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

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.