A Novel Stress-Diathesis Model to Predict Risk of Post-operative Delirium: Implications for Intra-operative Management

Renée El-Gabalawy, Ronak Patel, Kayla Kilborn, Caitlin Blaney, Christopher Hoban, Lawrence Ryner, Duane Funk, Regina Legaspi, Joseph A Fisher, James Duffin, David J Mikulis, W Alan C Mutch, Renée El-Gabalawy, Ronak Patel, Kayla Kilborn, Caitlin Blaney, Christopher Hoban, Lawrence Ryner, Duane Funk, Regina Legaspi, Joseph A Fisher, James Duffin, David J Mikulis, W Alan C Mutch

Abstract

Introduction: Risk assessment for post-operative delirium (POD) is poorly developed. Improved metrics could greatly facilitate peri-operative care as costs associated with POD are staggering. In this preliminary study, we develop a novel stress-diathesis model based on comprehensive pre-operative psychiatric and neuropsychological testing, a blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) carbon dioxide (CO2) stress test, and high fidelity measures of intra-operative parameters that may interact facilitating POD. Methods: The study was approved by the ethics board at the University of Manitoba and registered at clinicaltrials.gov as NCT02126215. Twelve patients were studied. Pre-operative psychiatric symptom measures and neuropsychological testing preceded MRI featuring a BOLD MRI CO2 stress test whereby BOLD scans were conducted while exposing participants to a rigorously controlled CO2 stimulus. During surgery the patient had hemodynamics and end-tidal gases downloaded at 0.5 hz. Post-operatively, the presence of POD and POD severity was comprehensively assessed using the Confusion Assessment Measure -Severity (CAM-S) scoring instrument on days 0 (surgery) through post-operative day 5, and patients were followed up at least 1 month post-operatively. Results: Six of 12 patients had no evidence of POD (non-POD). Three patients had POD and 3 had clinically significant confusional states (referred as subthreshold POD; ST-POD) (score ≥ 5/19 on the CAM-S). Average severity for delirium was 1.3 in the non-POD group, 3.2 in ST-POD, and 6.1 in POD (F-statistic = 15.4, p < 0.001). Depressive symptoms, and cognitive measures of semantic fluency and executive functioning/processing speed were significantly associated with POD. Second level analysis revealed an increased inverse BOLD responsiveness to CO2 pre-operatively in ST-POD and marked increase in the POD groups when compared to the non-POD group. An association was also noted for the patient population to manifest leucoaraiosis as assessed with advanced neuroimaging techniques. Results provide preliminary support for the interacting of diatheses (vulnerabilities) and intra-operative stressors on the POD phenotype. Conclusions: The stress-diathesis model has the potential to aid in risk assessment for POD. Based on these initial findings, we make some recommendations for intra-operative management for patients at risk of POD.

Keywords: neuroimaging; neuropathophysiology; neuropsychological; peri-operative care; post-operative delirium; stress-diathesis.

Figures

Figure 1
Figure 1
1st Level Analysis in SPM showing response to the CO2 stress test in (A) a patient at low risk for POD.In this instance the expected response to the CO2 stimulus as recorded during BOLD imaging is shown. A vigorous response to CO2 is evident from the hot voxel response—shades of orange. The response at the p = 0.001 level occurred in 84% of whole brain parenchyma. The numbers below each image are the distance in mm above or below the anterior-posterior commissure. This patient was a non-POD outcome. The color bar is the t-value for fit to the general linear model from the SPM analysis. Voxels are colored if the t-value exceeded 3.11 in this instance. (B) A patient at risk of POD. Here there is less response to the hypercapnic signal—a 64% response to hypercapnia and now an inverse or intracranial steal signal shown in cold voxels—shades of blue. The inverse voxel count was 4.3% of the total count. This patient had a subthreshold POD outcome.
Figure 2
Figure 2
(A) Demonstrates 2nd Level Analysis in SPM comparing the non-POD group (n = 6) and the subthreshold (ST) group (N = 3). The hot voxels represent where the BOLD response to CO2 is significantly more pronounced in the non-POD or control group. The cold voxels indicate where the inverse BOLD response is significantly more in the ST group. The color bar is for p = 0.05 in this circumstance. (B) 2nd Level Analysis in SPM comparing the non-POD group (n = 6) and the POD group (N = 3). The hot voxels represent where the BOLD response to CO2 is significantly more pronounced in the non-POD or control group. The cold voxels indicate where the inverse BOLD response is significantly more in the POD group. The color bar is for p = 0.05 in this circumstance.
Figure 3
Figure 3
Axial FLAIR images of two of the study patients. (A) Shows normal white matter imaging. This patient was scored Fazekas Grade 0. (B) Shows areas of hyperintensity in the periventricular regions (red arrow) and in the deep white matter (green arrow). This signature has been identified as a marker for leucoaraiosis. This image was blindly scored and on neuro-radiology report identified as Fazekas Grade 2.
Figure 4
Figure 4
(A) Repeated measures mixed effect analysis of variance examining change score in CO2 delta pre- and post-measurement across POD levels adjusting for sex, education, and age. (B) Controls for semantic fluency scaled score, processing speed scaled score (DKEFS color word interference condition 1 and 2 scaled score mean), and history of psychiatric illness. (C) Controls for sociodemographics and Type 1 and 2 hypercapnic responses from white and gray matter. (D) Controls for sociodemographics and duration of surgery, cerebral SAT < 60, and mean MAC.
Figure 5
Figure 5
Diagrammatic depiction of the stress-diathesis model for POD and ST-POD. See text for further details.

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