Poor olfaction prior to cardiac surgery: Association with cognition, plasma neurofilament light, and post-operative delirium.

OBJECTIVES: Post-operative delirium (POD) affects up to 50% of cardiac surgery patients, with higher incidence in older adults. There is increasing need for screening tools that identify individuals most vulnerable to POD. Here, we examined the relationship between pre-operative olfaction and both incident POD and POD severity in patients undergoing cardiac surgery. We also examined cross-sectional relationships between baseline olfaction, cognition, and plasma neurofilament light (NfL). METHODS: Individuals undergoing cardiac surgery (n = 189; mean age = 70 years; 75% men) were enrolled in a clinical trial of cerebral autoregulation monitoring. At baseline, odor identification performance (Brief Smell Identification Test), cognitive performance, and plasma concentrations of NfL levels (Simoa™ NF-Light Assay) were measured. Delirium was assessed with the Confusion Assessment Method (CAM) or CAM-ICU, and delirium severity was assessed using the Delirium Rating Scale-Revised-98. The association of baseline olfaction, delirium incidence, and delirium severity was examined in regression models adjusting for age, duration of cardiopulmonary bypass, logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE), and baseline cognition. RESULTS: Olfactory dysfunction was present in 30% of patients, and POD incidence was 44%. Pre-operative olfactory dysfunction was associated with both incident POD (OR = 3.17, p = 0.001) and greater severity of POD after cardiac surgery (OR = 3.94 p < 0.001) in models adjusted for age, duration of bypass, and a surgical risk score. The addition of baseline cognition attenuated the strength of the association, but it remained significant for incident POD (OR = 2.25, p = 0.04) and POD severity (OR 2.10, p = 0.04). Poor baseline olfaction was associated with greater baseline cognitive dysfunction (p < 0.001) and increased baseline plasma NfL concentrations (p = 0.04). Neither age, cognition, nor baseline NFL concentration modified the association of impaired olfaction and delirium outcomes. CONCLUSIONS: Olfactory assessment may be a useful pre-surgical screening tool for the identification of patients undergoing cardiac surgery at increased risk of POD. Identifying those at highest risk for severe delirium and poor cognitive outcomes following surgery would allow for earlier intervention and pre-operative rehabilitation strategies, which could ultimately impact the functional disability and morbidity associated with POD.

Association of perioperative plasma concentration of neurofilament light with delirium after cardiac surgery: a nested observational study.

BACKGROUND: Neurofilament light is a blood-based biomarker of neuroaxonal injury that can provide insight into perioperative brain vulnerability and injury. Prior studies have suggested that increased baseline and postoperative concentrations of neurofilament light are associated with delirium after noncardiac surgery, but results are inconsistent. Results have not been reported in cardiac surgery patients, who are among those at highest risk for delirium. We hypothesised that perioperative blood concentrations of neurofilament light (both baseline and change from baseline to postoperative day 1) are associated with delirium after cardiac surgery. METHODS: This study was nested in a trial of arterial blood pressure targeting during cardiopulmonary bypass using cerebral autoregulation metrics. Blood concentrations of neurofilament light were measured at baseline and on postoperative day 1. The primary outcome was postoperative delirium. Regression models were used to examine the associations between neurofilament light concentration and delirium and delirium severity, adjusting for age, sex, race, logistic European System for Cardiac Operative Risk Evaluation, bypass duration, and cognition. RESULTS: Delirium occurred in 44.6% of 175 patients. Baseline neurofilament light concentration was higher in delirious than in non-delirious patients (median 20.7 pg ml-1 [IQR 16.1-33.2] vs median 15.5 pg ml-1 [IQR 12.1-24.2], P<0.001). In adjusted models, greater baseline neurofilament light concentration was associated with delirium (odds ratio, 1.027; 95% confidence interval, 1.003-1.053; P=0.029) and delirium severity. From baseline to postoperative day 1, neurofilament light concentration increased by 42%, but there was no association with delirium. CONCLUSIONS: Baseline neurofilament light concentration, but not change from baseline to postoperative day 1, was associated with delirium after cardiac surgery.

Delirium Screening in Critically Ill Children: Secondary Analysis of the Multicenter PICU Up! Pilot Trial Dataset, 2019-2020.

