Age-Related Perioperative Neurocognitive Disorders: Experimental Models and Druggable Targets.

With the worldwide increase in life span, surgical patients are becoming older and have a greater propensity for postoperative cognitive impairment, either new onset or through deterioration of an existing condition; in both conditions, knowledge of the patient's preoperative cognitive function and postoperative cognitive trajectory is imperative. We describe the clinical utility of a tablet-based technique for rapid assessment of the memory and attentiveness domains required for executive function. The pathogenic mechanisms for perioperative neurocognitive disorders have been investigated in animal models in which excessive and/or prolonged postoperative neuroinflammation has emerged as a likely contender. The cellular and molecular species involved in postoperative neuroinflammation are the putative targets for future therapeutic interventions that are efficacious and do not interfere with the surgical patient's healing process.

Haloperidol for the Treatment of Delirium in ICU Patients.

BACKGROUND: Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. METHODS: In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. RESULTS: A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P = 0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. CONCLUSIONS: Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo. (Funded by Innovation Fund Denmark and others; AID-ICU ClinicalTrials.gov number, NCT03392376; EudraCT number, 2017-003829-15.).

Cerebral Embolic Protection during Transcatheter Aortic-Valve Replacement.

BACKGROUND: Transcatheter aortic-valve replacement (TAVR) for the treatment of aortic stenosis can lead to embolization of debris. Capture of debris by devices that provide cerebral embolic protection (CEP) may reduce the risk of stroke. METHODS: We randomly assigned patients with aortic stenosis in a 1:1 ratio to undergo transfemoral TAVR with CEP (CEP group) or without CEP (control group). The primary end point was stroke within 72 hours after TAVR or before discharge (whichever came first) in the intention-to-treat population. Disabling stroke, death, transient ischemic attack, delirium, major or minor vascular complications at the CEP access site, and acute kidney injury were also assessed. A neurology professional examined all the patients at baseline and after TAVR. RESULTS: A total of 3000 patients across North America, Europe, and Australia underwent randomization; 1501 were assigned to the CEP group and 1499 to the control group. A CEP device was successfully deployed in 1406 of the 1489 patients (94.4%) in whom an attempt was made. The incidence of stroke within 72 hours after TAVR or before discharge did not differ significantly between the CEP group and the control group (2.3% vs. 2.9%; difference, -0.6 percentage points; 95% confidence interval, -1.7 to 0.5; P = 0.30). Disabling stroke occurred in 0.5% of the patients in the CEP group and in 1.3% of those in the control group. There were no substantial differences between the CEP group and the control group in the percentage of patients who died (0.5% vs. 0.3%); had a stroke, a transient ischemic attack, or delirium (3.1% vs. 3.7%); or had acute kidney injury (0.5% vs. 0.5%). One patient (0.1%) had a vascular complication at the CEP access site. CONCLUSIONS: Among patients with aortic stenosis undergoing transfemoral TAVR, the use of CEP did not have a significant effect on the incidence of periprocedural stroke, but on the basis of the 95% confidence interval around this outcome, the results may not rule out a benefit of CEP during TAVR. (Funded by Boston Scientific; PROTECTED TAVR ClinicalTrials.gov number, NCT04149535.).

Mitochondrial Dysfunction of Peripheral Platelets as a Predictive Biomarker for Postoperative Delirium in Elderly Patients.

OBJECTIVE: To determine the association between the preoperative Bioenergetic Health Index (BHI) of platelets and the occurrence of postoperative delirium (POD) in elderly patients. METHODS: Elderly patients scheduled for major abdominal surgery under general anesthesia were included. The presence of POD was assessed within the 3 days after surgery. Seahorse XF analysis and transmission electron microscopy were utilized to evaluate the mitochondrial metabolism and morphology of platelets. RESULTS: A total of 20 out of 162 participants developed POD. Participants with POD showed lower preoperative Mini-Mental State Examination scores and total protein levels, fewer educational years, longer surgery duration, higher mean platelet volume, and lower platelet BHI compared with those without POD. Damaged mitochondria with swollen appearance and distorted cristae was detected in platelets from participants with POD. Preoperative platelet BHI was independently associated with the occurrence of POD after adjusting for age, education, preoperative Mini-Mental State Examination score, preoperative mean platelet volume and total protein levels, surgical type and duration, and lymphocyte counts on the first postoperative day (OR 0.11, 95% CI 0.03-0.37, p < 0.001). The areas under the receiver operating curves for predicting POD were 0.83 (95% CI 0.76-0.88) for platelet BHI. It showed a sensitivity of 85.00% and specificity of 73.24%, with an optimal cutoff value of 1.61. Using a serial combination (mean platelet volume followed by BHI) yielded a sensitivity of 80.00% and specificity of 82.39%. INTERPRETATION: Preoperative platelet BHI was independently associated with the occurrence of POD in elderly patients and has the potential as a screening biomarker for POD risk. ANN NEUROL 2024;96:74-86.

