This Month in Anesthesiology

To retrospectively identify factors associated with an increased risk of adverse cardiovascular or respiratory events during sedation of pediatric patients for imaging examinations. This HIPAA-compliant study was institutional review board approved; the requirement for informed consent was waived. All sedation information--including patient demographics, medications (doses and routes of administration), time required to sedate and before discharge, American Society of Anesthesiologists physical status classification, adverse events, and failed sedations--was maintained in a computerized database. A review of the data on all patients sedated between 1997 and 2003 for magnetic resonance imaging, computed tomography, and interventional radiology revealed associated adverse respiratory events in 70 patients. Adverse respiratory event was defined as oxygen desaturation of at least 5%, pulmonary aspiration, and need for airway resuscitation. Adverse cardiovascular events were defined as cardiac arrest and hemodynamic changes requiring medical therapy. Adverse events were compared between sedation regimens--which included fentanyl, chloral hydrate, pentobarbital, and midazolam hydrochloride--by using the Fisher exact test. Multiple logistic regression analysis was applied to identify potential predictors of adverse events. Among 16,467 sedations performed, 70 (0.4%) were associated with adverse respiratory events: 58 cases of oxygen desaturation, two pulmonary aspirations, 10 cases of airway resuscitation, and no cardiovascular events. Nearly 30% (n = 20) of the 70 patients who had an adverse event had a history of serious respiratory illness. Logistic regression analysis revealed that neither patient age, weight, or sex nor type of imaging procedure was associated with an increased risk of an adverse event. Use of a single sedation agent was associated with lower adverse event risk than was use of multiple agents (P < .001). Consideration should be given to using single agents, avoiding the use of multidrug sedation regimens, and recognizing that a history of pulmonary disease could be associated with an increased risk of adverse respiratory events despite a currently stable respiratory state.

The present studies were undertaken to investigate the neuroactive steroidal modulation of feeding behavior and possible involvement of gamma-aminobutyric acid type-A (GABA-A) and mitochondrial diazepam binding inhibitor (DBI) receptors (MDR) in food-deprived male mice. Allopregnanolone (0.5-2 mg/kg), a neurosteroid, progesterone (1-10 mg/kg), a neurosteroid precursor, and 4'-chlordiazepam (0.25-1 mg/kg), a specific high affinity MDR agonist, produced a dose-dependent hyperphagic effects. In contrast, neurosteroids pregnenolone sulfate (PS) (1-10 mg/kg) and dehydroepiandrosterone sulfate (DHEAS) (1-10 mg/kg) produced a hypophagic effect, in a dose-dependent manner. The allopregnanolone-, progesterone- and 4'-chlordiazepam-induced hyperphagic effect was blocked by picrotoxin (1 mg/kg), a GABA-A chloride channel antagonist, but not by flumazenil (2 mg/kg), a benzodiazepine (BZD) antagonist. The 4'-chlordiazepam-induced hyperphagic effect was prevented by pretreatment with PK11195 (2 mg/kg), a selective partial MDR antagonist. The hypophagic effect of DHEAS (10 mg/kg) was reversed by dizocilpine (10 microg/kg), an NMDA receptor antagonist, but resistant to muscimol (0.1 mg/kg), a selective GABA-A receptor agonist. In contrast, the PS (10 mg/kg)-induced hypophagic response was resistant to dizocilpine, but sensitive to muscimol (0.1 mg/kg). Both the sulfated neurosteroids PS and DHEAS also reversed the hyperphagic effect of allopregnanolone. In addition, the BZD agonist triazolam (0.05-0.25 mg/kg) also produced a flumazenil- and picrotoxin-sensitive hyperphagic effects, thereby suggesting the changes in feeding behavior by neurosteroids represent GABA-A receptor mediated hyperphagic action. Although the possible antistress or anxiolytic actions of neurosteroids may confound the hyperphagia, behavioral effects observed were specific to food because the mice were adopted to the test environment and diet, and of a possible variation between various neurosteroids in the extent to which antistress or anxiolytic effect produced at hyperphagic doses. The hyperphagic effects of progesterone and 4'-chlordiazepam resembled that of neurosteroid allopregnanolone. Therefore, the effect of progesterone may be imputed to its metabolism to allopregnanolone, while the 4'-chlordiazepam-induced hyperphagic response is related to its MDR-stimulated neurosteroidogenesis and subsequent modulation of GABA-A receptors. The hypophagic response following DHEAS may, at least partly, involve an NMDA receptor mechanism. However, PS-induced hypophagia may be mediated by GABA-A or other receptor systems. These data suggest a pivotal role for GABA-A and mitochondrial DBI receptors in the hyperphagic effects of neurosteroids and reinforces a role for endogenous neurosteroids in regulating feeding behavior. Future studies may lead to the development of neurosteroid-based anorectic/hyperphagic agents for therapeutic use.

