Associations of environmental and lifestyle factors with spatial navigation in younger and older adults.

OBJECTIVE: Advanced age is associated with prominent impairment in allocentric navigation dependent on the hippocampus. This study examined whether age-related impairment in allocentric navigation and strategy selection was associated with sleep disruption or circadian rest-activity fragmentation. Further, we examined whether associations with navigation were moderated by perceived stress and physical activity. METHOD: Sleep fragmentation and total sleep time over the course of 1 week were assayed in younger (n = 42) and older (n = 37) adults via wrist actigraphy. Subsequently, participants completed cognitive mapping and route learning tasks, as well a measure of spontaneous navigation strategy selection. Measurements of perceived stress and an actigraphy-based index of physical activity were also obtained. Circadian rest-activity fragmentation was estimated via actigraphy post-hoc. RESULTS: Age was associated with reduced cognitive mapping, route learning, allocentric strategy use, and total sleep time (ps < .01), replicating prior findings. Novel findings included that sleep fragmentation increased with advancing age (p = .009) and was associated with lower cognitive mapping (p = .022) within the older adult cohort. Total sleep time was not linearly associated with the navigation tasks (ps > .087). Post-hoc analyses revealed that circadian rest-activity fragmentation increased with advancing age within the older adults (p = .026) and was associated with lower cognitive mapping across the lifespan (p = .001) and within older adults (p = .005). Neither stress nor physical activity were robust moderators of sleep fragmentation associations with the navigation tasks (ps > .113). CONCLUSION: Sleep fragmentation and circadian rest-activity fragmentation are potential contributing factors to age effects on cognitive mapping within older adults.

Quiescence during burst suppression and postictal generalized EEG suppression are distinct patterns of activity.

OBJECTIVE: Periods of low-amplitude electroencephalographic (EEG) signal (quiescence) are present during both anesthetic-induced burst suppression (BS) and postictal generalized electroencephalographic suppression (PGES). PGES following generalized seizures induced by electroconvulsive therapy (ECT) has been previously linked to antidepressant response. The commonality of quiescence during both BS and PGES motivated trials to recapitulate the antidepressant effects of ECT using high doses of anesthetics. However, there have been no direct electrographic comparisons of these quiescent periods to address whether these are distinct entities. METHODS: We compared periods of EEG quiescence recorded from two human studies: BS induced in 29 healthy adult volunteers by isoflurane general anesthesia and PGES in 11 patients undergoing right unilateral ECT for treatment-resistant depression. An automated algorithm allowed detection of EEG quiescence based on a 10-microvolt amplitude threshold. Spatial, spectral, and temporal analyses compared quiescent epochs during BS and PGES. RESULTS: The median (interquartile range) voltage for quiescent periods during PGES was greater than during BS (1.81 (0.22) microvolts vs 1.22 (0.33) microvolts, p < 0.001). Relative power was greater for quiescence during PGES than BS for the 1-4 Hz delta band (p < 0.001), at the expense of power in the theta (4-8 Hz, p < 0.001), beta (13-30 Hz, p = 0.04) and gamma (30-70 Hz, p = 0.006) frequency bands. Topographic analyses revealed that amplitude across the scalp was consistently higher for quiescent periods during PGES than BS, whose voltage was within the noise floor. CONCLUSIONS: Quiescent epochs during PGES and BS have distinct patterns of EEG signals across voltage, frequency, and spatial domains. SIGNIFICANCE: Quiescent epochs during PGES and BS, important neurophysiological markers for clinical outcomes, are shown to have distinct voltage and frequency characteristics.

Evaluation of the 3-Minute Diagnostic Confusion Assessment Method for Identification of Postoperative Delirium in Older Patients.

