title: Higher C-Reactive Protein Levels Predict Postoperative Delirium in Older Patients Undergoing Major Elective Surgery: A Longitudinal Nested Case-Control Study.
abstract: Delirium is a common, morbid, and costly postoperative complication. We aimed to identify blood-based postoperative delirium markers in a nested case-control study of older surgical patients using a proteomics approach followed by enzyme-linked immunosorbent assay (ELISA) validation.
  
  
  
  The Successful Aging after Elective Surgery study enrolled dementia-free adults ≥70 years old undergoing major scheduled noncardiac surgery (N = 566; 24% delirium). Plasma was collected at four time points: preoperative, postanesthesia care unit, postoperative day 2, and 1 month postoperative. Matched pairs were selected for the independent discovery (39 pairs) and replication cohorts (36 pairs), which were subsequently combined into the pooled cohort (75 pairs). Isobaric tags for relative and absolute quantitation-based relative quantitation mass spectrometry proteomics were performed to identify the strongest delirium-related protein, which was selected for ELISA validation. Using the ELISA results, statistical analyses using nonparametric signed rank tests were performed in all cohorts examining the association between the identified protein and delirium.
  
  
  
  C-reactive protein emerged from the proteomics analysis as the strongest delirium-related protein. Validation by ELISA confirmed that compared with controls, cases had significantly higher C-reactive protein levels in the discovery, replication, and pooled cohorts at the preoperative (median paired difference [MPD] 1.97 mg/L [p < .05], 0.29 mg/L, 1.56 mg/L [p < .01]), postanesthesia care unit (MPD 2.83 mg/L, 2.22 mg/L [p < .05], 2.53 mg/L [p < .01]) and postoperative day 2 (MPD 71.97 mg/L [p < .01], 35.18 mg/L [p < .05], 63.76 mg/L [p < .01]) time points, but not 1 month postoperative (MPD 2.72 mg/L, -0.66 mg/L, 1.10 mg/L).
  
  
  
  Elevated preoperative and postoperative plasma levels of C-reactive protein were associated with delirium, suggesting that a preinflammatory state and heightened inflammatory response to surgery are potential pathophysiologic mechanisms of delirium.
authors.affiliation: Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Dillon
authors.affiliation: Division of Interdisciplinary Medicine and Biotechnology, Division of General Medicine and Primary Care, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts. Electronic address: svasunil@bidmc.harvard.edu.
authors.forename: Sarinnapha M
authors.initials: SM
authors.lastname: Vasunilashorn
authors.affiliation: Division of Interdisciplinary Medicine and Biotechnology, Division of General Medicine and Primary Care, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors.forename: Long
authors.initials: L
authors.lastname: Ngo
authors.affiliation: Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska.
authors.forename: Hasan H
authors.initials: HH
authors.lastname: Otu
authors.affiliation: Division of Gerontology, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts.
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Inouye
authors.affiliation: Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts; Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, Rhode Island.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Jones
authors.affiliation: Department of Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors.forename: David C
authors.initials: DC
authors.lastname: Alsop
authors.affiliation: University of Connecticut Center on Aging, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: George A
authors.initials: GA
authors.lastname: Kuchel
authors.affiliation: Division of Interdisciplinary Medicine and Biotechnology, Division of General Medicine and Primary Care, Boston, Massachusetts; Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts.
authors.forename: Eran D
authors.initials: ED
authors.lastname: Metzger
authors.affiliation: Harvard Medical School, Boston, Massachusetts; Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.affiliation: Division of Interdisciplinary Medicine and Biotechnology, Division of General Medicine and Primary Care, Boston, Massachusetts; Division of Gerontology, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Marcantonio
authors.affiliation: Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism*; D016022:Case-Control Studies; D003693:Delirium / Q000097:blood* / Q000175:diagnosis*; D017558:Elective Surgical Procedures; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D011183:Postoperative Complications / Q000097:blood* / Q000175:diagnosis*; D040901:Proteomics
chemical_list: D015415:Biomarkers; D002097:C-Reactive Protein
keywords: C-reactive protein; Case-control study; Delirium; Inflammation; Postoperative; Proteomics