OBJECTIVES: To determine the patient-level factors associated with performing daily delirium screening in PICUs with established delirium screening practices. DESIGN: A secondary analysis of 2019-2020 prospective data from the baseline phase of the PICU Up! pilot stepped-wedge multicenter trial (NCT03860168). SETTING: Six PICUs in the United States. PATIENTS: One thousand sixty-four patients who were admitted to a PICU for 3 or more days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1064 patients, 74% (95% CI, 71-76%) underwent delirium screening at least once during their PICU stay. On 57% of the 8965 eligible patient days, screening was conducted. The overall prevalence of delirium was 46% across all screened days, and 64% of screened patients experienced delirium at some point during their PICU stay. Factors associated with greater adjusted odds ratio (aOR) of increased daily delirium screening included PICU stay longer than 15 days compared with 1-3 days (aOR 3.36 [95% CI, 2.62-4.30]), invasive mechanical ventilation as opposed to room air (aOR 1.67 [95% CI, 1.32-2.12]), dexmedetomidine infusions (aOR 1.23 [95% CI, 1.04-1.44]) and propofol infusions (aOR 1.55 [95% CI, 1.08-2.23]). Conversely, decreased aOR of daily delirium screening was associated with female gender (aOR 0.78 [95% CI, 0.63-0.96]), and the administration of continuous infusions of opioids (aOR 0.75 [95% CI, 0.63-0.90]) or ketamine (aOR 0.48 [95% CI, 0.29-0.79]). Neither patient age, the presence of family or physical restraints, or benzodiazepine infusions were associated with daily delirium screening rates. CONCLUSIONS: In the 2019-2020 PICU UP! cohort, across six PICUs, delirium screening occurred on only 57% of days, despite the presence of established practices. Female gender, patients in the early stages of their PICU stay, and patients not receiving mechanical ventilation were associated with lower odds of daily delirium screening. Our results highlight the need for structured quality improvement processes to both standardize and increase the frequency of delirium screening.

Delirium, changes in cognitive function, and risk of diagnosed dementia after kidney transplantation.

Kidney transplant (KT) recipients with delirium, a preventable surgical complication, are likely to reap cognitive benefits from restored kidney function, but may be more vulnerable to longer-term neurotoxic stressors post-KT (i.e., aging, immunosuppression). In this prospective cohort study, we measured delirium (chart-based), global cognitive function (3MS), and executive function (Trail Making Test Part B minus Part A) in 894 recipients (2009-2021) at KT, 1/3/6-months, 1-year, and annually post-KT. Dementia was ascertained using linked Medicare claims. We described repeated measures of cognitive performance (mixed effects model) and quantified dementia risk (Fine & Gray competing risk) by post-KT delirium. Of 894 recipients, 43(4.8%) had post-KT delirium. Delirium was not associated with global cognitive function at KT (difference = -3.2 points, 95%CI: -6.7, 0.4) or trajectories post-KT (0.03 points/month, 95%CI: -0.27, 0.33). Delirium was associated with worse executive function at KT (55.1 s, 95%CI: 25.6, 84.5), greater improvements in executive function <2 years post-KT (-2.73 s/month, 95%CI: -4.46,-0.99), and greater decline in executive function >2 years post-KT (1.72 s/month, 95%CI: 0.22, 3.21). Post-KT delirium was associated with over 7-fold greater risk of dementia post-KT (adjusted subdistribution hazard ratio = 7.84, 95%CI: 1.22, 50.40). Transplant centers should be aware of cognitive risks associated with post-KT delirium and implement available preventative interventions to reduce delirium risk.

Delirium detection methodologies: Implications for outcome measurement in clinical trials in postoperative delirium.

OBJECTIVE: Delirium is a common postoperative complication of hip fracture. Various methods exist to detect delirium as a reference standard. The goal of this study was to characterize the properties of the measures obtained in a randomized controlled trial, to document their relationship to the Diagnostic and Statistical Manual of Mental Disorders:Text Revision based diagnosis of postoperative delirium by a consensus panel, and to describe the method in detail to allow replication by others. METHODS: A secondary analysis of the randomized trial STRIDE (A Strategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients) was conducted. Delirium assessments were performed in 200 consecutive hip fracture repair patients ≥65 years old. Assessors underwent extensive training in delirium assessment and the final delirium diagnosis was adjudicated by a consensus panel of three physicians with expertise in delirium assessment. RESULTS: A total of 680 consensus panel delirium diagnoses were completed. There were only 19 (2.8%, 19/678) evaluations where the delirium adjudication by the consensus panel differed from delirium findings by the Confusion Assessment Method (CAM). In 16 (84%, 16/19) of the cases, CAM was negative but the consensus panel diagnosed the patient as having delirium based on all of the available information including the CAM. CONCLUSION: The consensus panel diagnosis was more sensitive compared to CAM alone, however the magnitude of the difference was not large. When assessors are well trained and delirium assessments are closely supervised throughout the study, CAM may be adequate for delirium diagnosis in a clinical trial. Future studies are needed to test this hypothesis.