Impaired glucose utilization in the brain of patients with delirium following hip fracture.

Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and ß-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, ß-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.

An exploratory research report on brain mineralization in postoperative delirium and cognitive decline.

Delirium is a severe postoperative complication associated with poor overall and especially neurocognitive prognosis. Altered brain mineralization is found in neurodegenerative disorders but has not been studied in postoperative delirium and postoperative cognitive decline. We hypothesized that mineralization-related hypointensity in susceptibility-weighted magnetic resonance imaging (SWI) is associated with postoperative delirium and cognitive decline. In an exploratory, hypothesis-generating study, we analysed a subsample of cognitively healthy patients ≥65 years who underwent SWI before (N = 65) and 3 months after surgery (N = 33). We measured relative SWI intensities in the basal ganglia, hippocampus and posterior basal forebrain cholinergic system (pBFCS). A post hoc analysis of two pBFCS subregions (Ch4, Ch4p) was conducted. Patients were screened for delirium until the seventh postoperative day. Cognitive testing was performed before and 3 months after surgery. Fourteen patients developed delirium. After adjustment for age, sex, preoperative cognition and region volume, only pBFCS hypointensity was associated with delirium (regression coefficient [90% CI]: B = -15.3 [-31.6; -0.8]). After adjustments for surgery duration, age, sex and region volume, perioperative change in relative SWI intensities of the pBFCS was associated with cognitive decline 3 months after surgery at a trend level (B = 6.8 [-0.9; 14.1]), which was probably driven by a stronger association in subregion Ch4p (B = 9.3 [2.3; 16.2]). Brain mineralization, particularly in the cerebral cholinergic system, could be a pathomechanism in postoperative delirium and cognitive decline. Evidence from our studies is limited because of the small sample and a SWI dataset unfit for iron quantification, and the analyses presented here should be considered exploratory.

Treatment of Delirium During Critical Illness.

Delirium, an acute disturbance in mental status due to another medical condition, is common and morbid in the intensive care unit. Despite its clear association with multiple common risk factors and important outcomes, including mortality and long-term cognitive impairment, both the ultimate causes of and ideal treatments for delirium remain unclear. Studies suggest that neuroinflammation, hypoxia, alterations in energy metabolism, and imbalances in multiple neurotransmitter pathways contribute to delirium, but commonly used treatments (e.g., antipsychotic medications) target only one or a few of these potential mechanisms and are not supported by evidence of efficacy. At this time, the optimal treatment for delirium during critical illness remains avoidance of risk factors, though ongoing trials may expand on the promise shown by agents such as melatonin and dexmedetomidine.

New Onset Geriatric Syndromes and One-year Outcomes Following Elective Gastrointestinal Cancer Surgery.

