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Objective Postoperative delirium, a common neurocognitive complication after surgery and anesthesia, requires early detection for potential intervention. Herein, we constructed a multidimensional postoperative delirium risk‐prediction model incorporating multiple demographic parameters and blood biomarkers to enhance prediction accuracy. Methods We included 555 patients undergoing radical surgery for colorectal cancer. Demographic characteristics and lipid profiles were collected preoperatively, and perioperative anesthesia and surgical conditions were recorded; blood biomarkers were measured before and after surgery. The 3D‐CAM scale was used to assess postoperative delirium occurrence within 3 days after surgery. Patients were divided into the postoperative delirium (N = 100) and non‐postoperative delirium (N = 455) groups. Based on machine learning, linear and nine non‐linear models were developed and compared to select the optimal model. Shapley value‐interpretation methods and mediation analysis were used to assess feature importance and interaction. Results The median age of the participants was 65 years (interquartile range: 56–71 years; 57.8% male). Among the 10 machine‐learning models, the random forest model performed the best (validation cohort, area under the receiver operating characteristic curve of 0.795 [0.704–0.885]). Lipid profile (total cholesterol, triglycerides, and trimethylamine‐N‐oxide) levels were identified as key postoperative delirium predictors. Mediation analysis further confirmed mediating effects among total cholesterol, trimethylamine‐N‐oxide, and postoperative delirium; a nomogram model was developed as a web‐based tool for external validation and use by other clinicians. Interpretation Blood biomarkers are crucial in predicting postoperative delirium and aid anesthesiologists in identifying its risks in a timely manner. This model facilitates personalized perioperative management and reduces the occurrence of postoperative delirium. Trial Registration ChiCTR2300075723

Delirium's pathophysiology is poorly understood. We sought to determine if plasma biomarkers of inflammation, coagulation, endothelial activation, and blood brain barrier (BBB) injury were associated with emergency department (ED) delirium duration. We enrolled hospitalized patients who were 65 years or older from the ED. Plasma biomarkers of inflammation (interleukin-6 [IL-6], IL-8, soluble tumor necrosis factor receptor I [sTNFRI]), coagulation (Protein C), endothelial activation (plasminogen activating inhibitor-1 [PAI-1]), and BBB injury (S100B) at were measured using blood obtained at enrollment. The dependent variable was ED delirium duration which was determined by the Brief Confusion Assessment Method assessed in the ED and hospitalization. Proportional odds logistic regression analyses were performed adjusted for relevant confounders and allowing for interaction by baseline dementia status. A total of 156 patients were enrolled. IL-6 (POR = 1.59, 95%CI: 1.09-2.32) and PAI-1 (POR = 2.96, 95%CI: 1.48 to 6.85) were independently associated with more prominent ED delirium duration in subjects without dementia only. No significant associations between IL-8, Protein C, sTNRFI, and S100B and ED delirium duration were observed. Plasma Biomarkers of systemic inflammation and endothelial activation are associated with ED delirium duration in older ED patients without dementia.

Delirium is a common complication in patients with acute respiratory distress syndrome (ARDS) and is associated with poor clinical outcomes. However, studies investigating the associations between easily accessible biomarkers and early mortality or the risk of early invasive mechanical ventilation in this population remain poorly defined. This study aimed to investigate the association between the ratio of arterial partial pressure of oxygen to red cell distribution width (PaO2/RDW) and short-term outcomes in ICU patients with delirium associated with ARDS. Data were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 3.1), a large, publicly available critical care database that contains de-identified health records of patients admitted to Beth Israel Deaconess Medical Center. Adult ARDS patients with at least one positive Confusion Assessment Method for the ICU (CAM-ICU) evaluation were included. The primary outcome was all-cause mortality within seven days after delirium onset, and the secondary outcome was the initiation of invasive mechanical ventilation after ICU admission. Cox proportional hazards and cause-specific Cox regression models were applied to evaluate the associations between the PaO2/RDW ratio and clinical outcomes. Restricted cubic spline (RCS) modeling was used to explore potential nonlinear relationships, and subgroup analyses were performed to assess consistency across clinical strata. A total of 4,116 patients with ARDS were initially identified, and 1,665 patients with delirium were ultimately included in the final analysis. Compared with the highest PaO2/RDW tertile, patients in the lowest tertile had significantly higher risks of 7-day (adjusted HR = 2.12, 95% CI 1.46-3.09, P < 0.001) and 30-day mortality (adjusted HR = 1.72, 95% CI 1.33-2.22, P < 0.001). The lowest tertile was also associated with an increased risk of invasive mechanical ventilation (adjusted HR = 2.68, 95% CI 1.16-6.22, P = 0.021). Restricted cubic spline analysis revealed a U-shaped association between the PaO2/RDW ratio and 7-day mortality, with the lowest estimated hazard at approximately 6.7. Subgroup analyses showed consistent associations across age, sex, and comorbidity strata without significant interactions (P for interaction > 0.05). The PaO2/RDW ratio was independently associated with 7-day mortality after delirium onset and with the early risk of invasive mechanical ventilation among ICU patients with delirium associated with ARDS. As an easily obtainable composite index, the PaO2/RDW ratio may serve as a convenient and informative biomarker for early risk assessment and clinical decision-making in critical care settings.

