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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

Background Etomidate, barbiturates, alfaxalone, and propofol are anesthetics that allosterically modulate γ-aminobutyric acid type A (GABAA) receptors via distinct sets of molecular binding sites. Two-state concerted coagonist models account for anesthetic effects and predict supra-additive interactions between drug pairs acting at distinct sites. Some behavioral and molecular studies support these predictions, while other findings suggest potentially complex anesthetic interactions. We therefore evaluated interactions among four anesthetics in both animals and GABAA receptors. Methods The authors used video assessment of photomotor responses in zebrafish larvae and isobolography to evaluate hypnotic drug pair interactions. Voltage clamp electrophysiology and allosteric shift analysis evaluated coagonist interactions in α1β3γ2L receptors activated by γ-aminobutyric acid (GABA) versus anesthetics [log(d, AN):log(d, GABA) ratio]. Anesthetic interactions at concentrations relevant to zebrafish were assessed in receptors activated with low GABA. Results In zebrafish larvae, etomidate interacted additively with both propofol and the barbiturate R-5-allyl-1-methyl m-trifluoromethyl mephobarbital (R-mTFD-MPAB; mean ± SD α = 1.0 ± 0.07 and 0.96 ± 0.11 respectively, where 1.0 indicates additivity), while the four other drug pairs displayed synergy (mean α range 0.76 to 0.89). Electrophysiologic allosteric shifts revealed that both propofol and R-mTFD-MPAB modulated etomidate-activated receptors much less than GABA-activated receptors [log(d, AN):log(d, GABA) ratios = 0.09 ± 0.021 and 0.38 ± 0.024, respectively], while alfaxalone comparably modulated receptors activated by GABA or etomidate [log(d) ratio = 0.87 ± 0.056]. With low GABA activation, etomidate combined with alfaxalone was supra-additive (n = 6; P = 0.023 by paired t test), but etomidate plus R-mTFD-MPAB or propofol was not. Conclusions In both zebrafish and GABAA receptors, anesthetic drug pairs interacted variably, ranging from additivity to synergy. Pairs including etomidate displayed corresponding interactions in animals and receptors. Some of these results challenge simple two-state coagonist models and support alternatives where different anesthetics may stabilize distinct receptor conformations, altering the effects of other drugs. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Remimazolam is an ultrashort-acting benzodiazepine that is potentially a practical option for procedural sedation in colonoscopy.To test the hypothesis that remimazolam could provide a noninferior discharge time to propofol for ambulatory colonoscopy.A prospective, randomised, double-blind, noninferiority clinical trial.Ambulatory endoscopy centre.A total of 132 adult participants undergoing ambulatory colonoscopy were enrolled.Participants were randomly assigned in a 1 : 1 ratio to receive propofol or remimazolam for sedation.The primary outcome was discharge time after a colonoscopy, assessed using the Modified Postanaesthetic Discharge Scoring System scale. Secondary outcomes included induction time, emergence time, the extent of recovery upon arrival in the postanaethesia care unit, fatigue, endoscopist and patient satisfaction and adverse events.The median discharge time was 24 min in the remimazolam group versus 21 min in the propofol group, with a difference of 2 min [95% confidence interval (CI), 0 to 4 min], meeting the criteria for noninferiority. Injection pain occurred in 11 of 66 (17%) participants receiving remimazolam versus 32 of 66 (49%) participants receiving propofol ( P 0.001); hypotension occurrence was 20% versus 47%, ( P 0.001), respectively, and bradycardia 6% versus 20%, ( P = 0.019), respectively. Compared with propofol, the patient satisfaction score was higher in the remimazolam group ( P 0.001).For sedation in ambulatory colonoscopy, compared with propofol, remimazolam provides a noninferior discharge time. Furthermore, remimazolam is associated with less injection pain, lower risks of hypotension and bradycardia, and improved patient satisfaction.Chinese Clinical Trial Registry, identifier: ChiCTR2100048678.

Background Several retrospective studies using administrative or single-center data have failed to show any difference between general anesthesia using propofol versus inhaled volatiles on long-term survival after breast cancer surgery. Although randomized controlled trials are ongoing, validated data from national clinical registries may advance the reliability of existing knowledge. Methods Data on breast cancer surgery performed under general anesthesia between 2013 and 2019 from the Swedish PeriOperative Registry and the National Quality Registry for Breast Cancer were record-linked. Overall survival was compared between patients receiving propofol and patients receiving inhaled volatile for anesthesia maintenance. Results Of 18,674 subjects, 13,873 patients (74.3%) received propofol and 4,801 (25.7%) received an inhaled volatile for general anesthesia maintenance. The two cohorts differed in most respects. Patients receiving inhaled volatile were older (67 yr vs. 65 yr), sicker (888 [19.0%] American Society of Anesthesiologists status 3 to 5 vs. 1,742 [12.8%]), and the breast cancer to be more advanced. Median follow-up was 33 months (interquartile range, 19 to 48). In the full, unmatched cohort, there was a statistically significantly higher overall survival among patients receiving propofol (13,489 of 13,873 [97.2%]) versus inhaled volatile (4,039 of 4,801 [84.1%]; hazard ratio, 0.80; 95% CI, 0.70 to 0.90; P < 0.001). After 1:1 propensity score matching (4,658 matched pairs), there was no statistically significant difference in overall survival (propofol 4,284 of 4,658 [92.0%]) versus inhaled volatile (4,288 of 4,658 [92.1%]; hazard ratio, 0.98; 95% CI, 0.85 to 1.13; P = 0.756). Conclusions Among patients undergoing breast cancer surgery under general anesthesia, no association was observed between the choice of propofol or an inhaled volatile maintenance and overall survival. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Sedation is often used to reduce pain and anxiety in pediatric patients with acute lymphoblastic leukemia (ALL) undergoing lumbar punctures (LPs). There is a potential for long-term effects on neurocognition with repeat sedative exposures in young children. The purpose of this study is to determine the practice habits regarding sedation for LPs in pediatric patients with ALL among multiple institutions.This is a retrospective study of 48 hospitals in the Pediatric Health Information Systems (PHIS) between October 2015 and December 2019. Children 1 to 18 years old with ALL who received intrathecal chemotherapy in an outpatient setting were included. We analyzed the prevalence of anesthesia usage and the types of anesthetics used.Of the 16,785 encounters with documented use of anesthetic medications, intravenous and inhaled anesthetics were used in 16,486 (98.2%) and local anesthetics alone in 299 (1.8%). The most commonly used medications used for sedation were propofol (n=13,279; 79.1%), midazolam (n=4228; 25.2%), inhaled fluranes (n=3169; 18.9%), and ketamine (n=2100; 12.5%).The majority of children's hospitals in the United States use intravenous and inhaled anesthetics for routine therapeutic LPs in pediatric patients with ALL. Propofol is one of the most common medications used for sedation.

Many outpatient gastrointestinal procedures are completed with propofol anesthesia. A side effect of propofol is airway obstruction and subsequent hypoxia. This study was designed to determine whether the use of a high-flow nasal cannula is associated with a decreased incidence of hypoxia or airway obstruction in patients undergoing propofol sedation in the gastrointestinal laboratory with a STOP-BANG score ≥5. High-flow nasal cannula was administered at 70 L/min on 27 patients with a STOP-BANG score ≥5 receiving monitored anesthesia care sedation for an esophagogastroduodenoscopy, endoscopic ultrasound, or colonoscopy procedure. Patients were compared to a group from a previous project without the use of high-flow nasal cannula assessing whether hypoxia, apnea, or the need for airway maneuvers occurred. The non-high-flow nasal cannula group required an airway maneuver 53.3% (n = 8) whereas the high-flow nasal cannula group required an airway maneuver 18.5% (n = 5) (p = .021). High-flow nasal cannula was associated with a reduced need for airway maneuvers in patients with a high risk of obstructive sleep apnea undergoing propofol-assisted procedures.

Background The wakeful brain can easily access and coordinate a large repertoire of different states—dynamics suggestive of “criticality.” Anesthesia causes loss of criticality at the level of electroencephalogram waveforms, but the criticality of brain network connectivity is less well studied. The authors hypothesized that propofol anesthesia is associated with abrupt and divergent changes in brain network connectivity for different frequencies and time scales—characteristic of a phase transition, a signature of loss of criticality. Methods As part of a previously reported study, 16 volunteers were given propofol in slowly increasing brain concentrations, and their behavioral responsiveness was assessed. The network dynamics from 31-channel electroencephalogram data were calculated from 1 to 20 Hz using four phase and envelope amplitude–based functional connectivity metrics that covered a wide range of time scales from milliseconds to minutes. The authors calculated network global efficiency, clustering coefficient, and statistical complexity (using the Jensen–Shannon divergence) for each functional connectivity metric and compared their findings with those from an in silico Kuramoto network model. Results The transition to anesthesia was associated with critical slowing and then abrupt profound decreases in global network efficiency of 2 Hz power envelope metrics (from mean ± SD of 0.64 ± 0.15 to 0.29 ± 0.28 absolute value, P < 0.001, for medium; and from 0.47 ± 0.13 to 0.24 ± 0.21, P < 0.001, for long time scales) but with an increase in global network efficiency for 10 Hz weighted phase lag index (from 0.30 ± 0.20 to 0.72 ± 0.06, P < 0.001). Network complexity decreased for both the 10 Hz hypersynchronous (0.44 ± 0.13 to 0.23 ± 0.08, P < 0.001), and the 2 Hz asynchronous (0.73 ± 0.08 to 0.40 ± 0.13, P < 0.001) network states. These patterns of network coupling were consistent with those of the Kuramoto model of an order–disorder phase transition. Conclusions Around loss of behavioral responsiveness, a small increase in propofol concentrations caused a collapse of long time scale power envelope connectivity and an increase in 10 Hz phase-based connectivity—suggestive of a brain network phase transition. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Ketamine anesthesia increased glucose metabolism in most brain regions compared to another intravenous anesthetic propofol. However, whether the changes in cerebral metabolic networks induced by ketamine share the same mechanism with propofol remains to be explored. The purpose of the present study was to identify specific features of metabolic network in rat brains during ketamine-induced subanesthesia state and anesthesia state compared to awake state.We acquired fluorodeoxyglucose positron emission tomography (FDG-PET) images in 20 healthy adult Sprague-Dawley rats that were intravenously administrated saline and ketamine to achieve different conscious states: awake (normal saline), subanesthesia (30 mg kg -1 h -1 ), and anesthesia (160 mg kg -1 h -1 ). Based on the FDG-PET data, the alterations in cerebral glucose metabolism and metabolic topography were investigated by graph-theory analysis.The baseline metabolism in rat brains was found significantly increased during ketamine-induced subanesthesia and anesthesia. The graph-theory analysis manifested a reduction in metabolism connectivity and network global/local efficiency across cortical regions and an increase across subcortical regions during ketamine-induced anesthesia (nonparametric permutation test: global efficiency between awake and anesthesia, cortex: P = .016, subcortex: P = .015; global efficiency between subanesthesia and anesthesia, subcortex: P = .012).Ketamine broadly increased brain metabolism alongside decreased metabolic connectivity and network efficiency of cortex network. Modulation of these cortical metabolic networks may be a candidate mechanism underlying general anesthesia-induced loss of consciousness.