OBJECTIVE: To assess whether older adults who develop geriatric syndromes following elective gastrointestinal surgery have poorer 1-year outcomes. BACKGROUND: Within 10 years, 70% of all cancers will occur in older adults ≥65 years old. The rise in older adults requiring major surgery has brought attention to age-related complications termed geriatric syndromes. However, whether postoperative geriatric syndromes are associated with long-term outcomes is unclear. METHODS: A population-based retrospective cohort study using the New York State Cancer Registry and the Statewide Planning and Research Cooperative System was performed including patients >55 years with pathologic stage I-III esophageal, gastric, pancreatic, colon, or rectal cancer who underwent elective resection between 2004 and 2018. Those aged 55 to 64 served as the reference group. The exposure of interest was a geriatric syndrome [fracture, fall, delirium, pressure ulcer, depression, malnutrition, failure to thrive, dehydration, or incontinence (urinary/fecal)] during the surgical admission. Patients with any geriatric syndrome within 1 year of surgery were excluded. Outcomes included incident geriatric syndrome, 1-year days alive and out of the hospital, and 1-year all-cause mortality. RESULTS: In this study, 37,998 patients with a median age of 71 years without a prior geriatric syndrome were included. Of those 65 years or more, 6.4% developed a geriatric syndrome. Factors associated with an incident geriatric syndrome were age, alcohol/tobacco use, comorbidities, neoadjuvant therapy, ostomies, open surgery, and upper gastrointestinal cancers. An incident geriatric syndrome was associated with a 43% higher risk of 1-year mortality (hazard ratio, 1.43; 95% confidence interval, 1.27-1.60). For those aged 65+ discharged alive and not to hospice, a geriatric syndrome was associated with significantly fewer days alive and out of hospital (322 vs 346 days, P < 0.0001). There was an indirect relationship between the number of geriatric syndromes and 1-year mortality and days alive and out of the hospital after adjusting for surgical complications. CONCLUSIONS: Given the increase in older adults requiring major surgical intervention, and the establishment of geriatric surgery accreditation programs, these data suggest that morbidity and mortality metrics should be adjusted to accommodate the independent relationship between geriatric syndromes and long-term outcomes.

Improved Symptom Change Enhances Quality of Dying in Patients With Advanced Cancer: An East Asian Cross-Cultural Study.

BACKGROUND: Symptom burdens tend to increase for patients with cancer and their families over the disease trajectory. There is still a lack of evidence on the associations between symptom changes and the quality of dying and death. In this context, this research investigated how symptom changes influence the quality of dying and death. METHODS: This international prospective cohort study (the East Asian Collaborative Cross-Cultural Study to Elucidate the Dying Process (EASED), 2017-2019) included 22, 11, and 4 palliative care units across Japan, South Korea, and Taiwan. Eligible participants were adults (Japan and Korea, ≥18 years; Taiwan, ≥20 years) with locally advanced or metastatic cancer. Physical and psychological symptoms were assessed by physicians upon admission and within 3 days before death. Death quality was assessed using the Good Death Scale (GDS), developed in Taiwan. Univariate and multivariate regression analyses were used to identify correlations between symptom severity changes and GDS scores. RESULTS: Among 998 patients (542 [54.3%] men and 456 [45.7%] women; mean [SD] age = 70.1 [± 12.5] years), persistent dyspnea was associated with lower GDS scores when compared to stable dyspnea (ß = -0.427, 95% CI = -0.783 to -0.071). Worsened (-1.381, -1.932 to -0.831) and persistent (-1.680, -2.701 to -0.659) delirium were also significantly associated with lower GDS scores. CONCLUSIONS: Better quality of dying and death was associated with improved symptom control, especially for dyspnea and delirium. Integrating an outcome measurement for the quality of dying and death is important in the management of symptoms across the disease trajectory in a goal-concordant manner.

Spinal Anesthesia or General Anesthesia for Hip Surgery in Older Adults.

