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Background: Propofol is an i.v. anaesthetic commonly used during general anaesthesia and intensive care. It is known that the second transmembrane segment of the beta subunit in the GABA(A) receptor is an important target for the effects of propofol; however, this has not been investigated in human receptors. The aim of this study was to investigate the effect of propofol on human beta2 and beta3 GABA(A) subunits with point mutations corresponding to the N265M mutation in the rat beta2 and beta3 subunits.Methods: Asparagine-to-methionine replacement at amino acid position 289 and 290 (N289M and N290M) in the beta2 and beta3 GABA(A) receptor subunits, respectively, was accomplished by site-directed mutagenesis. Thereafter, subunits for three human wild-type (alpha1beta2gamma2, alpha2beta2gamma2, and alpha2beta3gamma2) and two mutant GABA(A) receptor channels [alpha1beta2(N289M)gamma2 and alpha2beta3(N290M)gamma2] were introduced into Xenopus oocytes and studied with two-electrode voltage clamp.Results: The mutant receptors left-shifted the GABA concentration-response curve. In comparison with the wild-type receptors, both the positive modulatory and the agonistic effects of propofol were strongly reduced in potency and amplitude at both mutated GABA(A) channels.Conclusions: We demonstrate that N289M or N290M mutation in human GABA(A) beta2 and beta3 subunits increases sensitivity to GABA, which is in contrast to the corresponding rat N265M mutation. Furthermore, the N289M and N289M mutations reduce both the potentiation of GABA-induced currents and the direct effect of propofol on channels incorporating either of the mutated subunits, which confirms earlier findings concerning the corresponding mutation in rat receptors and knock-in mice. [ABSTRACT FROM AUTHOR]

Background: Propofol is an i.v. anaesthetic commonly used during general anaesthesia and intensive care. It is known that the second transmembrane segment of the β subunit in the GABAA receptor is an important target for the effects of propofol; however, this has not been investigated in human receptors. The aim of this study was to investigate the effect of propofol on human β2 and β3 GABAA subunits with point mutations corresponding to the N265M mutation in the rat β2 and β3 subunits. [ABSTRACT FROM PUBLISHER]

BACKGROUND: Nondepolarizing neuromuscular blocking agents (NMBAs) are classic competitive-inhibitors at the muscle nicotinic acetylcholine receptor (nAChR). Although the fetal subtype muscle nAChR has been extensively studied at a molecular level, less is known about the interaction between nondepolarizing NMBAs and the human adult muscle nAChR. The aim of this study was to investigate the effect of clinically used nondepolarizing NMBAs at human adult muscle nAChRs and the mechanisms behind the inhibition. METHODS: Human subunits for the adult alpha(1)beta(1)delta(epsilon) muscle nAChR were cloned and expressed into Xenopus oocytes and thereafter studied with two-electrode voltage clamp. The effect of the clinically used nondepolarizing NMBAs, including atracurium, cis-atracurium, mivacurium, pancuronium, rocuronium, vecuronium, and d-tubocurarine, on acetylcholine-induced and dimethylphenylpiperazinium-induced currents were investigated. RESULTS: All nondepolarizing NMBAs tested inhibited acetylcholine- and dimethylphenylpiperazinium-induced currents in human adult alpha(1)beta(1)delta(epsilon) muscle nAChRs, and no receptor activation was seen. Interestingly, acetylcholine desensitized the human adult alpha(1)beta(1)delta(epsilon) muscle type receptor and attenuated the inhibition caused by nondepolarizing NMBAs, as evident by lack of increase in IC(50) values for the nondepolarizing NMBAs with increased concentrations of acetylcholine. In contrast, dimethylphenylpiperazinium-induced currents were competitively inhibited by the nondepolarizing NMBAs. CONCLUSIONS: This study demonstrates that nondepolarizing NMBAs inhibit human adult muscle nAChRs expressed in Xenopus oocytes by mixed mechanisms. When using the nondesensitizing agonist dimethylphenylpiperazinium, inhibition by the NMBA is competitive, whereas activation with high concentrations of acetylcholine in combination with NMBA induces a noncompetitive inhibition, which the authors speculate can involve receptor desensitization similar to that observed in the neuromuscular junction. [ABSTRACT FROM AUTHOR]

