Preoperative biomarkers associated with delayed neurocognitive recovery.

To identify baseline biomarkers of delayed neurocognitive recovery (dNCR) using monitors commonly used in anesthesia. In this sub-study of observational prospective cohorts, we evaluated adult patients submitted to general anesthesia in a tertiary academic center in the United States. Electroencephalographic (EEG) features and cerebral oximetry were assessed in the perioperative period. The primary outcome was dNCR, defined as a decrease of 2 scores in the global Montreal Cognitive Assessment (MoCA) between the baseline and postoperative period. Forty-six adults (median [IQR] age, 65 [15]; 57% females; 65% American Society of Anesthesiologists (ASA) 3 were analyzed. Thirty-one patients developed dNCR (67%). Baseline higher EEG power in the lower alpha band (AUC = 0.73 (95% CI 0.48-0.93)) and lower alpha peak frequency (AUC = 0.83 (95% CI 0.48-1)), as well as lower cerebral oximetry (68 [5] vs 72 [3], p = 0.011) were associated with dNCR. Higher EEG power in the lower alpha band, lower alpha peak frequency, and lower cerebral oximetry values can be surrogates of baseline brain vulnerability.

Heart failure-induced brain myelin changes and differences between sexes.

Heart failure (HF) leads to brain injury in autonomic, respiratory, mood, and cognitive control sites, revealed as tissue volume loss, altered metabolites, and impaired diffusion tissue properties. The extent of myelin changes in HF and variations within sexes are unclear. Our aim was to examine regional brain subcortical and white matter myelin integrity in HF patients over control subjects, as well as differences between sexes using T1- and T2-weighted clinical images. We acquired T1- and T2-weighted images from 63 HF patients and 129 controls using a 3.0-Tesla MRI scanner. Using T1- and T2-weighted images, ratio maps were computed, normalized to a common space, smoothed, and compared between groups (ANCOVA; covariates: age and sex; SPM12, false discovery rate, p < .010), as well as between male versus female HF (ANCOVA; covariate: age; SPM12, uncorrected p < .005). Multiple brain areas in HF showed decreased myelin integrity, including the amygdala, hippocampus, cingulate, insula, cerebellum, prefrontal cortices, and multiple white matter areas, compared to controls. Female HF patients showed more brain injuries in the parietal, prefrontal and frontal, hippocampus, amygdala, pons, cerebellar, insula, and corpus callosum compared to male HF patients. HF subjects showed compromised subcortical and white matter myelin integrity, especially in sites regulating autonomic, respiratory, mood, and cognition, with more changes in females over males. These findings provide a structural basis for the enhanced symptoms identified in female over male HF patients with similar disease severity.

Machine learning approach for obstructive sleep apnea screening using brain diffusion tensor imaging.

Patients with obstructive sleep apnea (OSA) show autonomic, mood, cognitive, and breathing dysfunctions that are linked to increased morbidity and mortality, which can be improved with early screening and intervention. The gold standard and other available methods for OSA diagnosis are complex, require whole-night data, and have significant wait periods that potentially delay intervention. Our aim was to examine whether using faster and less complicated machine learning models, including support vector machine (SVM) and random forest (RF), with brain diffusion tensor imaging (DTI) data can classify OSA from healthy controls. We collected two DTI series from 59 patients with OSA [age: 50.2 ± 9.9 years; body mass index (BMI): 31.5 ± 5.6 kg/m2 ; apnea-hypopnea index (AHI): 34.1 ± 21.2 events/h 23 female] and 96 controls (age: 51.8 ± 9.7 years; BMI: 26.2 ± 4.1 kg/m2 ; 51 female) using a 3.0-T magnetic resonance imaging scanner. Using DTI data, mean diffusivity maps were calculated from each series, realigned and averaged, normalised to a common space, and used to conduct cross-validation for model training and selection and to predict OSA. The RF model showed 0.73 OSA and controls classification accuracy and 0.85 area under the curve (AUC) value on the receiver-operator curve. Cross-validation showed the RF model with comparable fitting over SVM for OSA and control data (SVM; accuracy, 0.77; AUC, 0.84). The RF ML model performs similar to SVM, indicating the comparable statistical fitness to DTI data. The findings indicate that RF model has similar AUC and accuracy over SVM, and either model can be used as a faster OSA screening tool for subjects having brain DTI data.

