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Background The authors hypothesized that both perineural and systemic dexamethasone as adjuncts to bupivacaine increase the duration of an ulnar nerve block compared with bupivacaine alone, and that systemic dexamethasone is noninferior to perineural dexamethasone. Methods The authors performed bilateral ulnar nerve blocks with 3 ml bupivacaine 5 mg/ml in 16 healthy volunteers on two trial days. According to randomization, subjects received adjunct treatment with 1 ml dexamethasone 4 mg/ml + 1 ml of saline (perineural condition) in one arm and 2 ml saline in the other arm (systemic condition, through absorption and redistribution of the contralaterally administered perineural dexamethasone) on one trial day; and 2 ml saline in one arm (placebo condition) and 2 ml of lidocaine in the other arm (lidocaine condition) on the other trial day. The primary outcome was the duration of the sensory nerve block assessed by temperature discrimination. Results Mean sensory block duration was 706 ± 94 min for the perineural condition, 677 ± 112 min for the systemic condition, and 640 ± 121 min for the placebo condition. The duration of the sensory nerve block was greater with perineural dexamethasone versus placebo (mean difference 66 min (95% CI, 23 to 108). Block duration was similar between systemic dexamethasone and placebo (mean difference 36 min; 95% CI, –30 to 103). Conclusions Perineural dexamethasone as an adjunct to bupivacaine in healthy volunteers resulted in a greater duration of an ulnar nerve block when compared with placebo. Systemic dexamethasone resulted in a similar duration as placebo. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background The association between growth differentiation factor-15 concentrations and cardiovascular disease has been well described. The study hypothesis was that growth differentiation factor-15 may help cardiac risk stratification in noncardiac surgical patients, in addition to clinical evaluation. Methods The objective of the study was to determine whether preoperative serum growth differentiation factor-15 is associated with the composite primary outcome of myocardial injury after noncardiac surgery and vascular death at 30 days and can improve cardiac risk prediction in noncardiac surgery. This is a prospective cohort study of patients 45 yr or older having major noncardiac surgery. The association between preoperative growth differentiation factor-15 and the primary outcome was determined after adjusting for the Revised Cardiac Risk Index. Preoperative N-terminal-pro hormone brain natriuretic peptide was also added to compare predictive performance with growth differentiation factor-15. Results Between October 27, 2008, and October 30, 2013, a total of 5,238 patients were included who had preoperative growth differentiation factor-15 measured (median, 1,325; interquartile range, 880 to 2,132 pg/ml). The risk of myocardial injury after noncardiac surgery and vascular death was 99 of 1,705 (5.8%) for growth differentiation factor-15 less than 1,000 pg/ml, 161 of 1,332 (12.1%) for growth differentiation factor-15 1,000 to less than 1,500 pg/ml, 302 of 1476 (20.5%) for growth differentiation factor-15 1,500 to less than 3,000 pg/ml, and 247 of 725 (34.1%) for growth differentiation factor-15 concentrations 3,000 pg/ml or greater. Compared to patients who had growth differentiation factor-15 concentrations less than 1,000 pg/ml, the corresponding adjusted hazard ratio for each growth differentiation factor-15 category was 1.93 (95% CI, 1.50 to 2.48), 3.04 (95% CI, 2.41 to 3.84), and 4.8 (95% CI, 3.76 to 6.14), respectively. The addition of growth differentiation factor-15 improved cardiac risk classification by 30.1% (301 per 1,000 patients) compared to Revised Cardiac Risk Index alone. It also provided additional risk classification beyond the combination of preoperative N-terminal-pro hormone brain natriuretic peptide and Revised Cardiac Risk Index (16.1%; 161 per 1,000 patients). Conclusions Growth differentiation factor-15 is strongly associated with 30-day risk of major cardiovascular events and significantly improved cardiac risk prediction in patients undergoing noncardiac surgery. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Surgery causes transient impairment in cognition and function, which may impact driving safety. The authors hypothesized that the risk of a motor vehicle crash would increase after compared to before surgery. Methods The authors performed a nested case-crossover study within population-based observational data from the New Jersey Safety Health Outcomes Data Warehouse. The study included adults 18 yr or older with a valid driver’s license who underwent general surgery in an acute care hospital in New Jersey between January 1, 2016, and November 30, 2017, and were discharged home. Individuals served as their own controls within a presurgery interval (56 days to 28 days before surgery) and postsurgery interval (discharge through 28 days after surgery). General surgery was defined by Common Procedural Terminology Codes. The primary outcome was a police-reported motor vehicle crash. Results In a cohort of 70,722 drivers, the number of crashes after surgery was 263 (0.37%) compared to 279 (0.39%) before surgery. Surgery was not associated with a change in crash incidence greater than 28 days using a case-crossover design (adjusted incidence rate ratio, 0.92; 95% CI, 0.78 to 1.09; P = 0.340). Statistical interaction was present for sex and hospital length of stay. Younger versus older adults (adjusted risk ratio, 1.87; 95% CI, 1.10 to 3.18; P = 0.021) and non-Hispanic Black individuals (adjusted risk ratio, 1.96; 95% CI, 1.33 to 2.88; P = 0.001) and Hispanic individuals (adjusted risk ratio, 1.38; 95% CI, 1.00 to 1.91; P = 0.047) versus non-Hispanic White individuals had a greater risk of a crash after surgery. Conclusions Using population-based crash and hospital discharge data, the incidence of motor vehicle crashes over a 28-day period did not change on average before compared to after surgery. The authors provide data on crash risk after surgery and highlight specific populations at risk. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Maintenance of ion homeostasis is essential for normal brain function. Inhalational anesthetics are known to act on various receptors, but their effects on ion homeostatic systems, such as sodium/potassium-adenosine triphosphatase (Na+/K+-ATPase), remain largely unexplored. Based on reports demonstrating global network activity and wakefulness modulation by interstitial ions, the hypothesis was that deep isoflurane anesthesia affects ion homeostasis and the key mechanism for clearing extracellular potassium, Na+/K+-ATPase. Methods Using ion-selective microelectrodes, this study assessed isoflurane-induced extracellular ion dynamics in cortical slices of male and female Wistar rats in the absence of synaptic activity, in the presence of two-pore-domain potassium channel antagonists, during seizures, and during spreading depolarizations. The specific isoflurane effects on Na+/K+-ATPase function were measured using a coupled enzyme assay and studied the relevance of the findings in vivo and in silico. Results Isoflurane concentrations clinically relevant for burst suppression anesthesia increased baseline extracellular potassium (mean ± SD, 3.0 ± 0.0 vs. 3.9 ± 0.5 mM; P < 0.001; n = 39) and lowered extracellular sodium (153.4 ± 0.8 vs. 145.2 ± 6.0 mM; P < 0.001; n = 28). Similar changes in extracellular potassium and extracellular sodium and a substantial drop in extracellular calcium (1.5 ± 0.0 vs. 1.2 ± 0.1 mM; P = 0.001; n = 16) during inhibition of synaptic activity and two-pore-domain potassium suggested a different underlying mechanism. After seizure-like events and spreading depolarization, isoflurane greatly slowed extracellular potassium clearance (63.4 ± 18.2 vs. 196.2 ± 82.4 s; P < 0.001; n = 14). Na+/K+-ATPase activity was markedly reduced after isoflurane exposure (greater than 25%), affecting specifically the α2/3 activity fraction. In vivo, isoflurane-induced burst suppression resulted in impaired extracellular potassium clearance and interstitial potassium accumulation. A computational biophysical model reproduced the observed effects on extracellular potassium and displayed intensified bursting when Na+/K+-ATPase activity was reduced by 35%. Finally, Na+/K+-ATPase inhibition with ouabain induced burst-like activity during light anesthesia in vivo. Conclusions The results demonstrate cortical ion homeostasis perturbation and specific Na+/K+-ATPase impairment during deep isoflurane anesthesia. Slowed potassium clearance and extracellular accumulation might modulate cortical excitability during burst suppression generation, while prolonged Na+/K+-ATPase impairment could contribute to neuronal dysfunction after deep anesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

