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Endothelial Activation and Blood-Brain Barrier Injury as Risk Factors for Delirium in Critically Ill Patients.

ABSTRACT: During critical illness, impaired endothelial vascular reactivity predicts prolonged acute brain dysfunction, but relationships between endothelial activation, blood-brain barrier/neurological injury, and acute brain dysfunction, including delirium, remain unexamined. We tested the hypothesis that elevated plasma markers of endothelial activation and blood-brain barrier/neurological injury are associated with delirium duration during critical illness.Prospective cohort study.Medical and surgical ICUs in an academic medical center.Adults in acute respiratory failure and/or shock.None.We enrolled subjects within 72 hours of organ failure diagnosis in the ICU. We measured plasma concentrations of plasminogen activator inhibitor-1, E-selectin, and angiopoietin-2 as markers of endothelial activation and S100B as a marker of blood-brain barrier/neurological injury in blood collected at enrollment. We assessed patients for delirium and coma twice daily after enrollment using the Confusion Assessment Method for the ICU and the Richmond Agitation-Sedation Scale. Among 134 patients with a median (interquartile) age of 57 years (46-66 yr) and Acute Physiology and Chronic Health Evaluation II of 26 (19-31), delirium occurred in 94 patients (70%) with a median duration of 2 days (0-4 d). Higher plasminogen activator inhibitor-1 (p = 0.002), E-selectin (p = 0.02), and S100B (p < 0.001) concentrations were associated with fewer delirium/coma-free days after adjusting for age, Charlson comorbidity index, modified Sequential Organ Failure Assessment score, and severe sepsis. Similarly, higher plasminogen activator inhibitor-1 (p = 0.007) and S100B (p = 0.01) concentrations were associated with longer delirium duration in survivors. Adjusting for S100B did not alter plasminogen activator inhibitor-1 and E-selectin associations with delirium, suggesting that these associations were not mediated by blood-brain barrier/neurological injury.Elevated plasma markers of endothelial activation and blood-brain barrier/neurological injury during critical illness are associated with prolonged delirium after biomarker measurement. Future research is needed to determine whether these processes have pathophysiologic roles in delirium and whether therapies targeted at the endothelium or blood-brain barrier can prevent and/or treat delirium during critical illness.

SUBMITTER: Hughes CG

PROVIDER: S-EPMC4987204 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

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Endothelial Activation and Blood-Brain Barrier Injury as Risk Factors for Delirium in Critically Ill Patients.

Hughes Christopher G CG Pandharipande Pratik P PP Thompson Jennifer L JL Chandrasekhar Rameela R Ware Lorraine B LB Ely E Wesley EW Girard Timothy D TD

Critical care medicine 20160901 9

<h4>Objectives</h4>During critical illness, impaired endothelial vascular reactivity predicts prolonged acute brain dysfunction, but relationships between endothelial activation, blood-brain barrier/neurological injury, and acute brain dysfunction, including delirium, remain unexamined. We tested the hypothesis that elevated plasma markers of endothelial activation and blood-brain barrier/neurological injury are associated with delirium duration during critical illness.<h4>Design</h4>Prospective ...[more]

PMID: 27088157

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Project description:BACKGROUND:A common postoperative complication found among patients who are critically ill is delirium, which has a high mortality rate. A predictive model is needed to identify high-risk patients in order to apply strategies which will prevent and/or reduce adverse outcomes. OBJECTIVES:To identify the incidence of, and the risk factors for, postoperative delirium (POD) in surgical intensive care unit (SICU) patients, and to determine predictive scores for the development of POD. METHODS:This study enrolled adults aged over 18 years who had undergone an operation within the preceding week and who had been admitted to a SICU for a period that was expected to be longer than 24 h. The CAM - ICU score was used to determine the occurrence of delirium. RESULTS:Of the 250 patients enrolled, delirium was found in 61 (24.4%). The independent risk factors for delirium that were identified by a multivariate analysis comprised age, diabetes mellitus, severity of disease (SOFA score), perioperative use of benzodiazepine, and mechanical ventilation. A predictive score (age + (5 × SOFA) + (15 × Benzodiazepine use) + (20 × DM) + (20 × mechanical ventilation) + (20 × modified IQCODE > 3.42)) was created. The area under the receiver operating characteristic (ROC) curve (AUC) was 0.84 (95% CI: 0.786 to 0.897). The cut point of 125 demonstrated a sensitivity of 72.13% and a specificity of 80.95%, and the hospital mortality rate was significantly greater among the delirious than the non-delirious patients (25% vs. 6%, p < 0.01). CONCLUSIONS:POD was experienced postoperatively by a quarter of the surgical patients who were critically ill. A risk score utilizing 6 variables was able to predict which patients would develop POD. The identification of high-risk patients following SICU admission can provide a basis for intervention strategies to improve outcomes. TRIAL REGISTRATION:Thai Clinical Trials Registry TCTR20181204006 . Date registered on December 4, 2018. Retrospectively registered.

