Associations of markers of inflammation and coagulation with delirium during critical illness

Abstract

Purpose: To assess the associations between a priori-selected markers of inflammation and coagulation and delirium during critical illness.

Methods: In this prospective cohort study, we collected blood from mechanically ventilated medical intensive care unit (ICU) patients and measured nine plasma markers of inflammation and coagulation. We assessed patients daily for delirium using the Confusion Assessment Method for the ICU and used multivariable regression to analyze the associations between plasma markers and subsequent delirium, after adjusting for age, severity of illness, and sepsis.

Results: Among the 138 patients studied, with median age of 66 years and median Acute Physiology and Chronic Health Evaluation (APACHE) II of 27, 107 (78 %) were delirious at some point during the study. Two markers of inflammation and one of coagulation were significantly associated with delirium. After adjusting for covariates, lower plasma concentrations of matrix metalloproteinase-9 (MMP-9) and protein C were associated with increased probability of delirium (p = 0.04 and 0.01, respectively), and higher concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were associated with increased probability of delirium (p < 0.01). Concentrations of C-reactive protein (p = 0.82), myeloperoxidase (p = 0.11), neutrophil gelatinase-associated lipocalin (p = 0.70), D-dimer (p = 0.83), plasminogen activator inhibitor type 1 (p = 0.98), and Von Willebrand factor antigen (p = 0.65) were not associated with delirium.

Conclusions: In this study, MMP-9, protein C, and sTNFR1 were independently associated with subsequent ICU delirium. These results suggest that specific aspects of inflammation and coagulation may play a role in the evolution of delirium during critical illness and that these markers should be examined in larger studies of ICU patients.

Conflict of interest statement

CONFLICT OF INTEREST

Drs. Girard, Pandharipande, Shintani, and Ely have received honoraria from Hospira Inc. Dr. Pandharipande has received honoraria from Orion Corporation. Drs. Pandharipande and Ely have received grant support from Hospira Inc. Dr. Ely has also received grant support from Eli Lilly and Company and Masimo Corporation and is an advisor to Healthways Inc. All other authors have no disclosures.

Figures

Figure 1. Plasma Markers Associated with Delirium

The probability of delirium that was independently associated with matrix metalloproteinase-9 (MMP-9), soluble tumor necrosis factor receptor-1 (sTNFR1), and protein C concentrations, after adjusting for age, severity of illness, and sepsis at admission is indicated by solid black lines. The gray ribbons indicate the 95% confidence limits of these associations. Each black circle represents an observation with position along the x-axis indicating the biomarker value and position along the y-axis indicating presence (y=1) or absence (y=0) of delirium.