BackgroundFlexible bronchoscopy is widely used to diagnose and treat various respiratory diseases. However, caution is warranted for post-bronchoscopy adverse events. Although desaturation frequently occurs during bronchoscopy, its clinical impact and the optimal oxygen saturation level during the procedure remain unclear. This study aimed to investigate whether the percutaneous oxygen saturation (SpO2) level during bronchoscopy is associated with the development of post-bronchoscopy respiratory adverse events.MethodsIn this single-center retrospective cohort study conducted from March 2020 to February 2021, 569 patients were classified into high or low oxygen saturation groups based on the SpO2 level during bronchoscopy. The primary outcome was post-bronchoscopy respiratory adverse events, and secondary outcomes were other post-bronchoscopy adverse events and clinical outcomes.ResultsAmong 569 patients, 458 and 111 patients were classified into the high oxygen saturation (SpO2 > 96%) and low oxygen saturation (SpO2 ≤ 94%) groups, respectively. After propensity score matching, the low oxygen saturation group had more post-bronchoscopy respiratory and febrile adverse events than the high oxygen saturation group. In the multivariable regression analysis, low SpO2 level during bronchoscopy was an independent risk factor for post-bronchoscopy respiratory adverse events (odds ratio = 3.16 [95% confidence interval 1.37–7.30]). In the low oxygen saturation group, the high-risk subgroups for post-bronchoscopy respiratory adverse events were the elderly, women, current smokers, and patients with chronic obstructive pulmonary disease or acute decompensated heart failure before bronchoscopy. There was no significant difference in the length of hospital stay, intensive care unit admission, or mortality between the high and low oxygen saturation groups.ConclusionsClose monitoring is recommended for patients with SpO2 ≤ 94% during bronchoscopy due to the increased risk of respiratory adverse events after the procedure.

Gastrointestinal dysfunction is a severe and common complication in diabetic patients. Some evidence shows that gamma-aminobutyric acid (GABA) and glutamate contribute to diabetic gastrointestinal abnormalities. Therefore, we examined the impact of prolonged treatment with insulin and magnesium supplements on the expression pattern of GABA type A (GABA-A), GABA-B, and N-methyl-D-aspartate (NMDA) glutamate receptors as well as nitric oxide synthase 1 (NOS-1) in the stomach of type 2 diabetic rats. Twenty-four male Wistar rats were randomized to four groups (six rats each): 1) control, 2) type 2 diabetes: rats fed with a high-fat diet for three months + a low dose of streptozotocin (35 mg/kg), 3) type 2 diabetes + magnesium, and 4) type 2 diabetes + insulin. The expression of NOS-1, GABA-A, GABA-B, and NMDA receptors was detected using western blotting. The NOS-1 expression was substantially diminished (P<0.01), while the expression of GABA-A (P<0.001), GABA-B (P<0.001), and NMDA (P<0.001) receptors was enhanced in the stomach of diabetic rats relative to control. Treatment with magnesium and insulin improved NOS-1 expression in diabetic rats, although this effect was greater in magnesium treatment alone. Magnesium also restored the expression of GABA-A and GABA-B receptors in diabetic rats to control values. Moreover, insulin treatment improved GABA-A receptor expression in diabetic rats (P<0.05). No considerable alterations were detected in NMDA receptor levels in the treatment groups. The results suggest a significant role of magnesium and insulin in improving gastric motility and secretory disorders associated with diabetes through modifying the expression of GABAergic receptors.