Spinal Anesthesia with Targeted Sedation based on Bispectral Index Values Compared with General Anesthesia with Masked Bispectral Index Values to Reduce Delirium: The SHARP Randomized Controlled Trial.

BACKGROUND: Reducing depth of anesthesia and anesthetic exposure may help prevent delirium, but trials have been conflicting. Most studies were conducted under general anesthesia or in cognitively impaired patients. It is unclear whether reducing depth of anesthesia beyond levels consistent with general anesthesia reduces delirium in cognitively intact patients. The authors' objective was to determine whether a bundled approach to reduce anesthetic agent exposure as determined by Bispectral Index (BIS) values (spinal anesthesia with targeted sedation based on BIS values) compared with general anesthesia (masked BIS) reduces delirium. METHODS: Important eligibility criteria for this parallel-arm randomized trial were patients 65 yr or greater undergoing lumbar spine fusion. The intervention group received spinal anesthesia with targeted sedation to BIS greater than 60 to 70. The control group received general anesthesia (masked BIS). The primary outcome was delirium using the Confusion Assessment Method daily through postoperative day 3, with blinded assessment. RESULTS: The median age of 217 patients in the analysis was 72 (interquartile range, 69 to 77). The median BIS value in the spinal anesthesia with targeted sedation based on BIS values group was 62 (interquartile range, 53 to 70) and in the general anesthesia with masked BIS values group was 45 (interquartile range, 41 to 50; P < 0.001). Incident delirium was not different in the spinal anesthesia with targeted sedation based on BIS values group (25.2% [28 of 111] vs. the general anesthesia with masked BIS values group (18.9% [20 of 106]; P = 0.259; relative risk, 1.22 [95% CI, 0.85 to 1.76]). In prespecified subgroup analyses, the effect of anesthetic strategy differed according to the Mini-Mental State Examination, but not the Charlson Comorbidity Index or age. Two strokes occurred among patients receiving spinal anesthesia and one death among patients receiving general anesthesia. CONCLUSIONS: Spinal anesthesia with targeted sedation based on BIS values compared with general anesthesia with masked BIS values did not reduce delirium after lumbar fusion.

Effects of Ramelteon on the Prevention of Postoperative Delirium in Older Patients Undergoing Orthopedic Surgery: The RECOVER Randomized Controlled Trial.

OBJECTIVES: Postoperative delirium, associated with negative consequences including longer hospital stays and worse cognitive and physical outcomes, is frequently accompanied by sleep-wake disturbance. Our objective was to evaluate the efficacy and short-term safety of ramelteon, a melatonin receptor agonist, for the prevention of postoperative delirium in older patients undergoing orthopedic surgery. DESIGN: A quadruple-masked randomized placebo-controlled trial (Clinical Trials.gov NCT02324153) conducted from March 2017 to June 2019. SETTING: Tertiary academic medical center. PARTICIPANTS: Patients aged 65 years or older, undergoing elective primary or revision hip or knee replacement. INTERVENTION: Ramelteon (8 mg) or placebo MEASUREMENTS: Eighty participants were randomized to an oral gel cap of ramelteon or placebo for 3 consecutive nights starting the night before surgery. Trained research staff conducted delirium assessments for 3 consecutive days starting on postoperative day (POD) 0, after recovery from anesthesia, and on to POD2. A delirium diagnosis was based upon DSM-5 criteria determined by expert panel consensus. RESULTS: Of 80 participants, five withdrew consent (one placebo, four ramelteon) and four were excluded (four ramelteon) after randomization. Delirium incidence during the 2 days following surgery was 7% (5 of 71) with no difference between the ramelteon versus placebo: 9% (3 of 33) and 5% (2 of 38), respectively. The adjusted odds ratio for postoperative delirium as a function of assignment to the ramelteon treatment arm was 1.28 (95% confidence interval: 0.21-7.93; z-value 0.27; p-value = 0.79). Adverse events were similar between the two groups. CONCLUSION: In older patients undergoing elective primary or revision hip or knee replacement, ramelteon was not efficacious in preventing postoperative delirium.

Association of Depressive Symptoms With Postoperative Delirium and CSF Biomarkers for Alzheimer's Disease Among Hip Fracture Patients.

