Methoxyflurane as a volatile anesthetic and its place in modern pain management: a narrative review

Halogenated inhaled anesthetics modulate voltage-gated ion channels by unknown mechanisms. Biophysical analyses revealed novel activation of K(v) channels by the inhaled anesthetic sevoflurane. K(v) channel activation by sevoflurane results from the positive allosteric modulation of activation gating. The unique activation of K(v) channels by sevoflurane demonstrates novel anesthetic specificity and offers new insights into allosteric modulation of channel gating. Voltage-gated ion channels are modulated by halogenated inhaled general anesthetics, but the underlying molecular mechanisms are not understood. Alkanols and halogenated inhaled anesthetics such as halothane and isoflurane inhibit the archetypical voltage-gated Kv3 channel homolog K-Shaw2 by stabilizing the resting/closed states. By contrast, sevoflurane, a more heavily fluorinated ether commonly used in general anesthesia, specifically activates K-Shaw2 currents at relevant concentrations (0.05-1 mM) in a rapid and reversible manner. The concentration dependence of this modulation is consistent with the presence of high and low affinity interactions (K(D) = 0.06 and 4 mM, respectively). Sevoflurane (<1 mM) induces a negative shift in the conductance-voltage relation and increases the maximum conductance. Furthermore, suggesting possible roles in general anesthesia, mammalian Kv1.2 and Kv1.5 channels display similar changes. Quantitative description of the observations by an economical allosteric model indicates that sevoflurane binding favors activation gating and eliminates an unstable inactivated state outside the activation pathway. This study casts light on the mechanism of the novel sevoflurane-dependent activation of Kv channels, which helps explain how closely related inhaled anesthetics achieve specific actions and suggests strategies to develop novel Kv channel activators.

#36915 D37 – the green footprint of regional anesthesia

SummaryVolatile anesthetics induce hyperactivity during induction while producing anesthesia at higher concentrations. They also bidirectionally modulate many neuronal functions. However, the neuronal mechanism is unclear. The effects of isoflurane on sodium channel currents were analyzed in acute mouse brain slices, including sodium leak (NALCN) currents and voltage-gated sodium channels (Nav) currents. Isoflurane at sub-anesthetic concentrations increased the spontaneous firing rate of CA3 pyramidal neurons, whereas anesthetic concentrations of isoflurane decreased the firing rate. Isoflurane at sub-anesthetic concentrations enhanced NALCN conductance but minimally inhibited Nav currents. Isoflurane at anesthetic concentrations depressed Nav currents and action potential amplitudes. Isoflurane at sub-anesthetic concentrations depolarized resting membrane potential (RMP) of neurons, whereas hyperpolarized the RMP at anesthetic concentrations. Isoflurane at low concentrations induced hyperactivity in vivo, which was diminished in NALCN knockdown mice. In conclusion, enhancement of NALCN by isoflurane contributes to its bidirectional modulation of neuronal excitability and the hyperactivity during induction.

Hypothermia and Hyperthermia in the Ambulatory Surgical Patient

Volatile general anesthetics are used for inhalational anesthesia in hundreds of millions of surgical procedures annually, yet their mechanisms of action remain unclear. Membrane proteins involved in cell signaling are major targets for anesthetics, and voltage-gated ion channels that mediate neurotransmission, movement, and cognition are sensitive to volatile anesthetics (VAs). In many cases, the effects produced by VAs on mammalian ion channels are reproduced in prokaryotic orthologues, providing an opportunity to investigate VA interactions at high resolution using these structurally simpler prokaryotic proteins. We utilized the bacterial voltage-gated sodium channel (VGSC) NavMs from Magnetococcus marinus to investigate its interaction with the widely used VA sevoflurane. Sevoflurane interacted directly with NavMs, producing effects consistent with multisite binding models for VA actions on their targets. We report the identification of one of these interactions at atomic detail providing the first high-resolution structure of a VA bound to a voltage-gated ion channel. The X-ray crystal structure shows sevoflurane binding to NavMs within an intramembrane hydrophobic pocket formed by residues from the voltage sensor and channel pore, domains essential for channel gating. Mutation of the dominant sevoflurane binding-site residue within this pocket, and analogous residues found in similar sites in human VGSCs, profoundly affected channel properties, supporting a critical role for this site in VGSC function. These findings provide the basis for future work to understand the role of VA interactions with VGSCs in both the anesthetic and toxic effects associated with general anesthesia.

Anesthetic-sensitive 2P domain K+ channels.

