Classical and non-classical psychedelic drugs induce common network changes in human cortex.

The neurobiology of the psychedelic experience is not fully understood. Identifying common brain network changes induced by both classical (i.e., acting at the 5-HT2 receptor) and non-classical psychedelics would provide mechanistic insight into state-specific characteristics. We analyzed whole-brain functional connectivity based on resting-state fMRI data in humans, acquired before and during the administration of nitrous oxide, ketamine, and lysergic acid diethylamide. We report that, despite distinct molecular mechanisms and modes of delivery, all three psychedelics reduced within-network functional connectivity and enhanced between-network functional connectivity. More specifically, all three drugs increased connectivity between right temporoparietal junction and bilateral intraparietal sulcus as well as between precuneus and left intraparietal sulcus. These regions fall within the posterior cortical "hot zone," posited to mediate the qualitative aspects of experience. Thus, both classical and non-classical psychedelics modulate networks within an area of known relevance for consciousness, identifying a biologically plausible candidate for their subjective effects.

Electroencephalographic Biomarkers, Cerebral Oximetry, and Postoperative Cognitive Function in Adult Noncardiac Surgical Patients: A Prospective Cohort Study.

BACKGROUND: Perioperative neurocognitive disorders are a major public health issue, although there are no validated neurophysiologic biomarkers that predict cognitive function after surgery. This study tested the hypothesis that preoperative posterior electroencephalographic alpha power, alpha frontal-parietal connectivity, and cerebral oximetry would each correlate with postoperative neurocognitive function. METHODS: This was a single-center, prospective, observational study of adult (older than 18 yr) male and female noncardiac surgery patients. Whole-scalp, 16-channel electroencephalography and cerebral oximetry were recorded in the preoperative, intraoperative, and immediate postoperative settings. The primary outcome was the mean postoperative T-score of three National Institutes of Health Toolbox Cognition tests-Flanker Inhibitory Control and Attention, List Sorting Working Memory, and Pattern Comparison Processing Speed. These tests were obtained at preoperative baseline and on the first two postoperative mornings. The lowest average score from the first two postoperative days was used for the primary analysis. Delirium was a secondary outcome (via 3-min Confusion Assessment Method) measured in the postanesthesia care unit and twice daily for the first 3 postoperative days. Last, patient-reported outcomes related to cognition and overall well-being were collected 3 months postdischarge. RESULTS: Sixty-four participants were recruited with a median (interquartile range) age of 59 (48 to 66) yr. After adjustment for baseline cognitive function scores, no significant partial correlation (ρ) was detected between postoperative cognition scores and preoperative relative posterior alpha power (%; ρ = -0.03, P = 0.854), alpha frontal-parietal connectivity (via weight phase lag index; ρ = -0.10, P = 0.570, respectively), or preoperative cerebral oximetry (%; ρ = 0.21, P = 0.246). Only intraoperative frontal-parietal theta connectivity was associated with postoperative delirium (F[1,6,291] = 4.53, P = 0.034). No electroencephalographic or oximetry biomarkers were associated with cognitive or functional outcomes 3 months postdischarge. CONCLUSIONS: Preoperative posterior alpha power, frontal-parietal connectivity, and cerebral oximetry were not associated with cognitive function after noncardiac surgery.

Anesthetic Practice Trends and Perceptions Toward Postoperative Delirium: A Mixed-Methods Analysis.