OBJECTIVES: While there is growing evidence of an association between depressive symptoms and postoperative delirium, the underlying pathophysiological mechanisms remain unknown. The goal of this study was to explore the association between depression and postoperative delirium in hip fracture patients, and to examine Alzheimer's disease (AD) pathology as a potential underlying mechanism linking depressive symptoms and delirium. METHODS: Patients 65 years old or older (N = 199) who were undergoing hip fracture repair and enrolled in the study "A Strategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients" completed the 15-item Geriatric Depression Scale (GDS-15) preoperatively. Cerebrospinal fluid (CSF) was obtained during spinal anesthesia and assayed for amyloid-beta (Aß) 40, 42, total tau (t-tau), and phosphorylated tau (p-tau)181. RESULTS: For every one point increase in GDS-15, there was a 13% increase in odds of postoperative delirium, adjusted for baseline cognition (MMSE), age, sex, race, education and CSF AD biomarkers (OR = 1.13, 95%CI = 1.02-1.25). Both CSF Aß42/t-tau (ß = -1.52, 95%CI = -2.1 to -0.05) and Aß42/p-tau181 (ß = -0.29, 95%CI = -0.48 to -0.09) were inversely associated with higher GDS-15 scores, where lower ratios indicate greater AD pathology. In an analysis to identify the strongest predictors of delirium out of 18 variables, GDS-15 had the highest classification accuracy for postoperative delirium and was a stronger predictor of delirium than both cognition and AD biomarkers. CONCLUSIONS: In older adults undergoing hip fracture repair, depressive symptoms were associated with underlying AD pathology and postoperative delirium. Mild baseline depressive symptoms were the strongest predictor of postoperative delirium, and may represent a dementia prodrome.

Cerebral autoregulation in the operating room and intensive care unit after cardiac surgery.

BACKGROUND: Cerebral autoregulation monitoring is a proposed method to monitor perfusion during cardiac surgery. However, limited data exist from the ICU as prior studies have focused on intraoperative measurements. Our objective was to characterise cerebral autoregulation during surgery and early ICU care, and as a secondary analysis to explore associations with delirium. METHODS: In patients undergoing cardiac surgery (n=134), cerebral oximetry values and arterial BP were monitored and recorded until the morning after surgery. A moving Pearson's correlation coefficient between mean arterial proessure (MAP) and near-infrared spectroscopy signals generated the cerebral oximetry index (COx). Three metrics were derived: (1) globally impaired autoregulation, (2) MAP time and duration outside limits of autoregulation (MAP dose), and (3) average COx. Delirium was assessed using the 3-Minute Diagnostic Interview for CAM-defined Delirium (3D-CAM) and the Confusion Assessment Method for the ICU (CAM-ICU). Autoregulation metrics were compared using χ2 and rank-sum tests, and associations with delirium were estimated using regression models, adjusted for age, bypass time, and logEuroSCORE. RESULTS: The prevalence of globally impaired autoregulation was higher in the operating room vs ICU (40% vs 13%, P<0.001). The MAP dose outside limits of autoregulation was similar in the operating room and ICU (median 16.9 mm Hg×h; inter-quartile range [IQR] 10.1-38.8 vs 16.9 mm Hg×h; IQR 5.4-35.1, P=0.20). In exploratory adjusted analyses, globally impaired autoregulation in the ICU, but not the operating room, was associated with delirium. The MAP dose outside limits of autoregulation in the operating room and ICU was also associated with delirium. CONCLUSIONS: Metrics of cerebral autoregulation are altered in the ICU, and may be clinically relevant with respect to delirium. Further studies are needed to investigate these findings and determine possible benefits of autoregulation-based MAP targeting in the ICU.

Correction to: Screening for posttraumatic stress disorder in ARDS survivors: validation of the impact of event Scale-6 (IES-6).

In the publication of this article [1], there is an error in the Abstract. This has now been included in this correction article.

Prevalence and Improvement of Caine-Positive Wernicke-Korsakoff Syndrome in Psychiatric Inpatient Admissions.