Advancing our understanding of postoperative cognitive trajectories in older adults.

The use of large amounts of uniform electronic data over long periods provides a step toward understanding and ultimately shaping the perioperative cognitive trajectory of older patients. With the improvements in the quality, uniformity, and amount of data contained within the electronic health record, along with developments in machine learning and big data analysis, we can look forward to enhanced studies that will help advance clinical practice and scientific understanding of perioperative brain health, including the severe and debilitating risk of dementia.

Welfare practices for anaesthesiology trainees in Europe: A descriptive cross-sectional survey study.

BACKGROUND: Current regulations of anaesthesiology training programmes may affect gender equity, female representation and leadership. OBJECTIVE: To describe the work regulations of anaesthesiology training programs and working conditions during the early period of child-rearing in European countries. DESIGN: Cross-sectional survey. SETTING: National Anesthesiologists Societies Committee (NASC) representatives of the European Society of Anesthesiology and Intensive Care. PARTICIPANTS: Thirty-eight NASC representatives. MAIN OUTCOME MEASURES: Basic specialist training working conditions, gender-related data, return to work after childbirth and workplace policies against discrimination during anaesthesiology specialist training. INTERVENTIONS: A 48-item questionnaire to explore the work patterns and conditions for trainees especially for new parents, professional development opportunities and work discrimination regulations in each representative country was distributed to NASC representatives of 44 European countries. RESULTS: We collected the replies of each representative (38 representatives from 44 invited countries' representatives, 86% response rate). The median [IQR] proportion of female trainees was 60% [50 to 68]. There were no reported pay differences between sexes. In eight European countries, pregnant trainees worked fewer hours and were excused from night shifts. Women could not be laid off during pregnancy in all 38 countries (100%). The countries offered a median of 18 weeks of paid (total or partial) maternity leave (range, 13 to 60 weeks). Most countries (89%) accommodate paid paternity leaves. A significant proportion of parental leave was unpaid ( n =18, 42%). Twenty-one (55%) countries allowed part-time work after delivery. The UK was the only country with clear recommendations to formally complain after harassment. CONCLUSION: European countries have a wide variety of regulations. On paper, numerous countries have various paid maternal, paternal and parental leave; however, it remains to be determined if such leave takes place in practice. The practical consequences of these regulations on female trainees during the child-rearing period need to be explored further. TRIAL REGISTRATION: None.

Perioperative Brain Health in the Older Adult: A Patient Safety Imperative.

While people 65 years of age and older represent 16% of the population in the United States, they account for >40% of surgical procedures performed each year. Maintaining brain health after anesthesia and surgery is not only important to our patients, but it is also an increasingly important patient safety imperative for the specialty of anesthesiology. Aging is a complex process that diminishes the reserve of every organ system and often results in a patient who is vulnerable to the stress of surgery. The brain is no exception, and many older patients present with preoperative cognitive impairment that is undiagnosed. As we age, a number of changes occur in the human brain, resulting in a patient who is less resilient to perioperative stress, making older adults more susceptible to the phenotypic expression of perioperative neurocognitive disorders. This review summarizes the current scientific and clinical understanding of perioperative neurocognitive disorders and recommends patient-centered, age-focused interventions that can better mitigate risk, prevent harm, and improve outcomes for our patients. Finally, it discusses the emerging topic of sleep and cognitive health and other future frontiers of scientific inquiry that might inform clinical best practices.

