Direct Structural Insights into GABAA Receptor Pharmacology.

GABAA receptors are pentameric ligand-gated ion channels that mediate most fast neuronal inhibition in the brain. In addition to their important physiological roles, they are noteworthy in their rich pharmacology; prominent drugs used for anxiety, insomnia, and general anesthesia act through positive modulation of GABAA receptors. Direct structural information for how these drugs work was absent until recently. Efforts in structural biology over the past few years have revealed how important drug classes and natural products interact with the GABAA receptor, providing a foundation for studies in dynamics and structure-guided drug design. Here, we review recent developments in GABAA receptor structural pharmacology, focusing on subunit assemblies of the receptor found at synapses.

Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond.

Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.

HSP90 Inhibition Attenuated Isoflurane-Induced Neurotoxicity in Mice and Human Neuroglioma Cells.

Isoflurane, a widely used inhalation anesthetic in clinical practice, is associated with an increased risk of neuronal injury. Heat shock protein 90 (HSP90) plays a crucial role in maintaining neuronal homeostasis under stress conditions; however, its role during isoflurane exposure remains poorly understood. In this study, we aimed to investigate the protective effects of HSP90 inhibition and explore the regulatory mechanisms underlying these effects during isoflurane exposure. We found that the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17 AAG) has great protective effects in mitigating isoflurane-induced ferroptosis of mouse hippocampus and cultured neuronal cells. We focused on the activity of the crucial protein GPX4 in ferroptosis and found that 17 AAG exerted protective effects, preserving the physiological GPX4 activity under isoflurane exposure; further, 17 AAG restored the protein level of GPX4. Further, we observed that the chaperone-mediated autophagy (CMA) pathway was activated; 17 AAG also mediated GPX4 degradation under isoflurane exposure. Additionally, it interfered with the formation of complexes between HSP90 and Lamp-2a, inhibiting CMA activity, followed by the blockade of GPX4 degradation, further affecting the isoflurane-induced ferroptosis. Based on these findings, we proposed HSP90 inhibition as a protective mechanism against isoflurane-induced ferroptosis in neurons.

Mepivacaine instillation for pain reduction during intrauterine device placement in nulliparous women: a double-blinded randomized trial.

BACKGROUND: Fear of pain associated with intrauterine device (IUD) placement has been identified as a significant barrier to the adoption of long-acting reversible contraception, contributing to lower utilization of the most effective reversible contraceptive methods. OBJECTIVE: To assess whether instillation of intrauterine mepivacaine before IUD placement alleviates pain more effectively than a placebo. STUDY DESIGN: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving nulliparous women undergoing IUD placement. An intrauterine instillation of 10 mL of 20 mg/mL mepivacaine or 0.9 mg/mL sodium chloride was administrated through a hydrosonography catheter 2 minutes prior to IUD placement. Pain scores were assessed using a 100 mm visual analog scale (VAS) at prespecified time points. Primary outcome measured the difference in VAS pain scores between the intervention group and the placebo group during IUD placement. Secondary outcomes included VAS pain scores at instillation and 10 minutes after placement, tolerability of the placement pain, as well as acceptability of the analgesia method. RESULTS: We enrolled 151 participants, with 76 assigned to the mepivacaine group and 75 to the placebo group. The mean VAS pain score during IUD placement showed a difference of 13.3 mm (95% confidence interval (CI) 5.75-20.87; P<.001): the mepivacaine group had a mean of 53.9 mm (standard deviation [SD] 22.8), while the placebo group had a mean of 67.2 mm (SD 22.4). After adjusting for each individual provider's impact, the difference in mean pain scores remained statistically significant (12.2 mm 95% CI 4.85-19.62; P<.001). A greater proportion of women in the intervention group reported tolerable pain during placement with 70/75 participants (93.3%) compared to 53/66 participants (80.3%) in the placebo group (P=.021). CONCLUSION: The intrauterine instillation of mepivacaine results in statistically significant reduction in pain score among nulliparous women during IUD placement. Although the precise clinical impact of this pain reduction method remains uncertain, the observed reduction in pain score result in a higher proportion of women reporting tolerable pain. This finding and the high acceptance as a pain reduction method thereby suggests clinical relevance. Intrauterine instillation of mepivacaine is a possible strategy to increase IUD utilization, particularly among nulliparous women who are at high risk of unintended pregnancy.