Propofol has addictive properties, even with a single administration, and facilitates dopamine secretion in the nucleus accumbens (NAc). Activation of the dopaminergic circuits of the midbrain reward system, including the ventral tegmental area (VTA) and NAc, plays a crucial role in addiction. However, the effects of propofol on synaptic transmission and biochemical changes in the VTA-NAc circuit remain unclear.We investigated the effects of subanesthetic doses of propofol on rat VTA neurons and excitatory synaptic transmission in the NAc using slice patch-clamp experiments. Using immunohistochemistry and western blot analyses, we evaluated the effects of intraperitoneal propofol administration on the expression of addiction-associated transcription factor ΔFosB (truncated form of the FBJ murine osteosarcoma viral oncogene homolog B protein) in the NAcs in 5-week-old rats.In the current-clamp mode, a subanesthetic dose (0.5-5 µmol/L) of propofol increased the action potential frequency in about half the VTA neurons (excited neurons: control: 9.4 ± 3.0 Hz, propofol 0.5 µmol/L: 21.5 ± 6.0 Hz, propofol 5 µmol/L: 14.6 ± 5.3 Hz, wash: 2.0 ± 0.7 Hz, n = 14/27 cells; unchanged/suppressed neurons: control: 1.68 ± 0.94 Hz, propofol 0.5 µmol/L: 1.0 ± 0.67 Hz, propofol 5 µmol/L: 0.89 ± 0.87 Hz, wash: 0.16 ± 0.11 Hz, n = 13/27 cells). In the voltage-clamp mode, about half the VTA principal neurons showed inward currents with 5 µmol/L of propofol (inward current neurons: control: -20.5 ± 10.0 pA, propofol 0.5 µmol/L: -62.6 ± 14.4 pA, propofol 5 µmol/L: -85.2 ± 18.3 pA, propofol 50 µmol/L: -17.1 ± 39.2 pA, washout: +30.5 ± 33.9 pA, n = 6/11 cells; outward current neurons: control: -33.9 ± 14.6 pA, propofol 0.5 µmol/L: -29.5 ± 16.0 pA, propofol 5 µmol/L: -0.5 ± 20.9 pA, propofol 50 µmol/L: +38.9 ± 18.5 pA, washout: +40.8 ± 32.1 pA, n = 5/11 cells). Moreover, 0.5 µmol/L propofol increased the amplitudes of evoked excitatory synaptic currents in the NAc, whereas5 µmol/L propofol decreased them (control: 100.0 ± 2.0%, propofol 0.5 µmol/L: 118.4 ± 4.3%, propofol 5 µmol/L: 98.3 ± 3.3%, wash [within 10 min]: 70.7 ± 3.3%, wash [30 minutes later]: 89.9 ± 2.5%, n = 13 cells, P.001, Dunnett's test comparing control and propofol 0.5 µmol/L). Intraperitoneally administered subanesthetic dose of propofol increased ΔFosB expression in the NAc, but not in VTA, 2 and 24 hours after administration, compared with the Intralipid control group (propofol 2 hours: 0.94 ± 0.15, 24 hours: 0.68 ± 0.07; Intralipid 2 hours: 0.40 ± 0.03, 24 hours: 0.37 ± 0.06, P = .0002 for drug in the 2-way analysis of variance).Even a single administration of a subanesthetic dose of propofol may cause rewarding change in the central nervous system. Thus, there is a potential propofol rewarding effect among patients receiving anesthesia or sedation with propofol, as well as among health care providers exposed to propofol.

BACKGROUND The aim of the study was to investigate whether closed-loop compared to manual bispectral index (BIS)-guided target-controlled infusion of propofol and remifentanil could decrease the incidence of postoperative neurocognitive disorders after elective major noncardiac surgery. METHODS Patients aged >50 admitted for elective major noncardiac surgery were included in a single-blind randomized (ratio 2:1) trial. The anesthetic protocol was allocated by randomization into either closed-loop or manual BIS-guided propofol and remifentanil titration. The BIS target range was 40-60. All patients had cognitive assessment the day before surgery and within 72 hours after surgery using a battery of neuropsychological tests. The primary outcome was the rate of postoperative neurocognitive disorders. Postoperative neurocognitive disorders were defined as a decrease >20% from baseline on at least 3 scores. Intergroup comparison of the primary outcome was performed using the χ2 test. RESULTS A total of 143 and 61 patients were included in the closed-loop and manual groups, respectively (age: 66 [8] vs 66 [9] years). The primary outcome was observed in 18 (13%) and 10 (16%) patients of the closed-loop and manual groups, respectively (relative risk [95% confidence interval {CI}], 0.77 [0.38-1.57], P = .47). Intraoperative propofol consumption was lower (4.7 [1.4] vs 5.7 [1.4] mg·kg-1·h-1, mean difference [MD] [95% CI], -0.73 [-0.98 to -0.48], P < .0001) and the proportion of time within the BIS target range higher (84 [77-89] vs 74 [54-81]%, MD [95% CI], 0.94 [0.67-1.21], P < .0001) in the closed-loop group. CONCLUSIONS Closed-loop compared to manual BIS-guided total intravenous anesthesia provided a significant reduction in episodes of an excessive depth of anesthesia while decreasing intraoperative propofol requirement but no evidence for a reduction of the incidence of postoperative neurocognitive disorders after elective major noncardiac surgery was observed.

BACKGROUND Some older adults show exaggerated responses to drugs that act on the brain. The brain's response to anesthetic drugs is often measured clinically by processed electroencephalogram (EEG) indices. Thus, we developed a processed EEG-based measure of the brain's resistance to volatile anesthetics and hypothesized that low scores on it would be associated with postoperative delirium risk. METHODS We defined the Duke Anesthesia Resistance Scale (DARS) as the average bispectral index (BIS) divided by the quantity (2.5 minus the average age-adjusted end-tidal minimum alveolar concentration [aaMAC] inhaled anesthetic fraction). The relationship between DARS and postoperative delirium was analyzed in 139 older surgical patients (age ≥65) from Duke University Medical Center (n = 69) and Mt Sinai Medical Center (n = 70). Delirium was assessed by geriatrician interview at Duke, and by research staff utilizing the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) instrument at Mt Sinai. We examined the relationship between DARS and delirium and used the Youden index to identify an optimal low DARS threshold (for delirium risk), and its associated 95% bootstrap confidence bounds. We used multivariable logistic regression to examine the relationship between low DARS and delirium risk. RESULTS The relationship between DARS and delirium risk was nonlinear, with higher delirium risk at low DARS scores. A DARS threshold of 28.755 maximized the Youden index for the association between low DARS and delirium, with bootstrap 95% confidence bounds of 26.18 and 29.80. A low DARS (

Background Propofol and dexmedetomidine may cause hemodynamic adverse effects (AEs) and more data are needed in a trauma and surgical population. Objective The objective of this study was to evaluate the rate of hemodynamic AEs requiring an intervention between dexmedetomidine and propofol in a critically ill trauma and surgical population. Methods This was a retrospective cohort study at a Level 1 trauma center. Intensive care unit patients admitted from October 1, 2017, through October 31, 2018, were divided into two groups: dexmedetomidine or propofol. The primary end point was the proportion of patients who required a therapeutic intervention for a hemodynamic AE within the first 24 hr of initiation of dexmedetomidine or propofol. Results A total of 800 charts were reviewed and 85 patients (dexmedetomidine [n = 35] and propofol [n = 50]) were included. The study population consisted of Caucasian (86%) males (61%) with a median age of 61 [interquartile range-IQR 48, 72], and 18% and 24% required antihypertensive and vasopressor agents, respectively. No difference in the primary outcome was observed (17 [49%] vs. 27 [54%], p = .624). There was no difference in the overall incidence of hemodynamic AE (18 [51%] vs. 30 [60%], p = .433). Dexmedetomidine patients had a greater decrease in median heart rate (HR) compared with the propofol (23 [IQR 16, 41] vs. 14 [IQR 5, 24] beats/min, p = .002). Conclusions The rate of hemodynamic AEs requiring therapeutic interventions was similar between dexmedetomidine and propofol in a critically ill trauma and surgical population; however, dexmedetomidine may be associated with a larger decrease in HR.

BACKGROUND The cough reflex or aspiration under monitored anaesthesia care might be associated with sedative-induced changes in swallowing and intra-oral water-retaining abilities. OBJECTIVES To investigate the effects of moderate propofol sedation on swallowing and intra-oral water-retaining ability. DESIGN Prospective observational study. SETTING Single tertiary care centre during 2017. PARTICIPANTS A total of 13 healthy adult volunteers. INTERVENTION Volunteers in the supine position were asked to retain 10 ml of orally injected water for 5 min. After 5 minutes or when the water was spontaneously swallowed, the retention time and residual intra-oral water volume were measured. Subjects then voluntarily swallowed a further 10 ml of injected water and the residual water volume was measured. This whole process was repeated under sedation with propofol at effect-site concentrations of 0.5, 1.0 and 1.5 μg ml-1. MAIN OUTCOME MEASURES The primary outcome was the estimated volume swallowed (swallowing volume); the secondary outcome was water retention time. RESULTS Median water retention time decreased from 300 to 11 s (P

Deep sedation/general anesthesia is commonly used in pediatric oncoclogy patients undergoing lumbar puncture (LP). Propofol is often used for sedation, with or without a narcotic. We hypothesized that eutectic mixture of lidocaine and prilocaine (EMLA) would allow for lower cumulative doses of propofol and less movement. We performed a prospective, randomized, double blind, placebo-controlled trial in children undergoing sedation for LP. Standard initial weight-based doses of propofol and fentanyl were administered, with either EMLA cream or a placebo cream applied topically. The primary outcome was the total dose of propofol administered to each patient. We also tracked patient movement and complications. Twenty-seven patients underwent 152 LPs. Patients randomized to EMLA cream (n = 75) were significantly more likely to receive a lower dose of propofol (2.94 mg/kg, SE = 0.25, versus 3.22 mg/kg, SE = 0.19; p = 0.036) and to not require additional propofol doses (probability 0.49, SE = 0.08 versus 0.69, SE = 0.06; p = 0.001) compared to patients randomized to placebo cream (n = 77). In addition, patients with EMLA cream were significantly less likely to demonstrate minor or major movement. EMLA cream results in less movement and less propofol administration in pediatric oncology patients undergoing sedation for LP.

