Preoperative cognitive impairment and adverse geriatric surgical outcomes: role of dysfunctional immunity

Brigham And Women'S Hospital, Boston MA

Investigators

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Abstract

Program Director/Principal Investigator (Last, First, Middle): Culley, Deborah J ABSTRACT: Older patients account for over one-third of surgical procedures but unfortunately have disproportionately high morbidity. Many are cognitively impaired prior to surgery and this increases risk for postoperative delirium and other adverse outcomes. The critical unanswered questions are why this is so and what can be done about it. We propose that cognitively impaired patients have more morbidity because they are unable to adequately activate physiological resolution programs to combat surgery-induced inflammation and, consequently, that augmenting resolution will reverse that phenotype and improve outcomes. In support, we provide preliminary evidence that 25-40% of older elective patients are cognitively impaired before surgery and that this impairment is associated with postoperative delirium and failure to be discharged home. In addition, we show that surgery increases plasma IL6 more in older than younger patients and produces substantial postoperative changes in immune gene expression in circulating monocytes, but that plasma resolvins increase considerably less, particularly in individuals with cognitive impairment. This suggests there is an imbalance between pro-resolution and inflammatory responses at both the humoral and cellular levels after surgery in this population. We will investigate this possibility by characterizing resolution physiology in the older surgical patient, assessing inadequate resolution of inflammation as a mechanism for postoperative delirium, and by conducting a pilot clinical trial of a medication that increases plasma lipid pro-resolving mediators to potentially reduce delirium risk and improve outcomes. To do so, we will enroll a cohort of older patients (? 70 years) having elective major lower extremity joint replacement surgery and determine cognitive status preoperatively by MiniCog; delirium by direct testing (3D-CAM); failure to be discharged home by chart review; and resolution / inflammation state before and after surgery by plasma resolvin and cytokine assays, monocyte immune gene expression / pathway analysis, and in vitro monocyte functional assays. This proposal is significant because it deals with major clinical problems in older patients and is innovative because it will generate new information about fundamental aspects of resolution biology in the older person, provide a mechanism for why cognitive impairment is associated with delirium, and possibly discover an age- and cognition-specific novel medical management strategy to reduce the risk of delirium and improve outcomes of geriatric surgery. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page