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

Currently, the diagnosis of delirium is solely based on clinical observation, lacking objective diagnostic tools, and the regulatory networks and pathological mechanisms behind it are not yet fully understood. Exosomes have garnered considerable interest as potential biomarkers for a variety of illnesses. This research aimed to delineate both the proteomic and metabolomic landscapes inherent to exosomes, assessing their diagnostic utility in postoperative delirium (POD) and understanding the underlying pathophysiological frameworks. Integrated analyses of proteomics and metabolomics were conducted on exosomes derived from plasma of individuals from both the non-postoperative delirium (NPOD) control group and the POD group. Subsequently, the study utilized the Connectivity Map (CMap) methodology for the identification of promising small-molecule drugs and carried out molecular docking assessments to explore the binding affinities with the enzyme MMP9 of these identified molecules. We identified significant differences in exosomal metabolites and proteins between the POD and control groups, highlighting pathways related to neuroinflammation and blood-brain barrier (BBB) integrity. Our CMap analysis identified potential small-molecule therapeutics, and molecular docking studies revealed two compounds with high affinity to MMP9, suggesting a new therapeutic avenue for POD. This study highlights MMP9, TLR2, ICAM1, S100B, and glutamate as key biomarkers in the pathophysiology of POD, emphasizing the roles of neuroinflammation and BBB integrity. Notably, molecular docking suggests mirin and orantinib as potential inhibitors targeting MMP9, providing new therapeutic avenues. The findings broaden our understanding of POD mechanisms and suggest targeted strategies for its management, reinforcing the importance of multidimensional biomarker analysis and molecular targeting in POD intervention.

Acute kidney injury may contribute to distant organ dysfunction. Few studies have examined kidney injury as a risk factor for delirium and coma. To examine whether acute kidney injury is associated with delirium and coma in critically ill adults. In a prospective cohort study of intensive care unit patients with respiratory failure and/or shock, we examined the association between acute kidney injury and daily mental status using multinomial transition models adjusting for demographics, nonrenal organ failure, sepsis, prior mental status, and sedative exposure. Acute kidney injury was characterized daily using the difference between baseline and peak serum creatinine and staged according to Kidney Disease Improving Global Outcomes criteria. Mental status (normal vs. delirium vs. coma) was assessed daily with the Confusion Assessment Method for the ICU and Richmond Agitation-Sedation Scale. Among 466 patients, stage 2 acute kidney injury was a risk factor for delirium (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.07-2.26) and coma (OR, 2.04; 95% CI, 1.25-3.34) as was stage 3 injury (OR for delirium, 2.56; 95% CI, 1.57-4.16) (OR for coma, 3.34; 95% CI, 1.85-6.03). Daily peak serum creatinine (adjusted for baseline) values were also associated with delirium (OR, 1.35; 95% CI, 1.18-1.55) and coma (OR, 1.44; 95% CI, 1.20-1.74). Renal replacement therapy modified the association between stage 3 acute kidney injury and daily peak serum creatinine and both delirium and coma. Acute kidney injury is a risk factor for delirium and coma during critical illness.

Postoperative delirium (POD) is a significant complication of surgery that most severely affects older adults and patients with cognitive impairment. This study investigated the relationship between POD and oxidative stress, hypothesizing that increased oxidative stress, measured using diacron-reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) tests, is associated with the incidence of POD. This prospective cohort study, involving female patients who underwent unilateral or bilateral joint replacement, was conducted at the Osaka University Graduate School of Medicine from June 2022 to July 2023. Blood samples were collected preoperatively and postoperatively to measure oxidative stress markers using the REDOXLIBRA system. The primary endpoint was the association between changes in oxidative stress markers and the occurrence of POD as diagnosed using the Confusion Assessment Method for the Intensive Care Unit and Richmond Agitation–Sedation Scale. Of the 144 patients screened, 60 were eligible, of which 5 developed POD (8.3%). Analysis of oxidative stress markers revealed no significant changes between preoperative and postoperative values of d-ROMs (mean increase + 6.3 ± 54.2 U CARR) and BAP (mean decrease − 37.4 ± 322.9 µM) tests, or BAP/d-ROMs ratio (mean decrease − 0.4 ± 1.7). Further, no significant differences were observed in oxidative stress markers between patients who underwent unilateral and bilateral procedures. However, patients with POD exhibited a significantly higher increase in d-ROMs than those without complications ( p  = 0.015), whereas changes in BAP and BAP/d-ROM ratios were not statistically significant. Although general oxidative stress markers do not significantly change postoperatively, increased d-ROM levels are associated with POD occurrence, indicating that oxidative stress could be a contributing factor to its development. This study underscores the need for further research into specific oxidative markers that may predict POD and guide the development of targeted interventions to prevent this debilitating condition. Trial registration Name of the registry Association Between Changes in Blood Oxidative Stress and Postoperative Delirium Following Joint Replacement Surgery: A Retrospective Study. Trial registration number 22021. Date of registration 6/29/2022. URL of trial registry record https://bvits.dmi.med.osaka-u.ac.jp/esct/Apply/project.aspx?PROJECT_ID=6987 .