BACKGROUND: Delirium is the most common postoperative complication in older adults, though anesthesiologist awareness of delirium prevention guidelines-and associated practice trends-remains unknown. METHODS: This was a convergent mixed-methods study, which simultaneously analyzed quantitative and qualitative data to determine delirium guideline awareness among anesthesiologists and practice patterns based on guideline recommendations. Quantitative data were abstracted from the Multicenter Perioperative Outcomes Group database for noncardiac surgery patients (2009-2020) aged 65 years and older. Linear trends were reported for select guideline-based delirium prevention recommendations via regression modeling. Anesthesiologists (n = 40) from a major academic center without a structured delirium reduction program on hospital wards were then surveyed regarding knowledge and practices with respect to postoperative delirium. For qualitative data, 3 focus groups were held to further discuss guideline awareness and identify challenges with delirium prevention. RESULTS: Quantitative results demonstrated a significant decline in the proportion of cases with midazolam between 2009 and 2020, with the largest decrease observed with urologic surgeries (-3.9%/y; 95% confidence interval [CI], -4.2 to -3.6; P < .001). Use of regional anesthesia increased over this period, particularly with gynecologic surgeries (+2.3%/y; 95% CI, 1.2-3.4; P = .001). Anesthesiologist survey results revealed variable guideline awareness, as 21 of 39 (54%) respondents reported being aware of guidelines for anesthetic management of older adults. Importantly, unawareness of delirium management guidelines was the most frequently cited challenge (17 of 37, 46%) when caring for older adults. Finally, focus group participants were largely unaware of postoperative delirium guidelines. However, participants conveyed key barriers to delirium identification and prevention, including the unclear pathophysiology, nonmodifiable risk factors, and system-based hospital challenges. Participants also expressed a desire for decision-support systems, integrated within the perioperative workflow, that provide evidence-based recommendations for reducing delirium risk. CONCLUSIONS: Perioperative practice trends are indicative of an improving environment for postoperative delirium. However, delirium guideline awareness remains variable among anesthesiologists, and key barriers continue to exist for identifying and preventing postoperative delirium.

Barriers to delirium screening and management during hospital admission: a qualitative analysis of inpatient nursing perspectives.

BACKGROUND: Delirium in hospitalized patients is a major public health issue, yet delirium is often unrecognized and missed during inpatient admission. The objective of this study was to identify barriers to delirium screening, identification, and management from a nursing perspective on inpatient, acute care units. METHODS: This was a pre-implementation, diagnostic evaluation study to determine current practice patterns and potential barriers to optimizing delirium care at a major university hospital. A qualitative approach was used, which included focus groups of inpatient nurses working on major medical and surgical acute care units. Focus groups were conducted until signs of thematic saturation were present, and data were analyzed via inductive thematic analysis, without predetermined theories or structures. A consensus approach was utilized for transcript coding, and final themes were generated after multiple reviews of initial themes against transcript datasets. RESULTS: Focus group sessions (n = 3) were held with 18 nurses across two major inpatient units. Nurses reported several barriers to successful delirium screening and management. Specific challenges included difficulty with using delirium screening tools, an organizational culture not conducive to delirium prevention, and competing clinical priorities. Proposed solutions were also discussed, including decision-support systems with automated pager alerts and associated delirium order sets, which may help improve delirium care coordination and standardization. CONCLUSION: At a major university hospital, nurses affirm the difficulty experienced with delirium screening and identification, particularly due to screening tool challenges, cultural barriers, and clinical workload. These impediments may serve as targets for a future implementation trial to improve delirium screening and management.

Dynamic reconfiguration of frequency-specific cortical coactivation patterns during psychedelic and anesthetized states induced by ketamine.

Recent neuroimaging studies have demonstrated that spontaneous brain activity exhibits rich spatiotemporal structure that can be characterized as the exploration of a repertoire of spatially distributed patterns that recur over time. The repertoire of brain states may reflect the capacity for consciousness, since general anesthetics suppress and psychedelic drugs enhance such dynamics. However, the modulation of brain activity repertoire across varying states of consciousness has not yet been studied in a systematic and unified framework. As a unique drug that has both psychedelic and anesthetic properties depending on the dose, ketamine offers an opportunity to examine brain reconfiguration dynamics along a continuum of consciousness. Here we investigated the dynamic organization of cortical activity during wakefulness and during altered states of consciousness induced by different doses of ketamine. Through k-means clustering analysis of the envelope data of source-localized electroencephalographic (EEG) signals, we identified a set of recurring states that represent frequency-specific spatial coactivation patterns. We quantified the effect of ketamine on individual brain states in terms of fractional occupancy and transition probabilities and found that ketamine anesthesia tends to shift the configuration toward brain states with low spatial variability. Furthermore, by assessing the temporal dynamics of the occurrence and transitions of brain states, we showed that subanesthetic ketamine is associated with a richer repertoire, while anesthetic ketamine induces dynamic changes in brain state organization, with the repertoire richness evolving from a reduced level to one comparable to that of normal wakefulness before recovery of consciousness. These results provide a novel description of ketamine's modulation of the dynamic configuration of cortical activity and advance understanding of the neurophysiological mechanism of ketamine in terms of the spatial, temporal, and spectral structures of underlying whole-brain dynamics.

