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

Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, 6th Floor, MCE #6110, Nashville, TN, 37232-8300, USA, .
Intensive Care Medicine (Impact Factor: 7.21). 08/2012; 38(12). DOI: 10.1007/s00134-012-2678-x
Source: PubMed


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

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.

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.

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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    • "It was recently found that a low plasma concentration of matrix metalloproteinase-9 (MMP-9) is associated with the occurrence of delirium [16], and these proteins have been suggested to be involved in the pathophysiology of brain trauma, leading to an increase in hematoencephalic barrier permeability with exacerbation of posttraumatic edema [17]. Hence, chemical changes caused by a cerebral lesion would lead to functional changes, which manifest as an acute organic cerebral dysfunction with delirium. "
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    ABSTRACT: Background. We compare the incidence of delirium before and after extubation and identify the risk factors and possible predictors for the occurrence of delirium in this group of patients. Methods. Patients weaned from mechanical ventilation (MV) and extubated were included. The assessment of delirium was conducted using the confusion assessment method for the ICU and completed twice per day until discharge from the intensive care unit. Results. Sixty-four patients were included in the study, 53.1% of whom presented with delirium. The risk factors of delirium were age (P = 0.01), SOFA score (P = 0.03), APACHE score (P = 0.01), and a neurological cause of admission (P = 0.01). The majority of the patients began with delirium before or on the day of extubation. Hypoactive delirium was the most common form. Conclusion. Acute (traumatic or medical) neurological injuries were important risk factors in the development of delirium. During the weaning process, delirium developed predominantly before or on the same day of extubation and was generally hypoactive (more difficult to detect). Therefore, while planning early prevention strategies, attention must be focused on neurological patients who are receiving MV and possibly even on patients who are still under sedation.
    Critical care research and practice 05/2014; 2014(2):546349. DOI:10.1155/2014/546349
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    • "Previous studies have shown that STNFR levels, rather than TNFα itself, reflect the true biological activity of this cytokine, and were associated with poor neurologic outcomes after influenza-induced encephalopathy and other neuropsychiatric disorders [35-37]. In our cohort, STNFR1 and STNFR2 were independently associated with delirium, a finding in agreement with those from Girard and colleagues [24]. "
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    ABSTRACT: Introduction Delirium is a common occurrence in critically ill patients and is associated with an increase in morbidity and mortality. Septic patients with delirium may differ from a general critically ill population. The aim of this investigation was to study the relationship between systemic inflammation and the development of delirium in septic and non-septic critically ill patients. Methods We performed a prospective cohort study in a 20-bed mixed intensive care unit (ICU) including 78 (delirium = 31; non-delirium = 47) consecutive patients admitted for more than 24 hours. At enrollment, patients were allocated to septic or non-septic groups according to internationally agreed criteria. Delirium was diagnosed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) during the first 72 hours of ICU admission. Blood samples were collected within 12 hours of enrollment for determination of tumor necrosis factor (TNF)-α, soluble TNF Receptor (STNFR)-1 and -2, interleukin (IL)-1β, IL-6, IL-10 and adiponectin. Results Out of all analyzed biomarkers, only STNFR1 (P = 0.003), STNFR2 (P = 0.005), adiponectin (P = 0.005) and IL-1β (P < 0.001) levels were higher in delirium patients. Adjusting for sepsis and sedation, these biomarkers were also independently associated with delirium occurrence. However, none of them were significant influenced by sepsis. Conclusions STNFR1, STNFR2, adiponectin and IL-1β were associated with delirium. Sepsis did not modify the relationship between the biomarkers and delirium occurrence.
    Critical care (London, England) 05/2014; 18(3):R106. DOI:10.1186/cc13887 · 4.48 Impact Factor
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    • "After adjustment for potential confounders, including severity of illness, higher plasma concentrations of the inflammatory marker soluble tumor necrosis factor receptor-1, and lower plasma concentrations of the coagulation marker protein C were associated with increased risk of delirium. However, an unexpected finding was that lower plasma concentrations of matrix metalloproteinase-9, another inflammatory marker, were associated with higher risk of delirium [17]. Another mechanism implicated in the pathophysiology of delirium is overactivity of the dopaminergic system. "
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    ABSTRACT: Delirium is characterized by a disturbance of consciousness with accompanying change in cognition. Delirium typically manifests as a constellation of symptoms with an acute onset and a fluctuating course. Delirium is extremely common in the intensive care unit (ICU) especially amongst mechanically ventilated patients. Three subtypes have been recognized: hyperactive, hypoactive, and mixed. Delirium is frequently undiagnosed unless specific diagnostic instruments are used. The CAM-ICU is the most widely studied and validated diagnostic instrument. However, the accuracy of this tool may be less than ideal without adequate training of the providers applying it. The presence of delirium has important prognostic implications; in mechanically ventilated patients it is associated with a 2.5-fold increase in short-term mortality and a 3.2-fold increase in 6-month mortality. Nonpharmacological approaches, such as physical and occupational therapy, decrease the duration of delirium and should be encouraged. Pharmacological treatment for delirium traditionally includes haloperidol; however, more data for haloperidol are needed given the paucity of placebo-controlled trials testing its efficacy to treat delirium in the ICU. Second-generation antipsychotics have emerged as an alternative for the treatment of delirium, and they may have a better safety profile. Dexmedetomidine may prove to be a valuable adjunctive agent for patients with delirium in the ICU.
    Annals of Intensive Care 12/2012; 2(1):49. DOI:10.1186/2110-5820-2-49 · 3.31 Impact Factor
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