BACKGROUND: Wernicke-Korsakoff Syndrome (WKS) resulting from thiamine deficiency is classically defined as including encephalopathy, ataxia, and ophthalmoplegia. Only 16% of autopsy-confirmed patients with WKS exhibit all three signs. Caine-positive WKS criteria include two or more of the following: nutritional deficiency, delirium or mild memory impairment, cerebellar dysfunction/ataxia, and oculomotor abnormalities. OBJECTIVE: We describe Caine-positive WKS prevalence among psychiatric inpatients and compare pretreatment-versus-posttreatment neurocognitive improvement to an unaffected group. METHODS: This 6-month quality-improvement evaluation included two-stage screening for Caine-positive WKS, administering high-dose intravenous thiamine (day 1: 1200 mg; days 2-4: 200 mg) with reexamination on day 5. We used descriptive statistics and fitted random effects models to examine rate-of-change differences in pre-/posttreatment Montreal Cognitive Assessment (MoCA), delayed 5-item recall, and gait/coordination scores between treated Caine-positive patients with WKS and untreated Caine-negative patients. RESULTS: Of 262 patients, 32 (12%) had Caine-positive WKS; 17 (53%) used alcohol currently. Treated Caine-positive WKS (n = 26) versus Caine-negative comparison (n = 34) before and after treatment observed a mean change (standard deviation) in the MoCA score of 3.6 (2.5) versus 1.8 (2.5) (P < 0.01); 5-item recall: 1.8 (1.4) versus 0.5 (1.4) (P < 0.001); gait/coordination scores: -0.6 (1.2) versus -0.1 (0.6) (P < 0.001). Oculomotor abnormalities were infrequent (n = 4 in Caine-positive WKS, n = 2 in Caine-negative comparison groups). CONCLUSIONS: Caine-positive WKS prevalence among psychiatric inpatients was 12%; only half used alcohol. Patients treated with high-dose thiamine demonstrated clinically significant neurocognitive improvement.

Effect of baseline cognitive impairment on association between predicted propofol effect site concentration and Bispectral index or sedation score.

BACKGROUND: This study determined whether the relationship between predicted propofol effect site concentration (Ce) and observer's assessment of alertness/sedation scale (OAA/S) or Bispectral Index (BIS) was similar comparing cognitively intact vs impaired patients undergoing hip fracture repair with spinal anesthesia and sedation. METHODS: Following informed consent baseline mini-mental status exam (MMSE), Clinical Dementia Rating (CDR) and geriatric depression scale (GDS) were obtained. Intraoperatively OAA/S, BIS, and propofol (timing and exact amounts) administered were recorded. Cerebrospinal fluid was collected for Alzheimer's (AD) biomarkers. Mean Ce level (AvgCe) during surgery was calculated using the area under the Ce measurement series from incision to closure, divided by surgical time. Average OAA/S (AvgOAA/S), and BIS (AvgBIS) were similarly calculated. Pearson correlations of AvgCe with AvgOAA/S and AvgBIS were calculated overall and by CDR. Nonparametric locally weighted scatterplot smoothing (LOWESS) fits of AvgOAA/S and AvgBIS on AvgCe were produced, stratified by CDR. Multivariable regression incorporating baseline cognitive measurements or AD biomarkers assessed AvgOAA/S or AvgBIS associations with AvgCe. RESULTS: In 186 participants AvgBIS and AvgOAA/S correlated with AvgCe (Pearson ρ = - 0.72; p < 0.0001 and Pearson ρ = - 0.81; p < 0.0001, respectively), and remained unchanged across CDR levels. Association patterns of AvgOAA/S or AvgBIS on AvgCe guided by LOWESS fits and modeled through regression, were similar when stratified by CDR (p = 0.16). Multivariable modeling found no independent effect on AvgBIS or AvgOAA/S by MMSE, CDR, GDS, or AD biomarkers after accounting for AvgCe. CONCLUSIONS: When administering sedation in conjunction with spinal anesthesia, cognitive impairment does not affect the relationship between predicted propofol AvgCe and AvgOAA/S or AvgBIS.

Antipsychotics for Treating Delirium in Hospitalized Adults: A Systematic Review.

Background: Delirium is common in hospitalized patients and is associated with worse outcomes. Antipsychotics are commonly used; however, the associated benefits and harms are unclear. Purpose: To conduct a systematic review evaluating the benefits and harms of antipsychotics to treat delirium in adults. Data Sources: PubMed, Embase, CENTRAL, CINAHL, and PsycINFO from inception to July 2019 without language restrictions. Study Selection: Randomized controlled trials (RCTs) of antipsychotic versus placebo or another antipsychotic, and prospective observational studies reporting harms. Data Extraction: One reviewer extracted data and assessed strength of evidence (SOE) for critical outcomes, with confirmation by another reviewer. Risk of bias was assessed independently by 2 reviewers. Data Synthesis: Across 16 RCTs and 10 observational studies of hospitalized adults, there was no difference in sedation status (low and moderate SOE), delirium duration, hospital length of stay (moderate SOE), or mortality between haloperidol and second-generation antipsychotics versus placebo. There was no difference in delirium severity (moderate SOE) and cognitive functioning (low SOE) for haloperidol versus second-generation antipsychotics, with insufficient or no evidence for antipsychotics versus placebo. For direct comparisons of different second-generation antipsychotics, there was no difference in mortality and insufficient or no evidence for multiple other outcomes. There was little evidence demonstrating neurologic harms associated with short-term use of antipsychotics for treating delirium in adult inpatients, but potentially harmful cardiac effects tended to occur more frequently. Limitations: Heterogeneity was present in terms of dose and administration route of antipsychotics, outcomes, and measurement instruments. There was insufficient or no evidence regarding multiple clinically important outcomes. Conclusion: Current evidence does not support routine use of haloperidol or second-generation antipsychotics to treat delirium in adult inpatients. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018109552).