Constrained Functional Connectivity Dynamics in Pediatric Surgical Patients Undergoing General Anesthesia.

BACKGROUND: Functional connectivity in cortical networks is thought to be important for consciousness and can be disrupted during the anesthetized state. Recent work in adults has revealed dynamic connectivity patterns during stable general anesthesia, but whether similar connectivity state transitions occur in the developing brain remains undetermined. The hypothesis was that anesthetic-induced unconsciousness is associated with disruption of functional connectivity in the developing brain and that, as in adults, there are dynamic shifts in connectivity patterns during the stable maintenance phase of general anesthesia. METHODS: This was a preplanned analysis of a previously reported single-center, prospective, cross-sectional study of healthy (American Society of Anesthesiologists status I or II) children aged 8 to 16 yr undergoing surgery with general anesthesia (n = 50) at Michigan Medicine. Whole-scalp (16-channel), wireless electroencephalographic data were collected from the preoperative period through the recovery of consciousness. Functional connectivity was measured using a weighted phase lag index, and discrete connectivity states were classified using cluster analysis. RESULTS: Changes in functional connectivity were associated with anesthetic state transitions across multiple regions and frequency bands. An increase in prefrontal-frontal alpha (median [25th, 75th]; baseline, 0.070 [0.049, 0.101] vs. maintenance 0.474 [0.286, 0.606]; P < 0.001) and theta connectivity (0.038 [0.029, 0.048] vs. 0.399 [0.254, 0.488]; P < 0.001), and decrease in parietal-occipital alpha connectivity (0.171 [0.145, 0.243] vs. 0.089 [0.055, 0.132]; P < 0.001) were among those with the greatest effect size. Contrary to the hypothesis, connectivity patterns during the maintenance phase of general anesthesia were dominated by stable theta and alpha prefrontal-frontal and alpha frontal-parietal connectivity and exhibited high between-cluster similarity (r = 0.75 to 0.87). CONCLUSIONS: Changes in functional connectivity are associated with anesthetic state transitions but, unlike in adults, connectivity patterns are constrained during general anesthesia in late childhood and early adolescence.

Carbon Dioxide, Blood Pressure, and Perioperative Stroke: A Retrospective Case-Control Study.

BACKGROUND: The relationship between intraoperative physiology and postoperative stroke is incompletely understood. Preliminary data suggest that either hypo- or hypercapnia coupled with reduced cerebrovascular inflow (e.g., due to hypotension) can lead to ischemia. This study tested the hypothesis that the combination of intraoperative hypotension and either hypo- or hypercarbia is associated with postoperative ischemic stroke. METHODS: We conducted a retrospective, case-control study via the Multicenter Perioperative Outcomes Group. Noncardiac, nonintracranial, and nonmajor vascular surgical cases (18 yr or older) were extracted from five major academic centers between January 2004 and December 2015. Ischemic stroke cases were identified via manual chart review and matched to controls (1:4). Time and reduction below key mean arterial blood pressure thresholds (less than 55 mmHg, less than 60 mmHg, less than 65 mmHg) and outside of specific end-tidal carbon dioxide thresholds (30 mmHg or less, 35 mmHg or less, 45 mmHg or greater) were calculated based on total area under the curve. The association between stroke and total area under the curve values was then tested while adjusting for relevant confounders. RESULTS: In total, 1,244,881 cases were analyzed. Among the cases that screened positive for stroke (n = 1,702), 126 were confirmed and successfully matched with 500 corresponding controls. Total area under the curve was significantly associated with stroke for all thresholds tested, with the strongest combination observed with mean arterial pressure less than 55 mmHg (adjusted odds ratio per 10 mmHg-min, 1.17 [95% CI, 1.10 to 1.23], P < 0.0001) and end-tidal carbon dioxide 45 mmHg or greater (adjusted odds ratio per 10 mmHg-min, 1.11 [95% CI, 1.10 to 1.11], P < 0.0001). There was no interaction effect observed between blood pressure and carbon dioxide. CONCLUSIONS: Intraoperative hypotension and carbon dioxide dysregulation may each independently increase postoperative stroke risk.