Objective This study was to detect the protective effects of Houttuynia cordata extract on the damage induced by propofol in hippocampal neuron of rats. Methods Propofol-induced neuron injury model and H. cordata extract administration were conducted. Immunofluorescence and immunoblot were conducted for the effect of H. cordata extract on neuronal activity and inflammation were detected in this model. Results H. cordata extracts increased neuronal activity, and reduced propofol-induced neuronal inflammation levels. H. cordata extract also reduced propofol-induced neuronal apoptosis. Mechanically, we noticed H. cordata extract activated phosphoinositide 3-kinase/AKT pathway and suppressed Toll-like receptor 4/nuclear factor kappaB pathway, therefore protected propofol-induced injury of rat hippocampal neurons. Conclusion Our findings provide references for anesthetic use in infants and young children.

Background Several options exist for induction agents during rapid sequence intubation (RSI) in trauma patients, including etomidate, ketamine, and propofol. These drugs have reported variable hemodynamic effects (hypotension with propofol and sympathomimetic effects with ketamine) that could affect trauma resuscitations. The purpose of this study was to compare the hemodynamic effects of these three induction agents during emergency department RSI in adult trauma. We hypothesized that these drugs would display a differing hemodynamic profile during RSI. Methods We performed a retrospective (2014-2019), multicenter trial of adult (≥18 years) trauma patients admitted to eight ACS-verified Level I trauma centers who underwent emergency department RSI. Variables collected included systolic blood pressure (SBP) and pulse before and after RSI. The primary outcomes were change in heart rate and SBP before and after RSI. Results There were 2,092 patients who met criteria, 85% received etomidate (E), 8% ketamine (K), and 7% propofol (P). Before RSI, the ketamine group had a lower SBP (E, 135 vs. K, 125 vs. P, 135 mm Hg, p = 0.04) but there was no difference in pulse (E, 104 vs. K, 107 vs. P, 105 bpm, p = 0.45). After RSI, there were no differences in SBP (E, 135 vs. K, 130 vs. P, 133 mm Hg, p = 0.34) or pulse (E, 106 vs. K, 110 vs. P, 104 bpm, p = 0.08). There was no difference in the average change of SBP (E, 0.2 vs. K, 5.2 vs. P, -1.8 mm Hg, p = 0.4) or pulse (E, 1.7 vs. K, 3.5 bpm vs. P, -0.96, p = 0.24) during RSI. Conclusion Contrary to our hypothesis, there was no difference in the hemodynamic effect for etomidate versus ketamine versus propofol during RSI in trauma patients. Level of evidence Therapeutic, Level IV.

Aim The aim of the study is to investigate the influence of endosonographer experience and patient-related factors on the dose of sedation and sedation-related complications during endoscopic ultrasound (EUS). Methods Our retrospective analysis included EUS investigations performed between 2015 and 2018 at our institution. Sedation-related complications were defined as cardiorespiratory instability with oxygen saturation drop below 90% or prolonged low blood pressure or bradycardia. Results In total, 537 EUS examinations were analyzed (37.3% interventional). The median dose of propofol and midazolam were: 140 (30-570) and 3(1-7) mg, respectively. Sedation-related complications were documented in 1.8% of cases. All patients had transient, nonfatal respiratory insufficiency. Totally, 60% of the patients who developed complications were >75 years and 70% were male. The presence of cardiac and/or pulmonary comorbidities was associated with an OR = 8.77 [95% confidence interval (CI), 1.8-41.7] and American Society of Anesthesiologists class III with an OR = 7.64 (95% CI, 1.60-36.3) for the occurrence of sedation-related complications. Endosonographer experience did not influence the rate of sedation-related complications. In both diagnostic and interventional EUS, patients with comorbidities and older age received significantly less sedation. Experienced endosonographers used less sedation than trainees. Conclusion Endosonographer experience, patient age and the presence of comorbidities had a significant influence on sedation dose. Sedation-related complications occurred only in 1.8% of cases.

Background The purpose of this study was to determine the efficacy of a mandibular advancement device (MAD) for increasing patient safety during sedated total knee arthroplasty (TKA) and total hip replacement (THR). Methods Forty patients undergoing TKA or THR surgery in the supine or lateral recumbent positions under spinal anesthesia were enrolled. Sedation and oxygenation were administered. The MAD (Sweet Sleep Anti-Snoring Device®) was then placed after 15 min of observation. SpO2, PetCO2, blood pressure, and respiratory rate were recorded. Results Sedated patients in the decubitus position had higher saturation nadirs, shorter desaturation durations, shorter airway obstruction durations, and fewer rescue events than those in the supine position. In patients at a high risk of obstructive sleep apnea syndrome (OSAS), desaturation duration, obstruction duration, apnea duration, desaturation duration, and rescue events were significantly lower after MAD placement. However, the saturation nadir did not improve after MAD placement. Conclusion The MAD may shorten the duration of desaturation events during spontaneous breathing sedative procedures in the lateral recumbent position but not in the supine position. Breathing patterns did not change from nasal breathing to oral breathing or vice versa between pre- and post-placement of the MAD. Sedation score evaluation affects breathing pattern changes from oral breathing to nasal breathing and vice versa.

Introduction The incidence and quantification of inadvertent electroencephalographic burst suppression during total intravenous anesthesia (TIVA) for spine instrumentation surgery has not previously been reported. Methods The primary aim of this retrospective observational quality improvement project was to establish the prevalence of burst suppression during spine instrumentation surgery with TIVA. The secondary outcome was the incidence of postoperative delirium. Results One hundred twelve consecutive patients, aged between 20 and 88 years, underwent spinal instrumentation surgery. Seventy-eight (69.6%) patients experienced inadvertent burst suppression; the maximal degree of burst suppression ratio was 20% to 100%. Median (interquartile range [IQR]) time spent in burst suppression was 44 (77) minutes, and burst suppression was present for 22% (range: 2% to 93%) of the monitoring period. Average (±SD) propofol dose was lower in patients with burst suppression (87±19 vs. 93±15 µg/kg/min, P=0.04). Ten (8.9%) patients experienced postoperative delirium. Intraoperative burst suppression was more prevalent in those that experienced delirium (100% vs. 66.7%, P=0.03, relative risk: 1.5, 95% confidence interval: 1.3-1.7). The proportion of the monitoring period spent in maximal burst suppression (15.3 [25.9]% vs.11.7 [21.7]%) was similar between those that did, and did not, experience delirium. Conclusions High rates and prolonged periods of inadvertent burst suppression may be prevalent during spine instrumentation surgery with TIVA. Our findings suggest that usage of electroencephalography alone is incomplete without prompt interpretation and intervention, mandating close communication between neuromonitoring and anesthesia teams. The dose-response relationship between burst suppression, total time spent in maximal burst suppression, and their association with delirium warrants further evaluation.

Diabetes insipidus (DI) is an uncommon perioperative complication that can occur secondary to medications or surgical manipulation and can cause significant hypovolemia and electrolyte abnormalities. We reviewed and evaluated the current literature and identified 24 cases of DI related to medications commonly used in anesthesia such as propofol, dexmedetomidine, sevoflurane, ketamine, and opioids. This review summarizes the case reports and frequency of DI with each medication and presents possible pathophysiology. Medication-induced DI should be included in the differential diagnosis when intraoperative polyuria is identified. Early identification, removal of the agent, and treatment of intraoperative DI are critical to minimize complications.

Background The glycocalyx plays an important physiological role and may be damaged during cardiopulmonary bypass. Sevoflurane can protect the glycocalyx; however, its relevance in a clinical setting is unknown. Objective Glycocalyx degradation during cardiopulmonary bypass in patients was investigated. On the basis of the available experimental data, we hypothesised that sevoflurane-based anaesthesia would confer additional protection against cardiopulmonary bypass-induced glycocalyx damage. Design Randomised controlled study. Setting Clinical study at The First Affiliated Hospital of Wenzhou Medical University between June 2018 and March 2019. Patients Fifty-one patients. Interventions After intubation and mechanical ventilation, patients undergoing elective heart valve surgery were maintained under general anaesthesia with either propofol or sevoflurane during surgery. Main outcome measures Glycocalyx markers (such as syndecan-1, heparan sulphate and hyaluronan), sheddases responsible for the degradation of the endothelial glycocalyx (such as matrix metalloproteinase-9 and cathepsin-B), urine albumin-to-creatinine ratio and levels of lactic acid and myocardial enzymes were all measured. Postoperative mechanical ventilation time and length of stay in the cardiac care unit and hospital were also measured. Morbidity and mortality after 30 days and 1 year were evaluated. Results The vascular endothelial glycocalyx was damaged during cardiopulmonary bypass. The glycocalyx damage in the sevoflurane group was less extensive than that in the propofol group. The urine albumin-to-creatinine ratio increased in both groups but was lower in the sevoflurane group. Enzymes including matrix metalloproteinase-9 and cathepsin-B were positively correlated with glycocalyx marker concentrations. After operation, the sevoflurane group showed lower levels of lactic acid and myocardial enzyme, as well as shorter duration of postoperative mechanical ventilation than the propofol group. Conclusion Sevoflurane can decrease glycocalyx degradation in patients undergoing heart valve surgery under cardiopulmonary bypass. Trial registration Chinese Clinical Trial Registry, chictr.org.cn, identifier: ChiCTR1800016367.