Continuous flow local anesthetic wound infusion for post-operative analgesia following kidney transplantation.

BACKGROUND: Some patients with end stage renal disease are or will become narcotic-dependent. Chronic narcotic use is associated with increased graft loss and mortality following kidney transplantation. We aimed to compare the efficacy of continuous flow local anesthetic wound infusion pumps (CFLAP) with patient controlled analgesia pumps (PCA) in reducing inpatient narcotic consumption in patients undergoing kidney transplantation. MATERIALS AND METHODS: In this single-center, retrospective analysis of patients undergoing kidney transplantation, we collected demographic and operative data, peri-operative outcomes, complications, and inpatient oral morphine milligram equivalent (OME) consumption. RESULTS: Four hundred and ninety-eight patients underwent kidney transplantation from 2020 to 2022. 296 (59%) historical control patients received a PCA for postoperative pain control and the next 202 (41%) patients received a CFLAP. Median age [53.5 vs. 56.0 years, p = .08] and BMI [29.5 vs. 28.9 kg/m2, p = .17] were similar. Total OME requirement was lower in the CFLAP group [2.5 vs. 34 mg, p < .001]. Wound-related complications were higher in the CFLAP group [5.9% vs. 2.7%, p = .03]. Two (.9%) patients in the CFLAP group experienced cardiac arrhythmia due to local anesthetic toxicity and required lipid infusion. CONCLUSIONS: Compared to PCA, CFLAP provided a 93% reduction in OME consumption with a small increase in the wound-related complication rate. The utility of local anesthetic pumps may also be applicable to patients undergoing any unilateral abdominal or pelvic incision.

A review of local anesthetic-induced heart toxicity using human induced pluripotent stem cell-derived cardiomyocytes.

Local anesthetic (LA) cardiotoxicity is one of the main health problems in anesthesiology and pain management. This study reviewed the reported LA-induced cardiac toxicity types, risk factors, management, and mechanisms, with attention to the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in heart toxicity research. Important scientific databases were searched to find relevant articles. We briefly assessed the reported cardiotoxic effects of different types of LA drugs, including ester- and amide-linked LA agents. Furthermore, cardiotoxic effects and clinical manifestations, strategies for preventing and managing LA-induced cardiotoxic effects, pharmacokinetics, pharmacodynamics, and sodium channel dynamics regarding individual variability and genetic influences were discussed in this review. The applications and importance of hiPSC-CMs cellular model for evaluating the cardiotoxic effects of LA drugs were discussed in detail. This review also explored hiPSC-CMs' potential in risk assessment, drug screening, and developing targeted therapies. The main mechanisms underlying LA-induced cardiotoxicity included perturbation in sodium channels, ROS production, and disorders in the immune system response due to the presence of LA drugs. Furthermore, drug-specific characteristics including pharmacokinetics and pharmacodynamics are important determinants after LA drug injection. In addition, individual patient factors such as age, comorbidities, and genetic variability emphasize the need for a personalized approach to mitigate risks and enhance patient safety. The strategies outlined for the prevention and management of LA cardiotoxicity underscore the importance of careful dosing, continuous monitoring, and the immediate availability of resuscitation equipment. This comprehensive review can be used to guide future investigations into better understanding LA cardiac toxicities and improving patient safety.

Sustained effort network for treatment of status epilepticus/European academy of neurology registry on adult refractory status epilepticus (SENSE-II/AROUSE).