Project description:BackgroundPrior retrospective cross-sectional work has associated antimicrobials with a non-specific phrase: encephalopathy without seizures. The purpose of this study is to determine whether different classes of antimicrobials have differential associations with the daily risk of delirium after critical illness is adjusted for.MethodsOur study was a nested cohort that enrolled non-neurological critically ill adults from a medical or surgical intensive care unit (ICU) with daily follow-up to 30 days. Our independent variable was exposure to previous-day antimicrobial class: beta-lactams (subclasses: penicillins, first- to third-generation cephalosporins, fourth-generation cephalosporins, and carbapenems), macrolides, fluoroquinolones, and other. We adjusted for baseline covariates (age, comorbidities, cognition scores, sepsis, and mechanical ventilation), previous-day covariates (delirium, doses of analgesics/sedatives, and antipsychotic use), and same-day covariates (illness severity). Our primary outcome of delirium was measured by using the Confusion Assessment Method for the ICU. A daily delirium logistic regression model was used with an ICU time-restricted sensitivity analysis including daily adjustment for sepsis and mechanical ventilation.ResultsOf 418 ICU patients, delirium occurred in 308 (74%) with a median of 3 days (interquartile range 2-6) among those affected and 318 (76%) were exposed to antimicrobials. When covariates and ICU type were adjusted for, only first- to third-generation cephalosporins were associated with delirium (logistic regression model odds ratio (OR) = 2.2, 95% confidence interval (CI) 1.28-3.79, P = 0.004; sensitivity analysis OR = 2.13, 95% CI 1.10-4.10, P = 0.024).ConclusionsFirst-, second-, and third-generation cephalosporins doubled the odds of delirium after baseline co-morbidities, ICU type, the course of critical care, and other competing antimicrobial and psychotropic medication risks were adjusted for. We did not find an association between delirium and cefepime, penicillins, carbapenems, fluoroquinolones, or macrolides.

Project description:Delirium is associated with increased morbidity and mortality. We implemented a delirium prevention policy in intensive care unit (ICU) patients with a high risk of developing delirium, and evaluated if our policy resulted in quality improvement of relevant delirium outcome measures.This study was a before/after evaluation of a delirium prevention project using prophylactic treatment with haloperidol. Patients with a predicted risk for delirium of ? 50%, or with a history of alcohol abuse or dementia, were identified. According to the prevention protocol these patients received haloperidol 1 mg/8 h. Evaluation was primarily focused on delirium incidence, delirium free days without coma and 28-day mortality. Results of prophylactic treatment were compared with a historical control group and a contemporary group that did not receive haloperidol prophylaxis mainly due to non-compliance to the protocol mostly during the implementation phase.In 12 months, 177 patients received haloperidol prophylaxis. Except for sepsis, patient characteristics were comparable between the prevention and the historical (n = 299) groups. Predicted chance to develop delirium was 75 ± 19% and 73 ± 22%, respectively. Haloperidol prophylaxis resulted in a lower delirium incidence (65% vs. 75%, P = 0.01), and more delirium-free-days (median 20 days (IQR 8 to 27) vs. median 13 days (3 to 27), P = 0.003) in the intervention group compared to the control group. Cox-regression analysis adjusted for sepsis showed a hazard rate of 0.80 (95% confidence interval 0.66 to 0.98) for 28-day mortality. Beneficial effects of haloperidol appeared most pronounced in the patients with the highest risk for delirium. Furthermore, haloperidol prophylaxis resulted in less ICU re-admissions (11% vs. 18%, P = 0.03) and unplanned removal of tubes/lines (12% vs. 19%, P = 0.02). Haloperidol was stopped in 12 patients because of QTc-time prolongation (n = 9), renal failure (n = 1) or suspected neurological side-effects (n = 2). No other side-effects were reported. Patients who were not treated during the intervention period (n = 59) showed similar results compared to the untreated historical control group.Our evaluation study suggests that prophylactic treatment with low dose haloperidol in critically ill patients with a high risk for delirium probably has beneficial effects. These results warrant confirmation in a randomized controlled trial.clinicaltrial.gov Identifier: NCT01187667.