BACKGROUND Diastolic dysfunction is a risk factor for postoperative major cardiovascular events. During anesthesia, patients with diastolic dysfunction might experience impaired hemodynamic function and worsening of diastolic function, which in turn, might be associated with a higher incidence of postoperative complications.We aimed to investigate whether patients with diastolic dysfunction require higher doses of norepinephrine during general anesthesia. Furthermore, we aimed to examine the association between the grade of diastolic dysfunction and the E/e' ratio during anesthesia. A high E/e' ratio corresponds to elevated filling pressures and is an important measure of impaired diastolic function. METHODS We conducted a prospective observational cohort study at a German university hospital from February 2017 to September 2018. Patients aged ≥60 years and undergoing general anesthesia (ie, propofol and sevoflurane) for elective noncardiac surgery were enrolled. Exclusion: mitral valve disease, atrial fibrillation, and implanted mechanical device.The primary outcome parameter was the administered dose of norepinephrine within 30 minutes after anesthesia induction (μg·kg-1 30 min-1). The secondary outcome parameter was the change of Doppler echocardiographic E/e' from ECHO1 (baseline) to ECHO2 (anesthesia). Linear models and linear mixed models were used for statistical evaluation. RESULTS A total of 247 patients were enrolled, and 200 patients (75 female) were included in the final analysis. Diastolic dysfunction at baseline was not associated with a higher dose of norepinephrine during anesthesia (P = .6953). The grade of diastolic dysfunction at baseline was associated with a decrease of the E/e' ratio during anesthesia (P < .001). CONCLUSIONS We did not find evidence for an association between diastolic dysfunction and impaired hemodynamic function, as expressed by high vasopressor support during anesthesia. Additionally, our findings suggest that diastolic function, as expressed by the E/e' ratio, does not worsen during anesthesia.

SUMMARY A major complication of surgical scoliosis correction is permanent injury of the spinal cord. Intraoperative neuromonitoring continually evaluates spinal cord function through monitoring sensory and corticospinal motor tracts. There is no literature or manufacturer recommendation on whether transcranial motor evoked potential (tcMEP) monitoring can be performed safely in the presence of a deep brain stimulator (DBS) system. A 17-year-old adolescent boy with severe neuromuscular scoliosis presented for a posterior spinal fusion. The patient suffered from generalized dystonia treated with a DBS terminating in the left and right globus pallidus internus. The competing goals of monitoring motor function during the spinal fusion and preserving the integrity of the DBS system were discussed preoperatively. The DBS system was deactivated for the duration of surgery, and tcMEPs were used sparingly at the lowest suitable stimulation voltage. Intraoperative management focused on facilitating neurophysiologic monitoring through a total intravenous anesthetic of propofol, methadone, and remifentanil. The tcMEPS remained unchanged throughout the operation and the patient emerged able to move his lower extremities to command. Postoperatively, the DBS system was turned back on and showed retained settings, normal functioning, and unchanged impedance of the DBS leads. Neither the patient nor his parents reported any subjective changes in the symptoms of dystonia. The authors conclude that monitoring tcMEPs in the presence of a DBS implant may be done safely, when the clinical circumstances suggest that the added information gained from tcMEPs outweighs the theoretical risk to the DBS system and the course of the medical condition treated by the DBS.

Objective The aim of the study was to evaluate, in children undergoing procedural sedation for magnetic resonance imaging (MRI) scans, whether lower doses of propofol than previously published permitted a high rate of successful MRI completion, whether lower dosages result in a more rapid recovery, and whether age or behavioral diagnosis increases propofol requirements. Methods After institutional review board approval, we retrospectively reviewed the pediatric sedation team's sedation database of children receiving propofol infusion for MRI scans between 2007 and 2016. Data collected included propofol induction dose (in milligrams per kilogram), propofol infusion dose (in micrograms per kilogram per hour), total propofol dose (in milligrams per kilogram and in milligrams per kilogram per hour), and the number of administered ancillary sedative medications. Additional data included the American Society of Anesthesiologist status, sedation duration, recovery duration, and successful completion of MRI. Dosing data were also stratified by age. Results A total of 2354 patients met inclusion criteria. Eight percent of patients received propofol infusion alone, 79% received midazolam before their propofol induction, and 13% received a combination of propofol and other drugs. Mean induction dose was 2.2 + 0.9 mg/kg, mean infusion dose was 93.5 + 29.0 μg/kg per minute, and total mean dose was 9.0 + 3.0 mg/kg per hour. Mean recovery time was 44 minutes, and 99.3% of the scans were completed with good images. We noted an increase requirement in the mean induction dose and total dose in children younger than 1 year. Conclusions Propofol infusion doses lower than commonly reported permit successful completion of scans and similar recovery times in a single institution. Younger children require more propofol for successful procedural sedation.

Background Whether propofol elicits a survival benefit over volatile anesthetics during cancer surgery remains inconclusive. The primary aim of this systematic review and meta-analysis is to compare the effects of propofol-based total intravenous anesthesia (TIVA) with any volatile anesthesia on long-term oncological outcomes. The secondary aim is to compare propofol-based TIVA with specific volatile agents on long-term oncological outcomes. Methods We searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library from inception through March 3, 2020. Randomized control trials and observational studies that compared the effects of propofol-based TIVA and volatile anesthesia on long-term oncological outcomes, which also reported hazard ratios (HR) as effect estimates, were considered eligible for inclusion. Using the inverse variance method with a random-effects model, HR and 95% confidence intervals (CI) were calculated. Trial sequential analysis was incorporated to test if the results were subject to a type I or type II error. Results Nineteen retrospective observational studies were included. Patients who received propofol-based TIVA during cancer surgery were associated with significantly better overall survival than those who received volatile anesthesia (HR = 0.79, 95% CI, 0.66-0.94, P = .008, I2 = 82%). In contrast, no statistically significant difference was observed in recurrence-free survival between patients who received propofol-based TIVA and volatile anesthesia during cancer surgery (HR = 0.81, 95% CI, 0.61-1.07, P = .137, I2 = 85%). In the subgroup analysis by different volatile anesthetics, patients who received propofol-based TIVA were associated with better overall survival than those who received desflurane (HR = 0.54, 95% CI, 0.36-0.80, P = .003, I2 = 80%). In contrast, there was no statistically significant difference in overall survival between patients who received propofol-based TIVA and those who received sevoflurane (HR = 0.92, 95% CI, 0.74-1.14, P = .439, I2 = 70%). In the trial sequential analysis of overall survival, the cumulative Z curve reached the required heterogeneity-adjusted information size and crossed the traditional significance boundary. In contrast, in the trial sequential analysis of recurrence-free survival, the cumulative Z curve did not cross the traditional significance boundary. However, the required heterogeneity-adjusted information size has not yet been reached. Conclusions Propofol-based TIVA is generally associated with better overall survival than volatile anesthesia during cancer surgery. Further large-scaled, high-quality randomized control trials are warranted to confirm our findings.

Background Endoscopic retrograde cholangiopancreatography (ERCP) patients typically receive either tubeless anesthesia or general endotracheal anesthesia (GETA). Patients receiving propofol-based total intravenous anesthesia (TIVA) are at higher risk of sedation-related adverse events (SRAEs) than patients receiving GETA, primarily due to the need for additional airway maneuvers. The increasing use of non-operating room (OR) anesthesia and the perception of a higher incidence of adverse outcomes in non-OR areas has led to the development of devices to improve safety while maintaining efficiency. The purpose of this study was to evaluate if the LMA Gastro™ could be used as a safe alternative to tubeless anesthesia for successfully completing ERCPs. Methods Eligible subjects were identified within the patient population at MD Anderson Cancer Center. Inclusion criteria consisted of adult patients (≥18 years old) scheduled for elective ERCP with TIVA. This was a prospective observational study in which the following data were collected: number of attempts and time to successful supraglottic airway (SGA) placement, vital signs, peripheral oxygen saturation (SpO2), median end-tidal CO2, practitioner satisfaction, and any complications. Results A total of 30 patients were included in this study. The overall rate of successful SGA placement within 3 attempts was 96.7% (95% confidence interval [CI], 82.8-99.9) or 29/30. The rate of successful ERCP with SGA placement within 3 attempts was 93.3% (95% CI, 77.9-99.2) or 28/30. Both the gastroenterologist and anesthesiologist reported satisfaction with the device in 90% of the cases (in 66.7% of the cases both anesthesiologist and gastroenterologist scored the device a 7/7 for satisfaction). Patients maintained an SpO2 of 95%-100% from induction to discharge, with the exception of 1 patient who had an SpO2 of 93%. The median end-tidal CO2 during the procedure for all patients was 35 mm Hg. Observed aspiration did not occur in any patient. Symptoms of hoarseness (13.3%), mouth soreness (6.7%), sore throat (6.6%), and minor bleeding/cuts/redness/change in taste to the tongue (3.3%) were determined through patient questioning before postanesthesia care unit (PACU) discharge. Conclusions Our study suggests that the LMA Gastro might be a safe alternative for ERCP procedures. There was a high level of practitioner satisfaction. Only minor complications, such as hoarseness, mouth or throat soreness, or minor trauma to the tongue were experienced by patients. Similar incidences of complications may occur with GETA and tubeless anesthesia. The procedure was well tolerated by all patients; all patients maintained adequate oxygenation and required only minimal blood pressure support.

ObjectivePediatric dystonic storm is an underrecognized entity. We aimed to evaluate the profiles of children presenting with dystonic storm in a referral hospital. Management schema and treatment responsiveness of this uncommonly reported entity were analyzed.MethodsRetrospective review of all children (up to 18 years) hospitalized with dystonic storm over 39 months in the aforementioned facility.ResultsTwenty-three children whose ages ranged from 2 years 2 months to 14 years 4 months years (median: 6 years 11 months) (males: 13, females: 11) presented with dystonic storm. The annual incidence was 0.4 per 1,000 fresh admissions with an event rate of 0.9 per 1,000 for all admissions. All had Dystonia Severity Action Plan grades 4/5 with identifiable trigger in 13 (50%). Underlying dystonic disorder preexisted in 10 (43.4%); 8 of these had cerebral palsy. Polypharmacotherapy with >4 drugs out of trihexyphenidyl, tetrabenazine, clonazepam, gabapentin, levodopa-carbidopa, trichlorophos, and melatonin was needed. Supportive care and adequate sedation helped in symptom control. All children were managed with midazolam infusion over 2–10 days (median: 5 days). Mechanical ventilation was resorted to in 6 children (3–22 days). Vecuronium and propofol were used in 3/23 (13%) and 4/23 (17%) children, respectively. Deep brain stimulation was curative in 1 child. Hospitalization ranged from 5 to 31 (median: 11) days. Although there were no deaths, rhabdomyolysis was noted in 1 child. Postdischarge, 6 (26%) children relapsed.ConclusionsDystonic storm is a medical emergency mandating aggressive multimodal management. Supportive care, antidystonic drugs, and early elective ventilation alongside adequate sedation with benzodiazepines ameliorate complications. Relapses of dystonic storm are not uncommon.

