Inhaled volatile anesthetics in the intensive care unit

The discovery and utilization of volatile anesthetics has significantly transformed surgical practices since their inception in the mid-19th century.Recently,a paradigm shift is observed as volatile anesthetics extend beyond traditional confines of the operating theatres,finding diverse applications in intensive care settings.In the dynamic landscape of intensive care,volatile anesthetics emerge as a promising avenue for addressing complex sedation requirements,managing refractory lung pathologies including acute respiratory distress syndrome and status asthmaticus,conditions of high sedative requirements including burns,high opioid or alcohol use and neurological conditions such as status epilepticus.Volatile anesthetics can be administered through either inhaled route via anesthetic machines/devices or through extracorporeal membrane oxygenation circuitry,providing intensivists with multiple options to tailor therapy.Furthermore,their unique pharmacokinetic profiles render them titratable and empower clinicians to individualize management with heightened accuracy,mitigating risks associated with conventional sedation modalities.Despite the amounting enthusiasm for the use of these therapies,barriers to widespread utilization include expanding equipment availability,staff familiarity and training of safe use.This article delves into the realm of applying inhaled volatile anesthetics in the intensive care unit through discussing their pharmacology,administration considerations in intensive care settings,complication considerations,and listing indications and evidence of the use of volatile anesthetics in the critically ill patient population.

Anesthetic Action of Volatile Anesthetics by Using Paramecium as a Model

Although empirically well understood in their clinical administration, volatile anesthetics are not yet well comprehended in their mechanism studies. A major conundrum emerging from these studies is that there is no validated model to assess the presumed candidate sites of the anesthetics. We undertook this study to test the hypothesis that the single-celled Paramecium could be anesthetized and served as a model organism in the study of anesthetics. We assessed the motion of Paramecium cells with Expert Vision system and the chemoresponse of Paramecium cells with T-maze assays in the presence of four different volatile anesthetics, including isoflurane, sevoflurane, enflurane and ether. Each of those volatiles was dissolved in buffers to give drug concentrations equal to 0.8, 1.0, and 1.2 EC50, respectively, in clinical practice. We could see that after application of volatile anesthetics, the swimming of the Paramecium cells was accelerated and then suppressed, or even stopped eventually, and the index of the chemoresponse of the Paramecium cells （denoted as Iche） was decreased. All of the above impacts were found in a concentration-dependent fashion. The biphasic effects of the clinical concentrations of volatile anesthetics on Paramecium simulated the situation of high species in anesthesia, and the inhibition of the chemoresponse also indicated anesthetized. In conclusion, the findings in our studies suggested that the single-celled Paramecium could be anesthetized with clinical concentrations of volatile anesthetics and therefore be utilized as a model organism to study the mechanisms of volatile anesthetics.

Development of three Drosophila melanogaster strains with different sensitivity to volatile anesthetics

Background The mechanisms of action for volatile anesthetics remain unknown for centuries partly owing to the insufficient or ineffective research models. We designed this study to develop three strains derived from a wild-type Drosophila melanogaster with different sensitivities to volatile anesthetics, which may ultimately facilitate molecular and genetic studies of the mechanism involved. Methods Median effective doses （ED50） of sevoflurane in seven-day-old virgin female and male wild-type Drosophila melanogaster were determined. The sensitive males and females of percentile 6-10 were cultured for breeding sensitive offspring （$1）. So did median ones of percentile 48-52 for breeding median offspring （M1）, resistant ones of percentile 91-95 for breeding resistant offspring （R1）. Process was repeated through 31 generations, in the 37th generation, S37, M37 and R37 were used to determine ED5o for enflurane, isoflurane, sevoflurane, desfiurane, halothane, methoxyflurane, chloroform and trichloroethylene, then ED50 values were correlated with minimum alveolar concentration （MAC） values in human. Results From a wild-type Drosophila melanogaster we were able to breed three strains with high, median and low sevoflurane requirements. The ratio of sevoflurane requirements of three strains were 1.20：1.00：0.53 for females and 1.22：1.00：0.72 for males. Strains sensitive, median and resistant to sevoflurane were also sensitive, median and resistant to other volatile anesthetics. For eight anesthetics, ED50 values in three strains correlated directly with MAC values in human. Conclusions Three Drosophila melanogaster strains with high, median and low sensitivity to volatile anesthetics, but with same hereditary background were developed. The ED50 are directly correlated with MAC in human for eight volatile anesthetics.

Volatile anesthetics inhibit the activity of calmodulin by interacting with its hydrophobic site