Importance: Delirium is a common postoperative complication in older patients that often goes undetected and might lead to worse outcomes. The 3-Minute Diagnostic Confusion Assessment Method (3D-CAM) might be a practical tool for routine clinical diagnosis of delirium. Objective: To assess the 3D-CAM for detecting postoperative delirium compared with the long-form CAM used for research purposes. Design, Setting, and Participants: This cohort study of older patients enrolled in ongoing clinical trials between 2015 and 2018 was conducted at a single tertiary US hospital. Included participants were aged 60 years or older undergoing major elective surgical procedures that required at least a 2-day hospital stay. Data were analyzed between February and April 2019. Exposures: Surgical procedures of at least 2 hours in length requiring general anesthesia with planned extubation. Main Outcomes and Measures: Patients were concurrently assessed for delirium using the 3D-CAM assessment and the long-form CAM, scored based on a standardized cognitive assessment. Agreement between these 2 methods was tested using Cohen κ with repeated measures, a generalized linear mixed-effects model, and Bland-Altman analysis. Results: Sixteen raters conducted 471 concurrent CAM and 3D-CAM interviews including 299 patients (mean [SD] age, 69 [6.5] years), the majority of whom were men (152 [50.8%]), were White (263 [88.0%]), and had noncardiac operations (211 [70.6%]). Both instruments had good intraclass correlation (0.84 for the CAM and 0.98 for the 3D-CAM). Cohen κ demonstrated good overall agreement between the CAM and 3D-CAM (κ = 0.71; 95% CI, 0.58 to 0.83). According to the mixed-effects model, there was statistically significant disagreement between the 3D-CAM and CAM (estimated difference in fixed effect, -0.68; 95% CI, -1.32 to -0.05; P = .04). Bland-Altman analysis showed the probability of a delirium diagnosis with the 3D-CAM was more than twice the probability of a delirium diagnosis with the CAM (probability ratio, 2.78; 95% CI, 2.44 to 3.23). Conclusions and Relevance: The 3D-CAM instrument demonstrated agreement with the long-form CAM and might provide a pragmatic and sensitive clinical tool for detecting postoperative delirium, with the caveat that the 3D-CAM might overdiagnose delirium.

Effect of electroencephalogram-guided anaesthesia administration on 1-yr mortality: follow-up of a randomised clinical trial.

BACKGROUND: Intraoperative EEG suppression duration has been associated with postoperative delirium and mortality. In a clinical trial testing anaesthesia titration to avoid EEG suppression, the intervention did not decrease the incidence of postoperative delirium, but was associated with reduced 30-day mortality. The present study evaluated whether the EEG-guided anaesthesia intervention was also associated with reduced 1-yr mortality. METHODS: This manuscript reports 1 yr follow-up of subjects from a single-centre RCT, including a post hoc secondary outcome (1-yr mortality) in addition to pre-specified secondary outcomes. The trial included subjects aged 60 yr or older undergoing surgery with general anaesthesia between January 2015 and May 2018. Patients were randomised to receive EEG-guided anaesthesia or usual care. The previously reported primary outcome was postoperative delirium. The outcome of the current study was all-cause 1-yr mortality. RESULTS: Of the 1232 subjects enrolled, 614 subjects were randomised to EEG-guided anaesthesia and 618 subjects to usual care. One-year mortality was 57/591 (9.6%) in the guided group and 62/601 (10.3%) in the usual-care group. No significant difference in mortality was observed (adjusted absolute risk difference, -0.7%; 99.5% confidence interval, -5.8% to 4.3%; P=0.68). CONCLUSIONS: An EEG-guided anaesthesia intervention aiming to decrease duration of EEG suppression during surgery did not significantly decrease 1-yr mortality. These findings, in the context of other studies, do not provide supportive evidence for EEG-guided anaesthesia to prevent intermediate term postoperative death. CLINICAL TRIAL REGISTRATION: NCT02241655.

Recovery of consciousness and cognition after general anesthesia in humans.

Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for 3 hr and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics. We hypothesized that recovery of consciousness and cognition is an extended process, with differential recovery of cognitive functions that would commence with return of responsiveness and end with return of executive function, mediated by prefrontal cortex. We found that, just prior to the recovery of consciousness, frontal-parietal dynamics returned to baseline. Consistent with our hypothesis, cognitive reconstitution after anesthesia evolved over time. Contrary to our hypothesis, executive function returned first. Early engagement of prefrontal cortex in recovery of consciousness and cognition is consistent with global neuronal workspace theory.