Propofol anesthesia rapidly causes loss of consciousness, while the neural mechanism underlying this phenomenon is still unclear. Glutamatergic neurons in the basal forebrain play an important role in initiation and maintenance of wakefulness. Here, we selectively recorded the activity of glutamatergic neurons in vGlut-2-Cre mice. Propofol induced outward currents in a concentration-dependent manner. Bath application of propofol generated membrane hyperpolarization and suppressed the firing rates in these neurons. Propofol-induced stable outward currents persisted after blockade of the action potentials, implying a direct postsynaptic effect of propofol. Furthermore, propofol selectively increased the GABAergic inhibitory synaptic inputs via affecting the GABAARs, but did not affect the glutamatergic transmissions. Together, propofol inhibits the excitability of the glutamatergic neurons via direct influencing the membrane intrinsic properties and the inhibitory synaptic transmission. This inhibitory effect might provide a novel mechanism for the propofol-induced anesthesia.

Background Previous studies have suggested that monitoring the levels of both hypnosis and antinociception could reduce periods of inadequate anaesthesia. However, the evidence regarding associated benefits of this monitoring is still limited. Objective The primary objective of this study was to confirm that guidance of anaesthesia by depth of hypnosis and antinociception monitoring decreases the number of inadequate anaesthesia events in comparison with standard clinical practice. Design A multicentre, single-blinded, randomised controlled trial. Setting The study was conducted in four European University hospitals in four different countries between December 2013 and November 2016. Patients The study population consisted of a total of 494 adult patients undergoing elective surgery requiring tracheal intubation. Interventions The patients were allocated to one of two groups. The first group was treated using Entropy for depth of hypnosis and surgical pleth index to determine depth of antinociception (adequacy of anaesthesia group; AoA group). The second group was monitored using standard monitoring alone (control group). Anaesthesia was conducted with target-controlled infusions of propofol and remifentanil. Main outcome measures The primary outcome of the study was the number of total unwanted events for example signs of inadequately light or unintentionally deep anaesthesia. Results Evidence of inadequate anaesthesia had an incidence of around 0.7 events per patient in both groups with no difference between groups (P = 0.519). In the AoA group, the overall consumption of propofol was significantly reduced (6.9 vs. 7.5 mg kg h, P = 0.008) in comparison with the control group. The consumption of remifentanil was equal in both groups. The times to emergence [8.0 vs. 9.6 min (P = 0.005)] and full recovery in the postanaesthesia care unit (P = 0.043) were significantly shorter in the AoA group. No differences were seen in postoperative pain scores or in the use of analgesics. Conclusion In the current study, the guidance of total intravenous anaesthesia by Entropy and surgical pleth index in comparison with standard monitoring alone was not able to validate reduction of unwanted anaesthesia events. However, there was a reduction in the use of propofol, and shorter times for emergence and time spent in the postanaesthesia care unit. Trial registration at ClinicalTrials.gov NCT01928875.

Background The anesthetic management of supratentorial craniotomy (CR) necessitates tight intraoperative hemodynamic control. This type of surgery may also be associated with substantial postoperative pain. We aimed at evaluating the influence of regional scalp block (SB) on hemodynamic stability during the noxious events of supratentorial craniotomies and total intravenous anesthesia, its influence on intraoperative anesthetic agents' consumption, and its effect on postoperative pain control. Methods Sixty patients scheduled for elective CR were prospectively enrolled. Patient, anesthesiologist, and neurosurgeon were blind to the random performance of SB with either levobupivacaine 0.33% (intervention group [group SB], n = 30) or the same volume of saline (control group [group CO], placebo group, n = 30). General anesthesia was induced and maintained using target-controlled infusions of remifentanil and propofol that were adjusted according to hemodynamic parameters and state entropy of the electroencephalogram (SE), respectively. Mean arterial blood pressure (MAP), heart rate (HR), SE, and propofol and remifentanil effect-site concentrations (Ce) were recorded at the time of scalp block performance (Baseline), and 0, 1, 3, and 5 minutes after skull-pin fixation (SP), skin incision (SI), CR, and dura-mater incision (DM). Morphine consumption and postoperative pain intensity (0-10 visual analog scale [VAS]) were recorded 1, 3, 6, 24, and 48 hours after surgery. Propofol and remifentanil overall infusion rates were also recorded. Data were analyzed using 2-tailed Student unpaired t tests, 2-way mixed-design analysis of variance (ANOVA), and Tukey's honestly significant difference (HSD) tests for post hoc comparisons as appropriate. Results Demographics and length of anesthetic procedure of group CO and SB were comparable. SP, SI, and CR were associated with a significantly higher MAP in group CO than in group SB, at least at one of the time points of recording surrounding those noxious events. This was not the case at DM. Similarly, HR was significantly higher in group CO than in group SB during SP and SI, at least at 1 of the points of recording, but not during CR and DM. Propofol and remifentanil Ce and overall infusion rates were significantly higher in group CO than in group SB, except for propofol Ce during SP. Postoperative pain VAS and cumulative morphine consumption were significantly higher in group CO than in group SB. Conclusions In supratentorial craniotomies, SB improves hemodynamic control during noxious events and provides adequate and prolonged postoperative pain control as compared to placebo.

BACKGROUND The electroencephalogram (EEG) may be useful for monitoring anesthetic depth and avoiding overdose. We aimed to characterize EEG-recorded brain oscillations during increasing depth of anesthesia in a real-life surgical scenario. We hypothesized that alpha power and coherency will diminish as propofol dose increases between loss of consciousness (LOC) and an EEG burst suppression (BS) pattern. METHODS This nonrandomized dose-response clinical trial with concurrent control included EEG monitoring in 16 patients receiving slowly increasing doses of propofol. We assessed 3 intraoperative EEG segments (LOC, middle-dose, and BS) with spectral analysis. RESULTS Alpha band power diminished with each step increase in propofol dose. Average alpha power and average delta power during the BS step (-1.4±3.8 and 6.2±3.1 dB, respectively) were significantly lower than during the LOC step (2.8±2.6; P=0.004 and 10.1±5.2 dB; P=0.03, respectively). Peak alpha power was significantly higher during the LOC (5.4±2.6 dB) compared with middle-dose (2.6±3.6; P=0.04) and BS (0.7±3.2; P=0.0002) steps. In addition, as propofol dose increased, alpha band coherence between the F7 and F8 electrodes decreased, whereas delta band coherence exhibited a biphasic response (initial increase between LOC and middle-dose steps and decrease between middle-dose and BS steps). CONCLUSION We report compelling data regarding EEG patterns associated with increases in propofol dose. This information may more accurately define "therapeutic windows" for anesthesia and provide insights into brain dynamics that are sequentially affected by increased anesthetic doses.

Background Propofol and dexmedetomidine are used separately, and sometimes together, for paediatric deep sedation. Although their combination has been described in adults, the effect of dexmedetomidine as a potential synergist in children has not been studied before. Objectives The primary objective was to compare the propofol requirements of children who receive propofol alone with those who receive it in combination with dexmedetomidine for deep sedation for upper and lower endoscopic gastrointestinal procedures. Design This was a prospective, open-label, randomised study comparing patients who received propofol alone (group P) with those who received dexmedetomidine and propofol (group DP). The depth of sedation was titrated to a target bispectral (BIS) index. Setting A Gastroenterology Procedure Unit at a single, tertiary care academic medical centre from April 2018 until December 2019. Patients Eligible patients were scheduled for upper endoscopy, lower endoscopy or both. A total of 39 patients were enrolled (20 DP) and (19 P). Interventions Patients in Group DP received dexmedetomidine 0.5 μg kg administered over 1 min followed by an infusion of 0.15 μg kg h. In both groups, intravenous propofol was given in bolus increments titrated to a BIS index of 40 to 50 and then a continuous infusion of propofol to maintain BIS at 40 to 50. Main outcome measures The primary outcome measure was propofol requirement in each group. Secondary outcome measures were time to achieve the targeted sedation depth, time to achieve an Aldrete recovery score of 9, duration of sedation, mean BIS values, adverse events, 'PAED' scores and time to discharge from the postanaesthesia care unit (PACU). Results The median (range) total dose of propofol was 0.23 (0.10 to 0.50) mg kg min in group DP and 0.40 (0.20 to 0.50) mg kg min in group P (P = 0.0004). Time of discharge from the PACU was 60 (20 to 121) min in group DP and 63 (46 to 91) min in group P (P = 0.0409). Conclusion The combination of dexmedetomidine and propofol for paediatric procedural sedation achieved a significant reduction in median propofol dose and a slightly shorter median time to discharge from PACU. Large-scale studies may determine whether this reduction decreases the risk of significant adverse events. Trial registration ClinicalTrials.gov identifier NCT02952222.