BACKGROUND: Status Epilepticus (SE) is a common neurological emergency associated with a high rate of functional decline and mortality. Large randomized trials have addressed the early phases of treatment for convulsive SE. However, evidence regarding third-line anesthetic treatment and the treatment of nonconvulsive status epilepticus (NCSE) is scarce. One trial addressing management of refractory SE with deep general anesthesia was terminated early due to insufficient recruitment. Multicenter prospective registries, including the Sustained Effort Network for treatment of Status Epilepticus (SENSE), have shed some light on these questions, but many answers are still lacking, such as the influence exerted by distinct EEG patterns in NCSE on the outcome. We therefore initiated a new prospective multicenter observational registry to collect clinical and EEG data that combined may further help in clinical decision-making and defining SE. METHODS: Sustained effort network for treatment of status epilepticus/European Academy of Neurology Registry on refractory Status Epilepticus (SENSE-II/AROUSE) is a prospective, multicenter registry for patients treated for SE. The primary objectives are to document patient and SE characteristics, treatment modalities, EEG, neuroimaging data, and outcome of consecutive adults admitted for SE treatment in each of the participating centers and to identify factors associated with outcome and refractoriness. To reach sufficient statistical power for multivariate analysis, a cohort size of 3000 patients is targeted. DISCUSSION: The data collected for the registry will provide both valuable EEG data and information about specific treatment steps in different patient groups with SE. Eventually, the data will support clinical decision-making and may further guide the planning of clinical trials. Finally, it could help to redefine NCSE and its management. TRIAL REGISTRATION: NCT number: NCT05839418.

Effect of sedatives or anesthetics on the measurement of resting brain function in common marmosets.

Common marmosets are promising laboratory animals for the study of higher brain functions. Although there are many opportunities to use sedatives and anesthetics in resting brain function measurements in marmosets, their effects on the resting-state network remain unclear. In this study, the effects of sedatives or anesthetics such as midazolam, dexmedetomidine, co-administration of isoflurane and dexmedetomidine, propofol, alfaxalone, isoflurane, and sevoflurane on the resting brain function in common marmosets were evaluated using independent component analysis, dual regression analysis, and graph-theoretic analysis; and the sedatives or anesthetics suitable for the evaluation of resting brain function were investigated. The results show that network preservation tendency under light sedative with midazolam and dexmedetomidine is similar regardless of the type of target receptor. Moreover, alfaxalone, isoflurane, and sevoflurane have similar effects on resting state brain function, but only propofol exhibits different tendencies, as resting brain function is more preserved than it is following the administration of the other anesthetics. Co-administration of isoflurane and dexmedetomidine shows middle effect between sedatives and anesthetics.

Remimazolam has similar anesthetic effect and superior safety compared to propofol in elderly patients: A meta-analysis of randomized controlled trials.

BACKGROUND: The superiority between remimazolam and propofol for anesthesia is controversial in elderly patients (≥60 years). This meta-analysis aimed to systematically compare anesthetic effect and safety profile between remimazolam and propofol in elderly patients under any surgery. METHODS: Cochrane Library, Web of Science, and PubMed were searched until December 25, 2023 for relevant randomized controlled trials. RESULTS: Ten studies with 806 patients receiving remimazolam (experimental group) and 813 patients receiving propofol (control group) were included. Time to loss of consciousness [standard mean difference (SMD) (95% confidence interval (CI): 1.347 (-0.362, 3.055), p = 0.122] and recovery time [SMD (95% CI): -0.022 (-0.300, 0.257), p = 0.879] were similar between experimental and control groups. Mean arterial pressure at baseline minus 1 min after induction [SMD (95% CI): -1.800 (-3.250, -0.349), p = 0.015], heart rate at baseline minus 1 min after induction [SMD (95% CI): -1.041 (-1.537, -0.545), p < 0.001], incidences of hypoxemia [relative risk (RR) (95% CI): 0.247 (0.138, 0.444), p < 0.001], respiratory depression [RR (95% CI): 0.458 (0.300, 0.700), p < 0.001], bradycardia [RR (95% CI): 0.409 (0.176, 0.954), p = 0.043], hypotension [RR (95% CI): 0.415 (0.241, 0.714), p = 0.007], and injection pain [RR (95% CI): 0.172 (0.113, 0.263), p < 0.001] were lower in the experimental group compared to the control group. Postoperative nausea and vomiting was not different between groups [RR (95% CI): 1.194 (0.829, 1.718), p = 0.341]. Moreover, this meta-analysis displayed a low risk of bias, minimal publication bias, and good robustness. CONCLUSION: Remimazolam shows comparative anesthetic effect and better safety profile than propofol in elderly patients under any surgery.

