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.
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ABSTRACT: Two general forms of synaptic plasticity that operate on different timescales are thought to contribute to the activity-dependent refinement of neural circuitry during development: (1) long-term potentiation (LTP) and long-term depression (LTD), which involve rapid adjustments in the strengths of individual synapses in response to specific patterns of correlated synaptic activity, and (2) homeostatic synaptic scaling, which entails uniform adjustments in the strength of all synapses on a cell in response to prolonged changes in the cell's electrical activity. Without homeostatic synaptic scaling, neural networks can become unstable and perform suboptimally. Although much is known about the mechanisms underlying LTP and LTD, little is known about the mechanisms responsible for synaptic scaling except that such scaling is due, at least in part, to alterations in receptor content at synapses. Here we show that synaptic scaling in response to prolonged blockade of activity is mediated by the pro-inflammatory cytokine tumour-necrosis factor-alpha (TNF-alpha). Using mixtures of wild-type and TNF-alpha-deficient neurons and glia, we also show that glia are the source of the TNF-alpha that is required for this form of synaptic scaling. We suggest that by modulating TNF-alpha levels, glia actively participate in the homeostatic activity-dependent regulation of synaptic connectivity.Nature 05/2006; 440(7087):1054-9. DOI:10.1038/nature04671 · 42.35 Impact Factor
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ABSTRACT: Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large part, dependent on their interaction with the extracellular matrix (ECM). Given that matrix metalloproteinases (MMPs) are responsible for transient alterations in the ECM, we predicted that MMP function is critical for hippocampal-dependent learning. In support of this, it was observed that hippocampal MMP-3 and -9 increased transiently during water maze acquisition as assessed by western blotting and mRNA analysis. The ability of the NMDA receptor channel blocker MK801 to attenuate these changes indicated that the transient MMP changes were in large part dependent upon NMDA receptor activation. Furthermore, inhibition of MMP activity with MMP-3 and -9 antisense oligonucleotides and/or MMP inhibitor FN-439 altered long-term potentiation and prevented acquisition in the Morris water maze. The learning-dependent MMP alterations were shown to modify the stability of the actin-binding protein cortactin, which plays an essential role in regulating the dendritic cytoskeleton and synaptic efficiency. Together these results indicate that changes in MMP function are critical to synaptic plasticity and hippocampal-dependent learning.Journal of Neurochemistry 04/2006; 96(5):1227-41. DOI:10.1111/j.1471-4159.2005.03565.x · 4.24 Impact Factor
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ABSTRACT: To determine the costs associated with delirium in mechanically ventilated medical intensive care unit patients. Prospective cohort study. A tertiary care academic hospital. Patients were 275 consecutive mechanically ventilated medical intensive care unit patients. We prospectively examined patients for delirium using the Confusion Assessment Method for the Intensive Care Unit. Delirium was categorized as "ever vs. never" and by a cumulative delirium severity index. Costs were determined from individual ledger-level patient charges using cost-center-specific cost-to-charge ratios and were reported in year 2001 U.S. dollars. Fifty-one of 275 patients (18.5%) had persistent coma and died in the hospital and were excluded from further analysis. Of the remaining 224 patients, delirium developed in 183 (81.7%) and lasted a median of 2.1 (interquartile range, 1-3) days. Baseline demographics were similar between those with and without delirium. Intensive care unit costs (median, interquartile range) were significantly higher for those with at least one episode of delirium ($22,346, $15,083-$35,521) vs. those with no delirium ($13,332, $8,837-$21,471, p <.001). Total hospital costs were also higher in those who developed delirium ($41,836, $22,782-$68,134 vs. $27,106, $13,875-$37,419, p =.002). Higher severity and duration of delirium were associated with incrementally greater costs (all p <.001). After adjustment for age, comorbidity, severity of illness, degree of organ dysfunction, nosocomial infection, hospital mortality, and other potential confounders, delirium was associated with 39% higher intensive care unit (95% confidence interval, 12-72%) and 31% higher hospital (95% confidence interval, 1-70%) costs. Delirium is a common clinical event in mechanically ventilated medical intensive care unit patients and is associated with significantly higher intensive care unit and hospital costs. Future efforts to prevent or treat intensive care unit delirium have the potential to improve patient outcomes and reduce costs of care.Critical Care Medicine 04/2004; 32(4):955-62. DOI:10.1097/01.CCM.0000119429.16055.92 · 6.15 Impact Factor