Anesthesia is a state of reversable, controlled unconsciousness. It has enabled countless medical procedures. But it also serves as a tool for scientists to study how the brain regains consciousness after disruptions such as sleep, coma or medical procedures requiring general anesthesia. It is still unclear how exactly the brain regains consciousness, and less so, why some patients do not recover normally after general anesthesia or fail to recover from brain injury. To find out more, Mashour et al. studied the patterns of reemerging consciousness and cognitive function in 30 healthy adults who underwent general anesthesia for three hours. While the volunteers were under anesthesia, their brain activity was measured with an EEG; and their sleep-wake activity was measured before and after the experiment. Each participant took part in a series of cognitive tests designed to measure the reaction speed, memory and other functions before receiving anesthesia, right after the return of consciousness, and then every 30 minutes thereafter. Thirty healthy volunteers who did not have anesthesia also completed the scans and tests as a comparison group. The experiments showed that certain normal EEG patterns resumed just before a person wakes up from anesthesia. The return of thinking abilities was an extended, multistep process, but volunteers recovered their cognitive abilities to nearly the same level as the volunteers within three hours of being deeply anesthetized. Mashour et al. also unexpectedly found that abstract problem-solving resumes early in the process, while other functions such as reaction time and attention took longer to recover. This makes sense from an evolutionary perspective. Sleep leaves individuals vulnerable. Quick evaluation and decision-making skills would be key to respond to a threat upon waking. The experiments confirm that the front of the brain, which handles thinking and decision-making, was especially active around the time of recovery. This suggests that therapies targeting this part of the brain may help people who experience loss of consciousness after a brain injury or have difficulties waking up after anesthesia. Moreover, disorders of cognition, such as delirium, in the days following surgery may be caused by factors other than the lingering effects of anesthetic drugs on the brain.

Preoperative Cognitive Abnormality, Intraoperative Electroencephalogram Suppression, and Postoperative Delirium: A Mediation Analysis.

BACKGROUND: Postoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium. METHODS: This is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5. RESULTS: Among 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation). CONCLUSIONS: A small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect.

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.

Effect of Electroencephalography-Guided Anesthetic Administration on Postoperative Delirium Among Older Adults Undergoing Major Surgery: The ENGAGES Randomized Clinical Trial.

Importance: Intraoperative electroencephalogram (EEG) waveform suppression, often suggesting excessive general anesthesia, has been associated with postoperative delirium. Objective: To assess whether EEG-guided anesthetic administration decreases the incidence of postoperative delirium. Design, Setting, and Participants: Randomized clinical trial of 1232 adults aged 60 years and older undergoing major surgery and receiving general anesthesia at Barnes-Jewish Hospital in St Louis. Recruitment was from January 2015 to May 2018, with follow-up until July 2018. Interventions: Patients were randomized 1:1 (stratified by cardiac vs noncardiac surgery and positive vs negative recent fall history) to receive EEG-guided anesthetic administration (n = 614) or usual anesthetic care (n = 618). Main Outcomes and Measures: The primary outcome was incident delirium during postoperative days 1 through 5. Intraoperative measures included anesthetic concentration, EEG suppression, and hypotension. Adverse events included undesirable intraoperative movement, intraoperative awareness with recall, postoperative nausea and vomiting, medical complications, and death. Results: Of the 1232 randomized patients (median age, 69 years [range, 60 to 95]; 563 women [45.7%]), 1213 (98.5%) were assessed for the primary outcome. Delirium during postoperative days 1 to 5 occurred in 157 of 604 patients (26.0%) in the guided group and 140 of 609 patients (23.0%) in the usual care group (difference, 3.0% [95% CI, -2.0% to 8.0%]; P = .22). Median end-tidal volatile anesthetic concentration was significantly lower in the guided group than the usual care group (0.69 vs 0.80 minimum alveolar concentration; difference, -0.11 [95% CI, -0.13 to -0.10), and median cumulative time with EEG suppression was significantly less (7 vs 13 minutes; difference, -6.0 [95% CI, -9.9 to -2.1]). There was no significant difference between groups in the median cumulative time with mean arterial pressure below 60 mm Hg (7 vs 7 minutes; difference, 0.0 [95% CI, -1.7 to 1.7]). Undesirable movement occurred in 137 patients (22.3%) in the guided and 95 (15.4%) in the usual care group. No patients reported intraoperative awareness. Postoperative nausea and vomiting was reported in 48 patients (7.8%) in the guided and 55 patients (8.9%) in the usual care group. Serious adverse events were reported in 124 patients (20.2%) in the guided and 130 (21.0%) in the usual care group. Within 30 days of surgery, 4 patients (0.65%) in the guided group and 19 (3.07%) in the usual care group died. Conclusions and Relevance: Among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium. This finding does not support the use of EEG-guided anesthetic administration for this indication. Trial Registration: ClinicalTrials.gov Identifier: NCT02241655.

Early Postoperative Actigraphy Poorly Predicts Hypoactive Delirium.