Antipsychotics for Preventing Delirium in Hospitalized Adults: A Systematic Review.

Background: Delirium is an acute disorder marked by impairments in attention and cognition, caused by an underlying medical problem. Antipsychotics are used to prevent delirium, but their benefits and harms are unclear. Purpose: To conduct a systematic review evaluating the benefits and harms of antipsychotics for prevention of delirium in adults. Data Sources: PubMed, Embase, CENTRAL, CINAHL, and PsycINFO from inception through July 2019, without restrictions based on study setting, language of publication, or length of follow-up. Study Selection: Randomized, controlled trials (RCTs) that compared an antipsychotic with placebo or another antipsychotic, and prospective observational studies with a comparison group. Data Extraction: One reviewer extracted data and graded the strength of the evidence, and a second reviewer confirmed the data. Two reviewers independently assessed the risk of bias. Data Synthesis: A total of 14 RCTs were included. There were no differences in delirium incidence or duration, hospital length of stay (high strength of evidence [SOE]), and mortality between haloperidol and placebo used for delirium prevention. Little to no evidence was found to determine the effect of haloperidol on cognitive function, delirium severity (insufficient SOE), inappropriate continuation, and sedation (insufficient SOE). There is limited evidence that second-generation antipsychotics may lower delirium incidence in the postoperative setting. There is little evidence that short-term use of antipsychotics was associated with neurologic harms. In some of the trials, potentially harmful cardiac effects occurred more frequently with antipsychotic use. Limitations: There was significant heterogeneity in antipsychotic dosing, route of antipsychotic administration, assessment of outcomes, and adverse events. There were insufficient or no data available to draw conclusions for many of the outcomes. Conclusion: Current evidence does not support routine use of haloperidol or second-generation antipsychotics for prevention of delirium. There is limited evidence that second-generation antipsychotics may lower the incidence of delirium in postoperative patients, but more research is needed. Future trials should use standardized outcome measures. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018109552).

A roadmap to advance delirium research: Recommendations from the NIDUS Scientific Think Tank.

Delirium is an acute disorder of attention and cognition. It occurs across the life span, yet it is particularly common among older adults, and is closely linked with underlying neurocognitive disorders. Evidence is mounting that intervening on delirium may represent an important opportunity for delaying the onset or progression of dementia. To accelerate the current understanding of delirium, the Network for Investigation of Delirium: Unifying Scientists (NIDUS) held a conference "Advancing Delirium Research: A Scientific Think Tank" in June 2019. This White Paper encompasses the major knowledge and research gaps identified at the conference: advancing delirium definition and measurement, understanding delirium pathophysiology, and prevention and treatment of delirium. A roadmap of research priorities is proposed to advance the field in a systematic, interdisciplinary, and coordinated fashion. A call is made for an international consortium and biobank targeted to delirium, as well as a public health campaign to advance the field.

Screening for posttraumatic stress disorder in ARDS survivors: validation of the Impact of Event Scale-6 (IES-6).

BACKGROUND: Posttraumatic stress disorder (PTSD) symptoms are common in acute respiratory distress syndrome (ARDS) survivors. Brief screening instruments are needed for clinical and research purposes. We evaluated internal consistency, external construct, and criterion validity of the Impact of Event Scale-6 (IES-6; 6 items) compared to the original Impact of Event Scale-Revised (IES-R; 22 items) and to the Clinician Administered PTSD Scale (CAPS) reference standard evaluation in ARDS survivors. METHODS: This study is a secondary analysis from two independent multi-site, prospective studies of ARDS survivors. Measures of internal consistency, and external construct and criterion validity were evaluated. RESULTS: A total of 1001 ARDS survivors (51% female, 76% white, mean (SD) age 49 (14) years) were evaluated. The IES-6 demonstrated internal consistency over multiple time points up to 5 years after ARDS (Cronbach's alpha = 0.86 to 0.91) and high correlation with the IES-R (0.96; 95% confidence interval (CI): 0.94 to 0.97). The IES-6 demonstrated stronger correlations with related constructs (e.g., anxiety and depression; |r| = 0.32 to 0.52) and weaker correlations with unrelated constructs (e.g., physical function and healthcare utilization measures (|r| = 0.02 to 0.27). Criterion validity evaluation with the CAPS diagnosis of PTSD in a subsample of 60 participants yielded an area under receiver operating characteristic curve (95% CI) of 0.93 (0.86, 1.00), with an IES-6 cutoff score of 1.75 yielding 0.88 sensitivity and 0.85 specificity. CONCLUSIONS: The IES-6 is reliable and valid for screening for PTSD in ARDS survivors and may be useful in clinical and research settings.