This Month in Anesthesiology

Ketamine*

Can anaesthetic technique influence cancer outcome? The next steps…

Is protection by inhalation agents volatile? Controversies in cardioprotection

Prospective interventional trials and retrospective observational analyses provide conflicting evidence regarding the relationship between propofol versus inhaled volatile general anesthesia and long-term survival after cancer surgery. Specifically, bladder cancer surgery lacks prospective clinical trial evidence. Data on bladder cancer surgery performed under general anesthesia between 2014 and 2021 from the National Quality Registry for Urinary Tract and Bladder Cancer and the Swedish Perioperative Registry were record-linked. Overall survival was compared between patients receiving propofol or inhaled volatile for anesthesia maintenance. The minimum clinically important difference was defined as a 5-percentage point difference in 5-yr survival. Of 7,571 subjects, 4,519 (59.7%) received an inhaled volatile anesthetic, and 3,052 (40.3%) received propofol for general anesthesia maintenance. The two groups were quite similar in most respects but differed in American Society of Anesthesiologists Physical Status and tumor stage. Propensity score matching was used to address treatment bias. Survival did not differ during follow-up (median, 45 months [interquartile range, 33 to 62 months]) in the full unmatched cohort nor after 1:1 propensity score matching (3,052 matched pairs). The Kaplan-Meier adjusted 5-yr survival rates in the matched cohort were 898 of 3,052, 67.5% (65.6 to 69.3%) for propofol and 852 of 3,052, 68.5% (66.7 to 70.4%) for inhaled volatile general anesthesia, respectively (hazard ratio, 1.05 [95% CI, 0.96 to 1.15]; P = 0.332). A sensitivity analysis restricted to 1,766 propensity score-matched pairs of patients who received only one general anesthetic during the study period did not demonstrate a difference in survival; Kaplan-Meier adjusted 5-yr survival rates were 521 of 1,766, 67.1% (64.7 to 69.7%) and 482 of 1,766, 68.9% (66.5 to 71.4%) for propofol and inhaled volatile general anesthesia, respectively (hazard ratio, 1.09 [95% CI, 0.97 to 1.23]; P = 0.139). Among patients undergoing bladder cancer surgery under general anesthesia, there was no statistically significant difference in long-term overall survival associated with the choice of propofol or an inhaled volatile maintenance.

Background: Climate change has been identified as the greatest global health threat of the 21st century, with the healthcare sector contributing approximately 4–5% of global greenhouse gas (GHG) emissions. Within this sector, anesthetic practices are significant contributors due to the use of inhaled anesthetic gases such as desflurane, sevoflurane, and isoflurane, which possess high Global Warming Potentials (GWPs) and long atmospheric lifetimes. As concerns over climate change intensify, the anesthesia community must reassess its practices and adopt more sustainable approaches that align with environmental goals while maintaining patient safety. Methods: This manuscript reviews the environmental impacts of commonly used anesthetic gases and explores sustainable strategies, including the adoption of anesthetics with lower GWPs, enhancement of recycling and waste reduction methods, transition to intravenous anesthesia, and implementation of low-flow anesthesia techniques. Barriers to these strategies, such as technological limitations, resistance to change, policy restrictions, and educational gaps within the anesthesia community, are also examined. Results: The analysis indicates that transitioning to anesthetics with lower GWPs, such as replacing desflurane with sevoflurane and employing low-flow anesthesia, can significantly reduce GHG emissions. Although recycling and waste reduction pose logistical challenges, they offer additional environmental benefits. Transitioning to intravenous anesthesia can eliminate direct GHG emissions from volatile anesthetics. However, overcoming barriers to these strategies requires comprehensive education, advocacy for research and innovation, strategic change management, and supportive policy frameworks. Conclusions: Continuous monitoring and evaluation are essential for the success of sustainable practices in anesthesia. Establishing robust Key Performance Indicators (KPIs) and leveraging advanced analytical tools will enable adaptation and refinement of practices within the anesthesia community. Collaborative efforts among clinicians, policy makers, and stakeholders are crucial for reducing the environmental impact of anesthesia and promoting ecological responsibility within healthcare.