A Single-blind Study of Pulse Oximetry in Children. By CJ Coté, EA Goldstein, MA Cote, DC Hoaglin, and JF Ryan. Anesthesiology 1988; 68:184–8. Reprinted with permission.Oxygen saturation determined by pulse oximetry was monitored in 152 pediatric surgical patients divided into two groups. In one group, the oximeter data and alarms were available (N = 76) to the anesthesia team, and, in the other group, these data were unavailable (N = 76). A trained observer recorded all intraoperative hypoxic episodes and informed the anesthesia team of all major events (i.e., oxygen saturation 85% or less for 30 s or more; Pao2, approximately 52 mmHg). Thirty-five major events occurred: 24 in the unavailable group, and 11 in the available group (P = 0.021). A greater number of major events occurred in children 2 yr or younger (P = 0.013). Hypoxic events diagnosed by the oximeter, but not by the anesthesiologist, were more frequent in the unavailable group (13) than in the available group (5; P = 0.0495). American Society of Anesthesiologists (Schaumburg, Illinois) Physical Status III and IV patients were more likely to suffer a major event (P = 0.009 available, 0.006 unavailable). The pulse oximeter diagnosed hypoxemia before the signs and symptoms of hypoxemia were apparent (i.e., before observed cyanosis or bradycardia). Major hypoxic events were unrelated to duration of anesthesia. Major events were evenly distributed among induction, maintenance, and awakening from anesthesia; a greater number of hypoxic events occurred during induction in the unavailable group (P = 0.031). No morbidity was documented in any patient who suffered a hypoxic event. More patients experienced borderline oxygenation in room air at the end of anesthesia (90% saturation or less) in the unavailable group (12 of 60) than in the available group (3 of 57; P = 0.009). The authors conclude that pulse oximetry, in contrast to changes in vital signs, does provide an early warning of developing hypoxemia in anesthetized children.

Background Nonsense-mediated messenger RNA (mRNA) decay increases targeted mRNA degradation and has been implicated in the regulation of gene expression in neurons. The authors hypothesized that nonsense-mediated μ-opioid receptor mRNA decay in the spinal cord is involved in the development of neuropathic allodynia–like behavior in rats. Methods Adult Sprague-Dawley rats of both sexes received spinal nerve ligation to induce neuropathic allodynia–like behavior. The mRNA and protein expression contents in the dorsal horn of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by the von Frey test and the burrow test. Results On Day 7, spinal nerve ligation significantly increased phosphorylated upstream frameshift 1 (UPF1) expression in the dorsal horn (mean ± SD; 0.34 ± 0.19 in the sham ipsilateral group vs. 0.88 ± 0.15 in the nerve ligation ipsilateral group; P < 0.001; data in arbitrary units) and drove allodynia-like behaviors in rats (10.58 ± 1.72 g in the sham ipsilateral group vs. 1.19 ± 0.31 g in the nerve ligation ipsilateral group, P < 0.001). No sex-based differences were found in either Western blotting or behavior tests in rats. Eukaryotic translation initiation factor 4A3 (eIF4A3) triggered SMG1 kinase (0.06 ± 0.02 in the sham group vs. 0.20 ± 0.08 in the nerve ligation group, P = 0.005, data in arbitrary units)–mediated UPF1 phosphorylation, leading to increased nonsense-mediated mRNA decay factor SMG7 binding and µ-opioid receptor mRNA degradation (0.87 ± 0.11–fold in the sham group vs. 0.50 ± 0.11–fold in the nerve ligation group, P = 0.002) in the dorsal horn of the spinal cord after spinal nerve ligation. Pharmacologic or genetic inhibition of this signaling pathway in vivo ameliorated allodynia-like behaviors after spinal nerve ligation. Conclusions This study suggests that phosphorylated UPF1–dependent nonsense-mediated μ-opioid receptor mRNA decay is involved in the pathogenesis of neuropathic pain. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induced thrombocytopenia. Dabigatran provides anticoagulation for an in vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits. Methods Nonlinear mixed effects models were used to estimate dabigatran parameters for a two-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/ml was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy and anticoagulated with IV dabigatran (six animals) or heparin (four animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 min. Measurement of activated clotting time, thromboelastometric reaction time, and blood gases were performed during CPB. Then, the animals were euthanized, and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy. Results The observed dabigatran concentrations during CPB were greater than the target concentration, ranging from 137 ± 40 μg/ml at 5 min of CPB to 428 ± 150 μg/ml at 60 min, and 295 ± 35 μg/ml at 120 min. All rabbits completed 2 h of CPB without visible thrombosis. In the two groups, reaction time values were elevated, reaching 10,262 ± 4,198 s (dabigatran group) and 354 ± 141 s (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran- and heparin-treated animals. Conclusions In this first-use, proof-of-concept study, the authors have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Radial artery cannulation in young children is challenging. A single-operator laser-assisted ultrasound-guidance system was invented to project the path of the target artery on the skin surface. The hypothesis was that this system would improve the first-attempt success rate of radial arterial cannulation in young pediatric patients relative to traditional ultrasound guidance. Methods This single-center, prospective, parallel-group, randomized controlled study enrolled pediatric patients (n = 80, age less than 2 yr) requiring radial artery cannulation during general anesthesia. The participants were randomized into the traditional ultrasound-guidance group or the single-operator laser-assisted ultrasound-guidance group. After inducing general anesthesia, ultrasound-guided radial artery cannulation was performed by two experienced operators. The primary outcome was the first-attempt success rate. The secondary outcomes included the procedure time to success within the first attempt, midmost rate of first attempt, first needle-tip position, and average number of adjustments. Results In total, 80 children were included in the analysis. The first-attempt success rate in the single-operator laser-assisted ultrasound-guidance group (36 of 40 [90%]) was significantly greater than that in the traditional ultrasound-guidance group (28 of 40 [70%]; absolute difference, 20% [95% CI, 2.3% to 36.6%]; P = 0.025). The median procedure time to success within the first attempt was shorter in the single-operator laser-assisted ultrasound-guidance group compared with the traditional ultrasound-guidance group (31 s [27, 36 s] vs. 46 s [39, 52 s]; P < 0.001). The incidence of hematoma in the single-operator laser-assisted ultrasound-guidance group (1 of 40, 3%) was significantly lower than that in the traditional ultrasound-guidance group (11 of 40, 28%; P = 0.002). Regarding the initial needle-tip position after skin puncture, the median score (4 [3,4] vs. 2 [2,3]; P < 0.001); position 3, 4, or 5 (38 [95%] vs. 13 [33%]; P < 0.001); and position 4 or 5 (26 [65%] vs. 5 [13%]; P < 0.001) were all in favor of single-operator laser-assisted ultrasound guidance. Conclusions Compared with traditional ultrasound guidance, the single-operator laser-assisted ultrasound-guided system is a useful add-on to the ultrasound dynamic needle-tip puncture technique. It improves the first-attempt success rate of radial artery cannulation in children younger than 2 yr by projecting the path of the artery on the skin and provides better procedural conditions (stable ultrasound probe). Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Multiple neonatal exposures to sevoflurane induce neurocognitive dysfunctions in rodents. The lack of cell type–specific information after sevoflurane exposure limits the mechanistic understanding of these effects. In this study, the authors tested the hypothesis that sevoflurane exposures alter the atlas of hippocampal cell clusters and have neuronal and nonneuronal cell type–specific effects in mice of both sexes. Methods Neonatal mice were exposed to 3% sevoflurane for 2 h at postnatal days 6, 8, and 10 and analyzed for the exposure effects at postnatal day 37. Single-nucleus RNA sequencing was performed in the hippocampus followed by in situ hybridization to validate the results of RNA sequencing. The Morris Water Maze test was performed to test neurocognitive function. Results The authors found sex-specific distribution of hippocampal cell types in control mice alongside cell type– and sex-specific effects of sevoflurane exposure on distinct hippocampal cell populations. There were important changes in male but not in female mice after sevoflurane exposure regarding the proportions of cornu ammonis 1 neurons (control vs. sevoflurane, males: 79.9% vs. 32.3%; females: 27.3% vs. 24.3%), dentate gyrus (males: 4.2% vs. 23.4%; females: 36.2% vs. 35.8%), and oligodendrocytes (males: 0.6% vs. 6.9%; females: 5.9% vs. 7.8%). In male but not in female mice, sevoflurane altered the number of significantly enriched ligand–receptor pairs in the cornu ammonis 1, cornu ammonis 3, and dente gyrus trisynaptic circuit (control vs. sevoflurane, cornu ammonis 1–cornu ammonis 3: 18 vs. 42 in males and 15 vs. 21 in females; cornu ammonis 1–dentate gyrus: 21 vs. 35 in males and 12 vs. 20 in females; cornu ammonis 3–dentate gyrus: 25 vs. 45 in males and 17 vs. 20 in females), interfered with dentate gyrus granule cell neurogenesis, hampered microglia differentiation, and decreased cornu ammonis 1 pyramidal cell diversity. Oligodendrocyte differentiation was specifically altered in females with increased expressions of Mbp and Mag. In situ hybridization validated the increased expression of common differentially expressed genes. Conclusions This single-nucleus RNA sequencing study reveals the hippocampal atlas of mice, providing a comprehensive resource for the neuronal and nonneuronal cell type– and sex-specific effects of sevoflurane during development. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Advanced respiratory monitoring involves several mini- or noninvasive tools, applicable at bedside, focused on assessing lung aeration and morphology, lung recruitment and overdistention, ventilation–perfusion distribution, inspiratory effort, respiratory drive, respiratory muscle contraction, and patient–ventilator asynchrony, in dealing with acute respiratory failure. Compared to a conventional approach, advanced respiratory monitoring has the potential to provide more insights into the pathologic modifications of lung aeration induced by the underlying disease, follow the response to therapies, and support clinicians in setting up a respiratory support strategy aimed at protecting the lung and respiratory muscles. Thus, in the clinical management of the acute respiratory failure, advanced respiratory monitoring could play a key role when a therapeutic strategy, relying on individualization of the treatments, is adopted.

