title: 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.
authors.affiliation: 1Division of Anesthesiology Critical Care Medicine, Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN.2Center for Health Services Research, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.3Anesthesia Service, Department of Veterans Affairs Medical Center, Tennessee Valley Health Care System, Nashville, TN.4Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN.5Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.6Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN.7Geriatric Research, Education and Clinical Center (GRECC) Service, Department of Veterans Affairs Medical Center, Tennessee Valley Health Care System, Nashville, TN.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Hughes
authors.forename: Pratik P
authors.initials: PP
authors.lastname: Pandharipande
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Thompson
authors.forename: Rameela
authors.initials: R
authors.lastname: Chandrasekhar
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.forename: E Wesley
authors.initials: EW
authors.lastname: Ely
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Girard
mesh_terms: D000328:Adult; D042702:Angiopoietin-2 / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001812:Blood-Brain Barrier / Q000293:injuries*; D016638:Critical Illness; D003693:Delirium / Q000209:etiology*; D019040:E-Selectin / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011446:Prospective Studies; D012131:Respiratory Insufficiency / Q000097:blood / Q000523:psychology* / Q000628:therapy; D012307:Risk Factors; D064568:S100 Calcium Binding Protein beta Subunit / Q000097:blood; D012769:Shock / Q000097:blood / Q000523:psychology* / Q000628:therapy
chemical_list: D042702:Angiopoietin-2; D015415:Biomarkers; D019040:E-Selectin; D017395:Plasminogen Activator Inhibitor 1; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human