Lidocaine spray vs mepivacaine local infiltration for suturing 1st/2nd grade perineal lacerations: a randomised controlled non-inferiority trial.

BACKGROUND: Perineal lacerations are a very common complication of post-partum. Usually, the repair of 1st and 2nd-grade lacerations is performed after the administration of local anesthesia. Despite the great relevance of the problem, there are only a few studies about the best choice of local anesthetic to use during suturing. We performed a randomised controlled trial to evaluate the efficacy and safety of the use of a local anesthetic spray during the suturing of perineal lacerations in the post-partum. METHODS: We compared the spray with the standard technique, which involves the infiltration of lacerated tissues, using the NRS scale. 136 eligible women who had given birth at University Hospital of Udine were enrolled and randomly assigned to receive nebulization of Lidocaine hydrochloride 10% spray (experimental group) or subcutaneous/submucosal infiltration of mepivacaine hydrochloride (control group) during suturing of perineal laceration. RESULTS: The lacerations included 84 1st-grade perineal traumas (61.7%) and 52 2nd-grade perineal traumas (38.2%). All the procedures were successfully completed without severe complications or serious adverse reactions. There were no statistically significant differences between the two groups in terms of blood losses or total procedure time. Moreover, there were no statistically significant differences in terms of NRS to none of the intervals considered. Regarding the application of the spray in the B group, in 36 cases (52.9%) it was necessary to improve the number of puffs previously supposed to be sufficient (5 puffs). Just in 3 cases, an additional injection was necessary (4.4%). CONCLUSIONS: Our study demonstrates that lidocaine spray alone can be used as a first line of local anesthetic during the closure of I-II-grade perineal lacerations, as it has comparable efficacy to mepivacaine infiltration. TRIAL REGISTRATION: The trial was recorded on https://clinicaltrials.gov . Identification number: NCT05201313. First registration date: 21/01/2022. Unique Protocol ID: 0042698/P/GEN/ARCS.

The effect of multimodal care based on Peplau's interpersonal relationship theory on postoperative recovery in lung cancer surgery: a retrospective analysis.

BACKGROUND: Lung cancer remains a major global health concern due to its high incidence and mortality rates. With advancements in medical treatments, an increasing number of early-stage lung cancer cases are being detected, making surgical treatment the primary option for such cases. However, this presents challenges to the physical and mental recovery of patients. Peplau known as the "mother of psychiatric associations" has formulated a theory of interpersonal relationships in nursing. Through effective communication between nurses and patients over four periods, she has established a good therapeutic nurse-patient relationship. Therefore, this study aimed to explore the effect of perioperative multimodal nursing based on Peplau's interpersonal relationship theory on the rehabilitation of patients with surgical lung cancer. METHODS: We retrospectively analyzed 106 patients with non-small cell lung cancer who underwent thoracoscopic lobectomy at our department between June 2021 and April 2022. Patients were categorized into two groups according to the different nursing intervention techniques. The Peplau's group comprised 53 patients who received targeted nursing interventions, and the control group comprised 53 patients who received conventional nursing care. We observed the patients' illness uncertainty, quality of life, and clinical symptoms in both groups. RESULTS: Patients in the Peplau's group had significantly lower illness uncertainty scores and a significantly higher quality of recovery than those in the control group. However, there were no significant differences in length of post-anesthesia care unit stay, complication rates, and visual analog scores between both groups. CONCLUSION: The multimodal perioperative nursing based on Peplau's interpersonal relationship theory not only reduces the illness uncertainty of patients with lung cancer surgery and improves their QoR but also expands the application of this theory in clinical practice, guiding perioperative nursing of patients with lung cancer. IMPLICATIONS: These findings provide practical information for standardized care in a hectic anesthetic care setting. IMPACT: The assessed anesthesia nursing model helps reduce uncertainty and promote early recovery in patients with cancer at various stages of their disease, which expands the scope of therapeutic practice and existing theories. It also serves as a guide for care in the anesthesia recovery room. REPORTING METHOD: We adhered to the relevant Equator guidelines and the checklist of items in the case-control study report. PATIENT OR PUBLIC CONTRIBUTION: Patients cooperated with medical staff to complete relevant scales.