STUDY OBJECTIVES: Delirium is a postoperative complication accompanied by disturbances in attention, cognition, arousal, and psychomotor activity. Wrist actigraphy has been advocated to study inactivity and inferred sleep patterns during delirium. We hypothesized that altered patterns of motor activity or immobility, reflective of disordered sleep and wakefulness patterns, would serve as predictive markers of hypoactive postoperative delirium. METHODS: Eighty-four elderly surgical patients were classified into three groups based on the timing of hypoactive delirium following surgery: intact with no delirium throughout postoperative days (POD) 0-5 (n = 51), delirium during POD 0-1 (n = 24), and delirium during POD 2-5 (n = 13). Delirium was detected on daily Confusion Assessment Method evaluations and chart review. Actigraphy measures were calculated from accelerometry signals acquired on the first postoperative day (POD 0, 16:00-23:00) and night (POD 0, 23:00-POD 1, 06:00). RESULTS: Actigraphy metrics showed substantial interpatient variability. Among the three patient groups, only those without delirium showed greater movement during the day compared to night and also fewer minutes of night immobility (P = .03 and P = .02, Wilcoxon rank-sum tests). These patients were poorly discriminated from those with delirium during either POD 0-1 or POD 2-5, using differences in day and night activity (C-statistic, 95% confidence interval [CI]: 0.66 [0.53-0.79] and C-statistic, 95% CI: 0.71 [0.55-0.87], respectively). Inclusion of low-frequency signals improved performance of immobility measures without affecting those based on activity. Cognitively intact patients during POD 0-5 were distinguished from those with delirium during POD 0-1, based on differences in the number of day and night immobile minutes (C-statistic 0.65, 95% CI: [0.53-0.78]). Actigraphy metrics with the strongest association to delirium incidence were not reliably correlated with an increased risk during POD 0-5, when accounting for patient age, sex, intensive care unit admission, and Charlson Comorbidity Index (adjusted odds ratio of 1.7, 95% CI: [1.0-3.0], P = .09, likelihood ratio test). CONCLUSIONS: Early postoperative wrist actigraphy metrics that serve as markers of sleep and wakefulness offer limited capacity as sole predictors or markers of hypoactive delirium. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) Study; Identifier: NCT02241655; URL: https://clinicaltrials.gov/ct2/show/NCT02241655.

Reliability and accuracy of delirium assessments among investigators at multiple international centres.

INTRODUCTION: Delirium is a common, serious postoperative complication. For clinical studies to generate valid findings, delirium assessments must be standardised and administered accurately by independent researchers. The Confusion Assessment Method (CAM) is a widely used delirium assessment tool. The objective was to determine whether implementing a standardised CAM training protocol for researchers at multiple international sites yields reliable inter-rater assessment and accurate delirium diagnosis. METHODS: Patients consented to video recordings of CAM delirium assessments for research purposes. Raters underwent structured training in CAM administration. Training entailed didactic education, role-playing with intensive feedback, apprenticeship with experienced researchers and group discussions of complex cases. Raters independently viewed and scored nine video-recorded CAM interviews. Inter-rater reliability was determined using Fleiss kappa. Accuracy was judged by comparing raters' scores with those of an expert delirium researcher. RESULTS: Twenty-seven raters from eight international research centres completed the study and achieved almost perfect agreement for overall delirium diagnosis, kappa=0.88 (95% CI 0.85 to 0.92). Agreement of the four core CAM features ranged from fair to substantial. The sensitivity and specificity for identifying delirium were 72% (95% CI 60% to 81%) and 99% (95% CI 96% to 100%), considering an expert rater's scores as the reference standard (delirious, n=3; non-delirious, n=6). Delirium severity ratings were tightly clustered, with most scores within 5% of the median. CONCLUSION: Our results demonstrate that, with appropriate training and ongoing scoring discussions, researchers at multiple sites can reliably detect delirium in postsurgical patients. These results support the premise that methodologically rigorous multi-centre studies can yield standardised and accurate determinations of delirium.

Cognitive and Neurophysiological Recovery Following Electroconvulsive Therapy: A Study Protocol.