Background Volatile anesthetics moderately depress respiratory function at clinically relevant concentrations. Phox2b-expressing chemosensitive neurons in the retrotrapezoid nucleus, a respiratory control center, are activated by isoflurane, but the underlying mechanisms remain unclear. The hypothesis of this study was that the sodium leak channel contributes to the volatile anesthetics-induced modulation of retrotrapezoid nucleus neurons and to respiratory output. Methods The contribution of sodium leak channels to isoflurane-, sevoflurane-, and propofol-evoked activity of Phox2b-expressing retrotrapezoid nucleus neurons and respiratory output were evaluated in wild-type and genetically modified mice lacking sodium leak channels (both sexes). Patch-clamp recordings were performed in acute brain slices. Whole-body plethysmography was used to measure the respiratory activity. Results Isoflurane at 0.42 to 0.50 mM (~1.5 minimum alveolar concentration) increased the sodium leak channel–mediated holding currents and conductance from −75.0 ± 12.9 to −130.1 ± 34.9 pA (mean ± SD, P = 0.002, n = 6) and 1.8 ± 0.5 to 3.6 ± 1.0 nS (P = 0.001, n = 6), respectively. At these concentrations, isoflurane increased activity of Phox2b-expressing retrotrapezoid nucleus neurons from 1.1 ± 0.2 to 2.8 ± 0.2 Hz (P < 0.001, n = 5), which was eliminated by bath application of gadolinium or genetic silencing of sodium leak channel. Genetic silencing of sodium leak channel in the retrotrapezoid nucleus resulted in a diminished ventilatory response to carbon dioxide in mice under control conditions and during isoflurane anesthesia. Sevoflurane produced an effect comparable to that of isoflurane, whereas propofol did not activate sodium leak channel–mediated holding conductance. Conclusions Isoflurane and sevoflurane increase neuronal excitability of chemosensitive retrotrapezoid nucleus neurons partly by enhancing sodium leak channel conductance. Sodium leak channel expression in the retrotrapezoid nucleus is required for the ventilatory response to carbon dioxide during anesthesia by isoflurane and sevoflurane, thus identifying sodium leak channel as a requisite determinant of respiratory output during anesthesia of volatile anesthetics. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Intraoperative monitoring with pupillometry has shown promising results for nociception/antinociception balance monitoring. However, its benefits in clinical practice remain unproven. The aim of this study was to evaluate the efficacy of intraoperative pupillometry monitoring on intraoperative opioid consumption and postoperative pain compared to surgical pleth index (SPI), another widely investigated monitoring.American Society of Anesthesiologists (ASA) I-II patients scheduled for elective laparoscopic cholecystectomy were included. This prospective, parallel-arm, single-center study was conducted in 2 steps. First, we evaluated the feasibility of using pupillometry and SPI monitoring compared with conventional hemodynamic monitoring. Next, a parallel-arm, double-blind randomized study compared the peak postoperative pain measured with numerical rating scale (NRS) from 0 (no pain) to 10 (extreme pain) as a primary outcome between pupillometry (pupillometry group, n = 43) and SPI monitoring (SPI group, n = 43) using Mann-Whitney U test. Secondary outcomes included intraoperative remifentanil consumption, postoperative opioid responsiveness (a decrease in NRS by ≥1 after fentanyl administrations), number of analgesic administrations, and opioid-related complications.In the preliminary study (n = 50), remifentanil consumption was less under pupillometry monitoring compared to SPI monitoring, and peak postoperative pain was lower under pupillometry compared to conventional monitoring. In the main study (n = 86), peak postoperative pain and intraoperative remifentanil consumption were lower in the pupillometry group (median [first to third quartile], 5 [4-6]; mean ± standard deviation [SD], 0.078 ± 0.019 μg·kg·minute) compared to the SPI group (7 [5-8] and 0.0130 ± 0.051 μg·kg·minute; P.001), with the median difference in peak postoperative pain of -1 and its 95% confidence interval between -2 and -0.5. The pupillometry group had better responsiveness to fentanyl (84.6% vs 61.0%; P = .005) and lower number of analgesic administrations (2 [1-2] vs 2 [1-3]; P = .048) compared to the SPI group.Intraoperative pupillometry monitoring reduced intraoperative remifentanil consumption and postoperative pain. It may be an alternative option for intraoperative opioid control under general anesthesia in adult patients.

Background Previous experimental and clinical studies have shown that anesthetic agents have varying effects on cancer prognosis; however, the results were inconsistent among these studies. The authors compared overall and recurrence-free survival in patients given volatile or intravenous anesthesia for digestive tract cancer surgery. Methods The authors selected patients who had elective esophagectomy, gastrectomy, hepatectomy, cholecystectomy, pancreatectomy, colectomy, and rectal cancer surgery from July 2010 to March 2018 using the Japanese Diagnosis Procedure Combination database. Patients were divided into a volatile anesthesia group (desflurane, sevoflurane, or isoflurane with/without nitrous oxide) and a propofol-based total intravenous anesthesia group. The authors hypothesized that total intravenous anesthesia is associated with greater overall and recurrence-free survival than volatile anesthesia. Subgroup analyses were performed for each type of surgery. Results The authors identified 196,303 eligible patients (166,966 patients in the volatile anesthesia group and 29,337 patients in the propofol-based total intravenous anesthesia group). The numbers (proportions) of death in the volatile anesthesia and total intravenous anesthesia groups were 17,319 (10.4%) and 3,339 (11.4%), respectively. There were no significant differences between the two groups in overall survival (hazard ratio, 1.02; 95% CI, 0.98 to 1.07; P = 0.28) or recurrence-free survival (hazard ratio, 0.99; 95% CI, 0.96 to 1.03; P = 0.59), whereas instrumental variable analyses showed a slight difference in recurrence-free survival (hazard ratio, 0.92; 95% CI, 0.87 to 0.98; P = 0.01). Subgroup analyses showed no significant difference in overall or recurrence-free survival between the groups in any type of surgery. Conclusions Overall and recurrence-free survival were similar between volatile and intravenous anesthesia in patients having digestive tract surgery. Selection of the anesthetic approach for these patients should be based on other factors. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Propofol is a short-acting anesthetic used to induce sedation in various ambulatory and inpatient surgical procedures. It is a US Food and Drug Administration approved lipid-based intravenous hypnotic agent, which has been used clinically for the induction and maintenance of anesthesia for over 3 decades. In addition to general anesthesia, it is used to sedate patients undergoing mechanical ventilation or short procedures such as endoscopy, transesophageal echocardiogram, and abscess drainage. An infrequent but serious complication of propofol is acute pancreatitis (AP), with potentially significant morbidity and possible mortality. In this review, we will discuss the proposed mechanisms of AP secondary to propofol, a number of reported cases, studies conducted, and treatment strategies. Areas of uncertainty There are several case reports in the literature that have shown an association between propofol and pancreatitis. The exact mechanism behind propofol-induced pancreatitis is not fully understood, but proposed mechanisms include hypertriglyceridemia (HTG), hypersensitivity, or direct pancreatic toxicity of the drug. Although the association of propofol and pancreatitis has not been proven conclusively, clinicians should be aware of this possible rare complication to prevent the devastating consequences of AP. Data sources We gathered articles on previously documented case reports and up-to-date studies on propofol-induced pancreatitis by searching databases such as PubMed and Google Scholar. Results Based on previous studies and case reports, we suggest that propofol should be added to a list of drugs having a direct association with AP. Conclusions Although, the mechanism of propofol-induced pancreatitis is not fully understood, and the causal relationship of propofol-induced hypertriglyceridemia or idiosyncratic drug reaction has remained unproven. Clinicians should be aware of the association between propofol and pancreatitis, and any patient presenting with abdominal pain after propofol infusion should be evaluated for AP and treated promptly to avoid complications.

OBJECTIVE Two-photon laser-scanning microscopy allows for the monitoring of all brain neurons with single-cell and single-action potential accuracy. This study aimed to investigate the neural responses of the primary auditory cortex to sound stimuli in awake and propofol-anesthetized mice using 2-photon laser-scanning microscopy. METHODS Twelve healthy adult male C57BL/6 mice were used in the present study. In each mouse, the scalp was removed over the entire dorsal skull, and the right primary auditory cortex (A1) located. The test stimulus, used in the awake and propofol-induced anesthetic state, was a group of tones with a random combination of 3 sound intensities and 8 sound frequencies. The calcium indicator GCaMP6s was virally expressed in cortical neurons and neuronal activity was recorded using 2-photon imaging. RESULTS Calcium responses to sound stimuli in two thirds of the neuronal population of the A1 layer were significantly inhibited by propofol anesthesia. In a single neuron, the calcium responses were also inhibited by propofol anesthesia. In the waking state, △F/F (where F is the time series of fluorescence intensity) of all single neurons was significantly higher than that in the propofol-induced anesthetic state (n=669, P

Background The effect of anesthetic drugs on cancer outcomes remains unclear. This trial aimed to assess postoperative circulating tumor cell counts—an independent prognostic factor for breast cancer—to determine how anesthesia may indirectly affect prognosis. It was hypothesized that patients receiving sevoflurane would have higher postoperative tumor cell counts. Methods The parallel, randomized controlled trial was conducted in two centers in Switzerland. Patients aged 18 to 85 yr without metastases and scheduled for primary breast cancer surgery were eligible. The patients were randomly assigned to either sevoflurane or propofol anesthesia. The patients and outcome assessors were blinded. The primary outcome was circulating tumor cell counts over time, assessed at three time points postoperatively (0, 48, and 72 h) by the CellSearch assay. Secondary outcomes included maximal circulating tumor cells value, positivity (cutoff: at least 1 and at least 5 tumor cells/7.5 ml blood), and the association between natural killer cell activity and tumor cell counts. This trial was registered with ClinicalTrials.gov (NCT02005770). Results Between March 2014 and April 2018, 210 participants were enrolled, assigned to sevoflurane (n = 107) or propofol (n = 103) anesthesia, and eventually included in the analysis. Anesthesia type did not affect circulating tumor cell counts over time (median circulating tumor cell count [interquartile range]; for propofol: 1 [0 to 4] at 0 h, 1 [0 to 2] at 48 h, and 0 [0 to 1] at 72 h; and for sevoflurane: 1 [0 to 4] at 0 h, 0 [0 to 2] at 48 h, and 1 [0 to 2] at 72 h; rate ratio, 1.27 [95% CI, 0.95 to 1.71]; P = 0.103) or positivity. In one secondary analysis, administrating sevoflurane led to a significant increase in maximal tumor cell counts postoperatively. There was no association between natural killer cell activity and circulating tumor cell counts. Conclusions In this randomized controlled trial investigating the effect of anesthesia on an independent prognostic factor for breast cancer, there was no difference between sevoflurane and propofol with respect to circulating tumor cell counts over time. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