Correlation between brain tissue oxygen tension and regional cerebral oximetry in uninjured human brain under conditions of changing ventilation strategy.

Controversy surrounds regional cerebral oximetry (rSO2) because extracranial contamination and unmeasured changes in cerebral arterial:venous ratio confound readings. Correlation of rSO2 with brain tissue oxygen (PbrO2), a "gold standard" for cerebral oxygenation, could help resolve this controversy but PbrO2 measurement is highly invasive. This was a prospective cohort study. The primary aim was to evaluate correlation between PbrO2 and rSO2 and the secondary aim was to investigate the relationship between changing ventilation regimens and measurement of PbrO2 and rSO2. Patients scheduled for elective removal of cerebral metastases were anesthetized with propofol and remifentanil, targeted to a BIS range 40-60. rSO2 was measured using the INVOS 5100B monitor and PbrO2 using the Licox brain monitoring system. The Licox probe was placed into an area of normal brain within the tumor excision corridor. FiO2 and minute ventilation were sequentially adjusted to achieve two set points: (1) FiO2 0.3 and paCO2 30 mmHg, (2) FiO2 1.0 and paCO2 40 mmHg. PbrO2 and rSO2 were recorded at each. Nine participants were included in the final analysis, which showed a positive Spearman's correlation (r = 0.50, p = 0.036) between PbrO2 and rSO2. From set point 1 to set point 2, PbrO2 increased from median 6.0, IQR 4.0-11.3 to median 22.5, IQR 9.8-43.6, p = 0.015; rSO2 increased from median 68.0, IQR 62.5-80.5 to median 83.0, IQR 74.0-90.0, p = 0.047. Correlation between PbrO2 and rSO2 is evident. Increasing FiO2 and PaCO2 results in significant increases in cerebral oxygenation measured by both monitors.

Asymmetric neural dynamics characterize loss and recovery of consciousness.

Anesthetics are known to disrupt neural interactions in cortical and subcortical brain circuits. While the effect of anesthetic drugs on consciousness is reversible, the neural mechanism mediating induction and recovery may be different. Insight into these distinct mechanisms can be gained from a systematic comparison of neural dynamics during slow induction of and emergence from anesthesia. To this end, we used functional magnetic resonance imaging (fMRI) data obtained in healthy volunteers before, during, and after the administration of propofol at incrementally adjusted target concentrations. We analyzed functional connectivity of corticocortical and subcorticocortical networks and the temporal autocorrelation of fMRI signal as an index of neural processing timescales. We found that en route to unconsciousness, temporal autocorrelation across the entire brain gradually increased, whereas functional connectivity gradually decreased. In contrast, regaining consciousness was associated with an abrupt restoration of cortical but not subcortical temporal autocorrelation and an abrupt boost of subcorticocortical functional connectivity. Pharmacokinetic effects could not account for the difference in neural dynamics between induction and emergence. We conclude that the induction and recovery phases of anesthesia follow asymmetric neural dynamics. A rapid increase in the speed of cortical neural processing and subcorticocortical neural interactions may be a mechanism that reboots consciousness.

Stroke in Surgical Patients.

Stroke is associated with substantial morbidity and mortality. The aim of this review is to provide an evidence-based synthesis of the literature related to perioperative stroke, including its etiology, common risk factors, and potential risk reduction strategies. In addition, the authors will discuss screening methods for the detection of postoperative cerebral ischemia and how multidisciplinary collaborations, including endovascular interventions, should be considered to improve patient outcomes. Lastly, the authors will discuss the clinical and scientific knowledge gaps that need to be addressed to reduce the incidence and improve outcomes after perioperative stroke.

Neurophysiologic Complexity in Children Increases with Developmental Age and Is Reduced by General Anesthesia.