BackgroundNeuraxial modulation, including spinal cord stimulation, reduces cardiac sympathoexcitation and ventricular arrhythmogenesis. There is an incomplete understanding of the molecular mechanisms through which spinal cord stimulation modulates cardiospinal neural pathways. The authors hypothesize that spinal cord stimulation reduces myocardial ischemia–reperfusion—induced sympathetic excitation and ventricular arrhythmias through γ-aminobutyric acid (GABA)–mediated pathways in the thoracic spinal cord.MethodsYorkshire pigs were randomized to control (n = 11), ischemia–reperfusion (n = 16), ischemia–reperfusion plus spinal cord stimulation (n = 17), ischemia–reperfusion plus spinal cord stimulation plus γ-aminobutyric acid type A (GABAA) or γ-aminobutyric acid type B (GABAB) receptor antagonist (GABAA, n = 8; GABAB, n = 8), and ischemia–reperfusion plus GABA transaminase inhibitor (GABAculine, n = 8). A four-pole spinal cord stimulation lead was placed epidurally (T1 to T4). GABA modulating pharmacologic agents were administered intrathecally. Spinal cord stimulation at 50 Hz was applied 30 min before ischemia. A 56-electrode epicardial mesh was used for high-resolution electrophysiologic recordings, including activation recovery intervals and ventricular arrhythmia scores. Immunohistochemistry and Western blots were performed to measure GABA receptor expression in the thoracic spinal cord.ResultsCardiac ischemia led to myocardial sympathoexcitation with reduction in activation recovery interval (mean ± SD, –42 ± 11%), which was attenuated by spinal cord stimulation (–21 ± 17%, P = 0.001). GABAA and GABAB receptor antagonists abolished spinal cord stimulation attenuation of sympathoexcitation (GABAA, –9.7 ± 9.7%, P = 0.043 vs. ischemia–reperfusion plus spinal cord stimulation; GABAB, –13 ± 14%, P = 0.012 vs. ischemia–reperfusion plus spinal cord stimulation), while GABAculine alone caused a therapeutic effect similar to spinal cord stimulation (–4.1 ± 3.7%, P = 0.038 vs. ischemia–reperfusion). The ventricular arrhythmia score supported these findings. Spinal cord stimulation during ischemia–reperfusion increased GABAA receptor expression with no change in GABAB receptor expression.ConclusionsThoracic spinal cord stimulation reduces ischemia–reperfusion—induced sympathoexcitation and ventricular arrhythmias through activation of GABA signaling pathways. These data support the hypothesis that spinal cord stimulation–induced release of GABA activates inhibitory interneurons to decrease primary afferent signaling from superficial dorsal horn to sympathetic output neurons in the intermediolateral nucleus.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

BackgroundA clinically relevant mouse model of thoracic endovascular aortic repair–induced ischemic spinal cord injury has been lacking since the procedure was first employed in 1991. The hypothesis was that ligation of mouse intercostal arteries would simulate thoracic endovascular aortic repair–induced ischemic spinal cord injury and behavioral deficit. The aim was to create a mouse model of thoracic endovascular aortic repair–induced spinal cord hypoperfusion by ligating five pairs of mouse intercostal vessels.MethodsMice were divided into sham (n = 53) and ligation (n = 60) groups. The procedures called for double ligation of three pairs and single ligation of two pairs of thoracic intercostal arteries in adult C57BL/6 mice. A laser Doppler probe was used in vivo on the spinal cords and intercostal arteries to document the extent of arterial ligation and spinal cord hypoperfusion. The Basso Mouse Scale for Locomotion, histological studies, and electron microscopy demonstrated postligation locomotive and histopathological changes.ResultsLigation induced a significant and instantaneous drop in blood flow in the intercostal arteries (% change; mean = −63.81; 95% CI, −72.28 to −55.34) and the thoracic spinal cord (% change; mean = −68.55; 95% CI, −80.23 to −56.87). Paralysis onset was immediate and of varying degree, with behavioral deficit stratified into three groups: 9.4% exhibited severe paralysis, 37.5% moderate paralysis, and 53.1% mild paralysis at day 1 (n = 32; P < 0.001). Mild and moderate paralysis was transient, gradually improving over time. Severe paralysis showed no improvement and exhibited a higher mortality rate (83%; n = 15 of 18) compared to moderately (33%; n = 6 of 18) and mildly (24%; n = 6 of 25) paralyzed mice (P < 0.001). The overall ligation group survival rate (84%; n = 46 of 55) was significantly lower than the sham group (100%; n = 48 of 48) with P = 0.003.ConclusionsThe mouse model generates reproducible spinal cord hypoperfusion and accompanying histopathological ischemic spinal cord damage. The resulting anatomical changes and variable behavioral deficits mimic the variability in radiological and clinical findings in human patients.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

