Higher C-reactive Protein Levels Predict Postoperative Delirium in Older Patients Undergoing Major Elective Surgery: A Longitudinal Nested Case-Control Study

Authors

• Simon T. Dillon, BIDMC
• Sarinnapha M. Vasunilashorn, Harvard Medical SchoolFollow
• Long Ngo, Harvard Medical School
• Hasan H. Otu, University of Nebraska-LincolnFollow
• Sharon K. Inouye, Harvard Medical School
• Richard N. Jones, Hebrew SeniorLife
• David C. Alsop, Harvard Medical School
• George A. Kuchel, University of Connecticut Health Center
• Eran D. Metzger, BIDMC
• Steven E. Arnold, Harvard Medical School
• Edward R. Marcantonio, Harvard Medical School
• Towia A. Libermann, BIDMC

Document Type

Article

Date of this Version

2017

Citation

Biol Psychiatry. 2017 January 15; 81(2): 145–153

Comments

Copyright Society of Biological Psychiatry

doi:10.1016/j.biopsych.2016.03.2098

Abstract

Background—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.

Methods and Materials—The Successful Aging after Elective Surgery Study enrolled dementia-free adults age ≥70 undergoing major scheduled non-cardiac surgery (N=566; 24% delirium). Plasma was collected at 4 timepoints: preoperatively (PREOP), post-anesthesia care unit (PACU), postoperative day 2 (POD2) and 1 month follow-up (PO1MO). 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). iTRAQ-based relative quantitation mass spectrometry proteomics was performed to identify the strongest delirium-related protein, which was selected for ELISA validation. Using the ELISA results, statistical analyses using non-parametric signed-rank tests were performed in all cohorts examining the association between the identified protein and delirium.

Results—C-reactive protein (CRP) emerged from the proteomics analysis as the strongest delirium-related protein. ELISA validation confirmed that compared to controls, cases had significantly higher CRP levels (*p<.05, **p<.01) in the discovery, replication, and pooled cohorts at PREOP (median paired difference [mg/L] 1.97*, 0.29, 1.56**, respectively), PACU (2.83, 2.22*, 2.53**, respectively) and POD2 (71.97**, 35.18*, 63.76**, respectively), but not PO1MO (2.72, −0.66, 1.10, respectively).

Discussion—Elevated pre- and postoperative plasma levels of CRP were associated with delirium, suggesting that a pre-inflammatory state and heightened inflammatory response to surgery are potential pathophysiological mechanisms of delirium.