BACKGROUND: Neurophysiologic complexity in the cortex has been shown to reflect changes in the level of consciousness in adults but remains incompletely understood in the developing brain. This study aimed to address changes in cortical complexity related to age and anesthetic state transitions. This study tested the hypotheses that cortical complexity would (1) increase with developmental age and (2) decrease during general anesthesia. METHODS: This was a single-center, prospective, cross-sectional study of healthy (American Society of Anesthesiologists physical status I or II) children (n = 50) of age 8 to 16 undergoing surgery with general anesthesia at Michigan Medicine. This age range was chosen because it reflects a period of substantial brain network maturation. Whole scalp (16-channel), wireless electroencephalographic data were collected from the preoperative period through the recovery of consciousness. Cortical complexity was measured using the Lempel-Ziv algorithm and analyzed during the baseline, premedication, maintenance of general anesthesia, and clinical recovery periods. The effect of spectral power on Lempel-Ziv complexity was analyzed by comparing the original complexity value with those of surrogate time series generated through phase randomization that preserves power spectrum. RESULTS: Baseline spatiotemporal Lempel-Ziv complexity increased with age (yr; slope [95% CI], 0.010 [0.004, 0.016]; P < 0.001); when normalized to account for spectral power, there was no significant age effect on cortical complexity (0.001 [-0.004, 0.005]; P = 0.737). General anesthesia was associated with a significant decrease in spatiotemporal complexity (median [25th, 75th]; baseline, 0.660 [0.620, 0.690] vs. maintenance, 0.459 [0.402, 0.527]; P < 0.001), and spatiotemporal complexity exceeded baseline levels during postoperative recovery (0.704 [0.642, 0.745]; P = 0.009). When normalized, there was a similar reduction in complexity during general anesthesia (baseline, 0.913 [0.887, 0.923] vs. maintenance 0.851 [0.823, 0.877]; P < 0.001), but complexity remained significantly reduced during recovery (0.873 [0.840, 0.902], P < 0.001). CONCLUSIONS: Cortical complexity increased with developmental age and decreased during general anesthesia. This association remained significant when controlling for spectral changes during anesthetic-induced perturbations in consciousness but not with developmental age.

The Effects of Intraoperative Caffeine on Postoperative Opioid Consumption and Related Outcomes After Laparoscopic Surgery: A Randomized Controlled Trial.

BACKGROUND: Surgical patients are vulnerable to opioid dependency and related risks. Clinical-translational data suggest that caffeine may enhance postoperative analgesia. This trial tested the hypothesis that intraoperative caffeine would reduce postoperative opioid consumption. The secondary objective was to assess whether caffeine improves neuropsychological recovery postoperatively. METHODS: This was a single-center, randomized, placebo-controlled trial. Participants, clinicians, research teams, and data analysts were all blinded to the intervention. Adult (≥18 years old) surgical patients (n = 65) presenting for laparoscopic colorectal and gastrointestinal surgery were randomized to an intravenous caffeine citrate infusion (200 mg) or dextrose 5% in water (40 mL) during surgical closure. The primary outcome was cumulative opioid consumption through postoperative day 3. Secondary outcomes included subjective pain reporting, observer-reported pain, delirium, Trail Making Test performance, depression and anxiety screens, and affect scores. Adverse events were reported, and hemodynamic profiles were also compared between the groups. RESULTS: Sixty patients were included in the final analysis, with 30 randomized to each group. The median (interquartile range) cumulative opioid consumption (oral morphine equivalents, milligrams) was 77 mg (33-182 mg) for caffeine and 51 mg (15-117 mg) for placebo (estimated difference, 55 mg; 95% confidence interval [CI], -9 to 118; P = .092). After post hoc adjustment for baseline imbalances, caffeine was associated with increased opioid consumption (87 mg; 95% CI, 26-148; P = .005). There were otherwise no differences in prespecified pain or neuropsychological outcomes between the groups. No major adverse events were reported in relation to caffeine, and no major hemodynamic perturbations were observed with caffeine administration. CONCLUSIONS: Caffeine appears unlikely to reduce early postoperative opioid consumption. Caffeine otherwise appears well tolerated during anesthetic emergence.