Comparison of hypotension incidence between remimazolam and propofol in patients with hypertension undergoing neurosurgery: prospective, randomized, single-blind trial.

BACKGROUND: Remimazolam, a newer benzodiazepine that targets the GABAA receptor, is thought to allow more stable blood pressure management during anesthesia induction. In contrast, propofol is associated with vasodilatory effects and an increased risk of hypotension, particularly in patients with comorbidities. This study aimed to identify medications that can maintain stable vital signs throughout the induction phase. METHODS: We conducted a single-center, two-group, randomized controlled trial to investigate and compare the incidence of hypotension between remimazolam- and propofol-based total intravenous anesthesia (TIVA). We selected patients aged between 19 and 75 years scheduled for neurosurgery under general anesthesia, who were classified as American Society of Anesthesiologists Physical Status I-III and had a history of hypertension. RESULTS: We included 94 patients in the final analysis. The incidence of hypotension was higher in the propofol group (91.3%) than in the remimazolam group (85.4%; P = 0.057). There was no significant difference in the incidence of hypotension among the various antihypertensive medications despite the majority of patients being on multiple medications. In comparison with the propofol group, the remimazolam group demonstrated a higher heart rate immediately after intubation. CONCLUSIONS: Our study indicated that the hypotension incidence of remimazolam-based TIVA was comparable to that of propofol-based TIVA throughout the induction phase of EEG-guided anesthesia. Both remimazolam and propofol may be equally suitable for general anesthesia in patients undergoing neurosurgery. TRIAL REGISTRATION: Clinicaltrials.gov (NCT05164146).

Comparison of diffusion ranges at different local anesthetic volumes during superior laryngeal nerve block.

OBJECTIVES: Ultrasound-guided superior laryngeal nerve (SLN) block is a practical and painless approach to avoid the hemodynamic stress response during endotracheal intubation and relieve sore throat after laryngeal surgery. The main purpose of this study was to establish an optimal dosage of local anesthetic when performing SLN block to help anesthetists balance analgesia and side effects. METHODS: Twenty fresh larynx specimens were obtained immediately after resection and then injected with 2-, 3-, 4-, or 5- mL of a lidocaine-blue dye mixture at bilateral SLN puncture sites. Superficial areas of deposited blue dye were measured. Dye leakage and surrounding dyed tissue were recorded. Another 40 patients were included in the ultrasound investigation. Distances between the internal branch of the SLN (iSLN) and adjacent structures were calculated. RESULTS: The dye spread area was greater with the administration of larger doses, especially to the visceral space. A 2- or 3-mL injection of local anesthetic was sufficient to infiltrate the SLN gap. A higher incidence of dye leaking out of the thyrohyoid membrane and anterior epiglottis space was observed; furthermore, there was substantially more dyed hyoid/thyroid cartilage with 4 and 5 mL of injected dye mixture than 2 mL. There was no significant difference between the specimen and ultrasound measurements of for length of iSLN-adjacent structures. CONCLUSIONS: In the Chinese population, 2- or 3- mL of local anesthetic is a safe dose during SLN block. A larger volume could overflow from the cavity to cause complications. The thyrohyoid membrane combined with the superior laryngeal artery is a reliable target for positioning the iSLN during ultrasound-guided regional anesthesia.