BACKGROUND: The effects of spinal anesthesia as compared with general anesthesia on the ability to walk in older adults undergoing surgery for hip fracture have not been well studied. METHODS: We conducted a pragmatic, randomized superiority trial to evaluate spinal anesthesia as compared with general anesthesia in previously ambulatory patients 50 years of age or older who were undergoing surgery for hip fracture at 46 U.S. and Canadian hospitals. Patients were randomly assigned in a 1:1 ratio to receive spinal or general anesthesia. The primary outcome was a composite of death or an inability to walk approximately 10 ft (3 m) independently or with a walker or cane at 60 days after randomization. Secondary outcomes included death within 60 days, delirium, time to discharge, and ambulation at 60 days. RESULTS: A total of 1600 patients were enrolled; 795 were assigned to receive spinal anesthesia and 805 to receive general anesthesia. The mean age was 78 years, and 67.0% of the patients were women. A total of 666 patients (83.8%) assigned to spinal anesthesia and 769 patients (95.5%) assigned to general anesthesia received their assigned anesthesia. Among patients in the modified intention-to-treat population for whom data were available, the composite primary outcome occurred in 132 of 712 patients (18.5%) in the spinal anesthesia group and 132 of 733 (18.0%) in the general anesthesia group (relative risk, 1.03; 95% confidence interval [CI], 0.84 to 1.27; P = 0.83). An inability to walk independently at 60 days was reported in 104 of 684 patients (15.2%) and 101 of 702 patients (14.4%), respectively (relative risk, 1.06; 95% CI, 0.82 to 1.36), and death within 60 days occurred in 30 of 768 (3.9%) and 32 of 784 (4.1%), respectively (relative risk, 0.97; 95% CI, 0.59 to 1.57). Delirium occurred in 130 of 633 patients (20.5%) in the spinal anesthesia group and in 124 of 629 (19.7%) in the general anesthesia group (relative risk, 1.04; 95% CI, 0.84 to 1.30). CONCLUSIONS: Spinal anesthesia for hip-fracture surgery in older adults was not superior to general anesthesia with respect to survival and recovery of ambulation at 60 days. The incidence of postoperative delirium was similar with the two types of anesthesia. (Funded by the Patient-Centered Outcomes Research Institute; REGAIN ClinicalTrials.gov number, NCT02507505.).

Modification in ICU Design May Affect Delirium and Circadian Melatonin: A Proof of Concept Pilot Study.

OBJECTIVES: Nonpharmacologic delirium management is recommended by current guidelines, but studies on the impact of ICU design are still limited. The study's primary purpose was to determine if a multicomponent change in room design prevents ICU delirium. Second, the influence of lighting conditions on serum melatonin was assessed. DESIGN: Prospective observational cohort pilot study. SETTING: The new design concept was established in two two-bed ICU rooms of a university hospital. Besides modifications aimed at stress relief, it includes a new dynamic lighting system. PATIENTS: Seventy-four adult critically ill patients on mechanical ventilation with an expected ICU length of stay of at least 48 hours, treated in modified or standard rooms. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The clinical examination included a prospective assessment for depth of sedation, delirium, and pain every 8 hours using validated scores. Blood samples for serum melatonin profiles were collected every 4 hours for a maximum of three 24-hour periods. Seventy-four patients were included in the analysis. Seventy-six percent ( n = 28) of patients in the standard rooms developed delirium compared with 46% of patients ( n = 17) in the modified rooms ( p = 0.017). Patients in standard rooms (vs. modified rooms) had a 2.3-fold higher delirium severity (odds ratio = 2.292; 95% CI, 1.582-3.321; p < 0.0001). Light intensity, calculated using the measure of circadian effective irradiance, significantly influenced the course of serum melatonin ( p < 0.0001). Significant interactions ( p < 0.001) revealed that differences in serum melatonin between patients in standard and modified rooms were not the same over time but varied in specific periods of time. CONCLUSIONS: Modifications in ICU room design may influence the incidence and severity of delirium. Dedicated light therapy could potentially influence delirium outcomes by modulating circadian melatonin levels.

From Traditional Typing to Intelligent Insights: A Narrative Review of Directions Toward Targeted Therapies in Delirium.

Delirium is a heterogeneous syndrome characterized by an acute change in level of consciousness that is associated with inattention and disorganized thinking. Delirium affects most critically ill patients and is associated with poor patient-oriented outcomes such as increased mortality, longer ICU and hospital length of stay, and worse long-term cognitive outcomes. The concept of delirium and its subtypes has existed since nearly the beginning of recorded medical literature, yet robust therapies have yet to be identified. Analogous to other critical illness syndromes, we suspect the lack of identified therapies stems from patient heterogeneity and prior subtyping efforts that do not capture the underlying etiology of delirium. The time has come to leverage machine learning approaches, such as supervised and unsupervised clustering, to identify clinical and pathophysiological distinct clusters of delirium that will likely respond differently to various interventions. We use sedation in the ICU as an example of how precision therapies can be applied to critically ill patients, highlighting the fact that while for some patients a sedative drug may cause delirium, in another cohort sedation is the specific treatment. Finally, we conclude with a proposition to move away from the term delirium, and rather focus on the treatable traits that may allow precision therapies to be tested.

