 0. Second, we hypothesized that this relationship could be exploited to deliver therapeutic-range concentrations of anesthetic vapor. We therefore set out to determine the low temperature-vapor pressure relationships of each anesthetic agent, thereby identifying the saturated vapor concentration of each agent at any temperature below 0°C. To test our hypothesis, we measured the saturated vapor concentration at 1 atm of pressure for temperatures between -60 and 0°C, thus developing an empiric relationship for each agent. There was consistency in repeated experiments for all 3 agents. To test the empiric data, we constructed a digitally controlled thermoelectric anesthetic vaporizer, characterized the device, and used it to deliver anesthetic vapor to laboratory mice. We report, for the first time, the temperature-vapor pressure relationship at temperatures below 0°C for desflurane, isoflurane, and sevoflurane as well as the TMAC of these agents: the temperature at which the vapor pressure is equal to the minimum alveolar concentration. We describe the construction and limited validation of an anesthetic vaporizer prototype on the basis of this principle. We conclude that clinically relevant concentrations of volatile anesthetics may be achieved at low temperatures.

The Universal Anaesthesia Machine (UAM): assessment of a new anaesthesia workstation built with global health in mind.

The Universal Anaesthesia Machine has been developed as a complete anaesthesia workstation for use in low- and middle-income countries, where the provision of safe general anaesthesia is often compromised by unreliable supply of electricity and anaesthetic gases. We performed a functional and clinical assessment of this anaesthetic machine, with particular reference to novel features and functioning in the intended environment. The Universal Anaesthesia Machine was found to be reliable, safe and consistent across a range of tests during targeted functional testing.

Important role of calcium chloride in preventing carbon monoxide generation during desflurane degradation with alkali hydroxide-free carbon dioxide absorbents.

We investigated whether calcium chloride (CaCl2), a supplementary additive in carbon dioxide (CO2) absorbents, could affect carbon monoxide (CO) production caused by desflurane degradation, using a Japanese alkali-free CO2 absorbent Yabashi Lime®-f (YL-f), its CaCl2-free and 1% CaCl2-added derivatives, and other commercially available alkali-free absorbents with or without CaCl2. The reaction between 1 L of desflurane gas (3-10%) and 20 g of desiccated specimen was performed in an artificial closed-circuit anesthesia system for 3 min at 20 or 40 °C. The CO concentration was measured using a gas chromatograph equipped with a semiconductor sensor detector. The systems were validated by detecting dose-dependent CO production with an alkali hydroxide-containing CO2 absorbent, Sodasorb®. Compared with YL-f, the CaCl2-free derivative caused the production of significantly more CO, while the 1% CaCl2-added derivative caused the production of a comparable amount of CO. These phenomena were confirmed using commercially available absorbents AMSORB® PLUS, an alkali-free absorbent with CaCl2, and LoFloSorb™, an alkali-free absorbent without CaCl2. These results suggest that CaCl2 plays an important role in preventing CO generation caused by desflurane degradation with alkali hydroxide-free CO2 absorbents like YL-f.

Adsorbent comparisons for anesthetic gas capture in hospital air emissions.

For the development of emission control strategies, activated carbon, zeolite, molecular sieves, and a silica gel were tested for adsorption of the newer anesthetic gases isoflurane, sevoflurane, and desflurane from air. The activated carbon Norit GCA 48 was selected for the best performance, and adsorption isotherms at room temperature were developed for the three anesthetics. Equilibrium capacities for this carbon were in the range of 500 to 1,000 mg g(-1) for these anesthetics at partial pressures ranging from 5 to 45 Torr, with the most volatile compound (desflurane) showing the least favorable adsorption. Activated carbons are therefore suggested for use as effective adsorbents in emission control of these anesthetic gases from hospitals.

Modelling of noble anaesthetic gases and high hydrostatic pressure effects in lipid bilayers.

Our objective was to study molecular processes that might be responsible for inert gas narcosis and high-pressure nervous syndrome. The classical molecular dynamics trajectories (200 ns) of dioleoylphosphatidylcholine (DOPC) bilayers simulated by the Berger force field were evaluated for water and the atomic distribution of noble gases around DOPC molecules in the pressure range of 1-1000 bar and at a temperature of 310 K. Xenon and argon have been tested as model gases for general anaesthetics, and neon has been investigated for distortions that are potentially responsible for neurological tremors in hyperbaric conditions. The analysis of stacked radial pair distribution functions of DOPC headgroup atoms revealed the explicit solvation potential of the gas molecules, which correlates with their dimensions. The orientational dynamics of water molecules at the biomolecular interface should be considered as an influential factor, while excessive solvation effects appearing in the lumen of membrane-embedded ion channels could be a possible cause of inert gas narcosis. All the noble gases tested exhibit similar order parameter patterns for both DOPC acyl chains, which are opposite of the patterns found for the order parameter curve at high hydrostatic pressures in intact bilayers. This finding supports the 'critical volume' hypothesis of anaesthesia pressure reversal. The irregular lipid headgroup-water boundary observed in DOPC bilayers saturated with neon in the pressure range of 1-100 bar could be associated with the possible manifestation of neurological tremors at the atomic scale. The non-immobiliser neon also demonstrated the highest momentum impact on the normal component of the DOPC diffusion coefficient representing the monolayer undulation rate, which indicates that enhanced diffusivity rather than atomic size is the key factor.