Neuromuscular transmission at the skeletal muscle occurs when a quantum of acetylcholine from the nerve ending is released and binds to the nicotinic acetylcholine receptors on the postjunctional muscle membrane. The nicotinic acetylcholine receptors on the endplate respond by opening channels for the influx of sodium ions and subsequent endplate depolarisation leads to muscle contraction. The acetylcholine immediately detaches from the receptor and is hydrolysed by acetylcholinesterase enzyme. Suxamethonium is a cholinergic agonist stimulating the muscle nicotinic acetylcholine receptors prior to causing neuromuscular block. Non-depolarising neuromuscular blocking drugs bind to the nicotinic acetylcholine receptors preventing the binding of acetylcholine. Non-depolarising neuromuscular blocking drugs also inhibit prejunctional α3β2 nicotinic acetylcholine autoreceptors, which can be seen in the clinical setting as train-of-four fade. In some pathological states such as denervation, burns, immobilisation, inflammation and sepsis, there is expression of other subtypes of nicotinic acetylcholine receptors with upregulation of these receptors throughout the muscle membrane. The responses of these receptors to suxamethonium and non-depolarising neuromuscular blocking drugs are different and explain some of the aberrant responses to neuromuscular blocking drugs. [ABSTRACT FROM AUTHOR]

We agree that it would be interesting to include a larger sample of patients with obstructive sleep apnoea, particularly after they have received an initial 3 months of continuous positive airway pressure (CPAP) treatment. Studies targeting the effects of residual neuromuscular blockade on postoperative respiratory complications in obstructive sleep apnoea patients are lacking and further research is to be welcomed. [Extracted from the article]

Background.: Apnoeic oxygenation during anaesthesia has traditionally been limited by the rapid increase in carbon dioxide and subsequent decrease in pH. Using a Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE) technique a slower increase in carbon dioxide than earlier studies was seen. Notably, apnoeic oxygenation using THRIVE has not been systematically evaluated with arterial blood gases or in patients undergoing laryngeal surgery. The primary aim of this study was to characterize changes in arterial P O 2 , P CO 2 and pH during apnoeic oxygenation using THRIVE under general anaesthesia.Methods.: Adult patients, (ASA I-II), undergoing shorter laryngeal surgery under general anaesthesia, were oxygenated during apnoea using THRIVE, 100% oxygen, 40-70 litres min - 1 . A cohort was randomized to hyperventilate during pre-oxygenation. Vital parameters and blood gases were monitored.Results.: Thirty-one patients, age 51 (34-76) yr, BMI 25 (4) were included. Mean apnoea time was 22.5 (4.5) min. Patients were well oxygenated, S pO 2 was never below 91%. The increase in P aCO 2 and end-tidal CO 2 during apnoea was 0.24 (0.05) and 0.12 (0.04) kPa min -1 , respectively. Hyperventilation during pre-oxygenation generated no difference in P aCO 2 at the end of apnoea compared with normoventilation.Conclusions.: This physiological study of apnoeic oxygenation using THRIVE during laryngeal surgery shows that this technique is able to keep patients with mild systemic disease and a BMI <30 well oxygenated for a period of up to 30 min. The THRIVE concept makes it possible to extend the apnoeic window but monitoring of CO 2 and/or pH is recommended.Clinical Trial Registration.: NCT02706431. [ABSTRACT FROM AUTHOR]

Pre-oxygenation using high-flow nasal oxygen can decrease the risk of desaturation during rapid sequence induction in patients undergoing emergency surgery. Previous studies were single-centre and often in limited settings. This randomised, international, multicentre trial compared high-flow nasal oxygen with standard facemask pre-oxygenation for rapid sequence induction in emergency surgery at all hours of the day and night. A total of 350 adult patients from six centres in Sweden and one in Switzerland undergoing emergency surgery where rapid sequence induction was required were included and randomly allocated to pre-oxygenation with 100% oxygen using high-flow nasal oxygen or a standard tight-fitting facemask. The primary outcome was the number of patients developing oxygen saturations <93% from the start of pre-oxygenation until 1 min after tracheal intubation. Data from 349 of 350 patients who entered the study were analysed (174 in the high-flow nasal oxygen group and 175 in the facemask group). No difference was detected in the number of patients desaturating <93%, five (2.9%) vs. six (3.4%) patients in the high-flow nasal oxygen and facemask group, respectively (p = 0.77). The risk of desaturation was not increased during on-call hours. No difference was seen in end-tidal carbon dioxide levels in the first breath after tracheal intubation or in the number of patients with signs of regurgitation between groups. These results confirm that high-flow nasal oxygen maintains adequate oxygen levels during pre-oxygenation for rapid sequence induction. [ABSTRACT FROM AUTHOR]

