Science, Medicine, and the Anesthesiologist

Key Papers from the Most Recent Literature Relevant to AnesthesiologistsRecent studies suggest an increased likelihood of intraoperative awareness in female patients. However, most investigations were not designed to identify sex differences in anesthetic sensitivity. Using experiments in mice and data from the ReCCognition trial (NCT01911195), this study tested whether sexually dimorphic responses to general anesthesia exist, and if so, how they could be mechanistically explained. The righting reflex was used to generate induction and emergence dose-response curves using four volatile anesthetics in male and female mice. Female mice took longer to become anesthetized and emerged faster. Female mice were more likely to exhibit righting reflex at equal steady-state anesthetic concentration measured in the brain. These experimental findings could be confirmed by data collected in the ReCCognition trial showing faster emergence from anesthesia in female volunteers corroborated by psychomotor vigilance tests. Lower concentrations of testosterone contributed to resistance to general anesthesia. Experiments in castrated male mice showed that anesthetic sensitivity was increased by application of testosterone acting on specific hypothalamic neurons, which are involved in the induction of natural sleep. Interestingly, conventional electroencephalogram used to measure brain activity during anesthesia did not detect sex-based differences. This suggests that standard clinical practice might not fully capture depth of anesthesia in humans.Take home message: The female brain in mice and humans is more resistant to the hypnotic effects of volatile anesthetics, which may explain the higher incidence of awareness under anesthesia in females.Conflicting results have been reported with respect to the type of skin antisepsis used prior to surgical incision to repair limb fractures with regard to the development of postoperative surgical-site infections. This cluster-randomized crossover trial (25 Canadian and U.S. hospitals) randomly assigned hospitals to either 0.7% iodine povacrylex in 74% isopropyl alcohol (iodine group) or 2% chlorhexidine gluconate in 70% isopropyl alcohol (chlorhexidine group) for antisepsis for surgical repair of extremity fractures with hospitals alternating interventions every 2 months. Analyses were stratified by open versus closed fractures. The primary outcome was surgical-site infections (superficial incisional infection within 30 days or deep incisional or organ-space infection within 90 days after surgery). The secondary outcome was unplanned reoperation for fracture-healing complications. Enrollment included 8,485 patients (6,785 closed, 1,700 open fracture). With closed fracture, the primary outcome was significantly different between groups (2.4% iodine vs. 3.3% chlorhexidine; odds ratio, 0.74; 95% CI, 0.55 to 1.00; P = 0.049), while in the open-fracture group no difference was noted (6.5% vs. 7.3%; odds ratio, 0.86; 95% CI, 0.58 to 1.27; P = 0.45). No differences in the secondary outcome, 1-yr outcome, or adverse events between antisepsis groups were noted in either type of fracture population.Take home message: This multicenter, cluster-randomized trial of iodine povacrylex versus chlorhexidine gluconate skin antisepsis prior to surgical incision for repair of extremity fractures noted a small but statistically significant difference in surgical-site infections in patients with closed, but not open fractures.Various clinical trials have been performed to identify the optimal oxygenation for invasively ventilated children, but it remains unclear whether targeting lower oxygen saturation might be superior to a liberal oxygenation strategy. A multicenter, open, parallel-group randomized clinical trial at 15 United Kingdom pediatric intensive care units (ICUs) was performed including children aged 38 weeks up to 16 yr admitted to pediatric ICUs emergently to receiving invasive ventilation and supplemental oxygen. The aim of the study was to evaluate whether a conservative oxygenation target of Spo2 88% to 92% would decrease duration of organ support at 30 days following randomization in comparison to a liberal oxygenation target of Spo2 more than 94%. This primary endpoint was defined as a rank-based organ support received between days 1 and 30 with death as the worst outcome. One thousand eight hundred seventy-two children were randomized, of which 939 were allocated to the conservative oxygenation group (57% female) and 933 to the liberal group (56% female). In the conservative oxygenation group, duration of organ support or death in the first 30 days was significantly lower (probabilistic index, 0.53; 95% CI, 0.50 to 0.55; P = 0.04 [Wilcoxon rank-sum test]) with an adjusted odds ratio of 0.84 (95% CI, 0.72 to 0.99).Take home message: In this randomized trial including children admitted to pediatric ICUs emergently for invasive ventilation, the conservative oxygenation group