Background There is insufficient prospective evidence regarding the relationship between surgical experience and prolonged opioid use and pain. The authors investigated the association of patient characteristics, surgical procedure, and perioperative anesthetic course with postoperative opioid consumption and pain 3 months postsurgery. The authors hypothesized that patient characteristics and intraoperative factors predict opioid consumption and pain 3 months postsurgery. Methods Eleven U.S. and one European institution enrolled patients scheduled for spine, open thoracic, knee, hip, or abdominal surgery, or mastectomy, in this multicenter, prospective observational study. Preoperative and postoperative data were collected using patient surveys and electronic medical records. Intraoperative data were collected from the Multicenter Perioperative Outcomes Group database. The association between postoperative opioid consumption and surgical site pain at 3 months, elicited from a telephone survey conducted at 3 months postoperatively, and demographics, psychosocial scores, pain scores, pain management, and case characteristics, was analyzed. Results Between September and October 2017, 3,505 surgical procedures met inclusion criteria. A total of 1,093 cases were included; 413 patients were lost to follow-up, leaving 680 (64%) for outcome analysis. Preoperatively, 135 (20%) patients were taking opioids. Three months postsurgery, 96 (14%) patients were taking opioids, including 23 patients (4%) who had not taken opioids preoperatively. A total of 177 patients (27%) reported surgical site pain, including 45 (13%) patients who had not reported pain preoperatively. The adjusted odds ratio for 3-month opioid use was 18.6 (credible interval, 10.3 to 34.5) for patients who had taken opioids preoperatively. The adjusted odds ratio for 3-month surgical site pain was 2.58 (1.45 to 4.4), 4.1 (1.73 to 8.9), and 2.75 (1.39 to 5.0) for patients who had site pain preoperatively, knee replacement, or spine surgery, respectively. Conclusions Preoperative opioid use was the strongest predictor of opioid use 3 months postsurgery. None of the other variables showed clinically significant association with opioid use at 3 months after surgery. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

BackgroundNitrous oxide promotes absorption atelectasis in poorly ventilated lung segments at high inspired concentrations. The Evaluation of Nitrous oxide In the Gas Mixture for Anesthesia (ENIGMA) trial found a higher incidence of postoperative pulmonary complications and wound sepsis with nitrous oxide anesthesia in major surgery compared to a fraction of inspired oxygen of 0.8 without nitrous oxide. The larger ENIGMA II trial randomized patients to nitrous oxide or air at a fraction of inspired oxygen of 0.3 but found no effect on wound infection or sepsis. However, postoperative pulmonary complications were not measured. In the current study, post hoc data were collected to determine whether atelectasis and pneumonia incidences were higher with nitrous oxide in patients who were recruited to the Australian cohort of ENIGMA II.MethodsDigital health records of patients who participated in the trial at 10 Australian hospitals were examined blinded to trial treatment allocation. The primary endpoint was the incidence of atelectasis, defined as lung atelectasis or collapse reported on chest radiology. Pneumonia, as a secondary endpoint, required a diagnostic chest radiology report with fever, leukocytosis, or positive sputum culture. Comparison of the nitrous oxide and nitrous oxide–free groups was done according to intention to treat using chi-square tests.ResultsData from 2,328 randomized patients were included in the final data set. The two treatment groups were similar in surgical type and duration, risk factors, and perioperative management recorded for ENIGMA II. There was a 19.3% lower incidence of atelectasis with nitrous oxide (171 of 1,169 [14.6%] vs. 210 of 1,159 [18.1%]; odds ratio, 0.77; 95% CI, 0.62 to 0.97; P = 0.023). There was no difference in pneumonia incidence (60 of 1,169 [5.1%] vs. 52 of 1159 [4.5%]; odds ratio, 1.15; 95% CI, 0.77 to 1.72; P = 0.467) or combined pulmonary complications (odds ratio, 0.84; 95% CI, 0.69 to 1.03; P = 0.093).ConclusionsIn contrast to the earlier ENIGMA trial, nitrous oxide anesthesia in the ENIGMA II trial was associated with a lower incidence of lung atelectasis, but not pneumonia, after major surgery.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

Economic implications of pain management. By Loeser JD. Acta Anaesthesiol Scand 1999; 43:957–95. Reprinted with permission. Multidisciplinary pain management was an invention of John J. Bonica, M.D. He started the Multidisciplinary Pain Clinic at the University of Washington in 1960. This clinical service evolved over the years, and when John Loeser, M.D., became its director in 1982, he collaborated with Bill Fordyce, Ph.D., to create what was known as “the structured program.” The program has served as the model for pain treatment programs throughout the world, many of which have fared better than that at the University of Washington. The migration of Stephen Butler, M.D., to Uppsala, Sweden, in 2000 has given us the opportunity to contrast multidisciplinary pain management in the Nordic countries with that in the United States.

BackgroundThe authors tested the hypothesis that the effects of traumatic brain injury, surgery, and sevoflurane interact to induce neurobehavioral abnormalities in adult male rats and in their offspring (an animal model of intergenerational perioperative neurocognitive disorder).MethodsSprague-Dawley male rats (assigned generation F0) underwent a traumatic brain injury on postnatal day 60 that involved craniectomy (surgery) under 3% sevoflurane for 40 min followed by 2.1% sevoflurane for 3 h on postnatal days 62, 64, and 66 (injury group). The surgery group had craniectomy without traumatic brain injury, whereas the sevoflurane group had sevoflurane only. On postnatal day 90, F0 males and control females were mated to generate offspring (assigned generation F1).ResultsAcutely, F0 injury rats exhibited the greatest increases in serum corticosterone and interleukin-1β and -6, and activation of the hippocampal microglia. Long-term, compared to controls, F0 injury rats had the most exacerbated corticosterone levels at rest (mean ± SD, 2.21 ± 0.64 vs. 7.28 ± 1.95 ng/ml, n = 7 - 8; P < 0.001) and 10 min after restraint (133.12 ± 33.98 vs. 232.83 ± 40.71 ng/ml, n = 7 - 8; P < 0.001), increased interleukin-1β and -6, and reduced expression of hippocampal glucocorticoid receptor (Nr3c1; 0.53 ± 0.08 fold change relative to control, P < 0.001, n = 6) and brain-derived neurotrophic factor genes. They also exhibited greater behavioral deficiencies. Similar abnormalities were evident in their male offspring, whereas F1 females were not affected. The reduced Nr3c1 expression in F1 male, but not female, hippocampus was accompanied by corresponding Nr3c1 promoter hypermethylated CpG sites in F0 spermatozoa and F1 male, but not female, hippocampus.ConclusionsThese findings in rats suggest that young adult males with traumatic brain injury are at an increased risk of developing perioperative neurocognitive disorder, as are their unexposed male but not female offspring.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