Intravenous and volatile general anesthetics inhibit norepinephrine (NE) release from sympathetic neurons and other neurosecretory cells. However, the actions of general anesthetics on NE release from central nervous system (CNS) neurons are unclear. We investigated the effects of representative IV and volatile anesthetics on [(3)H]NE release from isolated rat cortical nerve terminals (synaptosomes). Purified synaptosomes prepared from rat cerebral cortex were preloaded with [(3)H]NE and superfused with buffer containing pargyline (a monoamine oxidase inhibitor) and ascorbic acid (an antioxidant). Basal (spontaneous) and stimulus-evoked [(3)H]NE release was evaluated in the superfusate in the absence or presence of various anesthetics. Depolarization with increased concentrations of KCl (15-20 mM) or 4-aminopyridine (0.5-1.0 mM) evoked concentration- and Ca(2+)-dependent increases in [(3)H]NE release from rat cortical synaptosomes. The IV anesthetics etomidate (5-40 microM), ketamine (5-30 microM), or pentobarbital (25-100 microM) did not affect basal or stimulus-evoked [(3)H]NE release. Propofol (5-40 microM) increased basal [(3)H]NE release and, at larger concentrations, reduced stimulus-evoked release. The volatile anesthetic halothane (0.15-0.70 mM) increased basal [(3)H]NE release, but did not affect stimulus-evoked release. These findings demonstrate drug-specific stimulation of basal NE release. Noradrenergic transmission may represent a presynaptic target for selected general anesthetics in the CNS. Given the contrasting effects of general anesthetics on the release of other CNS transmitters, the presynaptic actions of general anesthetics are both drug- and transmitter-specific. General anesthetics affect synaptic transmission both by altering neurotransmitter release and by modulating postsynaptic responses to transmitter. Anesthetics exert both drug-specific and transmitter-specific effects on transmitter release: therapeutic concentrations of some anesthetics stimulate basal, but not evoked, norepinephrine release, in contrast to evoked glutamate release, which is inhibited.

1. Completely isolated identified neurones from the right parietal ganglion of the pond snail Lymnaea stagnalis were investigated under two-electrode voltage clamp. Neuronal nicotinic acetylcholine receptor (AChR) currents were studied at low acetylcholine concentrations (< or = 200 nM). 2. Inhibition of the ACh-induced currents by three volatile general anaesthetics (halothane, isoflurane and methoxyflurane) and the specific inhibitor (+)-tubocurarine was studied as a function of temperature (over the range 4-25 degrees C). 3. The inhibition by the volatile anaesthetics increased (inhibition constants decreased) with decreasing temperature while the inhibition by (+)-tubocurarine did not change significantly near room temperature, but decreased at lower temperatures. The (+)-tubocurarine inhibition appeared to be competitive in nature and showed no significant voltage-dependence. 4. The van't Hoff plots (logarithms of the dissociation constants against reciprocal absolute temperature) were linear for the anaesthetics, but markedly non-linear for (+)-tubocurarine. From these plots, values for the changes in the standard Gibbs free energy delta G degrees water-->AChR, enthalpy delta H degree water-->AChR, entropy delta S degree water-->AChR and heat capacity delta Cp degree water-->AChR were determined. Tubocurarine was found to bind very much tighter to the receptor than the volatile anaesthetics due, entirely, to a favourable increase in entropy on binding. 5. A comparison between the temperature-dependence of the anaesthetic inhibition of the ACh receptor and that of general anaesthetic potencies in animals indicates that the temperature-dependence of animal potencies might be simply accounted for in terms of changes in anaesthetic/receptor binding.

1. A comparative descriptive analysis of systemic (sodium pentobarbital, sodium thiopentone, ketamine) and volatile (halothane, isoflurane, enflurane) general anesthetics revealed important differences in the neuronal responses of identified motor neurons and interneurons in the isolated central nervous system (CNS) and cultured identified neurons in single cell culture of Lymnaea stagnalis (L.).2. At high enough concentrations all anesthetics eventually caused cessation of spontaneous or evoked action potentials, but volatile anesthetics were much faster acting. Halothane at low concentrations caused excitation, thought to be equivalent to the early excitatory phase of anesthesia. Strong synaptic inputs were not always abolished by pentobarbital.3. There were cell specific concentration-dependent responses to halothane and pentobarbital in terms of membrane potential, action potential characteristics, the after hyperpolarization and patterned activity. Individual neurons generated specific responses to the applied anesthetics.4. The inhalation anesthetics, enflurane, and isoflurane, showed little concentration dependence of effect, in contrast to results obtained with halothane. Enflurane was faster acting than halothane and isoflurane was particularly different, producing quiescence in all cells types studied at all concentrations studied.5. Halothane, enflurane, the barbiturate general anesthetics, pentobarbital, and sodium thiopentone and the dissociative anesthetic ketamine, produced two distinctly different effects which could be correlated with cell type and their location in the isolated brain: either a decline in spontaneous and evoked activity prior to quiescence in interneurons or paroxysmal depolarizing shifts (PDS) in motor neurons, again prior to quiescence, which were reversed when the anesthetic was eliminated from the bath. In the strongly electrically coupled motor neurons, VD1 and RPD2, both types of response were observed, depending on the anesthetic used. Thus, with the exception isoflurane, all the motor neurons subjected to the anesthetic agents studied here were capable of generating PDS in situ, but the interneurons did not do so.6. The effects of halothane on isolated cultured neurons indicates that PDS can be generated by single identified neurons in the absence of synaptic inputs. Further, many instances of PDS in neurons that do not generate it in situ have been found in cultured neurons. The nature of PDS is discussed.