Healthcare workers involved in aerosol-generating procedures, such as tracheal intubation, may be at elevated risk of acquiring COVID-19. However, the magnitude of this risk is unknown. We conducted a prospective international multicentre cohort study recruiting healthcare workers participating in tracheal intubation of patients with suspected or confirmed COVID-19. Information on tracheal intubation episodes, personal protective equipment use and subsequent provider health status was collected via self-reporting. The primary endpoint was the incidence of laboratory-confirmed COVID-19 diagnosis or new symptoms requiring self-isolation or hospitalisation after a tracheal intubation episode. Cox regression analysis examined associations between the primary endpoint and healthcare worker characteristics, procedure-related factors and personal protective equipment use. Between 23 March and 2 June 2020, 1718 healthcare workers from 503 hospitals in 17 countries reported 5148 tracheal intubation episodes. The overall incidence of the primary endpoint was 10.7% over a median (IQR [range]) follow-up of 32 (18-48 [0-116]) days. The cumulative incidence within 7, 14 and 21 days of the first tracheal intubation episode was 3.6%, 6.1% and 8.5%, respectively. The risk of the primary endpoint varied by country and was higher in women, but was not associated with other factors. Around 1 in 10 healthcare workers involved in tracheal intubation of patients with suspected or confirmed COVID-19 subsequently reported a COVID-19 outcome. This has human resource implications for institutional capacity to deliver essential healthcare services, and wider societal implications for COVID-19 transmission. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnoea and residual neuromuscular blockade are, independently, known to be risk factors for respiratory complications after major surgery. Residual effects of neuromuscular blocking agents are known to reduce the hypoxic ventilatory response in healthy volunteers. Patients with obstructive sleep apnoea have impaired control of breathing, but it is not known to what extent neuromuscular blocking agents interfere with the regulation of breathing in such patients. In a physiological study in 10 unsedated men with untreated obstructive sleep apnoea, we wished to examine if partial neuromuscular blockade had an effect on hypoxic ventilatory response (isocapnic hypoxia to oxygen saturation of 80%) and hypercapnic ventilatory response (normoxic inspired carbon dioxide 5%). The hypoxic ventilatory response was reduced by 32% (p = 0.016) during residual neuromuscular block (rocuronium to train-of-four ratio 0.7), but the hypercapnic ventilatory response was unaffected. We conclude that neuromuscular blockade specifically depresses peripheral chemosensitivity, and not respiratory muscle function since the hypercapnic ventilatory response was unaffected. [ABSTRACT FROM AUTHOR]

Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) can prolong apnoea time in adults. Therefore, THRIVE used for pre-oxygenation in rapid sequence induction of anaesthesia could extend safe apnoea time during prolonged laryngoscopy and intubation. In this randomised controlled trial, we compared the lowest peripheral oxygen saturation (SpO2 ) during intubation when pre-oxygenating with either traditional facemask or THRIVE. Eighty adult patients, undergoing rapid sequence induction of anaesthesia for emergency surgery, were randomly allocated to pre-oxygenation with 100% oxygen with facemask or with THRIVE. Median (IQR [range]) lowest SpO2 until 1 min after intubation was 99% (97-100 [70-100]%) for the facemask group vs. 99% (99-100 [96-100]%) for the THRIVE group (p = 0.097). Five patients (12.5%) desaturated below 93% when pre-oxygenated with the facemask vs. none in the THRIVE group (p = 0.019). There were no differences in intubation time or apnoea time between the groups. Median intubation time was 51 (34-66 [22-261]) s in the facemask group vs. 48 (38-63 [10-146]) s in the THRIVE group (p = 0.99). Median apnoea time was 109 (86-142 [37-291]) s and 116 (92-146 [63-249]) s when using facemask and THRIVE, respectively (p = 0.49). No signs of regurgitation of gastric content were detected. The data on desaturation indicate potential benefits of oxygenation with THRIVE for rapid sequence induction compared with facemask pre-oxygenation. [ABSTRACT FROM AUTHOR]