Effect of intravenous anesthetic drugs on fertilization rate in oocyte retrieval.

BACKGROUND: The purpose of this study was to investigate the effects of intravenous anesthetic drugs on fertilization rate in subjects receiving oocyte retrieval by assisted reproduction technology (ART). METHODS: A retrospective cohort study was designed. The clinical information of subjects who received oocyte retrieval procedure was collected. The subjects were divided into two groups based on the type of anesthesia used: the no-anesthesia group and the intravenous anesthesia group. Propensity score matching (PSM) was performed and multiple linear regression analyses were conducted. Fertilization rate was compared between the two groups before and after PSM. RESULTS: A total of 765 subjects were divided into two groups: the no-anesthesia group (n = 482) and the intravenous anesthesia group (n = 283). According to propensity scores, 258 pairs of subjects were well matched, and the baseline data between the two groups were not significantly different (P > 0.05). Fertilization rate was 77% in the intravenous anesthesia group, and 76% in the no-anesthesia group, without significant between-group difference (P = 0.685). Before matching, Poisson regression analysis showed no effect of intravenous anesthetic drugs on fertilization rate (RR = 0.859, 95%CI: 0.59 to 1.25, P = 0.422). After matching, no difference was found either (RR = 0.935, 95%CI: 0.67 to 1.29, P = 0.618). CONCLUSION: Intravenous anesthetic drugs may exert no effects on fertilization rate in subjects receiving ART.

Anesthetic Management for Ventricular Tachycardia Ablation: A National Anesthesia Clinical Outcomes Registry Analysis.

OBJECTIVES: The authors analyzed anesthetic management trends during ventricular tachycardia (VT) ablation, hypothesizing that (1) monitored anesthesia care (MAC) is more commonly used than general anesthesia (GA); (2) MAC uses significantly increased after release of the 2019 Expert Consensus Statement on Catheter Ablation of Ventricular Arrhythmias; and (3) anesthetic approach varies based on patient and hospital characteristics. DESIGN: Retrospective study. SETTING: National Anesthesia Clinical Outcomes Registry data. PARTICIPANTS: Patients 18 years or older who underwent elective VT ablation between 2013 and 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Covariates were selected a priori within multivariate models, and interrupted time-series analysis was performed. Of the 15,505 patients who underwent VT ablation between 2013 and 2021, 9,790 (63.1%) received GA. After the 2019 Expert Consensus Statement on Catheter Ablation of Ventricular Arrhythmias supported avoidance of GA in idiopathic VT, no statistically significant increase in MAC was evident (immediate change in intercept post-consensus statement release adjusted odds ratio 1.41, p = 0.1629; change in slope post-consensus statement release adjusted odds ratio 1.06 per quarter, p = 0.1591). Multivariate analysis demonstrated that sex, American Society of Anesthesiologists physical status, age, and geographic location were statistically significantly associated with the anesthetic approach. CONCLUSIONS: GA has remained the primary anesthetic type for VT ablation despite the 2019 Expert Consensus Statement on Catheter Ablation of Ventricular Arrhythmias suggested its avoidance in idiopathic VT. Achieving widespread clinical practice change is an ongoing challenge in medicine, emphasizing the importance of developing effective implementation strategies to facilitate awareness of guideline release and subsequent adherence to and adoption of recommendations.