BACKGROUND Anesthesia in pregnant rodents causes neurotoxicity in fetal and offspring rodents. However, the underlying mechanisms and targeted treatments remain largely to be determined. Isoflurane and propofol are among commonly used anesthetics. Thus, we set out to investigate whether propofol can mitigate the isoflurane-induced neurotoxicity in mice. METHODS Pregnant C57BL/6 mice at gestational day 15 (G15) were randomly assigned to 4 groups: control, isoflurane, propofol, and isoflurane plus propofol. Levels of interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment were measured in the brains of G15 embryos, and levels of postsynaptic density (PSD)-95 and synaptophysin were determined in the hippocampal tissues of postnatal day 31 (P31) offspring using Western blotting and immunohistochemical staining. Learning and memory functions in P31 offspring were determined using a Morris water maze test. RESULTS Isoflurane anesthesia in pregnant mice at G15 significantly increased brain IL-6 (222.6% ± 36.45% vs 100.5% ± 3.43%, P < .0001) and PARP fragment (384.2% ± 50.87% vs 99.59% ± 3.25%, P < .0001) levels in fetal mice and reduced brain PSD-95 (30.76% ± 2.03% vs 100.8% ± 2.25%, P < .0001) and synaptophysin levels in cornu ammonis (CA) 1 region (57.08% ± 4.90% vs 100.6% ± 2.20%, P < .0001) and dentate gyrus (DG; 56.47% ± 3.76% vs 99.76% ± 1.09%, P < .0001) in P31 offspring. Isoflurane anesthesia also impaired cognitive function in offspring at P31. Propofol significantly mitigated isoflurane-induced increases in brain IL-6 (117.5% ± 10.37% vs 222.6% ± 36.45%, P < .0001) and PARP fragment (205.1% ± 35.99% vs 384.2% ± 50.87%, P < .0001) levels in fetal mice, as well as reductions in PSD-95 (49.79% ± 3.43% vs 30.76% ± 2.03%, P < .0001) and synaptophysin levels in CA1 region (85.57% ± 2.97% vs 57.08% ± 4.90%, P < .0001) and DG (85.05% ± 1.87% vs 56.47% ± 3.76%, P < .0001) in hippocampus of P31 offspring. Finally, propofol attenuated isoflurane-induced cognitive impairment in offspring. CONCLUSIONS These findings suggest that gestational isoflurane exposure in mice induces neuroinflammation and apoptosis in embryos and causes cognitive impairment in offspring. Propofol can attenuate these isoflurane-induced detrimental effects.

Background: For endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) under general anaesthesia, both rigid bronchoscopy and laryngeal masks (LMAs) with superimposed high-frequency jet ventilation can be used. Despite the fact that in Europe rigid bronchoscopy for EBUS-TBNA is still widely used, an increasing number of centres use jet ventilation via the LMA for this procedure. To our knowledge no clinical trials have ever been made to compare these two methods. This trial aimed to evaluate whether patients recover from the procedure more quickly when a LMA is used for ventilation compared with rigid bronchoscopy where muscle relaxants and deep anaesthesia are required. Objectives: We wanted to test the hypothesis that there is no difference in the postoperative recovery of patients in the postanaesthesia care unit (PACU) after EBUS-TBNA with jet ventilation via a rigid bronchoscope and a LMA. Secondary outcomes were the difference of duration of anaesthesia, the diagnostic outcome of the procedure and drug quantities for both groups. Design: Prospective randomised single blinded two centre controlled trial. Setting: Two centres in Austria participated. Patients were enrolled from December 2016 until January 2018. Patients: Ninety patients for elective EBUS-TBNA were enrolled and assigned to one of two intervention groups. Two patients were excluded before and eleven patients were excluded after EBUS-TBNA. Seventy-seven were analysed. Interventions: Patients assigned to group 1 were ventilated with a LMA; those assigned to group 2 were ventilated via a rigid bronchoscope. Vital signs, drug dosage, duration of anaesthesia, recovery, PACU stay and Aldrete score at the PACU were recorded. Main outcome measures: The primary endpoint was an integral over time of a modified Aldrete score. Secondary endpoints were the durations of the interventions, the recovery from anaesthesia and PACU stay, initial and mean Aldrete values at PACU, the effect site concentration of Propofol according to the Schnider pharmacokinetic model, the peak ultiva rates and the diagnostic outcome. Results: We were not able to show any significant difference regarding the postoperative recovery criteria based on the Aldrete score, the durations measured and the diagnostic outcomes. Vital signs remained stable and in an equal range in both groups. There were no differences in the mean effect site propofol concentration and the peak ultiva rates. Conclusion: EBUS-TBNA under general anaesthesia using a LMA with SHJV is equal to rigid bronchoscopy with superimposed high-frequency jet ventilation for the variables analysed. Trial registration: ISRCTN (ISRCTN58911367).

Background The aim of this systematic review and meta-analysis was to assess the effect of anesthesia maintenance with volatile agents compared with propofol on both short- and long-term mortality (primary outcomes) and major clinical events in adults undergoing cardiac surgery with cardiopulmonary bypass. Methods Randomized clinical trials on the effects of current volatile anesthetics versus propofol in adults undergoing cardiac surgery with cardiopulmonary bypass were searched (1965 to September 30, 2019) in PubMed, the Cochrane Library, and article reference lists. A random effect model on standardized mean difference for continuous outcomes and odds ratio for dichotomous outcomes were used to meta-analyze data. Results In total, 37 full-text articles (42 studies, 8,197 participants) were included. The class of volatile anesthetics compared with propofol was associated with lower 1-yr mortality (5.5 vs. 6.8%; odds ratio, 0.76 [95% CI, 0.60 to 0.96]; P = 0.023), myocardial infarction (odds ratio, 0.60 [95% CI, 0.39 to 0.92]; P = 0.023), cardiac troponin release (standardized mean difference, −0.39 [95% CI, −0.59 to −0.18], P = 0.0002), need for inotropic medications (odds ratio, 0.40 [95% CI, 0.24 to 0.67]; P = 0.0004), extubation time (standardized mean difference, −0.35 [95% CI, −0.68 to −0.02]; P = 0.038), and with higher cardiac index/output (standardized mean difference, 0.70 [95% CI, 0.37 to 1.04]; P < 0.0001). The class of volatile anesthetics was not associated with changes in short-term mortality (1.63 vs. 1.65%; odds ratio, 1.04 [95% CI, 0.73 to 1.49]; P = 0.820) and acute kidney injury (odds ratio, 1.25 [95% CI, 0.77 to 2.03]; P = 0.358). Conclusions In adults undergoing cardiac surgery with cardiopulmonary bypass, the class of volatile anesthetics was superior to propofol with regard to long-term mortality, as well as to many secondary outcomes indicating myocardial protection. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background This study was conducted to determine which type and dose of sedative drugs should be given to cirrhotic patients with compensation or decompensation during esophagogastroduodenoscopy (EGD) to prevent hepatic encephalopathy (HE) after sedation. Methods We reviewed the medical records of cirrhotic patients consecutively admitted to the hospital and conducted a number connection test (NCT) before and 2 h after EGD with moderate sedation. Sedation was performed using either propofol alone, midazolam alone, or combined propofol + midazolam. Results Sixty-seven patients were admitted for a screening EGD. The NCT before and after sedation were not significantly different in the propofol alone (pre-NCT = 47.3 ± 19.71 seconds vs. post-NCT = 49.4 ± 21.79 seconds, P = 0.6389). In the midazolam alone (pre-NCT = 50.3 ± 20.56 vs. post-NCT = 63.7 ± 33.17, P = 0.0021) and in the combined propofol + midazolam (pre-NCT = 47.4 ± 20.99 vs. post-NCT = 60.0 ± 30.79, P = 0.0002), NCT were significantly delayed. The propofol alone group received 52.3 ± 16.31 mg (0.82 ± 0.29 mg/kg). In 45 (67.2%) decompensated patients, only the propofol alone was not significantly different between pre-NCT (49.2 ± 22.92) and post-NCT (52.3 ± 24.90) (P = 0.4548). Serum sodium level was significantly correlated with delta-NCT (r = 0.3594, P = 0.0028). Conclusion Propofol alone could be the best sedation strategy for cirrhotic patients with compensation or decompensation without aggravation of covert or overt HE. Hyponatremia could be a risk factor for developing or worsening HE after EGD with sedation.

BACKGROUND Patients undergoing pancreaticoduodenectomy (PD) for periampullary lesions are usually elderly with a high risk of postoperative morbidity and mortality. This retrospective cohort study investigated whether postoperative preemptive light sedation aids in recovery of elderly patients following PD. METHODS Ninety-nine geriatric patients undergoing PD at one hospital were enrolled from 2009 to 2018. Patients in the sedation group received mechanical ventilation support and preemptively light sedation with fentanyl and propofol or dexmedetomidine in the first 5 days postoperatively in the intensive care unit (ICU). Patients in the control group underwent early extubation and received morphine for pain control but no postoperative sedatives in the ordinary ward. Patients in the two groups were matched 1:1 using propensity scoring. The postoperative complication rate, surgical mortality, and postoperative hospital length of stay (LOS) were recorded. We also tested inflammation in an immortal human bronchial epithelial cell line. RESULTS After 1:1 matching, 40 patients in the sedation group were compared with 40 patients in the control group. The sedation group had a significantly lower pulmonary complication rate and fewer patients with postoperative gastroparesis. Both groups had similar postoperative hospital LOS and identical surgical mortality rates. Patients in the sedation group had significantly better postoperative quality of life, including less pain and less heartbeat variation. In vitro cell experiments supported the above clinical observations, showing that adequate use of sedatives could significantly elevate the cell viability rate, protect cells from damage, decrease interleukin-6 production, and reduce inflammation. CONCLUSION Postoperative preemptive light sedation in the ICU in geriatric patients following PD may not only reduce the rates of postoperative pulmonary complications and gastroparesis but also improve postoperative quality of life without prolonging the postoperative hospital LOS.