The compound verboccidentafuran (1) was identified from the essential oil of the leaves of Baccharis punctulata DC. (Asteraceae) specimens for the first time in Brazil. The variation of this compound found in male and female specimens may be associated to the existence of more than one type of chemotype, influenced by geographic variation, climatic conditions, stage of the vegetative cycle, genetic and ecological factors. The furanocadinan-type sesquiterpenes verboccidentafuran (1) and curzerene (2) have molecular descriptors with high similarities. Compound 2, found in Eugenia uniflora L. (Myrtaceae) and species of the genus Smyrnium L. (Apiaceae), is active to control seizures induced by pentylenetetrazole, what suggests a possible binding to the benzodiazepine-site of the GABAA (gamma-aminobutyric acid type A) receptor. Considering the occurrence and availability of 1 in the species B. punctulata and its structural similarity to compound 2, docking calculations were performed for the interaction of both compounds with the human α1-β2-γ2 GABAA receptor. The results suggest that both compounds 1 and 2 must have affinity for the cavity at α1-γ2 interface and support the development of pharmacological research on the compound verboccidentafuran 1 as a drug candidate for modulating the GABA/benzodiazepine complex in the central nervous system.

Although it does not suppress movement in response to noxious stimuli, the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6, also known as 2N) does cause amnesia and seizures. These occur at 0.48 and 1.3 times, respectively, the concentrations that are predicted from its lipid solubility to cause immobility. The molecular and cellular basis of these effects is not known. The ionotropic gamma-aminobutyric acid type A (GABAA) receptor is modulated strongly by anesthetics, and it plays an important role in many seizure models. Also, the hippocampus is a structure central to the formation of memory and is susceptible to seizure generation. The authors therefore investigated the effect of F6 on GABAA receptor- mediated inhibition in hippocampal neurons. Transverse hippocampal slices were prepared from young (12- to 21-day-old) Sprague-Dawley rats. Inhibitory postsynaptic currents were recorded from hippocampal CA1 pyramidal cells in the presence of ionotropic glutamate receptor antagonists. F6 was applied with the bath solution. The concentration of F6 achieved during the experiment at the location of synaptic inhibition was derived using a diffusion model. At tissue concentrations of up to 75 microm (approximately 5 x predicted minimal alveolar concentration), F6 had no discernible effect on either the amplitude or the kinetics of GABA-mediated synaptic currents. Isoflurane, by contrast, prolonged the decay time constant of these currents at 100 microm (approximately 0.3 x minimal alveolar concentration). At concentrations that bracket the in vivo amnestic and seizure-inducing range, F6 has no discernible effect on fast synaptic GABAA receptors in hippocampal CA1 pyramidal neurons. Synaptic GABAA receptors sharply discriminate between volatile anesthetics and a prototype nonimmobilizer. Similar in vivo effects of anesthetics and nonimmobilizers may be mediated by different cellular mechanisms.

Gabapentin increases expression of δ subunit-containing GABAA receptors

The capacity of general anesthetics to produce immobility is primarily spinally mediated. Recently, compelling evidence has been provided that the spinal actions of propofol involve gamma-aminobutyric acid type A (GABAA) receptors, whereas the contribution of glycine receptors remains uncertain. The relevant molecular targets of the commonly used volatile anesthetic sevoflurane in the spinal cord are largely unknown, but indirect evidence suggests a mechanism of action distinct from propofol. The effects of sevoflurane and propofol on spontaneous action potential firing were investigated by extracellular voltage recordings from ventral horn interneurons in cultured spinal cord tissue slices obtained from embryonic rats (embryonic days 14-15). Propofol and sevoflurane reduced spontaneous action potential firing of neurons. Concentrations causing half-maximal effects (0.11 microm propofol, 0.11 mm sevoflurane) were lower than the median effective concentration immobility (1-1.5 microm propofol, 0.35 mm sevoflurane). At higher concentrations, complete inhibition of action potential activity was observed with sevoflurane but not with propofol. Effects of sevoflurane were mediated predominantly by glycine receptors (45%) and GABAA receptors (38%), whereas propofol acted almost exclusively via GABAA receptors (96%). The authors' results suggest that glycine and GABAA receptors are the most important molecular targets mediating depressant effects of sevoflurane in the spinal cord. They provide evidence that sevoflurane causes immobility by a mechanism distinct from the actions of the intravenous anesthetic propofol. The finding that propofol acts exclusively via GABAA receptors can explain its limited capacity to depress spinal neurons in the authors' study.