Peripheral Regional Anesthetic Techniques in Cardiac Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this systematic review was to investigate postoperative pain outcomes and adverse events after peripheral regional anesthesia (PRA) compared to no regional anesthesia (RA), placebo, or neuraxial anesthesia in children and adults undergoing cardiac surgery. DESIGN: A systematic review and meta-analysis with an assessment of the risk of bias (Cochrane RoB 1) and certainty of evidence (Grading of Recommendations, Assessment, Development, and Evaluation). SETTING: Randomized controlled trials (RCTs). PARTICIPANTS: Adults and children undergoing heart surgery. INTERVENTIONS: Any kind of PRA compared to no RA or placebo or neuraxial anesthesia. MEASUREMENTS AND MAIN RESULTS: In total, 33 RCTs (2,044 patients) were included-24 of these had a high risk of bias, and 28 were performed in adults. Compared to no RA, PRA may reduce pain intensity at rest 24 hours after surgery (mean difference [MD] -0.81 points, 95% CI -1.51 to -0.10; I2 = 92%; very low certainty evidence). Peripheral regional anesthesia, compared to placebo, may reduce pain intensity at rest (MD -1.36 points, 95% CI -1.59 to -1.13; I2 = 54%; very low certainty evidence) and during movement (MD -1.00 points, 95% CI -1.34 to -0.67; I² = 72%; very low certainty evidence) 24 hours after surgery. No data after pediatric cardiac surgery could be meta-analyzed due to the low number of included trials. CONCLUSIONS: Compared to no RA or placebo, PRA may reduce pain intensity at rest and during movement. However, these results should be interpreted cautiously because the certainty of evidence is only very low.

Report of the 2022 Perfusion Perspectives of Waste Anesthetic Gas Exposure Survey.

OBJECTIVES: To describe perfusionist perspectives regarding waste anesthetic gas (WAG) management during cardiopulmonary bypass (CPB) and compare results to existing American Society of Extracorporeal Technology (AmSECT) guidelines and the 2016 National Institute of Occupational Safety and Health Survey of healthcare workers and anesthesia care providers. DESIGN: We developed a questionnaire with 26 questions covering institutional demographics, use of anesthetic gases, scavenging systems, and air monitoring practices. SETTING: Web-based survey. PARTICIPANTS: Self-identified board-eligible perfusionist members of AmSECT, the American Academy of Cardiovascular Perfusion, and the Maryland and Wisconsin State Perfusion Societies in 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 4,303 providers sent the survey, 365 (8.5%) participated. Although 92% of the respondents (335/364) routinely administered inhaled anesthetics via the oxygenator, only 73.2% (259/354) routinely scavenged WAG during CPB cases. Only 6.6% of the respondents (22/336) conducted environmental monitoring for WAG levels. Cited reasons for not scavenging waste gases included a lack of applicable protocols and waste gas scavenging systems, excessive cost, and no need for scavenging. CONCLUSIONS: Our findings identify a gap between AmSECT guidelines and current perfusionist behavior and suggest potential strategies for reducing WAG leakage during CPB. Effective management should incorporate hazard awareness training, availability of standard procedures to minimize exposure, scavenging systems, regular equipment inspection, and prompt attention to spills and leaks. In high-risk environments, environmental surveillance for waste gas levels would also contribute to waste gas safety. A comprehensive approach to managing waste anesthetic gases will reduce WAG leakage, help improve health care worker safety, and prevent potential adverse effects of exposure.

Serum Levels of Bupivacaine After Bilateral Ultrasound-Guided Deep Parasternal Intercostal Plane Block in Cardiac Surgery with Median Sternotomy.