Regional brain tissue changes in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) patients present with a variety of symptoms, including mood and cognition deficits, in addition to classical respiratory, and autonomic issues. This suggests that brain injury, which can be examined with non-invasive magnetic resonance imaging (MRI), is a manifestation of this condition. However, brain tissue integrity in sites that regulate cognitive, autonomic, respiratory, and mood functions in CF patients is unclear. Our aim was to assess regional brain changes using high-resolution T1-weighted images based gray matter (GM) density and T2-relaxometry procedures in CF over control subjects. METHODS: We acquired high-resolution T1-weighted images and proton-density (PD) and T2-weighted images from 5 CF and 15 control subjects using a 3.0-Tesla MRI. High-resolution T1-weighted images were partitioned to GM-tissue type, normalized to a common space, and smoothed. Using PD- and T2-weighted images, whole-brain T2-relaxation maps were calculated, normalized, and smoothed. The smoothed GM-density and T2-relaxation maps were compared voxel-by-voxel between groups using analysis of covariance (covariates, age and sex; SPM12, p < 0.001). RESULTS: Significantly increased GM-density, indicating tissues injury, emerged in multiple brain regions, including the cerebellum, hippocampus, amygdala, basal forebrain, insula, and frontal and prefrontal cortices. Various brain areas showed significantly reduced T2-relaxation values in CF subjects, indicating predominant acute tissue changes, in the cerebellum, cerebellar tonsil, prefrontal and frontal cortices, insula, and corpus callosum. CONCLUSIONS: Cystic fibrosis subjects show predominant acute tissue changes in areas that control mood, cognition, respiratory, and autonomic functions and suggests that tissue changes may contribute to symptoms resulting from ongoing hypoxia accompanying the condition.

Loss of spectral alpha power during spine surgery: what could be wrong?

The electroencephalographic signatures of anesthetic drugs relate to a specific set of action mechanisms within the neural circuits. During intraoperative care, the recognition and correct interpretation of the EEG spectrogram can be used as a tool to guide anesthetic administration. For example, loss of alpha power during propofol anesthesia may be a sign of lighter level of hypnosis and/or of an increase in nociceptive inputs. We describe a case report of inadvertent interruption of propofol delivery that was first detected by changes in the electroencephalogram spectrogram.

Anesthetic Management Using Multiple Closed-loop Systems and Delayed Neurocognitive Recovery: A Randomized Controlled Trial.

BACKGROUND: Cognitive changes after anesthesia and surgery represent a significant public health concern. We tested the hypothesis that, in patients 60 yr or older scheduled for noncardiac surgery, automated management of anesthetic depth, cardiac blood flow, and protective lung ventilation using three independent controllers would outperform manual control of these variables. Additionally, as a result of the improved management, patients in the automated group would experience less postoperative neurocognitive impairment compared to patients having standard, manually adjusted anesthesia. METHODS: In this single-center, patient-and-evaluator-blinded, two-arm, parallel, randomized controlled, superiority study, 90 patients having noncardiac surgery under general anesthesia were randomly assigned to one of two groups. In the control group, anesthesia management was performed manually while in the closed-loop group, the titration of anesthesia, analgesia, fluids, and ventilation was performed by three independent controllers. The primary outcome was a change in a cognition score (the 30-item Montreal Cognitive Assessment) from preoperative values to those measures 1 week postsurgery. Secondary outcomes included a battery of neurocognitive tests completed at both 1 week and 3 months postsurgery as well as 30-day postsurgical outcomes. RESULTS: Forty-three controls and 44 closed-loop patients were assessed for the primary outcome. There was a difference in the cognition score compared to baseline in the control group versus the closed-loop group 1 week postsurgery (-1 [-2 to 0] vs. 0 [-1 to 1]; difference 1 [95% CI, 0 to 3], P = 0.033). Patients in the closed-loop group spent less time during surgery with a Bispectral Index less than 40, had less end-tidal hypocapnia, and had a lower fluid balance compared to the control group. CONCLUSIONS: Automated anesthetic management using the combination of three controllers outperforms manual control and may have an impact on delayed neurocognitive recovery. However, given the study design, it is not possible to determine the relative contribution of each controller on the cognition score.

Interventions to improve perioperative neurologic outcomes.

