Inflammation and Coagulation during Critical Illness and Long-Term Cognitive Impairment and Disability

Abstract

Rationale: The biological mechanisms of long-term cognitive impairment and disability after critical illness are unclear.Objectives: To test the hypothesis that markers of acute inflammation and coagulation are associated with subsequent long-term cognitive impairment and disability.Methods: We obtained plasma samples from adults with respiratory failure or shock on Study Days 1, 3, and 5 and measured concentrations of CRP (C-reactive protein), IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12, MMP-9 (matrix metalloproteinase-9), TNF-α (tumor necrosis factor-α), soluble TNF receptor 1, and protein C. At 3 and 12 months after discharge, we assessed global cognition, executive function, and activities of daily living. We analyzed associations between markers and outcomes using multivariable regression, adjusting for age, sex, education, comorbidities, baseline cognition, doses of sedatives and opioids, stroke risk (in cognitive models), and baseline disability scores (in disability models).Measurements and Main Results: We included 548 participants who were a median (interquartile range) of 62 (53-72) years old, 88% of whom were mechanically ventilated, and who had an enrollment Sequential Organ Failure Assessment score of 9 (7-11). After adjusting for covariates, no markers were associated with long-term cognitive function. Two markers, CRP and MMP-9, were associated with greater disability in basic and instrumental activities of daily living at 3 and 12 months. No other markers were consistently associated with disability outcomes.Conclusions: Markers of systemic inflammation and coagulation measured early during critical illness are not associated with long-term cognitive outcomes and demonstrate inconsistent associations with disability outcomes. Future studies that pair longitudinal measurement of inflammation and related pathways throughout the course of critical illness and during recovery with long-term outcomes are needed.

Keywords: coagulation; critical illness; dementia; disability; inflammation.

Figure 1.

Flow of participant enrollment and follow-up.

Figure 2.

Associations of markers of inflammation and coagulation with long-term cognition. These figures display the difference in score on the (A) RBANS or (B) Trails B tests for each of the 11 biomarkers of interest. Blue triangles represent the point estimate at 3 months and red circles represent the point estimate at 12 months. Horizontal lines represent the 95% confidence interval. Each comparison is of participants with biomarker concentration at the 75th percentile to participants with a biomarker concentration at the 25th percentile, with all covariates adjusted to their mean or mode value. Negative changes in scores (i.e., point estimates to the left of 0) represent worse cognitive function. CRP = C-reactive protein; MMP = matrix metalloproteinase; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; TNF = tumor necrosis factor; TNFR = tumor necrosis factor receptor; Trails B = Trail Making Test Part B.

Figure 3.

Associations of markers of inflammation and coagulation with disability in activities of daily living. These figures display the incident rate ratio for (A) Katz ADL or (B) FAQ scores for each of the 11 biomarkers of interest. Blue triangles represent the point estimate at 3 months and red circles represent the point estimate at 12 months. Horizontal lines represent the 95% confidence interval. Each comparison is of participants with biomarker concentration at the 75th percentile to participants with a biomarker concentration at the 25th percentile, with all covariates adjusted to their mean or mode value. Incident rate ratios (IRRs) of 1 represent no change in disability, IRRs greater than 1 (i.e., to the right of 1.0) represent greater disability, and IRRs less than 1 (i.e., to the left of 1.0) represent less disability. CRP = C-reactive protein; FAQ = Functional Activities Questionnaire; Katz ADL = Katz Index of Independence in Activities of Daily Living; MMP = matrix metalloproteinase; TNF = tumor necrosis factor; TNFR = tumor necrosis factor receptor.