OBJECTIVE: To evaluate systemic levels of bupivacaine after bilateral ultrasound-guided deep parasternal intercostal plan (PIP) block in cardiac surgical patients undergoing median sternotomy. DESIGN: Prospective, observational study SETTING: Single institution; academic university hospital PARTICIPANTS: Twenty-eight adult patients undergoing cardiac surgery with median sternotomy received a PIP block with 2.5 mg/kg bupivacaine with or without dexamethasone and dexmedetomidine. MEASUREMENTS: Arterial blood samples were analyzed for total serum bupivacaine concentration at 5, 15, 30, 45, 60, 90, 120, and 150 minutes after placement of PIP. Local anesthetic volume, local anesthetic adjuncts, time to extubation, postoperative pain scores, and opioid consumption were recorded. MAIN RESULTS: The mean peak bupivacaine concentration was 0.60 ± 0.62 µg/mL, and the mean time to maximum concentration (Tmax) was 16.92 ± 12.97 minutes. Two patients (7.1%) had a concentration >2.0 µg/mL within 15 minutes of block placement. The mean Tmax of bupivacaine was significantly greater in patients who did not receive additives compared to those patients who did (22.86 ± 14.77 minutes v 10.0 ± 5.22 minutes; p = .004). The times to extubation and postoperative pain were not improved with additives. CONCLUSIONS: Bilateral PIP placed at the end of cardiac surgery resulted in low systemic bupivacaine levels. The inclusion of additives shortened Tmax without improving outcome.

Mechanistic basis of propofol-induced disruption of kinesin processivity.

Propofol is a widely used general anesthetic to induce and maintain anesthesia, and its effects are thought to occur through impact on the ligand-gated channels including the GABAA receptor. Propofol also interacts with a large number of proteins including molecular motors and inhibits kinesin processivity, resulting in significant decrease in the run length for conventional kinesin-1 and kinesin-2. However, the molecular mechanism by which propofol achieves this outcome is not known. The structural transition in the kinesin neck-linker region is crucial for its processivity. In this study, we analyzed the effect of propofol and its fluorine derivative (fropofol) on the transition in the neck-linker region of kinesin. Propofol binds at two crucial surfaces in the leading head: one at the microtubule-binding interface and the other in the neck-linker region. We observed in both the cases the order-disorder transition of the neck-linker was disrupted and kinesin lost its signal for forward movement. In contrast, there was not an effect on the neck-linker transition with propofol binding at the trailing head. Free-energy calculations show that propofol at the microtubule-binding surface significantly reduces the microtubule-binding affinity of the kinesin head. While propofol makes pi-pi stacking and H-bond interactions with the propofol binding cavity, fropofol is unable to make a suitable interaction at this binding surface. Therefore, the binding affinity of fropofol is much lower compared to propofol. Hence, this study provides a mechanism by which propofol disrupts kinesin processivity and identifies transitions in the ATPase stepping cycle likely affected.

Modulation of α1ß3γ2 GABAA receptors expressed in X. laevis oocytes using a propofol photoswitch tethered to the transmembrane helix.

Tethered photoswitches are molecules with two photo-dependent isomeric forms, each with different actions on their biological targets. They include reactive chemical groups capable of covalently binding to their target. Our aim was to develop a ß-subunit-tethered propofol photoswitch (MAP20), as a tool to better study the mechanism of anesthesia through the GABAA α1ß3γ2 receptor. We used short spacers between the tether (methanethiosulfonate), the photosensitive moiety (azobenzene), and the ligand (propofol), to allow a precise tethering adjacent to the putative propofol binding site at the ß+α- interface of the receptor transmembrane helices (TMs). First, we used molecular modeling to identify possible tethering sites in ß3TM3 and α1TM1, and then introduced cysteines in the candidate positions. Two mutant subunits [ß3(M283C) and α1(V227C)] showed photomodulation of GABA responses after incubation with MAP20 and illumination with lights at specific wavelengths. The α1ß3(M283C)γ2 receptor showed the greatest photomodulation, which decreased as GABA concentration increased. The location of the mutations that produced photomodulation confirmed that the propofol binding site is located in the ß+α- interface close to the extracellular side of the transmembrane helices. Tethering the photoswitch to cysteines introduced in the positions homologous to ß3M283 in two other subunits (α1W288 and γ2L298) also produced photomodulation, which was not entirely reversible, probably reflecting the different nature of each interface. The results are in agreement with a binding site in the ß+α- interface for the anesthetic propofol.