PURPOSE OF REVIEW: Few outcomes in surgery are as important to patients as that of their neurologic status. The purpose of this review is to discuss and categorize the most common perioperative neurologic complications. We will also discuss strategies to help prevent and mitigate these complications for our patients. RECENT FINDINGS: There are several strategies the anesthesiologist can undertake to prevent or treat conditions, such as perioperative neurocognitive disorders, spinal cord ischemia, perioperative stroke, and postoperative visual loss. SUMMARY: A thorough understanding of threats to patients' neurologic well-being is essential to excellent clinical practice.

Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein-induced Inflammation through a Vagomimetic Action in Mice.

BACKGROUND: Inflammation initiated by damage-associated molecular patterns has been implicated for the cognitive decline associated with surgical trauma and serious illness. We determined whether resolution of inflammation mediates dexmedetomidine-induced reduction of damage-associated molecular pattern-induced cognitive decline. METHODS: Cognitive decline (assessed by trace fear conditioning) was induced with high molecular group box 1 protein, a damage-associated molecular pattern, in mice that also received blockers of neural (vagal) and humoral inflammation-resolving pathways. Systemic and neuroinflammation was assessed by proinflammatory cytokines. RESULTS: Damage-associated molecular pattern-induced cognitive decline and inflammation (mean ± SD) was reversed by dexmedetomidine (trace fear conditioning: 58.77 ± 8.69% vs. 41.45 ± 7.64%, P < 0.0001; plasma interleukin [IL]-1ß: 7.0 ± 2.2 pg/ml vs. 49.8 ± 6.0 pg/ml, P < 0.0001; plasma IL-6: 3.2 ± 1.6 pg/ml vs. 19.5 ± 1.7 pg/ml, P < 0.0001; hippocampal IL-1ß: 4.1 ± 3.0 pg/mg vs. 41.6 ± 8.0 pg/mg, P < 0.0001; hippocampal IL-6: 3.4 ± 1.3 pg/mg vs. 16.2 ± 2.7 pg/mg, P < 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and α7 nicotinic acetylcholine receptors but not by α2 adrenoceptor blockade. Netrin-1, the orchestrator of inflammation-resolution, was upregulated (fold-change) by dexmedetomidine (lung: 1.5 ± 0.1 vs. 0.7 ± 0.1, P < 0.0001; spleen: 1.5 ± 0.2 vs. 0.6 ± 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A4: 1.7 ± 0.2 vs. 0.9 ± 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B4: 1.0 ± 0.2 vs. 3.0 ± 0.3, P < 0.0001) humoral mediators that was prevented by α7 nicotinic acetylcholine receptor blockade. CONCLUSIONS: Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-associated molecular pattern-mediated cognitive decline.

Electroencephalographic Arousal Patterns Under Dexmedetomidine Sedation.

BACKGROUND: The depth of dexmedetomidine-induced sedation is difficult to assess without arousing the patient. We evaluated frontal electroencephalogram (EEG) as an objective measure of dexmedetomidine-induced sedation. Our aims were to characterize the response patterns of EEG during a wide range of dexmedetomidine-induced sedation and to determine which spectral power best correlated with assessed levels of dexmedetomidine-induced sedation. METHODS: Sedline EEG sensor was positioned on the forehead of 16 volunteers. Frontal EEG data were collected at 250 Hz using the Sedline monitor. A computer-controlled infusion pump was used to infuse dexmedetomidine to four 15-minute target plasma concentrations of 0.3, 0.6, 1.2, and 2.4 ng/mL. Arterial blood samples for dexmedetomidine plasma concentration and sedation (self-reported numerical rating scale) and arousal were measured at baseline and at the end of each infusion step. The EEG signal was used to estimate spectral power in sequential 4-second data segments with 75% overlap for 3 power bands: delta = 0.5-1.5 Hz, alpha = 9-14 Hz, beta = 15-24 Hz. We quantified the relationships among the plasma concentrations of dexmedetomidine, level of sedation, and various EEG parameters. RESULTS: EEG data at the end of the dexmedetomidine infusion steps show progressive loss of high frequencies (beta) and increase in alpha and delta powers, with increasing dexmedetomidine concentrations. Beta prearousal spectral power was best in predicting dexmedetomidine-induced level of sedation (R = -0.60, 95% CI, -0.43 to -0.75). The respective values for delta and alpha powers were R = 0.28 (95% CI, 0.03-0.45) and R = 0.16 (95% CI, -0.09 to 0.38). When the beta power has dropped below -16 dB or the delta power is above 15 dB, the subjects show moderate to deep levels of sedation. When awakening the subject, there is a reduction in power in the delta and alpha bands at the 0.6, 1.2, and 2.4 ng/mL dexmedetomidine target levels (P < .001 for all). In beta band, there is a rapid awakening-induced increase in power (P < .001) followed by a slow return toward baseline values. After arousing the subjects, the EEG powers returned toward baseline values significantly slower than our clinical observation of the subjects' wakefulness would have suggested. CONCLUSIONS: Using a wide range of dexmedetomidine doses, we found that frontal EEG beta power of less than -16 dB and/or a delta power of over 15 dB was associated with a state of moderate to deep sedation and that poststimulus return of EEG powers toward baseline values took significantly longer than expected from observation of the arousal response. It is unclear whether these observations are robust enough for clinical applicability.