Management of Acute Ischemic Stroke-Specific Focus on Anesthetic Management for Mechanical Thrombectomy.

Acute ischemic stroke is a neurological emergency with a high likelihood of morbidity, mortality, and long-term disability. Modern stroke care involves multidisciplinary management by neurologists, radiologists, neurosurgeons, and anesthesiologists. Current American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend thrombolytic therapy with intravenous (IV) alteplase within the first 3-4.5 hours of initial stroke symptoms and endovascular mechanical thrombectomy within the first 16-24 hours depending on specific inclusion criteria. The anesthesia and critical care provider may become involved for airway management due to worsening neurologic status or to enable computerized tomography (CT) or magnetic resonance imaging (MRI) scanning, to facilitate mechanical thrombectomy, or to manage critical care of stroke patients. Existing data are unclear whether the mechanical thrombectomy procedure is best performed under general anesthesia or sedation. Retrospective cohort trials favor sedation over general anesthesia, but recent randomized controlled trials (RCT) neither suggest superiority nor inferiority of sedation over general anesthesia. Regardless of anesthesia type, a critical element of intraprocedural stroke care is tight blood pressure management. At different phases of stroke care, different blood pressure targets are recommended. This narrative review will focus on the anesthesia and critical care providers' roles in the management of both perioperative stroke and acute ischemic stroke with a focus on anesthetic management for mechanical thrombectomy.

Dynamic Cortical Connectivity during General Anesthesia in Healthy Volunteers.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Anesthetic-induced loss of consciousness is accompanied by changes in functional connectivity within and between brain networks. WHAT THIS ARTICLE TELLS US THAT IS NEW: Despite a stable surgical level of anesthesia and the absence of noxious stimuli, connectivity patterns are not static but rather fluctuate dynamically and nonrandomly over time. These results suggest that single or static connectivity patterns may not be able to discriminate levels of consciousness. BACKGROUND: Recent studies of anesthetic-induced unconsciousness in healthy volunteers have focused on functional brain connectivity patterns, but the protocols rarely parallel the depth and duration of surgical anesthesia. Furthermore, it is unknown whether there is a single functional connectivity pattern that correlates with general anesthesia for the duration of prolonged anesthetic exposure. METHODS: The authors analyzed electroencephalographic data in 30 healthy participants who underwent induction of anesthesia with propofol followed by 3 h of isoflurane anesthesia at age-adjusted 1.3 minimum alveolar concentration. Functional connectivity was assessed by frequency-resolved weighted phase lag index between frontal and parietal channels and between prefrontal and frontal channels, which were classified into a discrete set of states through k-means cluster analysis. Temporal dynamics were evaluated by the occurrence rate and dwell time distribution for each state as well as the transition probabilities between states. RESULTS: Burst suppression was present, with mean suppression ratio reducing from 44.8 ± 32.3% to 14.0 ± 20.2% (mean ± SD) during isoflurane anesthesia (P < 0.001). Aside from burst suppression, eight connectivity states were classified by optimizing the reproducibility of clustering solutions, with each characterized by distinct properties. The temporal progression of dominant states revealed a successive shifting trajectory from the state associated with alpha frontal-parietal connectivity to those associated with delta and alpha prefrontal-frontal connectivity during induction, which was reversed during emergence. Cortical connectivity was dynamic during maintenance period, and it was more probable to remain in the same state (82.0 ± 8.3%) than to switch to a different state (P < 0.001). However, transitions to other states were structured, i.e., occurred more frequently than expected by chance. CONCLUSIONS: Anesthesia-induced alterations of functional connectivity are dynamic despite the stable and prolonged administration of isoflurane, in the absence of any noxious stimuli. Changes in connectivity over time will likely yield more information as a marker or mechanism of surgical anesthesia than any single pattern.

Dynamic Cortical Connectivity during General Anesthesia in Surgical Patients.