Comparative safety of abatacept in rheumatoid arthritis with COPD: A real-world population-based observational study

Interhospital transport of critically unwell children exacerbates physiological stress, increasing the risk of deterioration during transport. Due to the nature of illness and interventions occurring in this cohort, defining “normal” vital sign ranges is impossible, which can make identifying deterioration events difficult.A novel data-driven approach was developed to identify adverse respiratory and cardiovascular events in critically ill children during interhospital transport. In this retrospective cohort study of 1,519 transports (July 2016 to May 2021), vital signs were recorded at one-second intervals and then analysed using an adaptation of Bollinger Bands, a technique borrowed from financial market analysis. This method dynamically established each patient’s stable ranges for heart rate, blood pressure, oxygen saturation, and other respiratory parameters, and flagged adverse events when multiple parameters simultaneously fell outside their expected ranges.Adverse respiratory events were identified when oxygen saturation deviated below a dynamically defined threshold alongside at least one additional respiratory parameter. Cardiovascular events were defined by concurrent deviations in blood pressure and heart rate. Overall, 15.6 percent of transports had one or more adverse respiratory events, and 21.5 percent had at least one adverse cardiovascular event.To validate these labels, the number of adverse events and the cumulative duration of vital sign instability during transport were compared against clinical markers of deterioration. Each additional respiratory event was associated with increased odds of receiving respiratory support during transport and higher 30-day mortality, while each additional cardiovascular event was associated with increased odds of receiving vasoactive support during transport.Our method detects clinically meaningful respiratory and cardiovascular adverse events during transport. The approach is readily adaptable to other high-resolution intensive care datasets, for both retrospective labelling as well as automated, real-time identification of adverse events in the clinical setting, offering a foundation for improved monitoring and early intervention in critically ill patients.Author SummaryTransporting critically ill children between hospitals is challenging because their condition can worsen during the journey. Previously, studies have relied on fixed vital-sign cutoffs to identify “adverse events,” but these rigid thresholds may not account for individual differences in heart rate, blood pressure, and oxygen baseline levels.Here, we used a tool borrowed from financial market analysis to track minute-by-minute vital signs in over 1,500 transport episodes. Our approach identified sudden, patient-specific changes that signalled respiratory or cardiovascular problems. We found that around 15 percent of transfers had at least one breathing-related event and over 20 percent had a heart-related event. Moreover, these events were linked to worse outcomes, such as the need for extra breathing or blood-pressure support.By considering each child’s own “stable” vital sign range, this method can detect meaningful changes that standard fixed thresholds might miss. This personalised tracking of vital signs opens the door for further research on routinely collected vital-sign datasets. It could also be deployed in the clinical environment helping clinicians detect a child’s deterioration earlier and respond in real time. Although we focused on children in transport, our approach could be adapted to other intensive care settings to improve patient monitoring.