Cerebral Function and Muscle Afferent Activity Following Intravenous Succinylcholine in Dogs Anesthetized with Halothane: The Effects of Pretreatment with a Defasciculating Dose of Pancuronium. By WL Lanier, PA Iaizzo, and JH Milde. Anesthesiology 1989; 71:87–95. Reprinted with permission. By the mid-1980s, it was widely assumed that if the depolarizing muscle relaxant, succinylcholine, given IV, produced increases in intracranial pressure, it did so because fasciculations produced increases in intrathoracic and central venous pressures that were transferred to the brain; however, there was no direct evidence that this was true. In contrast, we explored the possibility that the succinylcholine effect on the brain was explained by the afferentation theory of cerebral arousal, which predicts that agents or maneuvers that stimulate muscle stretch receptors will tend to stimulate the brain. Our research in tracheally intubated, lightly anesthetized dogs discovered that IV succinylcholine (which does not cross the blood-brain barrier) produced a doubling of cerebral blood flow that lasted for 30 min and corresponded to activation of the electroencephalogram and increases in intracranial pressure. Later, in our Classic Paper, we were able to assess simultaneously cerebral physiology and afferent nerve traffic emanating from muscle stretch receptors (primarily muscle spindles). We affirmed that the cerebral arousal response to succinylcholine was indeed driven by muscle afferent traffic and was independent of fasciculations or increases in intrathoracic or central venous pressures. Later research in complementary models demonstrated that endogenous movement (e.g., coughing, hiccups) produced a cerebral response very similar to IV succinylcholine, apparently as a result of the same muscle afferent mechanisms, independent of intrathoracic and central venous pressures. Thus, the importance of afferentation theory as a driver of the cerebral state of arousal and cerebral physiology during anesthesia was affirmed.

These practice guidelines are a modular update of the “Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: Application to healthy patients undergoing elective procedures.” The guidance focuses on topics not addressed in the previous guideline: ingestion of carbohydrate-containing clear liquids with or without protein, chewing gum, and pediatric fasting duration.

BackgroundGradually changing respiratory rate (RR) during time to reduce ventilation-induced lung injury has not been investigated. The authors hypothesized that gradual, compared with abrupt, increments in RR would mitigate ventilation-induced lung injury and that recruitment maneuver before abruptly increasing RR may prevent injurious biologic impact.MethodsTwenty-four hours after intratracheal administration of Escherichia coli lipopolysaccharide, 49 male Wistar rats were anesthetized and mechanically ventilated (tidal volume, 6 ml/kg; positive end-expiratory pressure, 3 cm H2O) with RR increase patterns as follows (n = 7 per group): (1) control 1, RR = 70 breaths/min for 2 h; (2) and (3) abrupt increases of RR for 1 and 2 h, respectively, both for 2 h; (4) shorter RR adaptation, gradually increasing RR (from 70 to 130 breaths/min during 30 min); (5) longer RR adaptation, more gradual increase in RR (from 70 to 130 breaths/min during 60 min), both for 2 h; (6) control 2, abrupt increase of RR maintained for 1 h; and (7) control 3, recruitment maneuver (continuous positive airway pressure, 30 cm H2O for 30 s) followed by control-2 protocol.ResultsAt the end of 1 h of mechanical ventilation, cumulative diffuse alveolar damage scores were lower in shorter (11.0 [8.0 to 12.0]) and longer (13.0 [11.0 to 14.0]) RR adaptation groups than in animals with abrupt increase of RR for 1 h (25.0 [22.0 to 26.0], P = 0.035 and P = 0.048, respectively) and 2 h (35.0 [32.0 to 39.0], P = 0.003 and P = 0.040, respectively); mechanical power and lung heterogeneity were lower, and alveolar integrity was higher, in the longer RR adaptation group compared with abruptly adjusted groups; markers of lung inflammation (interleukin-6), epithelial (club cell secretory protein [CC-16]) and endothelial cell damage (vascular cell adhesion molecule 1 [VCAM-1]) were higher in both abrupt groups, but not in either RR adaptation group, compared with controls. Recruitment maneuver prevented the increase in VCAM-1 and CC-16 gene expressions in the abruptly increased RR groups.ConclusionsIn mild experimental acute respiratory distress syndrome in rats, gradually increasing RR, compared with abruptly doing so, can mitigate the development of ventilation-induced lung injury. In addition, recruitment maneuver prevented the injurious biologic impact of abrupt increases in RR.Editor’s PerspectiveWhat We Already Know about This TopicWhat This Article Tells Us That Is New

Anesthesiologists routinely manage patients receiving drugs and agents, all of which have the potential for anaphylaxis, the life-threatening presentation of an allergic reaction. Clinicians must be ready to diagnose and manage the acute cardiopulmonary dysfunction that occurs.