Fragmented Sleep Enhances Postoperative Neuroinflammation but Not Cognitive Dysfunction.

BACKGROUND: Sleep is integral to biologic function, and sleep disruption can result in both physiological and psychologic dysfunction including cognitive decline. Surgery activates the innate immune system, inducing neuroinflammatory changes that interfere with cognition. Because surgical patients with sleep disorders have an increased likelihood of exhibiting postoperative delirium, an acute form of cognitive decline, we investigated the contribution of perioperative sleep fragmentation (SF) to the neuroinflammatory and cognitive responses of surgery. METHODS: The effects of 24-hour SF and surgery were explored in adult C57BL/6J male mice. The SF procedure started at 7 AM with cages being placed on a large platform orbital shaker that cycled every 120 seconds (30 seconds on/90 seconds off) for 24 hours. In separate cohorts, stabilized tibial fracture was performed either before or after the 24-hour SF procedure and assessed for systemic and hippocampal inflammation and cognition. RESULTS: SF-induced nonhippocampal memory dysfunction (mean ± standard deviation [SD] of the difference in time spent between novel and familiar object for control was 4.7 ± 1.4 seconds, n = 8 versus SF -0.5 ± 0.2 seconds, n = 11, yielding an estimated treatment effect of 5.2 seconds [95% confidence interval {CI}, 2.6-7.7]; P < .001) and increased systemic interleukin-6 (median [25%-75% quartile] for control 0.0 [0.0-2.4] pg/mL versus 9.7 [6.3-12.9] pg/mL, n = 8/group, yielding an estimated treatment effect of 9.7 pg/mL [95% CI, 5.8-11.8]; P < .0001). SF reduced freezing time in hippocampal-dependent memory test (mean ± SD for control 49.3% ± 5.8% versus for SF 32.9% ± 5.8%, n = 10/group, estimated treatment effect = 16.4% [95% CI, 11.0-21.8]; P < .0001). Although surgery also reduced freezing time (mean ± SD for control 49.3% ± 5.8% versus for surgery 30.3% ± 3.3%, n = 10/group, estimated treatment effect = 19.0% [95% CI, 14.6-23.4]; P < .0001), memory impairment was not further exacerbated by combining SF with surgery. One day after SF, there was an increase in hippocampal messenger RNA expression of tumor necrosis factor-α (relative quantitation [RQ] 5.12-fold, n = 5/group [95% CI, 1.64-15.97]; P < .01), and 1 day after surgery, there was an increase in messenger RNA interleukin-6 (RQ 4.64-fold, n = 5 [95% CI, 1.48-14.56]; P < .05) and tumor necrosis factor-α (RQ 5.54-fold, n = 5 [95% CI, 2.92-10.51]; P < .01). These increments were more pronounced when either pre- or postoperative SF was combined with surgery. CONCLUSIONS: Although SF and surgery can independently produce significant memory impairment, perioperative SF significantly increased hippocampal inflammation without further cognitive impairment. The dissociation between neuroinflammation and cognitive decline may relate to the use of a sole memory paradigm that does not capture other aspects of cognition, especially learning.

Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery.

BACKGROUND: Postoperative delirium is prevalent in older patients and associated with worse outcomes. Recent data in animal studies demonstrate increases in inflammatory markers in plasma and cerebrospinal fluid (CSF) even after aseptic surgery, suggesting that inflammation of the central nervous system may be part of the pathogenesis of postoperative cognitive changes. We investigated the hypothesis that neuroinflammation was an important cause for postoperative delirium and cognitive dysfunction after major non-cardiac surgery. METHODS: After Institutional Review Board approval and informed consent, we recruited patients undergoing major knee surgery who received spinal anesthesia and femoral nerve block with intravenous sedation. All patients had an indwelling spinal catheter placed at the time of spinal anesthesia that was left in place for up to 24 h. Plasma and CSF samples were collected preoperatively and at 3, 6, and 18 h postoperatively. Cytokine levels were measured using ELISA and Luminex. Postoperative delirium was determined using the confusion assessment method, and cognitive dysfunction was measured using validated cognitive tests (word list, verbal fluency test, digit symbol test). RESULTS: Ten patients with complete datasets were included. One patient developed postoperative delirium, and six patients developed postoperative cognitive dysfunction. Postoperatively, at different time points, statistically significant changes compared to baseline were present in IL-5, IL-6, I-8, IL-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, IL-6/IL-10, and receptor for advanced glycation end products in plasma and in IFN-γ, IL-6, IL-8, IL-10, MCP-1, MIP-1α, MIP-1ß, IL-8/IL-10, and TNF-α in CSF. CONCLUSIONS: Substantial pro- and anti-inflammatory activity in the central neural system after surgery was found. If confirmed by larger studies, persistent changes in cytokine levels may serve as biomarkers for novel clinical trials.

The Feasibility and Utility of Continuous Sleep Monitoring in Critically Ill Patients Using a Portable Electroencephalography Monitor.

BACKGROUND: Sleep disruption in critically ill adults can result in acute decrements in cognitive function, including delirium, but it is underdiagnosed in the setting of the intensive care unit (ICU). Although sleep stages can be assessed by polysomnography (PSG), acquisition and interpretation of PSG is costly, is labor intensive, is difficult to do over an extended period of time with critically ill patients (multiple days of continuous recording), and may interfere with patient care. In this pilot study, we investigated the feasibility and utility of monitoring sleep in the ICU setting using a portable electroencephalography (EEG) monitor, the SedLine brain monitor. METHODS: We first performed a baseline comparison study of the SedLine brain monitor by comparing its recordings to PSG recorded in a sleep laboratory (n = 3). In a separate patient cohort, we enrolled patients in the ICU who were monitored continuously with the SedLine monitor for sleep disruption (n = 23). In all enrolled patients, we continuously monitored their EEG. The raw EEG was retrieved and sleep stages and arousals were analyzed by a board-certified technologist. Delirium was measured by a trained research nurse using the Confusion Assessment Method developed for the ICU. RESULTS: For all enrolled patients, we continuously monitored their EEGs and were able to retrieve the raw EEGs for analysis of sleep stages. Overall, the SedLine brain monitor was able to differentiate sleep stages, as well as capture arousals and transitions between sleep stages compared with the PSG performed in the sleep laboratory. The percentage agreement was 67% for the wake stage, 77% for the non-rapid eye movement (REM) stage (N1 = 29%, N2 = 88%, and N3 = 6%), and 89% for the REM stage. The overall agreement was measured with the use of weighted kappa, which was 0.61, 95% confidence interval, 0.58 to 0.64. In the ICU study, the mean recording time for the 23 enrolled patients was 19.10 hours. There were several signs indicative of poor-quality sleep, where sleep was distributed throughout the day, with reduced time spent in REM (1.38% ± 2.74% of total sleep time), and stage N3 (2.17% ± 5.53% of total sleep time) coupled with a high arousal index (34.63 ± 19.04 arousals per hour). The occurrence of ICU delirium was not significantly different between patients with and without sleep disruption. CONCLUSIONS: Our results suggest the utility of a portable EEG monitor to measure different sleep stages, transitions, and arousals; however, the accuracy in measuring different sleep stages by the SedLine monitor varies compared with PSG. Our results also support previous findings that sleep is fragmented in critically ill patients. Further research is necessary to develop portable EEG monitors that have higher agreement with PSG.