Background A number of recent studies have reported an association between intraoperative burst suppression and postoperative delirium. These studies suggest that anesthesia-induced burst suppression may be an indicator of underlying brain vulnerability. A prominent feature of electroencephalogram (EEG) under propofol and sevoflurane anesthesia is the frontal alpha oscillation. This frontal alpha oscillation is known to decline significantly during aging and is generated by prefrontal brain regions that are particularly prone to age-related neurodegeneration. Given that burst suppression and frontal alpha oscillations are both associated with brain vulnerability, we hypothesized that anesthesia-induced frontal alpha power could also be associated with burst suppression. Methods We analyzed EEG data from a previously reported cohort in which 155 patients received propofol (n = 60) or sevoflurane (n = 95) as the primary anesthetic. We computed the EEG spectrum during stable anesthetic maintenance and identified whether or not burst suppression occurred during the anesthetic. We characterized the relationship between burst suppression and alpha power using logistic regression. We proposed 5 different models consisting of different combinations of potential contributing factors associated with burst suppression: (1) a Base Model consisting of alpha power; (2) an Extended Mechanistic Model consisting of alpha power, age, and drug dosing information; (3) a Clinical Confounding Factors Model consisting of alpha power, hypotension, and other confounds; (4) a Simplified Model consisting only of alpha power and propofol bolus administration; and (5) a Full Model consisting of all of these variables to control for as much confounding as possible. Results All models show a consistent significant association between alpha power and burst suppression while adjusting for different sets of covariates, all with consistent effect size estimates. Using the Simplified Model, we found that for each decibel decrease in alpha power, the odds of experiencing burst suppression increased by 1.33-fold. Conclusions In this study, we show how a decrease in anesthesia-induced frontal alpha power is associated with an increased propensity for burst suppression, in a manner that captures individualized information above and beyond a patient's chronological age. Lower frontal alpha band power is strongly associated with higher propensity for burst suppression and, therefore, potentially higher risk of postoperative neurocognitive disorders. We hypothesize that low frontal alpha power and increased propensity for burst suppression together characterize a "vulnerable brain" phenotype under anesthesia that could be mechanistically linked to brain metabolism, cognition, and brain aging.

Background Investigations of the electrophysiology of gaseous anesthetics xenon and nitrous oxide are limited revealing inconsistent frequency-dependent alterations in spectral power and functional connectivity. Here, the authors describe the effects of sedative, equivalent, stepwise levels of xenon and nitrous oxide administration on oscillatory source power using a crossover design to investigate shared and disparate mechanisms of gaseous xenon and nitrous oxide anesthesia. Methods Twenty-one healthy males underwent simultaneous magnetoencephalography and electroencephalography recordings. In separate sessions, sedative, equivalent subanesthetic doses of gaseous anesthetic agents nitrous oxide and xenon (0.25, 0.50, and 0.75 equivalent minimum alveolar concentration–awake [MACawake]) and 1.30 MACawake xenon (for loss of responsiveness) were administered. Source power in various frequency bands were computed and statistically assessed relative to a conscious/pre-gas baseline. Results Observed changes in spectral-band power (P < 0.005) were found to depend not only on the gas delivered, but also on the recording modality. While xenon was found to increase low-frequency band power only at loss of responsiveness in both source-reconstructed magnetoencephalographic (delta, 208.3%, 95% CI [135.7, 281.0%]; theta, 107.4%, 95% CI [63.5, 151.4%]) and electroencephalographic recordings (delta, 260.3%, 95% CI [225.7, 294.9%]; theta, 116.3%, 95% CI [72.6, 160.0%]), nitrous oxide only produced significant magnetoencephalographic high-frequency band increases (low gamma, 46.3%, 95% CI [34.6, 57.9%]; high gamma, 45.7%, 95% CI [34.5, 56.8%]). Nitrous oxide—not xenon—produced consistent topologic (frontal) magnetoencephalographic reductions in alpha power at 0.75 MACawake doses (44.4%; 95% CI [−50.1, −38.6%]), whereas electroencephalographically nitrous oxide produced maximal reductions in alpha power at submaximal levels (0.50 MACawake, −44.0%; 95% CI [−48.1,−40.0%]). Conclusions Electromagnetic source-level imaging revealed widespread power changes in xenon and nitrous oxide anesthesia, but failed to reveal clear universal features of action for these two gaseous anesthetics. Magnetoencephalographic and electroencephalographic power changes showed notable differences which will need to be taken into account to ensure the accurate monitoring of brain state during anaesthesia. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Propofol is a common sedative-hypnotic drug traditionally used for inducing and maintaining general anesthesia. Recent studies have drawn attention to the nonanesthetic effects of propofol, but the potential mechanism by which propofol suppresses non-small-cell lung cancer (NSCLC) progression has not been fully elucidated. Methods For the in vitro experiments, we used propofol (0, 2, 5, and 10 µg/mL) to treat A549 cells for 1, 4, and 12 hours and Cell Counting Kit-8 (CCK-8) to detect proliferation. Apoptosis was measured with flow cytometry. We also transfected A549 cells with an microribonucleic acid-21 (miR-21) mimic or negative control ribonucleic acid (RNA) duplex and phosphatase and tensin homolog, deleted on chromosome 10 (PTEN) small interfering ribonucleic acid (siRNA) or negative control. PTEN, phosphorylated protein kinase B (pAKT), and protein kinase B (AKT) expression were detected using Western blotting, whereas miR-21 expression was examined by real-time polymerase chain reaction (RT-PCR). In vivo, nude mice were given injections of A549 cells to grow xenograft tumors; 8 days later, the mice were intraperitoneally injected with propofol (35 mg/kg) or soybean oil. Tumors were then collected from mice and analyzed by immunohistochemistry and Western blotting. Results Propofol inhibited growth (1 hour, P = .001; 4 hours, P ≤ .0001; 12 hours, P = .0004) and miR-21 expression (P ≤ .0001) and induced apoptosis (1 hour, P = .0022; 4 hours, P = .0005; 12 hours, P ≤ .0001) in A549 cells in a time and concentration-dependent manner. MiR-21 mimic and PTEN siRNA transfection antagonized the suppressive effects of propofol on A549 cells by decreasing PTEN protein expression (mean differences [MD] [95% confidence interval {CI}], -0.51 [-0.86 to 0.16], P = .0058; MD [95% CI], 0.81 [0.07-1.55], P = .0349, respectively), resulting in an increase in pAKT levels (MD [95% CI] = -0.82 [-1.46 to -0.18], P = .0133) following propofol exposure. In vivo, propofol treatment reduced NSCLC tumor growth (MD [95% CI] = -109.47 [-167.03 to -51.91], P ≤ .0001) and promoted apoptosis (MD [95% CI] = 38.53 [11.69-65.36], P = .0093). Conclusions Our study indicated that propofol inhibited A549 cell growth, accelerated apoptosis via the miR-21/PTEN/AKT pathway in vitro, suppressed NSCLC tumor cell growth, and promoted apoptosis in vivo. Our findings provide new implications for propofol in cancer therapy and indicate that propofol is extremely advantageous in surgical treatment.

Purpose Anesthetic fade refers to the time-dependent decrease in the amplitude of the intraoperative motor-evoked potential. It is thought to be caused by the accumulation of propofol. The authors examined whether normalization by the compound muscle action potential (CMAP) after peripheral nerve stimulation could compensate for anesthetic fade. Methods In 1,842 muscles in 578 surgeries, which did not exhibit a motor-neurologic change after the operation, the motor-evoked potential amplitude was normalized by the CMAP amplitude after peripheral nerve stimulation, and the CMAP amplitude and operation times were analyzed. Results The amplitudes of both motor-evoked potential and CMAP increased over time after peripheral nerve stimulation because of the disappearance of muscle-relaxant action. Especially, after peripheral nerve stimulation, CMAP significantly increased from the beginning to the end of the operation. Anesthetic fade in transcranial motor-evoked potential monitoring seemed to occur at more than 235 minutes of surgery based on the results of a receiver operating characteristic analysis of the operation time and relative amplitudes. Although the mean amplitude without CMAP normalization at more than 235 minutes was significantly lower than that at less than 235 minutes, the mean amplitude with normalization by CMAP after peripheral nerve stimulation at more than 235 minutes was not significantly different from that at less than 235 minutes. Conclusions Compound muscle action potential after peripheral nerve stimulation normalization was able to avoid the effect of anesthetic fade. Anesthetic fade was seemed to be caused by a decrease in synaptic transmission at the neuromuscular junction because of propofol accumulation by this result.

OBJECTIVES We sought to evaluate dexmedetomidine efficacy in assuring comfort and sparing conventional drugs when used for prolonged sedation (≥24 hr) in critically ill patients, by using validated clinical scores while systematically collecting drug dosages. We also evaluated the safety profile of dexmedetomidine and the risk factors associated with adverse events. DESIGN Observational prospective study. SETTING Nine tertiary-care PICUs. PATIENTS Patients less than 18 years who received dexmedetomidine for greater than or equal to 24 hours between January 2016 and December 2017. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS One-hundred sixty-three patients (median age, 13 mo; interquartile range, 4-71 mo) were enrolled. The main indication for dexmedetomidine use was as an adjuvant for drug-sparing (42%). Twenty-three patients (14%) received dexmedetomidine as monotherapy. Seven percent of patients received a loading dose. The median infusion duration was 108 hours (interquartile range, 60-168 hr), with dosages between 0.4 (interquartile range, 0.3-0.5) and 0.8 µg/kg/hr (interquartile range, 0.6-1.2 µg/kg/hr). At 24 hours of dexmedetomidine infusion, values of COMFORT-B Scale (n = 114), Withdrawal Assessment Tool-1 (n = 43) and Cornell Assessment of Pediatric Delirum (n = 6) were significantly decreased compared with values registered immediately pre dexmedetomidine (p < 0.001, p < 0.001, p = 0.027). Dosages/kg/hr of benzodiazepines, opioids, propofol, and ketamine were also significantly decreased (p < 0.001, p < 0.001, p = 0.001, p = 0.027). The infusion was weaned off in 85% of patients, over a median time of 36 hours (interquartile range, 12-48 hr), and abruptly discontinued in 15% of them. Thirty-seven percent of patients showed hemodynamic changes, and 9% displayed hemodynamic adverse events that required intervention (dose reduction in 79% of cases). A multivariate logistic regression model showed that a loading dose (odds ratio, 4.8; CI, 1.2-18.7) and dosages greater than 1.2 µg/kg/hr (odds ratio, 5.4; CI, 1.9-15.2) increased the odds of hemodynamic changes. CONCLUSIONS Dexmedetomidine used for prolonged sedation assures comfort, spares use of other sedation drugs, and helps to attenuate withdrawal syndrome and delirium symptoms. Adverse events are mainly hemodynamic and are reversible following dose reduction. A loading dose and higher infusion dosages are independent risk factors for hemodynamic adverse events.