Background The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented. The hypothesis was that sugammadex would attract rocuronium and vecuronium via interaction with the sugammadex side-chain “tentacles,” as previously suggested. Methods Computational molecular dynamics simulations were done to investigate docking of sugammadex with rocuronium and vecuronium. To validate these methods, strength of binding was assessed between sugammadex and a heterogeneous group of nine other drugs, the binding affinities of which have been experimentally determined. These observations hinted that high concentrations of unbound sugammadex could bind to propofol, potentially altering its pharmacokinetic profile. This was tested experimentally in in vitro cortical slices. Results Sugammadex encapsulation of rocuronium involved a sequential progression down a series of metastable states. After initially binding beside the sugammadex molecule (mean ± SD center-of-mass distance = 1.17 ± 0.13 nm), rocuronium then moved to the opposite side to that hypothesized, where it optimally aligned with the 16 hydroxyl groups (distance, 0.82 ± 0.04 nm) before entering the sugammadex cavity to achieve energetically stable encapsulation by approximately 120 ns (distance, 0.35 ± 0.12 nm). Vecuronium formed fewer hydrogen bonds with sugammadex than did rocuronium; hence, it was less avidly bound. For the other molecules, the computational results showed good agreement with the available experimental data, showing a clear bilogarithmic relation between the relative binding free energy and the association constant (R2 = 0.98). Weaker binding was manifest by periodic unbinding. The brain slice results confirmed the presence of a weak propofol–sugammadex interaction. Conclusions Computational simulations demonstrate the dynamics of neuromuscular blocking drug encapsulation by sugammadex occurring from the opposite direction to that hypothesized and also how high concentrations of unbound sugammadex can potentially weakly bind to other drugs given during general anesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background The objective was to assess changes over time in prescriptions filled for nonopioid analgesics for older postoperative patients in the immediate postdischarge period. The authors hypothesized that the number of patients who filled a nonopioid analgesic prescription increased during the study period. Methods The authors performed a population-based cohort study using linked health administrative data of 278,366 admissions aged 66 yr or older undergoing surgery between fiscal year 2013 and 2019 in Ontario, Canada. The primary outcome was the percentage of patients with new filled prescriptions for nonopioid analgesics within 7 days of discharge, and the secondary outcome was the analgesic class. The authors assessed whether patients filled prescriptions for a nonopioid only, an opioid only, both opioid and nonopioid prescriptions, or a combination opioid/nonopioid. Results Overall, 22% (n = 60,181) of patients filled no opioid prescription, 2% (n = 5,534) filled a nonopioid only, 21% (n = 59,608) filled an opioid only, and 55% (n = 153,043) filled some combination of opioid and nonopioid. The percentage of patients who filled a nonopioid prescription within 7 days postoperatively increased from 9% (n = 2,119) in 2013 to 28% (n = 13,090) in 2019, with the greatest increase for acetaminophen: 3% (n = 701) to 20% (n = 9,559). The percentage of patients who filled a combination analgesic prescription decreased from 53% (n = 12,939) in 2013 to 28% (n = 13,453) in 2019. However, the percentage who filled both an opioid and nonopioid prescription increased: 4% (n = 938) to 21% (n = 9,880) so that the overall percentage of patients who received both an opioid and a nonopioid remained constant over time 76% (n = 18,642) in 2013 to 75% (n = 35,391) in 2019. Conclusions The proportion of postoperative patients who fill prescriptions for nonopioid analgesics has increased. However, rather than a move to use of nonopioids alone for analgesia, this represents a shift away from combination medications toward separate prescriptions for opioids and nonopioids. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Postamputation phantom pain is notoriously persistent with few validated treatments. Cryoneurolysis involves the application of low temperatures to reversibly ablate peripheral nerves. The authors tested the hypothesis that a single cryoneurolysis treatment would decrease phantom pain 4 months later. Methods The authors enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. The primary outcome was the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10), after which an optional crossover treatment was offered. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. Results Pretreatment phantom pain scores were similar in both groups, with a median [quartiles] of 5.0 [4.0, 6.0] for active treatment and 5.0 [4.0, 7.0] for sham. After 4 months, pain intensity decreased by 0.5 [–0.5, 3.0] in patients given cryoneurolysis (n = 71) versus 0 [0, 3] in patients given sham (n = 73), with an estimated difference (95% CI) of –0.1 (–1.0 to 0.7), P = 0.759. Following their statistical gatekeeping protocol, the authors did not make inferences or draw conclusions on secondary endpoints. One serious adverse event occurred after a protocol deviation in which a femoral nerve cryolesion was induced just below the inguinal ligament—instead of the sensory-only saphenous nerve—which resulted in quadriceps weakness, and possibly a fall and clavicle fracture. Conclusions Percutaneous cryoneurolysis did not decrease chronic lower extremity phantom limb pain 4 months after treatment. However, these results were based upon the authors’ specific study protocol, and since the optimal cryoneurolysis treatment parameters such as freeze duration and anatomic treatment location remain unknown, further research is warranted. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Acute kidney injury (AKI) after noncardiac surgery is common and has substantial health impact. Preclinical and clinical studies examining the influence of sex on AKI have yielded conflicting results, although they typically do not account for age-related changes. The objective of the study was to determine the association of age and sex groups on postoperative AKI. The authors hypothesized that younger females would display lower risk of postoperative AKI than males of similar age, and the protection would be lost in older females. Methods This was a multicenter retrospective cohort study across 46 institutions between 2013 and 2019. Participants included adult inpatients without pre-existing end-stage kidney disease undergoing index major noncardiac, nonkidney/urologic surgeries. The authors’ primary exposure was age and sex groups defined as females 50 yr or younger, females older than 50 yr, males 50 yr or younger, and males older than 50 yr. The authors’ primary outcome was development of AKI by Kidney Disease-Improving Global Outcomes serum creatinine criteria. Exploratory analyses included associations of ascending age groups and hormone replacement therapy home medications with postoperative AKI. Results Among 390,382 patients, 25,809 (6.6%) developed postoperative AKI (females 50 yr or younger: 2,190 of 58,585 [3.7%]; females older than 50 yr: 9,320 of 14,4047 [6.5%]; males 50 yr or younger: 3,289 of 55,503 [5.9%]; males older than 50 yr: 11,010 of 132,447 [8.3%]). When adjusted for AKI risk factors, compared to females younger than 50 yr (odds ratio, 1), the odds of AKI were higher in females older than 50 yr (odds ratio, 1.51; 95% CI, 1.43 to 1.59), males younger than 50 yr (odds ratio, 1.90; 95% CI, 1.79 to 2.01), and males older than 50 yr (odds ratio, 2.06; 95% CI, 1.96 to 2.17). Conclusions Younger females display a lower odds of postoperative AKI that gradually increases with age. These results suggest that age-related changes in women should be further studied as modifiers of postoperative AKI risk after noncardiac surgery. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Intraoperative supplemental oxygen may reduce postoperative nausea and vomiting by mitigating hypoxic stress on the gastrointestinal tract. The authors therefore tested the hypothesis that supplemental oxygen reduces nausea and vomiting in adults recovering from colorectal surgery at the Cleveland Clinic between January 28, 2013, and March 11, 2016. Methods Initially, the authors conducted an unplanned subanalysis of a previous trial that evaluated the effect of 80% versus 30% intraoperative inspired oxygen on surgical site infection. Specifically, they assessed the effect of 80% versus 30% oxygen concentration on the incidence of postoperative nausea and/or vomiting. Thereafter, the authors conducted a systematic review and meta-analysis of the effect of supplemental oxygen on postoperative nausea and vomiting. Results The authors’ underlying analysis included 5,057 colorectal surgeries on 4,001 patients. For 2,554 surgeries, assignment was to 80% oxygen, and in 2,503 surgeries, to 30%. Postoperative nausea and vomiting was 852 of 2,554 (33%) in 80% oxygen and 814 of 2,503 (33%) in 30% oxygen. The estimated relative risk (95% CI) of 80% versus 30% oxygen on postoperative nausea and vomiting was 1.04 (0.96 to 1.12) in a generalized estimating equation model adjusting for within-patient correlation for patients with multiple surgeries, P = 0.355. Furthermore, supplemental oxygen did not reduce antiemetic use (P = 0.911) or the severity of nausea and vomiting (P = 0.924). The authors’ meta-analysis included 10 qualifying trials (6,749 patients) and did not find a difference in postoperative nausea and vomiting: relative risk, 0.97 [95% CI, 0.86 to 1.08], P = 0.55, I2 = 52%. Conclusions The incidence of postoperative nausea and vomiting did not differ in patients assigned to 80% or 30% inspired oxygen. A meta-analysis of available trials similarly indicated that supplemental intraoperative oxygen does not reduce postoperative nausea and vomiting. Therefore, supplemental oxygen should not be given in the expectation that it will reduce nausea and vomiting. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Postoperative pain associated with open partial hepatectomy can be intense and persistent. The multimodal approach used to lessen this problem includes an intraoperative intravenous infusion of lidocaine hydrochloride. Decreased hepatic metabolism after resection raises concerns about safe lidocaine dosing in this patient population. The hypothesis was that the elimination clearance of lidocaine and its metabolites, monoethylglycinexylidide and glycinexylidide, is reduced after a partial hepatectomy, as reflected by observed plasma concentrations that are higher and have a longer half-life than expected based on pharmacokinetic modeling (estimated for normal liver function). Secondarily, this study postulated that plasma concentrations of lidocaine, monoethylglycinexylidide, and glycinexylidide do not reach toxic concentrations with institutional protocol up to 24 h after surgery. Methods Blood samples were collected from 15 patients undergoing a partial hepatectomy for living liver donation, at the following specific time points: before and immediately after induction of anesthesia, during hepatectomy, 30 min after hepatectomy completion, at case end, and 24 h after the end of surgery. Plasma concentrations of lidocaine and metabolites were measured by liquid chromatography–mass spectrometry. The population lidocaine pharmacokinetics were estimated, and total body weight and the fraction of remaining liver mass as potential model covariates were evaluated. The detection of any lidocaine, monoethylglycinexylidide, or glycinexylidide toxic plasma concentrations at any time point during and after hepatectomy were also evaluated. Results The typical value for lidocaine elimination clearance was 0.55 ± 0.12 l/min (± standard error of the estimate) which, on average, was reduced to about one third of the baseline clearance, 0.17 ± 0.02 l/min, once the donor graft was surgically isolated, and remained so for 24 h according to the current data and model. The fraction of remaining liver was a significant covariate for the posthepatectomy lidocaine clearance‚ such that if 50% of the liver is removed the clearance is reduced by approximately 60%. Plasma concentrations of lidocaine and its metabolites remained below their theoretical combined toxic threshold concentrations throughout the surgical and postoperative course in all patients, with one exception obtained near induction of anesthesia. Plasma lidocaine concentrations decreased at case end and postoperatively, while metabolite concentrations continued to rise at the end of surgery with reduction postoperatively. Pharmacokinetic modeling revealed that the only significant covariate in the model was the fraction of liver remaining after isolation of the donor graft. Conclusions Intravenous lidocaine infusions are an acceptable option for multimodal pain management in patients undergoing a hepatectomy for living donation if the lidocaine infusion is stopped when the liver resection is complete. Clearance of lidocaine is decreased proportionally to the remaining liver mass, which should guide lidocaine infusion administration or dosing adjustments for patients undergoing liver resection surgery. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