Whole cell patch-clamp recordings were used to investigate the properties of the gamma-aminobutyric acid type A (GABAA) receptor-mediated spontaneous synaptic events in immature granule cells of the developing, early postnatal day (P0-P6) rat dentate gyrus. With Cs-gluconate-filled whole cell patch pipettes at 0 mV in control medium, spontaneous inhibitory postsynaptic currents (sIPSCs) occurred in prominent bursts (peak amplitude of the bursts 406.9 +/- 58.4 pA; intraburst IPSC frequency 71.0 +/- 12.4 Hz) at 0.05 +/- 0.02 Hz in every immature granule cell younger than P7. Between the bursts of IPSCs, lower frequency (1.7 +/- 0.7 Hz), interburst IPSCs could be observed. Bicuculline and picrotoxin as well as the intracellularly applied chloride-channel blockers CsF- and 4,4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS) abolished the intraburst as well as the interburst IPSCs, indicating that the IPSCs were mediated by GABAA receptor channels. The bursts of IPSCs, but not the interburst IPSCs, were blocked by the simultaneous application of the glutamate receptor antagonists 2-amino-5-phosphovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione, indicating the importance of the glutamatergic excitatory drive onto the interneurons in the early postnatal dentate gyrus. The spontaneously occurring excitatory postsynaptic currents in immature granule cells, observable after the intracellular blockade of GABAA receptor channels with CsF- and DIDS, appeared exclusively as single events at low frequencies, i.e., they did not occur in prominent bursts. Gramicidin-based perforated patch-clamp recordings determined that the reversal potential for the burst of IPSCs (-46.6 +/- 3.1 mV) was more depolarized than the resting membrane potential (-54.2 +/- 4.2 mV) but more hyperpolarized than the action potential threshold (-41. 8 +/- 1.7 mV). The depolarizing action of the bursts of synaptic events most often evoked only a single action potential per burst. Simultaneous whole cell patch recordings, with KCl-filled patch pipettes at -60 mV in current clamp from pairs of immature granule cells of the developing dentate gyrus, determined that the bursts of IPSPs took place in a similar temporal pattern but with imperfect synchrony in neighboring granule cells (average lag between the onsets of the bursts between granule cell pairs 77.7 +/- 8.6 ms). These results show that the spontaneous activation of GABAA receptors in immature dentate granule cells displays unique properties that are distinct from the temporal patterns and biophysical features of spontaneous GABAA receptor activation taking place in the developing Ammon's horn and in the adult dentate gyrus.

The anesthetic effect of Alpinia galanga oil (AGO) has been reported. However, knowledge of its pathway in mammals is limited. In the present study, the binding of AGO and its key compounds, methyl eugenol, 1,8-cineole, and 4-allylphenyl acetate, to gamma-aminobutyric acid type A (GABAA) receptors in rat cortical membranes, was investigated using a [3H]muscimol binding assay and an in silico modeling platform. The results showed that only AGO and methyl eugenol displayed a positive modulation at the highest concentrations, whereas 1,8-cineole and 4-allylphenyl acetate were inactive. The result of AGO correlated well to the amount of methyl eugenol in AGO. Computational docking and dynamics simulations into the GABAA receptor complex model (PDB: 6X3T) showed the stable structure of the GABAA receptor–methyl eugenol complex with the lowest binding energy of −22.16 kcal/mol. This result shows that the anesthetic activity of AGO and methyl eugenol in mammals is associated with GABAA receptor modulation. An oil-in-water nanoemulsion containing 20% w/w AGO (NE-AGO) was formulated. NE-AGO showed a significant increase in specific [3H]muscimol binding, to 179% of the control, with an EC50 of 391 µg/mL. Intracellular studies show that normal human cells are highly tolerant to AGO and the nanoemulsion, indicating that NE-AGO may be useful for human anesthesia.

Objective: To analyze the short-term (3 weeks) adverse respiratory events after bronchial thermoplasty(BT) in patients with severe asthma. Methods: The China-Japan Friendship Hospital recruited 62 patients with severe asthma for BT treatment from March 2014 to July 2016, with a total of 183 BT procedures. The data of adverse respiratory events within 3 weeks after procedure were collected to analyze the factors that might potentially influence the occurrence of adverse events. Results: Forty-three patients (69.4%) experienced adverse respiratory events within 3 weeks after treatment. Totally 153 adverse respiratory events occurred after 87 procedures(47.5%). The main adverse events were cough (15 events, 8.20%), sputum production (37 events, 20.22%), temporary PEF reduction (37 events, 20.22%), chest distress (12 events, 6.56%), blood in sputum (11 events, 6.01%), asthma exacerbation (10 events, 5.46%), and pneumonia(6 events, 3.28%). Most events were relieved or resolved with standard therapy in 1 week. No severe adverse events including tracheal intubation, malignant arrhythmias or death occurred within 3 weeks after procedure. The baseline eosinophil percentage in induced sputum and blood, operation times, and preoperative FEV(1) (% predicted) might influence the occurrence of adverse events after treatment. Patients with preoperative FEV(1) (% predicted) ≥60% had lower risk of adverse events. Conclusion: BT showed a good security profile in treating patients with severe asthma within 3 weeks after procedure.