Clinical Impact of the Implementation Strategies Used to Apply the 2013 Pain, Agitation/Sedation, Delirium or 2018 Pain, Agitation/Sedation, Delirium, Immobility, Sleep Disruption Guideline Recommendations: A Systematic Review and Meta-Analysis.

OBJECTIVES: To summarize the effectiveness of implementation strategies for ICU execution of recommendations from the 2013 Pain, Agitation/Sedation, Delirium (PAD) or 2018 PAD, Immobility, Sleep Disruption (PADIS) guidelines. DATA SOURCES: PubMed, CINAHL, Scopus, and Web of Science were searched from January 2012 to August 2023. The protocol was registered with PROSPERO (CRD42020175268). STUDY SELECTION: Articles were included if: 1) design was randomized or cohort, 2) adult population evaluated, 3) employed recommendations from greater than or equal to two PAD/PADIS domains, and 4) evaluated greater than or equal to 1 of the following outcome(s): short-term mortality, delirium occurrence, mechanical ventilation (MV) duration, or ICU length of stay (LOS). DATA EXTRACTION: Two authors independently reviewed articles for eligibility, number of PAD/PADIS domains, quality according to National Heart, Lung, and Blood Institute assessment tools, implementation strategy use (including Assess, prevent, and manage pain; Both SAT and SBT; Choice of analgesia and sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; Family engagement and empowerment [ABCDEF] bundle) by Cochrane Effective Practice and Organization of Care (EPOC) category, and clinical outcomes. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation. DATA SYNTHESIS: Among the 25 of 243 (10.3%) full-text articles included ( n = 23,215 patients), risk of bias was high in 13 (52%). Most studies were cohort ( n = 22, 88%). A median of 5 (interquartile range [IQR] 4-7) EPOC strategies were used to implement recommendations from two (IQR 2-3) PAD/PADIS domains. Cohort and randomized studies were pooled separately. In the cohort studies, use of EPOC strategies was not associated with a change in mortality (risk ratio [RR] 1.01; 95% CI, 0.9-1.12), or delirium (RR 0.92; 95% CI, 0.82-1.03), but was associated with a reduction in MV duration (weighted mean difference [WMD] -0.84 d; 95% CI, -1.25 to -0.43) and ICU LOS (WMD -0.77 d; 95% CI, -1.51 to 0.04). For randomized studies, EPOC strategy use was associated with reduced mortality and MV duration but not delirium or ICU LOS. CONCLUSIONS: Using multiple implementation strategies to adopt PAD/PADIS guideline recommendations may reduce mortality, duration of MV, and ICU LOS. Further prospective, controlled studies are needed to identify the most effective strategies to implement PAD/PADIS recommendations.

Delirium During Critical Illness and Subsequent Change of Treatment in Patients With Cancer: A Mediation Analysis.

OBJECTIVES: To assess whether delirium during ICU stay is associated with subsequent change in treatment of cancer after discharge. DESIGN: Retrospective cohort study. SETTING: A 50-bed ICU in a dedicated cancer center. PATIENTS: Patients greater than or equal to 18 years old with a previous proposal of cancer treatment (chemotherapy, target therapy, hormone therapy, immunotherapy, radiotherapy, oncologic surgery, and bone marrow transplantation). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We considered delirium present if Confusion Assessment Method for the ICU was positive. We assessed the association between delirium and modification of the treatment after discharge. We also performed a mediation analysis to assess both the direct and indirect (i.e., mediated by the development of functional dependence after discharge) of delirium on modification of cancer treatment and whether the modification of cancer treatment was associated with mortality at 1 year. We included 1,134 patients, of whom, 189 (16.7%) had delirium. Delirium was associated with the change in cancer treatment (adjusted odds ratio [OR], 3.80; 95% CI, 2.72-5.35). The association between delirium in ICU and change of treatment was both direct and mediated by the development of functional dependence after discharge. The proportion of the total effect of delirium on change of treatment mediated by the development of functional dependence after discharge was 33.0% (95% CI, 21.7-46.0%). Change in treatment was associated with increased mortality at 1 year (adjusted OR, 2.68; 95% CI, 2.01-3.60). CONCLUSIONS: Patients who had delirium during ICU stay had a higher rate of modification of cancer treatment after discharge. The effect of delirium on change in cancer treatment was only partially mediated by the development of functional dependence after discharge. Change in cancer treatment was associated with increased 1-year mortality.