BACKGROUND: Functional connectivity across the cortex has been posited to be important for consciousness and anesthesia, but functional connectivity patterns during the course of surgery and general anesthesia are unknown. The authors tested the hypothesis that disrupted cortical connectivity patterns would correlate with surgical anesthesia. METHODS: Surgical patients (n = 53) were recruited for study participation. Whole-scalp (16-channel) wireless electroencephalographic data were prospectively collected throughout the perioperative period. Functional connectivity was assessed using weighted phase lag index. During anesthetic maintenance, the temporal dynamics of connectivity states were characterized via Markov chain analysis, and state transition probabilities were quantified. RESULTS: Compared to baseline (weighted phase lag index, 0.163, ± 0.091), alpha frontal-parietal connectivity was not significantly different across the remaining anesthetic and perioperative epochs, ranging from 0.100 (± 0.041) to 0.218 (± 0.136) (P > 0.05 for all time periods). In contrast, there were significant increases in alpha prefrontal-frontal connectivity (peak = 0.201 [0.154, 0.248]; P < 0.001), theta prefrontal-frontal connectivity (peak = 0.137 [0.091, 0.182]; P < 0.001), and theta frontal-parietal connectivity (peak = 0.128 [0.084, 0.173]; P < 0.001) during anesthetic maintenance. Additionally, shifts occurred between states of high prefrontal-frontal connectivity (alpha, beta) with suppressed frontal-parietal connectivity, and high frontal-parietal connectivity (alpha, theta) with reduced prefrontal-frontal connectivity. These shifts occurred in a nonrandom manner (P < 0.05 compared to random transitions), suggesting structured transitions of connectivity during general anesthesia. CONCLUSIONS: Functional connectivity patterns dynamically shift during surgery and general anesthesia but do so in a structured way. Thus, a single measure of functional connectivity will likely not be a reliable correlate of surgical anesthesia.

Electroencephalographic slow wave dynamics and loss of behavioural responsiveness induced by ketamine in human volunteers.

BACKGROUND: Previous work on the electroencephalographic (EEG) effects of anaesthetic doses of ketamine has identified a characteristic signature of increased high frequency (beta-gamma) and theta waves alternating with episodic slow waves. It is unclear which EEG parameter is optimal for pharmacokinetic-pharmacodynamic modelling of the hypnotic actions of ketamine, or which EEG parameter is most closely linked to loss of behavioural responsiveness. METHODS: We re-analysed previously published 128-channel scalp EEG data from 15 subjects who had received a 1.5 mg kg-1 bolus i.v. dose of ketamine. We applied standard sigmoid pharmacokinetic-pharmacodynamic models to the drug-induced changes in slow wave activity, theta, and beta-gamma EEG power; and examined the morphology of the slow waves in the time domain for Fz, F3, T3, P3, and Pz average-referenced channels. RESULTS: Hypnotic doses of ketamine i.v. induced medio-frontal EEG slow waves, and loss of behavioural response when the estimated brain concentration was 1.64 (0.17) µg ml-1. Recovery of responsiveness occurred at 1.06 (0.21) µg.ml-1 after slow wave activity had markedly diminished. Pharmacokinetic-pharmacodynamic modelling fitted best to the slow wave activity and theta power (almost half the beta-gamma channels could not be modelled). Slow wave effect-site equilibration half-time (23 [4] s), and offset, was faster than for theta (47 [22] s). CONCLUSIONS: Changes in EEG slow wave activity after a hypnotic dose of ketamine could be fitted by a standard sigmoid dose-response model. Their onset, but not their offset, was consistently associated with loss of behavioural response in our small study group.

Perioperative Epidural Use and Risk of Delirium in Surgical Patients: A Secondary Analysis of the PODCAST Trial.