Electroconvulsive therapy (ECT) employs the elective induction of generalizes seizures as a potent treatment for severe psychiatric illness. As such, ECT provides an opportunity to rigorously study the recovery of consciousness, reconstitution of cognition, and electroencephalographic (EEG) activity following seizures. Fifteen patients with major depressive disorder refractory to pharmacologic therapy will be enrolled (Clinicaltrials.gov, NCT02761330). Adequate seizure duration will be confirmed following right unilateral ECT under etomidate anesthesia. Patients will then undergo randomization for the order in which they will receive three sequential treatments: etomidate + ECT, ketamine + ECT, and ketamine + sham ECT. Sessions will be repeated in the same sequence for a total of six treatments. Before each session, sensorimotor speed, working memory, and executive function will be assessed through a standardized cognitive test battery. After each treatment, the return of purposeful responsiveness to verbal command will be determined. At this point, serial cognitive assessments will begin using the same standardized test battery. The presence of delirium and changes in depression severity will also be ascertained. Sixty-four channel EEG will be acquired throughout baseline, ictal, and postictal epochs. Mixed-effects models will correlate the trajectories of cognitive recovery, clinical outcomes, and EEG metrics over time. This innovative research design will answer whether: (1) time to return of responsiveness will be prolonged with ketamine + ECT compared with ketamine + sham ECT; (2) time of restoration to baseline function in each cognitive domain will take longer after ketamine + ECT than after ketamine + sham ECT; (3) postictal delirium is associated with delayed restoration of baseline function in all cognitive domains; and (4) the sequence of reconstitution of cognitive domains following the three treatments in this study is similar to that occurring after an isoflurane general anesthetic (NCT01911195). Sub-studies will assess the relationships of cognitive recovery to the EEG preceding, concurrent, and following individual ECT sessions. Overall, this study will lead the development of biomarkers for tailoring the cogno-affective recovery of patients undergoing ECT.

Ability of postoperative delirium to predict intermediate-term postoperative cognitive function in patients undergoing elective surgery at an academic medical centre: protocol for a prospective cohort study.

INTRODUCTION: Postoperative delirium (POD) is a common complication in elderly patients, characterised by a fluctuating course of altered consciousness, disordered thinking and inattention. Preliminary research has linked POD with persistent cognitive impairment and decreased quality of life. However, these findings maybe confounded by patient comorbidities, postoperative complications and frailty. Our objective is to determine whether POD is an independent risk factor for persistent impairments in attention and executive function after elective surgery. Our central hypothesis is that patients with POD are more likely to have declines in cognition and quality of life 1 year after surgery compared with patients without POD. We aim to clarify whether these associations are independent of potentially confounding factors. We will also explore the association between POD and incident dementia. METHODS AND ANALYSIS: This study will recruit 200 patients from the ongoing Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study. Patients who live ≤45 miles from the study centre or have a planned visit to the centre 10-16 months postoperatively will be eligible. Patients with POD, measured by the Confusion Assessment Method, will be compared with patients without delirium. The primary outcome of cognitive function and secondary outcomes of quality of life and incident dementia will be compared between cohorts. Cognition will be measured by Trails A and B and Stroop Color and Word Test, quality of life with Veteran's RAND 12-item Health Survey and incident dementia with the Short Blessed Test. Multivariable regression analyses and a Cox proportional hazards analysis will be performed. All results will be reported with 95% CIs and α=0.05. ETHICS AND DISSEMINATION: The study has been approved by the Washington University in St. Louis Institutional Review Board (IRB no 201601099). Plans for dissemination include scientific publications and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: NCT02241655.

Achieving Milestones as a Prerequisite for Proceeding With a Clinical Trial.

BACKGROUND: Although the National Institutes of Health (NIH) invests $30 billion in research annually, many funded studies fail to generate results that can inform practice. The National Institutes of Health introduced a phased funding mechanism as one potential solution. Study-specific milestones are established for an initial pilot phase. We assess the utility of this phased approach through the ongoing Electroencephalography (EEG) Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) pragmatic clinical trial. The hypothesis of the trial is that EEG guidance of general anesthesia, through prevention of EEG suppression, can decrease postoperative delirium and its downstream negative sequelae. METHODS: In collaboration with study stakeholders, we identified critical milestones for the ENGAGES study, with themes common to many clinical trials. These themes include: regulatory tasks; enrollment targets; feasibility and impact of study intervention; primary outcome incidence; measurement reliability of primary outcome; and follow-up. Progress in achieving the milestones was assessed at regular intervals during the pilot phase by ENGAGES investigators, a National Institute on Aging program officer, and a nonpartisan research organization (Westat). RESULTS: Regulatory tasks, including institutional review board approval, infrastructure establishment, and trial registration, were completed on schedule. A total of 117 patients were randomized, exceeding the target by 51. The EEG-guided protocol was successfully implemented, and a relevant effect on anesthetic practice was demonstrated (decrease in median age-adjusted minimum alveolar anesthetic concentration from 0.93 to 0.78 [P < .001] and increase in median proportion of zero EEG suppression time from 87% to 94% [P < .01]). Nearly all patients (115 of 117, 98.3%) were assessed for delirium using the Confusion Assessment Method, and the delirium incidence was similar (28.1%; 95% CI, 20%-37%) to the estimate (25%) used for the sample size calculation. Good interrater reliability of delirium assessment was demonstrated (κ = 0.94 [95% CI, 0.86-1]). Finally, 1-month follow-up vital status data were obtained for 96.9% of patients, with 85.7% of patients completing at least 1 survey. CONCLUSIONS: With the ENGAGES trial, we demonstrated that key milestones can be identified and progressively assessed during a pilot phase. Success in attaining appropriate milestones hypothetically predicts meaningful completion of a study, and can provide justification for proceeding beyond a pilot phase. The impact of this phased approach on return on investment and scientific yield requires additional study.