Antipsychotics in the Treatment of Delirium in Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To conduct a systematic review and meta-analysis assessing whether the use of antipsychotic medications in critically ill adult patients with delirium impacts patient-important outcomes. DATA SOURCES: A medical librarian searched Ovid MEDLINE, EMBASE, APA PsycInfo, and Wiley's Cochrane Library as well as clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform up to November 2023. STUDY SELECTION: Independently and in duplicate, reviewers screened abstracts and titles for eligibility, then full text of qualifying studies. We included parallel-group randomized controlled trials (RCTs) that included critically ill adult patients with delirium. The intervention group was required to receive antipsychotic medications at any dose, whereas the control group received usual care or placebo. DATA EXTRACTION: Reviewers extracted data independently and in duplicate using a piloted abstraction form. Statistical analyses were conducted using RevMan software (version 5.4). DATA SYNTHESIS: Five RCTs ( n = 1750) met eligibility criteria. The use of antipsychotic medications compared with placebo did not increase the number of delirium- or coma-free days (mean difference 0.90 d; 95% CI, -0.32 to 2.12; moderate certainty), nor did it result in a difference in mortality, duration of mechanical ventilation, ICU, or hospital length of stay. The use of antipsychotics did not result in an increased risk of adverse events (risk ratio 1.27; 95% CI, 0.71-2.30; high certainty). Subgroup analysis of typical versus atypical antipsychotics did not identify any subgroup effect for any outcome. CONCLUSIONS: In conclusion, our systematic review and meta-analysis demonstrated with moderate certainty that there is no difference in delirium- or coma-free days when delirious critically ill adults are treated with antipsychotic medications. Further studies in the subset of patients with hyperactive delirium may be of benefit.

The Role of Delirium on Short- and Long-Term Postoperative Outcomes Following Major Gastrointestinal Surgery for Cancer.

INTRODUCTION: The growing burden of an aging population has raised concerns about demands on healthcare systems and resources, particularly in the context of surgical and cancer care. Delirium can affect treatment outcomes and patient recovery. We sought to determine the prevalence of postoperative delirium among patients undergoing digestive tract surgery for malignant indications and to analyze the role of delirium on surgical outcomes. METHODS: Medicare claims data were queried to identify patients diagnosed with esophageal, gastric, hepatobiliary, pancreatic, and colorectal cancers between 2018 and 2021. Postoperative delirium, occurring within 30 days of operation, was identified via International Classification of Diseases, 10th edition codes. Clinical outcomes of interested included "ideal" textbook outcome (TO), characterized as the absence of complications, an extended hospital stay, readmission within 90 days, or mortality within 90 days. Discharge disposition, intensive care unit (ICU) utilization, and expenditures also were examined. RESULTS: Among 115,654 cancer patients (esophageal: n = 1854, 1.6%; gastric: n = 4690, 4.1%; hepatobiliary: n = 6873, 5.9%; pancreatic: n = 8912, 7.7%; colorectal: n = 93,325, 90.7%), 2831 (2.4%) were diagnosed with delirium within 30 days after surgery. On multivariable analysis, patients with delirium were less likely to achieve TO (OR 0.27 [95% CI 0.25-0.30]). In particular, patients who experienced delirium had higher odds of complications (OR 3.00 [2.76-3.25]), prolonged length of stay (OR 3.46 [3.18-3.76]), 90-day readmission (OR 1.96 [1.81-2.12]), and 90-day mortality (OR 2.78 [2.51-3.08]). Furthermore, patients with delirium had higher ICU utilization (OR 2.85 [2.62-3.11]). Upon discharge, patients with delirium had a decreased likelihood of being sent home (OR 0.40 [0.36-0.46]) and instead were more likely to be transferred to a skilled nursing facility (OR 2.17 [1.94-2.44]). Due to increased utilization of hospital resources, patients with delirium incurred in-hospital expenditures that were 55.4% higher (no delirium: $16,284 vs. delirium: $28,742) and 90-day expenditures that were 100.7% higher (no delirium: $2564 vs. delirium: $8226) (both p < 0.001). Notably, 3-year postoperative survival was adversely affected by delirium (no delirium: 55.5% vs. delirium: 37.3%), even after adjusting risk for confounding factors (HR 1.79 [1.70-1.90]; p < 0.001). CONCLUSIONS: Postoperative delirium occurred in one in 50 patients undergoing surgical resection of a digestive tract cancer. Delirium was linked to a reduced likelihood of achieving an optimal postoperative outcome, increased ICU utilization, higher expenditures, and a worse long-term prognosis. Initiatives to prevent delirium are vital to improve postoperative outcomes among cancer surgery patients.