This article presents current literature and scientific evidence on hemoglobin thresholds and physiologic parameters to guide decisions regarding perioperative erythrocyte transfusions in pediatric patients based on the most up-to-date studies and expert consensus recommendations.

The authors reviewed perioperative ocular complications and implications of ocular diseases during nonocular surgeries. Exposure keratopathy, the most common perioperative eye injury, is preventable. Ischemic optic neuropathy, the leading cause of perioperative blindness, has well-defined risk factors. The incidence of ischemic optic neuropathy after spine fusion, but not cardiac surgery, has been decreasing. Central retinal artery occlusion during spine fusion surgery can be prevented by protecting eyes from compression. Perioperative acute angle closure glaucoma is a vision-threatening emergency that can be successfully treated by rapid reduction of elevated intraocular pressure. Differential diagnoses of visual dysfunction in the perioperative period and treatments are detailed. Although glaucoma is increasingly prevalent and often questions arise concerning perioperative anesthetic management, evidence-based recommendations to guide safe anesthesia care in patients with glaucoma are currently lacking. Patients with low vision present challenges to the anesthesia provider that are becoming more common as the population ages.

Background Patients resuscitated from cardiac arrest are routinely sedated during targeted temperature management, while the effects of sedation on cerebral physiology and outcomes after cardiac arrest remain to be determined. The authors hypothesized that sedation would improve survival and neurologic outcomes in mice after cardiac arrest. Methods Adult C57BL/6J mice of both sexes were subjected to potassium chloride–induced cardiac arrest and cardiopulmonary resuscitation. Starting at the return of spontaneous circulation or at 60 min after return of spontaneous circulation, mice received intravenous infusion of propofol at 40 mg · kg–1 · h–1, dexmedetomidine at 1 µg · kg–1 · h–1, or normal saline for 2 h. Body temperature was lowered and maintained at 33°C during sedation. Cerebral blood flow was measured for 4 h postresuscitation. Telemetric electroencephalogram (EEG) was recorded in freely moving mice from 3 days before up to 7 days after cardiac arrest. Results Sedation with propofol or dexmedetomidine starting at return of spontaneous circulation improved survival in hypothermia-treated mice (propofol [13 of 16, 81%] vs. no sedation [4 of 16, 25%], P = 0.008; dexmedetomidine [14 of 16, 88%] vs. no sedation [4 of 16, 25%], P = 0.002). Mice receiving no sedation exhibited cerebral hyperemia immediately after resuscitation and EEG power remained less than 30% of the baseline in the first 6 h postresuscitation. Administration of propofol or dexmedetomidine starting at return of spontaneous circulation attenuated cerebral hyperemia and increased EEG slow oscillation power during and early after sedation (40 to 80% of the baseline). In contrast, delayed sedation failed to improve outcomes, without attenuating cerebral hyperemia and inducing slow-wave activity. Conclusions Early administration of sedation with propofol or dexmedetomidine improved survival and neurologic outcomes in mice resuscitated from cardiac arrest and treated with hypothermia. The beneficial effects of sedation were accompanied by attenuation of the cerebral hyperemic response and enhancement of electroencephalographic slow-wave activity. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Tobacco use will kill a projected 1 billion people in the 21st century in one of the deadliest pandemics in history. Tobacco use disorder is a disease with a natural history, pathophysiology, and effective treatment options. Anesthesiologists can play a unique role in fighting this pandemic, providing both immediate (reduction in perioperative risk) and long-term (reduction in tobacco-related diseases) benefits to their patients who are its victims. Receiving surgery is one of the most powerful stimuli to quit tobacco. Tobacco treatments that combine counseling and pharmacotherapy (e.g., nicotine replacement therapy) can further increase quit rates and reduce risk of morbidity such as pulmonary and wound-related complications. The perioperative setting provides a great opportunity to implement multimodal perianesthesia tobacco treatment, which combines multiple evidence-based tactics to implement the four core components of consistent ascertainment and documentation of tobacco use, advice to quit, access to pharmacotherapy, and referral to counseling resources.