BACKGROUND: Postoperative delirium is an important public health concern without effective prevention strategies. This study tested the hypothesis that perioperative epidural use would be associated with decreased risk of delirium through postoperative day 3. METHODS: This was a secondary, observational, nonrandomized analysis of data from The Prevention of Delirium and Complications Associated With Surgical Treatments Trial (PODCAST; NCT01690988). The primary outcome of the current study was the incidence of delirium (ie, any positive delirium screen, postanesthesia care unit through postoperative day 3) in surgical patients (gastrointestinal, hepatobiliary-pancreatic, gynecologic, and urologic) receiving postoperative epidural analgesia compared to those without an epidural. As a secondary outcome, all delirium assessments were then longitudinally analyzed in relation to epidural use throughout the follow-up period. Given the potential relevance to delirium, postoperative pain, opioid consumption, sleep disturbances, and symptoms of depression were also analyzed as secondary outcomes. A semiparsimonious multivariable logistic regression model was used to test the association between postoperative epidural use and delirium incidence, and generalized estimating equations were used to test associations with secondary outcomes described. Models included relevant covariates to adjust for confounding. RESULTS: In total, 263 patients were included for analysis. Epidural use was not independently associated with reduced delirium incidence (adjusted odds ratio, 0.65 [95% CI, 0.32-1.35]; P = .247). However, when analyzing all assessments over the follow-up period, epidural patients were 64% less likely to experience an episode of delirium (adjusted odds ratio, 0.36 [95% CI, 0.17-0.78]; P = .009). Adjusted pain scores (visual analog scale, 0-100 mm) were significantly lower in the epidural group on postoperative day 1 (morning, -16 [95% CI, -26 to -7], P < .001; afternoon, -15 [95% CI, -25 to -5], P < .01) and postoperative day 3 (morning, -13 [95% CI, -20 to -5], P < .01). Adjusted mean oral and IV morphine equivalents were also significantly lower on postoperative day 1 in the epidural group (74% lower [95% CI, 55%-85%]; P < .0001). Finally, postoperative epidural use was not significantly associated with new sleep disturbances or changes in depression symptoms. CONCLUSIONS: Postoperative epidural use was not associated with a reduced overall incidence of delirium. However, longitudinal analysis revealed reduced adjusted odds of experiencing an episode of delirium in the epidural group. Epidural use was also associated with reduced postoperative pain and opioid consumption. An appropriately designed follow-up study is warranted to further analyze the relationship among epidural use, postoperative delirium, and related outcomes.

Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial.

BACKGROUND: Delirium is a common and serious postoperative complication. Subanaesthetic ketamine is often administered intraoperatively for postoperative analgesia, and some evidence suggests that ketamine prevents delirium. The primary purpose of this trial was to assess the effectiveness of ketamine for prevention of postoperative delirium in older adults. METHODS: The Prevention of Delirium and Complications Associated with Surgical Treatments [PODCAST] study is a multicentre, international randomised trial that enrolled adults older than 60 years undergoing major cardiac and non-cardiac surgery under general anaesthesia. Using a computer-generated randomisation sequence we randomly assigned patients to one of three groups in blocks of 15 to receive placebo (normal saline), low-dose ketamine (0·5 mg/kg), or high dose ketamine (1·0 mg/kg) after induction of anaesthesia, before surgical incision. Participants, clinicians, and investigators were blinded to group assignment. Delirium was assessed twice daily in the first 3 postoperative days using the Confusion Assessment Method. We did analyses by intention-to-treat and assessed adverse events. This trial is registered with clinicaltrials.gov, number NCT01690988. FINDINGS: Between Feb 6, 2014, and June 26, 2016, 1360 patients were assessed, and 672 were randomly assigned, with 222 in the placebo group, 227 in the 0·5 mg/kg ketamine group, and 223 in the 1·0 mg/kg ketamine group. There was no difference in delirium incidence between patients in the combined ketamine groups and the placebo group (19·45% vs 19·82%, respectively; absolute difference 0·36%, 95% CI -6·07 to 7·38, p=0·92). There were more postoperative hallucinations (p=0·01) and nightmares (p=0·03) with increasing ketamine doses compared with placebo. Adverse events (cardiovascular, renal, infectious, gastrointestinal, and bleeding), whether viewed individually (p value for each >0·40) or collectively (36·9% in placebo, 39·6% in 0·5 mg/kg ketamine, and 40·8% in 1·0 mg/kg ketamine groups, p=0·69), did not differ significantly across groups. INTERPRETATION: A single subanaesthetic dose of ketamine did not decrease delirium in older adults after major surgery, and might cause harm by inducing negative experiences. FUNDING: National Institutes of Health and Cancer Center Support.