Role of Blood-Brain Barrier Dysfunction in Delirium following Non-cardiac Surgery in Older Adults.

OBJECTIVE: Although animal models suggest a role for blood-brain barrier dysfunction in postoperative delirium-like behavior, its role in postoperative delirium and postoperative recovery in humans is unclear. Thus, we evaluated the role of blood-brain barrier dysfunction in postoperative delirium and hospital length of stay among older surgery patients. METHODS: Cognitive testing, delirium assessment, and cerebrospinal fluid and blood sampling were prospectively performed before and after non-cardiac, non-neurologic surgery. Blood-brain barrier dysfunction was assessed using the cerebrospinal fluid-to-plasma albumin ratio (CPAR). RESULTS: Of 207 patients (median age = 68 years, 45% female) with complete CPAR and delirium data, 26 (12.6%) developed postoperative delirium. Overall, CPAR increased from before to 24 hours after surgery (median change = 0.28, interquartile range [IQR] = -0.48 to 1.24, Wilcoxon p = 0.001). Preoperative to 24 hours postoperative change in CPAR was greater among patients who developed delirium versus those who did not (median [IQR] = 1.31 [0.004 to 2.34] vs 0.19 [-0.55 to 1.08], p = 0.003). In a multivariable model adjusting for age, baseline cognition, and surgery type, preoperative to 24 hours postoperative change in CPAR was independently associated with delirium occurrence (per CPAR increase of 1, odds ratio = 1.30, 95% confidence interval [CI] = 1.03-1.63, p = 0.026) and increased hospital length of stay (incidence rate ratio = 1.15, 95% CI = 1.09-1.22, p < 0.001). INTERPRETATION: Postoperative increases in blood-brain barrier permeability are independently associated with increased delirium rates and postoperative hospital length of stay. Although these findings do not establish causality, studies are warranted to determine whether interventions to reduce postoperative blood-brain barrier dysfunction would reduce postoperative delirium rates and hospital length of stay. ANN NEUROL 2023;94:1024-1035.

Circadian Rest-Activity Rhythms, Delirium Risk, and Progression to Dementia.

OBJECTIVE: Delirium is a complex neurocognitive syndrome suspected to be bidirectionally linked to dementia. Circadian rhythm disturbances likely contribute to dementia pathogenesis, but whether these disturbances are related to delirium risk and progression to all-cause dementia is unknown. METHODS: We analyzed continuous actigraphy data from 53,417 middle-aged or older UK Biobank participants during a median 5 years of follow-up. Four measures were used to characterize the 24-hour daily rest-activity rhythms (RARs): normalized amplitude, acrophase representing the peak activity time, interdaily stability, and intradaily variability (IV) for fragmentation of the rhythm. Cox proportional hazards models examined whether RARs predicted incident delirium (n = 551) and progression to dementia (n = 61). RESULTS: Suppressed 24-hour amplitude, lowest (Q1) versus highest (Q4) quartile (hazard ratio [HR]Q1 vs Q4 = 1.94, 95% confidence interval [CI] = 1.53-2.46, p < 0.001), and more fragmented (higher IV: HRQ4 vs Q1 = 1.49, 95% CI = 1.18-1.88, p < 0.001) rhythms predicted higher delirium risk, after adjusting for age, sex, education, cognitive performance, sleep duration/disturbances, and comorbidities. In those free from dementia, each hour of delayed acrophase was associated with delirium risk (HR = 1.13, 95% CI = 1.04-1.23, p = 0.003). Suppressed 24-hour amplitude was associated with increased risk of progression from delirium to new onset dementia (HR = 1.31, 95% CI = 1.03-1.67, p = 0.03 for each 1-standard deviation decrease). INTERPRETATION: Twenty-four-hour daily RAR suppression, fragmentation, and potentially delayed acrophase were associated with delirium risk. Subsequent progression to dementia was more likely in delirium cases with suppressed rhythms. The presence of RAR disturbances before delirium and prior to progression to dementia suggests that these disturbances may predict higher risk and be involved in early disease pathogenesis. ANN NEUROL 2023;93:1145-1157.

