Use of inhalational anaesthetic agents in paediatric and adult patients for status asthmaticus, status epilepticus and difficult sedation scenarios: a protocol for a systematic review

IntroductionInhaled volatile anaesthetics have a long tradition of use as hypnotic agents in operating rooms and are gaining traction as sedatives in intensive care units (ICUs). However, uptake is impeded by low familiarity with volatiles, unique equipment and education needs. Inhaled anaesthetics are often reserved in ICUs as therapies for refractory and life threatening status asthmaticus, status epilepticus, high and difficult sedation need scenarios given they possess unique pharmacological properties to manage these medical conditions while providing sedation to acutely ill patients. The objective of this systematic review is to collate evidence regarding the efficacy, safety and feasibility of volatile anaesthetics in adult and paediatric ICU patients for these three emergency conditions.Methods and analysisWe will conduct a systematic review of the primary studies in adult and paediatric ICU patients with status asthmaticus, status epilepticus and high/difficult sedation needs. We will include observational and interventional studies published from 1970 to 2021 in English or French investigating patients who have received a volatile inhalational agent for the above indications. We will evaluate the efficacy, safety, feasibility and implementation barriers for the volatile anaesthetics for each of three specified indications. Included studies will not be limited by necessity of a comparator arm. We will also evaluate clinical characteristics, patient demographics and provider attitudes towards volatile anaesthetic administration in defined critical care scenarios. Data will be extracted and analysed across these domains. The databases MEDLINE, EMBASE, the Science Citation Index as well as the Cochrane Central Controlled Trials Register will be queried with our search strategy.Descriptive and statistical analysis will be employed where appropriate. Data extraction and quality assessment will be performed in duplicate using a standardised tool. A narrative approach and statistical analyses will be used to describe patient characteristics, volatile efficacy, safety concerns, technical administration, attitudes towards administration and other implementation barriers.Ethics and disseminationNo ethics board approval will be necessary for this systematic review. This research is independently funded. Results will be disseminated in a peer-reviewed journal and conference presentation.PROSPERO numberCRD42021233083.

A COMPARATIVE STUDY OF ANAESTHETIC AGENTS ON HIGH VOLTAGE ACTIVATED CALCIUM CHANNEL CURRENTS IN IDENTIFIED MOLLUSCAN NEURONS

SUMMARYUsing the two electrode voltage clamp configuration, a high voltage activated whole-cell Ca2+ channel current (IBa) was recorded from a cluster of neurosecretory ‘Light Yellow’ Cells (LYC) in the right parietal ganglion of the pond snail Lymnaea stagnalis.Recordings of IBa from LYCs show a reversible concentration-dependent depression of current amplitude in the presence of the volatile anaesthetics halothane, isoflurane and sevoflurane, or the non-volatile anaesthetic pentobarbitone at clinical concentrations.In the presence of the anaesthetics investigated, IBa measured at the end of the depolarizing test pulse showed proportionally greater depression than that at measured peak amplitude, as well as significant decrease in the rate of activation or increase in inactivation or both.Within the range of concentrations used, the concentration-response plots for all the anaesthetics investigated correlate strongly to straight line functions, with linear regression R2 values > 0.99 in all instances.For volatile anaesthetics, the dose-response regression slopes for IBa increase in magnitude, in order of gradient: sevoflurane, isoflurane and halothane, a sequence which reflects their order of clinical potency in terms of MAC value.

Global genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers

We previously documented that the CaV3.3 isoform of T-type calcium channels (T-channels) is inhibited by clinically relevant concentrations of volatile anaesthetics, including isoflurane. However, little is understood about the functional role of CaV3.3 channels in anaesthetic-induced hypnosis and underlying neuronal oscillations. To address this issue, we used CaV3.3 knock-out (KO) mice and a panselective T-channel blocker 3,5-dichloro-N-[1-(2,2-dimethyltetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2). We found that mutant mice injected with the vehicle showed faster induction of hypnosis than wild-type (WT) mice, while the percent isoflurane at which hypnosis and immobility occurred was not different between two genotypes. Furthermore, we found that TTA-P2 facilitated isoflurane induction of hypnosis in the CaV3.3 KO mice more robustly than in the WT mice. Isoflurane-induced hypnosis following injections of TTA-P2 was accompanied with more prominent delta and theta EEG oscillations in the mutant mice, and reached burst-suppression pattern earlier when compared to the WT mice. Our findings point to a relatively specific value of CaV3.3 channels in anaesthetic induced hypnosis. Furthermore, we propose that T-channel blockers may be further explored as a valuable adjunct to reducing the usage of potent volatile anaesthetics, thereby improving their safety.

Polymorphism in GSTM1 and GSTT1 genes influence DNA damage in personnel occupationally exposed to volatile anaesthetics (VA), from Peshawar, Pakistan

ObjectivesThe objective of this study was to assess the influence of antioxidant gene GSTM1 and GSTT1 on DNA damage in personnel occupationally exposed to volatile anaesthetics (VA).MethodsThe study groups were composed of 50 exposed subjects (anaesthesia workers) and 49 controls. Blood samples were collected from both subjects. DNA damage was analysed through the comet assay technique. Biomarker genes GSTM1 and GSTT1 were inspected through PCR technique for polymorphism.ResultsThe comet assay technique showed that the Total Comet Score (TCS) in exposed subjects was significantly higher (p=0.0001) than the control. Age and smoking had significant effects on TCS in the study groups (p<0.05). Duration of occupational exposure had significant positive correlation (r=0.755, p<0.001) with DNA damage. The null polymorphism in GSTM1 and GSTT1 gene showed a significant effect (p<0.001 and p<0.000) on the DNA damage.ConclusionsThe polymorphism in GSTM1 and GSTT1 gene significantly damage DNA in personnel occupationally exposed to VA.

Volatile anaesthetic for treatment of respiratory failure from status asthmaticus requiring extracorporeal membrane oxygenation

A 37-year-old male smoker with asthma presented with status asthmaticus refractory to terbutaline, intravenous magnesium, continuous bronchodilators, steroids, heliox and theophylline infusion. He was intubated on hospital day 2 and cannulated for veno-venous extracorporeal membrane oxygenation (V-V ECMO) on hospital day 3 for refractory respiratory acidosis secondary to hypercapnia and hypoxemia despite maximum medical management over 4 days. He was started on inhaled isoflurane with improvement in peak airway pressures and respiratory acidosis, allowing for prompt weaning from V-V ECMO and extubation. Inhaled volatile anaesthetics exert a direct action on bronchiole smooth muscle causing relaxation with significant effect despite severely impaired pulmonary function. This treatment in patients on ECMO may allow for earlier decannulation and decreased risk of coagulopathy, ECMO circuit failure, infection, renal failure, pulmonary haemorrhage and central nervous system haemorrhage. However, major limitations exist in delivering volatile anaesthetics, which may make use inefficient and costly despite efficacy.