BackgroundImpaired respiratory function remains underrecognized in patients with type 2 diabetes (T2D), despite common pulmonary impairment. Meanwhile, there is little data available on the respiratory effects of sodium glucose cotransporter 2 inhibitors (SGLT2i). Hence, we examined the association between SGLT2i use and the risk of adverse respiratory events in a real-world setting.MethodsWe conducted a population-based, nationwide cohort study using an active-comparator new-user design and nationwide claims data of South Korea from January 2015 to December 2020. Among individuals aged 18 years or older, propensity score matching was done to match each new user of SGLT2is with dipeptidyl peptidase 4 inhibitors (DPP4is), with patients followed up according to an as-treated definition. The primary outcome was respiratory events, a composite endpoint of acute pulmonary edema, acute respiratory distress syndrome (ARDS), pneumonia, and respiratory failure. Secondary outcomes were the individual components of the primary outcome and in-hospital death. Cox models were used to estimate hazard ratios (HRs) and 95% CIs.ResultsOf 205,534 patient pairs in the propensity score matched cohort, the mean age of the entire cohort was 53.8 years and 59% were men, with a median follow-up of 0.66 years; all baseline covariates achieved balance between the two groups. Incidence rates for overall respiratory events were 4.54 and 7.54 per 1000 person-years among SGLT2i and DPP4i users, respectively, corresponding to a rate difference of 3 less events per 1000 person-years (95% CI − 3.44 to − 2.55). HRs (95% CIs) were 0.60 (0.55 to 0.64) for the composite respiratory endpoint, 0.35 (0.23 to 0.55) for acute pulmonary edema, 0.44 (0.18 to 1.05) for ARDS, 0.61 (0.56 to 0.66) for pneumonia, 0.49 (0.31 to 0.76) for respiratory failure, and 0.46 (0.41 to 0.51) for in-hospital death. Similar trends were found across individual SGLT2is, subgroup analyses of age, sex, history of comorbidities, and a range of sensitivity analyses.ConclusionsThese findings suggest a lower risk of adverse respiratory events associated with patients with T2D initiating SGLT2is versus DPP4is. This real-world evidence helps inform patients, clinicians, and guideline writers regarding the respiratory effects of SGLT2i in routine practice.

Upper gastrointestinal endoscopies (UGEs) performed under ketamine sedation may increase the risk of respiratory adverse events (RAEs) due to pharyngeal stimulation. Topical lidocaine prevents general anesthesia-induced laryngospasm. Our objective was to determine whether topical lidocaine may reduce the incidence of RAEs induced by pharyngeal stimulation in UGEs performed on children sedated with ketamine. We conducted a single-center prospective study. We included every patient admitted for an elective diagnostic UGE under ketamine sedation who received lidocaine prior to the technique. Patients requiring any other medication were excluded. Our main outcome measure was the number of desaturation episodes. We then compared these results with those obtained in an historic group who did not receive topical lidocaine, in which we registered a total of 54 desaturation episodes. In total, 88 children (52.3% boys) were included. The median age was 7years [interquartile range (IQR) 3-11]. The mean duration of the procedure was 6.5 ± 2.4min, and the median initial ketamine dose was 1.76mg/kg (IQR 1.56-2.03). The total number of desaturation episodes was 3 (3.4%), and two of these occurred prior to the introduction of the endoscope. This result represents a lower incidence than in previously reported series, and a significant decrease (p < 0.0001) with respect to the 54 RAEs registered in the historic group of 87 children. Topical lidocaine premedication significantly reduced the incidence of RAEs in children during UGEs under ketamine sedation. Our findings should be confirmed by a double-blind randomized controlled trial.