Efficacy and Safety of Risperidone in Patients With Delirium: The RIDDLE Pilot Study.

BACKGROUND: The cornerstone treatment of delirium is to assess and treat its underlying causes and prevent further complications. Drug therapy may be necessary to control agitation and behavioral symptoms associated with delirium. The aim of this pilot study was to evaluate the feasibility of a randomized placebo controlled trial to evaluate the efficacy and safety of risperidone in the treatment of delirium. METHODS: This was a randomized double-blinded placebo-controlled trial. Patients were enrolled in the study if they were hospitalized and 65 years or older and had a diagnosis of delirium. Delirium Rating Scale revised 98 was used to determine delirium and motor agitation. RESULTS: A total of 14 participants with 57% being men and having a mean age of 86 years were included. There were no statistically significant differences between the risperidone and placebo group for the Delirium Rating Scale revised 98 score. There were no severe adverse reactions reported in the study, and no patients discontinued the study for adverse reactions. CONCLUSIONS: Risperidone at low doses (1 mg daily or less) was well tolerated for the treatment of delirium. Future large-scale trials are needed to evaluate the safety and efficacy of risperidone in the treatment of delirium. This pilot study taught us that the phase 2 RIsperDone DELirium trial will need a multicenter design with more research personnel to increase the number of participants enrolled.

Preventive Effects of Ramelteon, Suvorexant, and Lemborexant on Delirium in Hospitalized Patients With Physical Disease: A Retrospective Cohort Study.

BACKGROUND: New sleep-inducing drugs (eg, ramelteon, suvorexant, and lemborexant) have been shown to prevent delirium in high-risk groups. However, no single study has simultaneously evaluated the delirium-preventing effects of all novel sleep-inducing drugs in hospitalized patients. Therefore, this study aimed to clarify the relationship between sleep-inducing drugs and delirium prevention in patients hospitalized in general medical-surgical settings for nonpsychiatric conditions who underwent liaison interventions for insomnia. METHODS: This retrospective cohort study included patients treated in general medical-surgical settings for nonpsychiatric conditions with consultation-liaison psychiatry consult for insomnia. Delirium was diagnosed by fully certified psychiatrists using the Diagnostic and Statistical Manual of Mental Disorders 5 th edition. The following items were retrospectively examined from medical records as factors related to delirium development: type of sleep-inducing drugs, age, sex, and delirium risk factors. The risk factors of delirium development were calculated using adjusted odds ratios (aORs) via multivariate logistic regression analysis. RESULTS: Among the 710 patients analyzed, 257 (36.2%) developed delirium. Suvorexant (aOR, 0.61; 95% confidence interval [CI], 0.40-0.94; P = 0.02) and lemborexant (aOR, 0.23; 95% CI, 0.14-0.39; P < 0.0001) significantly reduced the risk of developing delirium. Benzodiazepines (aOR, 1.90; 95% CI, 1.15-3.13; P = 0.01) significantly increased this risk. Ramelteon (aOR, 1.30; 95% CI, 0.84-2.01; P = 0.24) and Z-drugs (aOR, 1.27; 95% CI, 0.81-1.98; P = 0.30) were not significantly associated with delirium development. CONCLUSIONS: The use of suvorexant and lemborexant may prevent delirium in patients with a wide range of medical conditions.