had a higher probability of a better outcome regarding organ support and death at 30 days.The efficacy of percutaneous coronary interventions (PCIs) on symptom relief in patients with stable angina on little or no antianginal medications is uncertain. This double-blinded trial (14 United Kingdom sites) randomized 301 patients (mean ± SD age, 64 ± 9 yr; 79% male) with stable angina (in whom antianginal medications had been temporarily discontinued) to either PCI (N = 151) or a sham procedure (N = 150). Before randomization, subjects reported angina episodes using a smart phone app. After the procedure, subjects were discharged on dual antiplatelet therapy and followed for 12 weeks. The primary endpoint was the angina symptom score calculated on the number of angina episodes and the units of antianginal medication taken each day recorded on the smartphone app. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the sham group (odds ratio, 2.21; 95% CI, 1.41 to 3.47; P < 0.001). One sham patient was unblinded because of unacceptable angina. Acute coronary syndromes occurred in four PCI patients and in six sham procedure patients.Take home message: In this double-blind randomized trial, PCI in patients with angina receiving little to no antianginal medication resulted in a significant reduction in a mean angina symptom score over 12 weeks relative to a sham procedure.The presence of patent ductus arteriosus in preterm infants beyond 3 days of age, particularly 1.5 mm or larger in diameter, is associated with increased risk of bronchopulmonary dysplasia and mortality. Bedside echocardiography has greatly facilitated detection of larger patent ductus arteriosus that are unlikely to close spontaneously and may be amenable to pharmacologic intervention such as cyclooxygenase inhibitors (e.g., ibuprofen or indomethacin). This multicenter (32 United Kingdom neonatal intensive care units), double-blind, placebo-controlled trial evaluated selective early treatment of large patent ductus arteriosus with ibuprofen (loading dose 10 mg/kg then two doses of 5 mg/kg 24 h apart) on short-term outcome, randomizing extremely premature infants (born between 23 weeks’ and 28 weeks’ gestation) to ibuprofen (N = 324) or placebo (N = 322). The primary outcome was a composite of death, or moderate or severe bronchopulmonary dysplasia evaluated at 36 weeks postmenstrual age. There was no difference in the composite primary outcome between groups (69.2% ibuprofen vs. 63.5% placebo; adjusted risk ratio, 1.09; 95% CI, 0.98 to 1.20; P = 0.10) nor in mortality (13.6% vs. 10.3%; adjusted risk ratio, 1.32; 95% CI, 0.92 to 1.90) or development of moderate or severe bronchopulmonary dysplasia (64.2% vs. 59.3%; adjusted risk ratio, 1.09; 95% CI, 0.96 to 1.23). Two serious adverse events occurred in the ibuprofen group.Take home message: In this randomized multicenter trial of extremely premature infants with a large patent ductus arteriosus, mortality or moderate or severe bronchopulmonary dysplasia at 36 weeks was not significantly different with early treatment with ibuprofen versus placebo.The subjective drug craving is the core driver of methamphetamine use disorder and its relapse rate. There are no reliable biomarkers of this, but it is possible that there are distinct brain functional connectivity patterns that indicate craving. Localized sources of brain activity can be derived from multichannel electroencephalography (EEG), and the “imaginary” coherence between these sources is an accepted measure of coupling between brain regions. Fourier transformation of the spectral density produces a “real” and “imaginary” part from which synchrony parameters can be calculated. The latter is felt to be more resistant to noise. The imaginary coherence between 31 brain regions-of-interest was calculated from 57 patients (mean ± SD age, =34.8 ± 7.2 yr) with methamphetamine use disorder, and 52 matched controls (36.6 ± 10.0 yr). After exposure to a video of methamphetamine use, visual analogue craving scores for each subject were obtained. There were significant correlations between craving scores and brain region coupling (mainly between the left posterior middle frontal gyrus and medial prefrontal cortex, r = 0.5, P = 0.03) for delta and beta frequency bands, but no correlations with standard spectral analysis. Using machine learning and testing on a second methamphetamine use disorder database (n = 44), the beta connectivity model had an 80.1% classification accuracy (sensitivity, 82.1%; specificity, 79.6%).Take home message: These results suggest that functional connectivity between certain brain regions in the beta frequency range is a better indicator of methamphetamine use disorder than the simple EEG spectrum.Prolonged physical inactivity results in detrimental alterations in many physiologic processes including insulin insensitivity, but the kinetics and cellular mechanisms of these changes in human skeletal muscle are unknown. Healthy volunteers (8 female, 16 male) participating