Depth of sedation as an interventional target to reduce postoperative delirium: mortality and functional outcomes of the Strategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients randomised clinical trial.

BACKGROUND: The Strategy to Reduce the Incidence of Postoperative Delirium in the Elderly trial tested the hypothesis that limiting sedation during spinal anaesthesia decreases in-hospital postoperative delirium after hip fracture repair. This manuscript reports the secondary outcomes of this trial, including mortality and function. METHODS: Two hundred patients (≥65 yr) undergoing hip fracture repair with spinal anaesthesia were randomised to heavier [modified Observer's Assessment of Alertness/Sedation score (OAA/S) 0-2] or lighter (OAA/S 3-5) sedation, and were assessed for postoperative delirium. Secondary outcomes included mortality and return to pre-fracture ambulation level at 1 yr. Kaplan-Meier analysis, multivariable Cox proportional hazard model, and logistic regression were used to evaluate intervention effects on mortality and odds of ambulation return. RESULTS: One-year mortality was 14% in both groups (log rank P=0.96). Independent risk factors for 1-yr mortality included: Charlson comorbidity index [hazard ratio (HR)=1.23, 95% confidence interval (CI), 1.02-1.49; P=0.03], instrumental activities of daily living [HR=0.74, 95% CI, 0.60-0.91; P=0.005], BMI [HR=0.91, 95% CI 0.84-0.998; P=0.04], and delirium severity [HR=1.20, 95% CI, 1.03-1.41; P=0.02]. Ambulation returned to pre-fracture levels, worsened, or was not obtained in 64%, 30%, and 6% of 1 yr survivors, respectively. Lighter sedation did not improve odds of ambulation return at 1 yr [odds ratio (OR)=0.76, 95% CI, 0.24-2.4; P=0.63]. Independent risk factors for ambulation return included Charlson comorbidity index [OR=0.71, 95% CI, 0.53-0.97; P=0.03] and delirium [OR=0.32, 95% CI, 0.10-0.97; P=0.04]. CONCLUSIONS: This study found that in elderly patients having hip fracture surgery with spinal anaesthesia supplemented with propofol sedation, heavier intraoperative sedation was not associated with significant differences in mortality or return to pre-fracture ambulation up to 1 yr after surgery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00590707.

Use of an expert panel to identify domains and indicators of delirium severity.

PURPOSE: Our purpose was to create a content domain framework for delirium severity to inform item development for a new instrument to measure delirium severity. METHODS: We used an established, multi-stage instrument development process during which expert panelists discussed best approaches to measure delirium severity and identified related content domains. We conducted this work as part of the Better ASsessment of ILlness (BASIL) study, a prospective, observational study aimed at developing and testing measures of delirium severity. Our interdisciplinary expert panel consisted of twelve national delirium experts and four expert members of the core research group. Over a one-month period, experts participated in two rounds of review. RESULTS: Experts recommended that the construct of delirium severity should reflect both the phenomena and the impact of delirium to create an accurate, patient-centered instrument useful to interdisciplinary clinicians and family caregivers. Final content domains were Cognitive, Level of consciousness, Inattention, Psychiatric-Behavioral, Emotional dysregulation, Psychomotor features, and Functional. Themes debated by experts included reconciling clinical geriatrics and psychiatric content, mapping symptoms to one specific domain, and accurate capture of unclear clinical presentations. CONCLUSIONS: We believe this work represents the first application of instrument development science to delirium. The identified content domains are inclusive of various, wide-ranging domains of delirium severity and are reflective of a consistent framework that relates delirium severity to potential clinical outcomes. Our content domain framework provides a foundation for development of delirium severity instruments that can help improve care and quality of life for patients with delirium.

Observational Study Examining the Association of Baseline Frailty and Postcardiac Surgery Delirium and Cognitive Change.