Project description:Background:Multi-organ failure occurs during critical illness and is mediated in part by destructive neutrophil-to-endothelial interactions. The ?2 integrin receptor, CR3 (complement receptor 3; Mac-1; CD11b/CD18), which binds endothelial intercellular adhesion molecule-1 (ICAM-1), plays a key role in promoting the adhesion of activated neutrophils to inflamed endothelia which, when prolonged and excessive, can cause vascular damage. Leukadherin-1 (LA-1) is a small molecule allosteric activator of CR3 and has been shown to promote adhesion of blood neutrophils to inflamed endothelium and restrict tissue infiltration. Therefore, LA-1 offers a novel mechanism of anti-inflammatory action by activation, rather than inhibition, of the neutrophil CR3 integrin. However, whether promotion of neutrophil-to-endothelial interaction by this novel therapeutic is of benefit or detriment to endothelial barrier function is not known. Methods:Critically ill septic and trauma patients were prospectively enrolled from the surgical and the trauma ICU. Blood was collected from these patients and healthy volunteers. Neutrophils were isolated by dextran sedimentation and adhered to TNF-? (tumor necrosis factor-?)-activated human umbilical vein endothelial (HUVEC) monolayers in the presence or absence of fMLP (formylmethionine-leucine-phenylalanine) and/or LA-1. Electric cell-substrate impedance sensing (ECIS) and exposure of underlying collagen were used to quantify endothelial barrier function and permeability. Results:Neutrophils from critically ill trauma and septic patients caused similar degrees of endothelial barrier disruption which exceeded that caused by cells obtained from healthy controls both kinetically and quantitatively. LA-1 protected barrier function in the absence and presence of fMLP which served as a secondary stimulant to cause maximal loss of barrier function. LA-1 protection was also observed by quantifying collagen exposure underlying endothelial cells challenged with fMLP-stimulated neutrophils. LA-1 treatment resulted in decreased migration dynamics of neutrophils crawling on an endothelial monolayer with reduced speed (?m/s?=?0.25?±?0.01 vs. 0.06?±?0.01, p?<?0.05), path length (?m?=?199.5?±?14.3 vs. 42.1?±?13.0, p?<?0.05), and displacement (?m?=?65.2?±?4.7 vs. 10.4?±?1.3; p?<?0.05). Conclusion:Neutrophils from patients with trauma or sepsis cause endothelial barrier disruption to a similar extent relative to each other. The CR3 agonist LA-1 protects endothelial barrier function from damage caused by neutrophils obtained from both populations of critically ill patients even when exposed to secondary stimulation.

Project description:BackgroundTo date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae.MethodsThis multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged ≥18 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression.FindingsBetween Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40·0 (30·0 to 53·0). 1397 (66·9%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87·5%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64·0%) of 2088 patients were given benzodiazepines for a median of 7·0 days (4·0 to 12·0) and 1481 (70·9%) were given propofol for a median of 7·0 days (4·0 to 11·0). Median Richmond Agitation-Sedation Scale score while on invasive mechanical ventilation was -4 (-5 to -3). 1704 (81·6%) of 2088 patients were comatose for a median of 10·0 days (6·0 to 15·0) and 1147 (54·9%) were delirious for a median of 3·0 days (2·0 to 6·0). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p≤0·04), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p<0·0001). During the 21-day study period, patients were alive without delirium or coma for a median of 5·0 days (0·0 to 14·0). At baseline, older age, higher SAPS II scores, male sex, smoking or alcohol abuse, use of vasopressors on day 1, and invasive mechanical ventilation on day 1 were independently associated with fewer days alive and free of delirium and coma (all p<0·01). 601 (28·8%) of 2088 patients died within 28 days of admission, with most of those deaths occurring in the ICU.InterpretationAcute brain dysfunction was highly prevalent and prolonged in critically ill patients with COVID-19. Benzodiazepine use and lack of family visitation were identified as modifiable risk factors for delirium, and thus these data present an opportunity to reduce acute brain dysfunction in patients with COVID-19.FundingNone.TranslationsFor the French and Spanish translations of the abstract see Supplementary Materials section.

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Endothelial Activation and Blood-Brain Barrier Injury as Risk Factors for Delirium in Critically Ill Patients.

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Endothelial Activation and Blood-Brain Barrier Injury as Risk Factors for Delirium in Critically Ill Patients.

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