in aerospace research underwent a 60-day bed rest protocol with physiologic measurements and blood and skeletal muscle sampling at baseline and after 6 or 55 days. Intracellular glycogen accumulation, insulin insensitivity, and reduced glucose transporter (GLUT4) membrane localization occurred within 6 days but did not worsen further at a 55-day time point. In contrast, lipids associated with lipotoxicity (e.g,. ceramides, sphingomyelins) and inflammation continued to increase with a metabolic change from fatty acid to glucose oxidation. Plasma levels of proinflammatory cytokines interleukin-6 and tumor necrosis factor-α were elevated after prolonged bed rest without changes in C-reactive protein or cortisol. Inactivity resulted in increased lipid droplets near mitochondria along with elongation of triglycerides and lipotoxic species that did not affect the protein components of the electron transport chain but resulted in fewer and smaller mitochondria accounting for a reduction in oxidative phosphorylation. Therefore, it is hypothesized that excessive nutrients enhance lipid-mediated mitochondrial damage whose reduced activity allows for further lipid accumulation in a detrimental feedback process.Take home message: Reduced insulin sensitivity in skeletal muscle is an adaptation to prevent nutrient overload. Prolonged inactivity shifts fatty acid to glucose oxidation, increases lipotoxic and proinflammatory species, and reduces mitochondrial size. The imbalance of an elevated nutrient supply with concurrent reduced metabolic substrate may be a potential therapeutic target in the setting of prolonged physical inactivity.Prosocial behaviors are pivotal for promoting survival and social cohesion among animals. Injury triggers instinctive responses alleviating pain and reducing infection risks through behaviors like licking. In social contexts, animals exhibit caring behaviors to counterparts, such as wound licking, to tend to the injuries. However, the characterization of such behaviors and the underlying neural circuitry remains elusive. Employing sophisticated approaches encompassing behavioral analysis, micro-endoscopic calcium imaging, and opto- and chemogenetic analyses in mice, the authors characterized allogrooming and allolicking behaviors from naive cagemates (observers) toward animals suffering from acute injury (demonstrators). To explore the neural circuitry governing prosocial behaviors, the authors analyzed neuronal activity within the anterior cingulate cortex (ACC), implicated in perceiving and socially transmitting others’ pain. Findings revealed distinct subsets of ACC neurons displaying activity specific to others’ pain states, separate from responses to others’ stress. ACC neurons selectively exhibited increased activation to either self-pain or observation of others’ pain, but not both. Chemogenetic manipulation of ACC neuronal activity altered prosocial behaviors in observer animals. Ultimately, utilizing subsets of 297 neurons during allolicking and 354 neurons during allogrooming behaviors, the authors demonstrate that the ACC encoded specific pattern of neuronal activation with minimal overlap (60 neurons) between the two behaviors.Take home message: This study highlights the neural mechanisms orchestrating prosocial responses to injury, shedding light on the nuanced functioning of the ACC in these behaviors. It may ultimately aid in developing treatments for impaired prosocial behaviors in a variety of brain disorders.An industry-sponsored randomized study of outcome of transcatheter aortic valve replacement (TAVR) versus surgical replacement (Edwards Lifesciences PARTNER trial; SAPIEN-3 valve) in patients with severe, symptomatic aortic stenosis at low surgical risk has previously reported lower rates of a first primary composite endpoint of death, stroke, or rehospitalization at 1 and 1 yr with TAVR. This report presents outcomes through 5 yr. A second primary endpoint included a hierarchical composite of death, disabling stroke, nondisabling stroke, and the number of rehospitalization days, analyzed with the use of a win ratio analysis. A total of 1,000 patients were randomized to TAVR (N = 503) or surgery (N = 497). No significant difference was noted in the first primary outcome (Kaplan–Meier estimates, 22.8% TAVR vs. 27.2% surgery; difference, −4.3 percentage points; 95% CI, −9.9 to 1.3; P = 0.07). The win ratio for the second primary endpoint was 1.17 (95% CI, 0.90 to 1.51; P = 0.25). Echocardiographic assessment of mean valve gradients was similar (12.8 ± 6.5 [SD] mmHg TAVR group vs.11.7 ± 5.6 mmHg surgery), as was the incidence of bioprosthetic valve failure (3.3% TAVR vs. 3.8% surgery).Take home message: Five-year follow-up of patients with severe, symptomatic aortic stenosis at low surgical risk recruited to a large, randomized trial of TAVR versus surgery has reported no significant between-group difference in two primary composite outcomes.

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