This study aimed to demonstrate whether plasma galectin-3 could predict the development of postoperative delirium (POD) in patients with acute aortic dissection (AAD). Prospective, observational study. Cardiac surgery intensive care unit. Consecutive patients who were diagnosed with AAD and operated at the Cardiac Medical Center of Fujian Province between December 2020 and December 2022. Patients were classiffed into two groups according to the Confusion Assessment Method for the Intensive Care Unit: POD group and NON-POD group. Each patient’s plasma was tested before emergency surgery. Baseline demographic data and preoperative, intraoperative, and postoperative clinical data were collected. The short-term clinical outcomes were followed up daily. The rate of POD was calculated. The risk factors for POD were analyzed through univariate analysis and multivariate logistic regression. Receiver operating characteristic (ROC) curves were used to assess the ability of plasma galectin-3 to predict POD. A total of 309 study subjects were included in this study, and the rate of POD was 38.8%. Patients with AAD were categorized into the POD and NON-POD cohorts postoperatively based on their CAM-ICU scores. There was no statistically significant difference in the baseline characteristics between the two groups ( P  > 0.05). However, patients in the POD group had significantly elevated plasma galectin-3 levels ( P  < 0.001). The ROC curves showed that plasma galectin-3 had a sensitivity of 72.5% and a specificity of 70.9% as a potential biomarker for the diagnosis of POD. The critical value of plasma galectin-3 for diagnosing POD was 9.18 ng/mL. Plasma galectin-3 levels remained an independent predictor of POD after controlling for different variables ( P  < 0.001). Elevated plasma galectin-3 levels are associated with an increased risk of POD. Plasma galectin-3 may be a prospective biomarker for predicting POD.

PurposeThe purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness.MethodsIn this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU). We collected blood samples on study days 1, 3, and 5, measuring levels of C-reactive protein (CRP), interferon gamma (IFN-γ), interleukin (IL)-1 beta (IL-1β), IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1), and protein C using validated protocols. We used multinomial logistic regression to analyze associations between biomarkers and the odds of delirium or coma versus normal mental status the following day, adjusting for age, sepsis, Sequential Organ Failure Assessment (SOFA), study day, corticosteroids, and sedatives.ResultsAmong 991 participants with a median age (interquartile range, IQR) of 62 [53–72] years and enrollment SOFA of 9 [7–11], higher concentrations of IL-6 (odds ratio [OR] [95% CI]: 1.8 [1.4–2.3]), IL-8 (1.3 [1.1–1.5]), IL-10 (1.5 [1.2–1.8]), TNF-α (1.2 [1.0–1.4]), and TNFR1 (1.3 [1.1–1.6]) and lower concentrations of protein C (0.7 [0.6–0.8])) were associated with delirium the following day. Higher concentrations of CRP (1.4 [1.1–1.7]), IFN-γ (1.3 [1.1–1.5]), IL-6 (2.3 [1.8–3.0]), IL-8 (1.8 [1.4–2.3]), and IL-10 (1.5 [1.2–2.0]) and lower concentrations of protein C (0.6 [0.5–0.8]) were associated with coma the following day. IL-1β, IL-12, and MMP-9 were not associated with mental status.ConclusionMarkers of inflammation and possibly endogenous anticoagulant activity are associated with delirium and coma during critical illness.

Delirium is a neuropsychiatric syndrome that is pathophysiologically related to both mental (dementia, depression) and physical illness. Its occurrence results in a poor prognosis. This study investigates whether specific miRNAs (miR-9-3p, miR-34c-5p, miR-96-5p, miR-183-5p, and miR-374-3p) related to brain function are associated with an increased risk of postoperative delirium. A total of 224 adult individuals scheduled for elective cardiac surgery were eligible to participate in the study. Delirium diagnosis was established with the use of the Confusion Assessment Method. Following miRNA expression profiling, cDNA synthesis was conducted on the samples obtained one day before and the day after surgery, from 60 delirium patients and 60 randomly selected non-delirium individuals. Univariate comparisons revealed that preoperative miR-96-5p (p = 0.05) and miR-183-5p (p = 0.001), along with postoperative miR-34c-5p (p = 0.009), miR-96-5p (p = 0.07), and miR-183-5p (p = 0.05), were associated with the risk of post-surgery delirium. However, after conducting multivariate logistic regression analysis, only miR-183-5p was found to be independently associated with the risk of delirium development. Other predictors of delirium included an ongoing episode of depression, peripheral vascular disease, female gender, active smoking, and increased postoperative pCO2 concentration. The current study revealed that preoperatively decreased expression of miR-183-5p predicts delirium development after cardiac surgery.