Background Improper endotracheal tube (ETT) positioning is frequently observed and potentially hazardous in the intensive care unit. The authors developed a deep learning–based automatic detection algorithm detecting the ETT tip and carina on portable supine chest radiographs to measure the ETT–carina distance. This study investigated the hypothesis that the algorithm might be more accurate than frontline critical care clinicians in ETT tip detection, carina detection, and ETT–carina distance measurement. Methods A deep learning–based automatic detection algorithm was developed using 1,842 portable supine chest radiographs of 1,842 adult intubated patients, where two board-certified intensivists worked together to annotate the distal ETT end and tracheal bifurcation. The performance of the deep learning–based algorithm was assessed in 4-fold cross-validation (1,842 radiographs), external validation (216 radiographs), and an observer performance test (462 radiographs) involving 11 critical care clinicians. The performance metrics included the errors from the ground truth in ETT tip detection, carina detection, and ETT–carina distance measurement. Results During 4-fold cross-validation and external validation, the median errors (interquartile range) of the algorithm in ETT–carina distance measurement were 3.9 (1.8 to 7.1) mm and 4.2 (1.7 to 7.8) mm, respectively. During the observer performance test, the median errors (interquartile range) of the algorithm were 2.6 (1.6 to 4.8) mm, 3.6 (2.1 to 5.9) mm, and 4.0 (1.7 to 7.2) mm in ETT tip detection, carina detection, and ETT–carina distance measurement, significantly superior to that of 6, 10, and 7 clinicians (all P < 0.05), respectively. The algorithm outperformed 7, 3, and 0, 9, 6, and 4, and 5, 5, and 3 clinicians (all P < 0.005) regarding the proportions of chest radiographs within 5 mm, 10 mm, and 15 mm error in ETT tip detection, carina detection, and ETT–carina distance measurement, respectively. No clinician was significantly more accurate than the algorithm in any comparison. Conclusions A deep learning–based algorithm can match or even outperform frontline critical care clinicians in ETT tip detection, carina detection, and ETT–carina distance measurement. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Inhalational anesthetics are known to disrupt PDZ2 domain–mediated protein–protein interactions of the postsynaptic density (PSD)-95 protein. The aim of this study is to investigate the underlying mechanisms in response to early isoflurane exposure on synaptic PSD-95 PDZ2 domain disruption that altered spine densities and cognitive function. The authors hypothesized that activation of protein kinase-G by the components of nitric oxide (NO) signaling pathway constitutes a mechanism that prevents loss of early dendritic spines and synapse in neurons and cognitive impairment in mice in response to disruption of PDZ2 domain of the PSD-95 protein. Methods Postnatal day 7 mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active PSD-95 wild-type PDZ2 peptide or soluble guanylyl cyclase activator YC-1 along with their respective controls. Primary neurons at 7 days in vitro were exposed to isoflurane or PSD-95 wild-type PDZ2 peptide for 4 h. Coimmunoprecipitation, spine density, synapses, cyclic guanosine monophosphate–dependent protein kinase activity, and novel object recognition memory were assessed. Results Exposure of isoflurane or PSD-95 wild-type PDZ2 peptide relative to controls causes the following. First, there is a decrease in PSD-95 coimmunoprecipitate relative to N-methyl-d-aspartate receptor subunits NR2A and NR2B precipitate (mean ± SD [in percentage of control]: isoflurane, 54.73 ± 16.52, P = 0.001; and PSD-95 wild-type PDZ2 peptide, 51.32 ± 12.93, P = 0.001). Second, there is a loss in spine density (mean ± SD [spine density per 10 µm]: control, 5.28 ± 0.56 vs. isoflurane, 2.23 ± 0.67, P < 0.0001; and PSD-95 mutant PDZ2 peptide, 4.74 ± 0.94 vs. PSD-95 wild-type PDZ2 peptide, 1.47 ± 0.87, P < 0.001) and a decrease in synaptic puncta (mean ± SD [in percentage of control]: isoflurane, 41.1 ± 14.38, P = 0.001; and PSD-95 wild-type PDZ2 peptide, 50.49 ± 14.31, P < 0.001). NO donor or cyclic guanosine monophosphate analog prevents the spines and synapse loss and decline in the cyclic guanosine monophosphate–dependent protein kinase activity, but this prevention was blocked by soluble guanylyl cyclase or protein kinase-G inhibitors in primary neurons. Third, there were deficits in object recognition at 5 weeks (mean ± SD [recognition index]: male, control, 64.08 ± 10.57 vs. isoflurane, 48.49 ± 13.41, P = 0.001, n = 60; and female, control, 67.13 ± 11.17 vs. isoflurane, 53.76 ± 6.64, P = 0.003, n = 58). Isoflurane-induced impairment in recognition memory was preventable by the introduction of YC-1. Conclusions Activation of soluble guanylyl cyclase or protein kinase-G prevents isoflurane or PSD-95 wild-type PDZ2 peptide–induced loss of dendritic spines and synapse. Prevention of recognition memory with YC-1, a NO-independent activator of guanylyl cyclase, supports a role for the soluble guanylyl cyclase mediated protein kinase-G signaling in countering the effects of isoflurane-induced cognitive impairment. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background COVID-19 causes hypercoagulability, but the association between coagulopathy and hypoxemia in critically ill patients has not been thoroughly explored. This study hypothesized that severity of coagulopathy would be associated with acute respiratory distress syndrome severity, major thrombotic events, and mortality in patients requiring intensive care unit–level care. Methods Viscoelastic testing by rotational thromboelastometry and coagulation factor biomarker analyses were performed in this prospective observational cohort study of critically ill COVID-19 patients from April 2020 to October 2020. Statistical analyses were performed to identify significant coagulopathic biomarkers such as fibrinolysis-inhibiting plasminogen activator inhibitor 1 and their associations with clinical outcomes such as mortality, extracorporeal membrane oxygenation requirement, occurrence of major thrombotic events, and severity of hypoxemia (arterial partial pressure of oxygen/fraction of inspired oxygen categorized into mild, moderate, and severe per the Berlin criteria). Results In total, 53 of 55 (96%) of the cohort required mechanical ventilation and 9 of 55 (16%) required extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation–naïve patients demonstrated lysis indices at 30 min indicative of fibrinolytic suppression on rotational thromboelastometry. Survivors demonstrated fewer procoagulate acute phase reactants, such as microparticle-bound tissue factor levels (odds ratio, 0.14 [0.02, 0.99]; P = 0.049). Those who did not experience significant bleeding events had smaller changes in ADAMTS13 levels compared to those who did (odds ratio, 0.05 [0, 0.7]; P = 0.026). Elevations in plasminogen activator inhibitor 1 (odds ratio, 1.95 [1.21, 3.14]; P = 0.006), d-dimer (odds ratio, 3.52 [0.99, 12.48]; P = 0.05), and factor VIII (no clot, 1.15 ± 0.28 vs. clot, 1.42 ± 0.31; P = 0.003) were also demonstrated in extracorporeal membrane oxygenation–naïve patients who experienced major thrombotic events. Plasminogen activator inhibitor 1 levels were significantly elevated during periods of severe compared to mild and moderate acute respiratory distress syndrome (severe, 44.2 ± 14.9 ng/ml vs. mild, 31.8 ± 14.7 ng/ml and moderate, 33.1 ± 15.9 ng/ml; P = 0.029 and 0.039, respectively). Conclusions Increased inflammatory and procoagulant markers such as plasminogen activator inhibitor 1, microparticle-bound tissue factor, and von Willebrand factor levels are associated with severe hypoxemia and major thrombotic events, implicating fibrinolytic suppression in the microcirculatory system and subsequent micro- and macrovascular thrombosis in severe COVID-19. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Accurate estimation of surgical transfusion risk is essential for efficient allocation of blood bank resources and for other aspects of anesthetic planning. This study hypothesized that a machine learning model incorporating both surgery- and patient-specific variables would outperform the traditional approach that uses only procedure-specific information, allowing for more efficient allocation of preoperative type and screen orders. Methods The American College of Surgeons National Surgical Quality Improvement Program Participant Use File was used to train four machine learning models to predict the likelihood of red cell transfusion using surgery-specific and patient-specific variables. A baseline model using only procedure-specific information was created for comparison. The models were trained on surgical encounters that occurred at 722 hospitals in 2016 through 2018. The models were internally validated on surgical cases that occurred at 719 hospitals in 2019. Generalizability of the best-performing model was assessed by external validation on surgical cases occurring at a single institution in 2020. Results Transfusion prevalence was 2.4% (73,313 of 3,049,617), 2.2% (23,205 of 1,076,441), and 6.7% (1,104 of 16,053) across the training, internal validation, and external validation cohorts, respectively. The gradient boosting machine outperformed the baseline model and was the best- performing model. At a fixed 96% sensitivity, this model had a positive predictive value of 0.06 and 0.21 and recommended type and screens for 36% and 30% of the patients in internal and external validation, respectively. By comparison, the baseline model at the same sensitivity had a positive predictive value of 0.04 and 0.144 and recommended type and screens for 57% and 45% of the patients in internal and external validation, respectively. The most important predictor variables were overall procedure-specific transfusion rate and preoperative hematocrit. Conclusions A personalized transfusion risk prediction model was created using both surgery- and patient-specific variables to guide preoperative type and screen orders and showed better performance compared to the traditional procedure-centric approach. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New