Background Volatile anesthetics （VAs） may affect varied and complex physiology processes by manipulating Ca2＋-calmodulin （CAM）. However, the detailed mechanism about the action of VAs on CaM has not been elucidated. This study was undertaken to examine the effects of VAs on the conformational change, hydrophobic site, and downstream signaling pathway of CaM, to explore the possible mechanism of anesthetic action of VAs. Methods Real-time second-harmonic generation （SHG） was performed to monitor the conformational change of CaM in the presence of VAs, each plus 100 μmol/L Ca2＋. A hydrophobic fluorescence indicator, 8-anilinonaphthalene-l-sulfonate （ANS）, was utilized to define whether the VAs would interact with CaM at the hydrophobic site or not. High-performance liquid chromatography （HPLC） was carried out to analyze the activity of CaM-dependent phosphodiesterase （PDE1） in the presence of VAs. The VAs studied were ether, enflurane, isoflurane, and sevoflurane, with their aqueous concentrations 7.6, 9.5, 11.4 mmol/L; 0.42, 0.52, 0.62 mmol/L; 0.25, 0.31, 0.37 mmol/L and 0.47, 0.59, 0.71 mmol/L respectively, each were equivalent to their 0.8, 1.0 and 1.2 concentration for 50% of maximal effect （EC50） for general anesthesia. Results The second-harmonic radiation of CaM in the presence of Ca2＋ was largely inhibited by the VAs. The fluorescence intensity of ANS, generated by binding of Ca2＋ to CaM, was reversed by the VAs. HPLC results also showed that AMP, the product of the hydrolysis of cAMP by CaM-dependent PDE1, was reduced by the VAs. Conclusions Our findings demonstrate that the above VAs interact with the hydrophobic core of Ca2＋-CaM and the interaction results in the inhibition of the conformational change and activity of CaM. This in vitro study may provide us insight into the possible mechanism of anesthetic action of VAs in vivo.

Effects of isoflurane and sevoflurane postconditioning and changes in JNK1/2 pathway activity on rat brain slices subjected to oxygen and glucose deprivation in vitro

Recent research shows that the JNK1/2 signaling pathway plays a neuroprotective role against ischemia-reperfusion injury by cross-talk with other pathways.The present study investigated the effects of isoflurane and sevoflurane postconditioning on JNK1/2 pathway activity and neuronal cell viability after oxygen and glucose deprivation injury in hippocampal slices in vitro.Techniques used included population spike analysis,propidium iodide fluorescent staining,western blot assay,and the use of JNK1/2-specific pharmacological tools such as anisomycin （agonist） and SP600125 （inhibitor）.We found that both isoflurane and sevoflurane inhibited JNK pathway activity and had neuroprotective effects against oxygen and glucose deprivation injury in slices of rat hippocampus in vitro.Postconditioning with volatile anesthetics exerted neuroprotective effects on nerve cells and preserved the function of the CA1 region by inhibiting JNK1/2 phosphorylation.This suppression of JNK1/2 activity could underlie the observed synergistic neuroprotective effect produced by volatile anesthetic postconditioning.

Extracorporeal membrane oxygenation and inhaled sedation in coronavirus disease 2019-related acute respiratory distress syndrome

Coronavirus disease 2019(COVID-19)related acute respiratory distress syndrome(ARDS)is a severe complication of infection with severe acute respiratory syndrome coronavirus 2,and the primary cause of death in the current pandemic.Critically ill patients often undergo extracorporeal membrane oxygenation(ECMO)therapy as the last resort over an extended period.ECMO therapy requires sedation of the patient,which is usually achieved by intravenous administration of sedatives.The shortage of intravenous sedative drugs due to the ongoing pandemic,and attempts to improve treatment outcome for COVID-19 patients,drove the application of inhaled sedation as a promising alternative for sedation during ECMO therapy.Administration of volatile anesthetics requires an appropriate delivery.Commercially available ones are the anesthetic gas reflection systems AnaConDa®and MIRUSTM,and each should be combined with a gas scavenging system.In this review,we describe respiratory management in COVID-19 patients and the procedures for inhaled sedation during ECMO therapy of COVID-19 related ARDS.We focus particularly on the technical details of administration of volatile anesthetics.Furthermore,we describe the advantages of inhaled sedation and volatile anesthetics,and we discuss the limitations as well as the requirements for safe application in the clinical setting.

Selective breeding of mice strains with different sensitivity to isoflurane

Background The mechanisms of action of volatile anesthetics are still unknown. Recently, the use of genetics as a means to investigate anesthetic action has increased in scale. However, only limited forward genetic approach studies were performed in mammals, especially with volatile anesthetics as the selection agent. In the present study, a selective breeding process was designed to produce strains of mice with different sensitivity to isoflurane. Methods One hundred and sixty male and female virgin outbred ICR/CD-1 mice at 65-70 days of age were selected as original generation, and the median effective dose （ED50） of inhaled isoflurane were measured by probit analysis with the loss of righting reflex as the endpoint of anesthesia. The most sensitive males and females were selected and mated one another randomly, as with the most resistant males and females. Thus two branches of mice （sensitive and resistant to isoflurane） were created and allowed to produce the next generation. At 65-70 days of age, screening experiment was performed in offspring, by selecting the most sensitive mice in sensitive branch and the most resistant mice in resistant branch. Selected males and females within each branch were mated one another randomly to produce the following generation. The same procedure was performed in the offspring. The process of screening and breeding was repeated for 8 generations, and then strains were conserved by mating the offspring one another randomly within each branch for 3 generations. Each pair of mice was allowed to produce the second litters as a backup, and isoflurane EDs0 was measured in mice from the second litters. Results Isoflurane righting reflex ED5os （95% confidence limit （CL）） in original mice were 0.65% （0.58%-0.72%） in females and 0.63% （0.56%-0.69%） in males. After the 4th generation, isoflurane ED50S in resistant branch were significantly higher than those in sensitive branch （P 〈0.05）, for both in females and males. In the 11th generation, isoflurane ED50 in the two branches differed by 32% in females and 36% in males. Conclusions After 8 generations of selective breeding and 3 generations of strain conservation, two strains of mice with high and low sensitivity to isoflurane were developed. The separation of inhaled anesthetic requirement in parents could be transferred to the offspring in mice.