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.

Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium.

BACKGROUND: Postoperative delirium is a common complication associated with increased morbidity and mortality, longer hospital stays, and greater health care expenditures. Intraoperative electroencephalogram (EEG) slowing has been associated previously with postoperative delirium, but the relationship between intraoperative EEG suppression and postoperative delirium has not been investigated. METHODS: In this observational cohort study, 727 adult patients who received general anesthesia with planned intensive care unit admission were included. Duration of intraoperative EEG suppression was recorded from a frontal EEG channel (FP1 to F7). Delirium was assessed twice daily on postoperative days 1 through 5 with the Confusion Assessment Method for the intensive care unit. Thirty days after surgery, quality of life, functional independence, and cognitive ability were measured using the Veterans RAND 12-item survey, the Barthel index, and the PROMIS Applied Cognition-Abilities-Short Form 4a survey. RESULTS: Postoperative delirium was observed in 162 (26%) of 619 patients assessed. When we compared patients with no EEG suppression with those divided into quartiles based on duration of EEG suppression, patients with more suppression were more likely to experience delirium (χ(4) = 25, P < 0.0001). This effect remained significant after we adjusted for potential confounders (odds ratio for log(EEG suppression) 1.22 [99% confidence interval, 1.06-1.40, P = 0.0002] per 1-minute increase in suppression). EEG suppression may have been associated with reduced functional independence (Spearman partial correlation coefficient -0.15, P = 0.02) but not with changes in quality of life or cognitive ability. Predictors of EEG suppression included greater end-tidal volatile anesthetic concentration and lower intraoperative opioid dose. CONCLUSIONS: EEG suppression is an independent risk factor for postoperative delirium. Future studies should investigate whether anesthesia titration to minimize EEG suppression decreases the incidence of postoperative delirium. This is a substudy of the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) surgical outcomes registry (NCT02032030).

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial.

INTRODUCTION: Postoperative delirium is one of the most common complications of major surgery, affecting 10-70% of surgical patients 60 years and older. Delirium is an acute change in cognition that manifests as poor attention and illogical thinking and is associated with longer intensive care unit (ICU) and hospital stay, long-lasting cognitive deterioration and increased mortality. Ketamine has been used as an anaesthetic drug for over 50 years and has an established safety record. Recent research suggests that, in addition to preventing acute postoperative pain, a subanaesthetic dose of intraoperative ketamine could decrease the incidence of postoperative delirium as well as other neurological and psychiatric outcomes. However, these proposed benefits of ketamine have not been tested in a large clinical trial. METHODS: The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study is an international, multicentre, randomised controlled trial. 600 cardiac and major non-cardiac surgery patients will be randomised to receive ketamine (0.5 or 1 mg/kg) or placebo following anaesthetic induction and prior to surgical incision. For the primary outcome, blinded observers will assess delirium on the day of surgery (postoperative day 0) and twice daily from postoperative days 1-3 using the Confusion Assessment Method or the Confusion Assessment Method for the ICU. For the secondary outcomes, blinded observers will estimate pain using the Behavioral Pain Scale or the Behavioral Pain Scale for Non-Intubated Patients and patient self-report. ETHICS AND DISSEMINATION: The PODCAST trial has been approved by the ethics boards of five participating institutions; approval is ongoing at other sites. Recruitment began in February 2014 and will continue until the end of 2016. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement and popular media. REGISTRATION DETAILS: The study is registered at clinicaltrials.gov, NCT01690988 (last updated March 2014). The PODCAST trial is being conducted under the auspices of the Neurological Outcomes Network for Surgery (NEURONS). TRIAL REGISTRATION NUMBER: NCT01690988 (last updated December 2013).