High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages.

BACKGROUND: Aseptic trauma engages the innate immune response to trigger a neuroinflammatory reaction that results in postoperative cognitive decline. The authors sought to determine whether high-mobility group box 1 protein (HMGB1), an ubiquitous nucleosomal protein, initiates this process through activation and trafficking of circulating bone marrow-derived macrophages to the brain. METHODS: The effects of HMGB1 on memory (using trace fear conditioning) were tested in adult C57BL/6J male mice; separate cohorts were tested after bone marrow-derived macrophages were depleted by clodrolip. The effect of anti-HMGB1 neutralizing antibody on the inflammatory and behavioral responses to tibial surgery were investigated. RESULTS: A single injection of HMGB1 caused memory decline, as evidenced by a decrease in freezing time (52 ± 11% vs. 39 ± 5%; n = 16-17); memory decline was prevented when bone marrow-derived macrophages were depleted (39 ± 5% vs. 50 ± 9%; n = 17). Disabling HMGB1 with a blocking monoclonal antibody, before surgery, reduced postoperative memory decline (52 ± 11% vs. 29 ± 5%; n = 15-16); also, hippocampal expression of monocyte chemotactic protein-1 was prevented by the neutralizing antibody (n = 6). Neither the systemic nor the hippocampal inflammatory responses to surgery occurred in mice pretreated with anti-HMGB1 neutralizing antibody (n = 6). CONCLUSION: Postoperative neuroinflammation and cognitive decline can be prevented by abrogating the effects of HMGB1. Following the earlier characterization of the resolution of surgery-induced memory decline, the mechanisms of its initiation are now described. Together, these data may be used to preoperatively test the risk to surgical patients for the development of exaggerated and prolonged postoperative memory decline that is reflected in delirium and postoperative cognitive dysfunction, respectively.

Enzyme-inducing anticonvulsants increase plasma clearance of dexmedetomidine: a pharmacokinetic and pharmacodynamic study.

BACKGROUND: Dexmedetomidine is useful during mapping of epileptic foci as it facilitates electrocorticography unlike most other anesthetic agents. Patients with seizure disorders taking enzyme-inducing anticonvulsants appear to be resistant to its sedative effects. The objective of the study was to compare the pharmacokinetic and pharmacodynamic profile of dexmedetomidine in healthy volunteers with volunteers with seizure disorders receiving enzyme-inducing anticonvulsant medications. METHODS: Dexmedetomidine was administered using a step-wise, computer-controlled infusion to healthy volunteers (n = 8) and volunteers with seizure disorders (n = 8) taking phenytoin or carbamazapine. Sedation and dexmedetomidine plasma levels were assessed at baseline, during the infusion steps, and after discontinuation of the infusion. Sedation was assessed by using the Observer's Assessment of Alertness/Sedation Scale, Ramsay Sedation Scale, and Visual Analog Scale and processed electroencephalography (entropy) monitoring. Pharmacokinetic analysis was performed on both groups, and differences between groups were determined using the standard two-stage approach. RESULTS: A two-compartment model was fit to dexmedetomidine concentration-time data. Dexmedetomidine plasma clearance was 43% higher in the seizure group compared with the control group (42.7 vs. 29.9 l/h; P = 0.007). In contrast, distributional clearance and the volume of distribution of the central and peripheral compartments were similar between the groups. No difference in sedation was detected between the two groups during a controlled range of target plasma concentrations. CONCLUSION: This study demonstrates that subjects with seizure disorders taking enzyme-inducing anticonvulsant medications have an increased plasma clearance of dexmedetomidine as compared with healthy control subjects.