BACKGROUND: Frailty is a geriatric syndrome thought to identify the most vulnerable older adults, and morbidity and mortality has been reported to be higher for frail patients after cardiac surgery compared to nonfrail patients. However, the cognitive consequences of frailty after cardiac surgery have not been well described. In this study, we examined the hypothesis that baseline frailty would be associated with postoperative delirium and cognitive change at 1 and 12 months after cardiac surgery. METHODS: This study was nested in 2 trials, each of which was conducted by the same research team with identical measurement of exposures and outcomes. Before surgery, patients were assessed with the validated "Fried" frailty scale, which evaluates 5 domains (shrinking, weakness, exhaustion, low physical activity, and slowed walking speed) and classifies patients as nonfrail, prefrail, and frail. The primary outcome was postoperative delirium during hospitalization, which was assessed using the Confusion Assessment Method, Confusion Assessment Method for the Intensive Care Unit, and validated chart review. Neuropsychological testing was a secondary outcome and was generally performed within 2 weeks of surgery and then 4-6 weeks and 1 year after surgery, and the outcome of interest was change in composite Z-score of the test battery. Associations were analyzed using logistic and linear regression models, with adjustment for variables considered a priori (age, gender, race, education, and logistic European System for Cardiac Operative Risk Evaluation). Multiple imputation was used to account for missing data at the 12-month follow-up. RESULTS: Data were available from 133 patients with baseline frailty assessments. Compared to nonfrail patients (13% delirium incidence), the incidence of delirium was higher in prefrail (48% delirium incidence; risk difference, 35%; 95% CI, 10%-51%) and frail patients (48% delirium incidence; risk difference, 35%; 95% CI, 7%-53%). In both univariable and multivariable models, the odds of delirium were significantly higher for prefrail (adjusted odds ratio, 6.43; 95% CI, 1.31-31.64; P = .02) and frail patients (adjusted odds ratio, 6.31; 95% CI, 1.18-33.74; P = .03) compared to nonfrail patients. The adjusted decline in composite cognitive Z-score was greater from baseline to 1 month only in frail patients compared to nonfrail patients. By 1 year after surgery, there were no differences in the association of baseline frailty with change in cognition. CONCLUSIONS: Compared to nonfrail patients, both prefrail and frail patients were at higher risk for the primary outcome of delirium after cardiac surgery. Frail patients were also at higher risk for the secondary outcome of greater decline in cognition from baseline to 1 month, but not baseline to 1 year, after surgery.

Shaping anesthetic techniques to reduce post-operative delirium (SHARP) study: a protocol for a prospective pragmatic randomized controlled trial to evaluate spinal anesthesia with targeted sedation compared with general anesthesia in older adults undergoing lumbar spine fusion surgery.

BACKGROUND: Postoperative delirium is common in older adults, especially in those patients undergoing spine surgery, in whom it is estimated to occur in > 30% of patients. Although previously thought to be transient, it is now recognized that delirium is associated with both short- and long-term complications. Optimizing the depth of anesthesia may represent a modifiable strategy for delirium prevention. However, previous studies have generally not focused on reducing the depth of anesthesia beyond levels consistent with general anesthesia. Additionally, the results of prior studies have been conflicting. The primary aim of this study is to determine whether reduced depth of anesthesia using spinal anesthesia reduces the incidence of delirium after lumbar fusion surgery compared with general anesthesia. METHODS: This single-center randomized controlled trial is enrolling 218 older adults undergoing lumbar fusion surgery. Patients are randomized to reduced depth of anesthesia in the context of spinal anesthesia with targeted sedation using processed electroencephalogram monitoring versus general anesthesia without processed electroencephalogram monitoring. All patients are evaluated for delirium using the Confusion Assessment Method for 3 days after surgery or until discharge and undergo assessments of cognition, function, health-related quality of life, and pain at 3- and 12-months after surgery. The primary outcome is any occurrence of delirium. The main secondary outcome is change in the Mini-Mental Status Examination (or telephone equivalent) at 3-months after surgery. DISCUSSION: Delirium is an important complication after surgery in older adults. The results of this study will examine whether reduced depth of anesthesia using spinal anesthesia with targeted depth of sedation represents a modifiable intervention to reduce the incidence of delirium and other long-term outcomes. The results of this study will be presented at national meetings and published in peer-reviewed journals with the goal of improving perioperative outcomes for older adults. TRIAL REGISTRATION: Clinicaltrials.gov , NCT03133845. This study was submitted to Clinicaltrials.gov on October 23, 2015; however, it was not formally registered until April 28, 2017 due to formatting requirements from the registry, so the formal registration is retrospective.