Pre-oxygenation using high-flow nasal oxygen vs. tight facemask during rapid sequence induction: a reply We thank Drs Loo and Chrimes for their interesting and important letter [1] in response to our study [2]. We agree that it is possible to measure etO SB 2 sb as a measure of denitrogenation, but then without subsequent tracheal intubation, as in the volunteer study by Hanouz et al. [5]; however, our goal was to evaluate whether the incidence of oxygen desaturation during tracheal intubation can be reduced by maintaining oxygenation delivery rather than creating an oxygen store that, sooner or later, will be consumed. [Extracted from the article]

Background Volatile anaesthetics are known to affect cholinergic receptors. Perturbation of cholinergic signalling can cause cognitive deficits. In this study, we wanted to evaluate acetylcholine-induced intracellular signalling following sevoflurane exposure. Methods Pheochromocytoma12 PC12 cells were exposed to 4.6% sevoflurane for 2 h. Subsequently, Western blotting was used to measure acetylcholine-induced phosphorylation of extracellular signal-regulated kinase 1/2 ( ERK) 1/2 and basal Protein kinase B ( AKT) phosphorylation. Results After exposure, acetylcholine-induced ERK 1/2 phosphorylation was reduced to 58 ± 8% [95% confidence interval ( CI): 38-77%, P = 0.003] compared with non-exposed controls. At 30 min after the end of sevoflurane administration [at 0.7% sevoflurane (0.102 mM)], ERK 1/2 phosphorylation remained reduced to 57 ± 7% (95% CI: 39-74%, P = 0.001) and was at 120 min [0.02% (0.003 mM] still reduced to 63 ± 10% (95% CI: 37-88%, P = 0.01), compared with control. At 360 min after exposure, acetylcholine-induced ERK 1/2 phosphorylation had recovered to 98 ± 16% (95% CI: 45-152%, P = 0.98) compared with control. In contrast, immediately after sevoflurane exposure, basal AKT phosphorylation was increased by 228 ± 37% (95% CI: 133-324%, P = 0.02) but had returned to control levels at 30 min after exposure, 172 ± 67% (95% CI: 0-356%, P = 0.34). Conclusion Sevoflurane exposure has differential effects on different intracellular signalling pathways. On one hand, we observed a prolonged attenuation of acetylcholine-induced ERK 1/2 phosphorylation that persisted even when sevoflurane concentrations close to detection level. On the other hand, basal AKT phosphorylation was increased twofold during sevoflurane exposure, with a rapid return to baseline levels after exposure. We speculate that the effects on acetylcholine-induced intracellular signalling observed in our in vitro model could be of relevance also for cholinergic signalling in vivo following sevoflurane exposure. [ABSTRACT FROM AUTHOR]

Objectives – Analysis of the relationship between the symptoms, digital nerve somatosensory evoked potentials (D-SEP) and MRI, in patients with symptomatic cervical spine disorders (CSD). Materials and methods – MRI and D-SEP following electrical stimulation of digits I, III and V in 44 patients. Results – Symptoms in the fingers correlated significantly with disk herniation at the corresponding cervical level and with spinal cord impingement at one or two adjacent rostral segments on MRI. D-SEP was abnormal in 52% of all patients. Among them, the groups with multiple and single level involved on MRI had 62% and 30% of abnormal somatosensory evoked potentials (SEP), respectively. Digit I-SEP abnormality was more often localized at the root level, while digit V-SEP at the spinal cord level above the dorsal nucleus. D-SEP correlated best with compression of the spinal cord at adjacent upper and especially the most rostral (C3-5) levels on MRI. Conclusions – Accurate correlation of D-SEP and symptoms with MRI is essential for correct localization of lesions in patients with CSD. [ABSTRACT FROM AUTHOR]

Pre-oxygenation using high-flow nasal oxygen vs. tight facemask during rapid sequence induction: a reply A randomised controlled trial comparing transnasal humidified rapid insufflation ventilatory exchange (THRIVE) pre-oxygenation with facemask pre-oxygenation in patients undergoing rapid sequence induction of anaesthesia. We thank Dr Smith [1] for his interest in our study [2]. [Extracted from the article]