Aleksandar R. Zivkovic

Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study

Abstract Objectives: The impact of TREM-1-mediated inflammation was investigated in different inflammatory settings. Methods: Secondary analyses of an observational clinical pilot study, including 60 patients with septic shock, 30 postoperative controls and 30 healthy volunteers. Results: Plasma levels of sTREM-1 were found to identify patients with septic shock more effectively than procalcitonin and C-reactive protein. Moreover, sTREM-1 was identified to be an early predictor for survival in patients with septic shock. Conclusion: Due to its diagnostic as well as prognostic value in sepsis syndrome, implementation of sTREM-1 measurements in routine diagnostics should be taken into account.

Time-dependent effect of clonidine on microvascular permeability during endotoxemia.

BACKGROUND Endothelial leakage with accompanying tissue edema and increased leukocyte adhesion are characteristics of the vascular inflammatory response. Tissue edema formation is a key mechanism in sepsis pathophysiology contributing to impaired tissue oxygenation and the development of shock. Sepsis mortality is directly associated with the severity of these microcirculatory alterations. Dysfunction of the sympathetic nervous system can have deleterious effects in generalized inflammation. This study evaluated the effect of the adrenergic alpha 2 agonist clonidine on microvascular permeability and leukocyte adhesion during endotoxemia. METHODS Macromolecular leakage, leukocyte adhesion, and venular wall shear rate were examined in mesenteric postcapillary venules of rats by using intravital microscopy (IVM). Lipopolysaccharide (LPS) (4mg/kg/h) or equivalent volumes of saline were continuously infused following baseline IVM at 0min. IVM was repeated after 60 and 120min in endotoxemic and nonendotoxemic animals. Clonidine (10μg/kg) was applied as an i.v. bolus. Animals received either (i) saline alone, (ii) clonidine alone, (iii) clonidine 45min prior to LPS, (iv) clonidine 10min prior to LPS, (v) clonidine 30min after LPS, or (vi) LPS alone. Due to nonparametric data distribution, Wilcoxon test and Dunns multiple comparisons test were used for data analysis. Data were considered statistically significant at p<0.05. RESULTS LPS significantly increased microvascular permeability and leukocyte adhesion and decreased venular wall shear rate. Clonidine significantly reduced microvascular permeability when applied 45min before or 30min after LPS administration. Leukocyte adhesion and venular wall shear rate were not affected by clonidine during endotoxemia. CONCLUSION Clonidine reduces microvascular permeability in endotoxemic animals in a time-dependent manner. Adrenergic alpha 2 agonists might prove beneficial in stabilizing capillary leakage during inflammation.

Reduced butyrylcholinesterase activity is an early indicator of trauma-induced acute systemic inflammatory response

Purpose Early diagnosis of systemic inflammatory response syndrome is fundamentally important for an effective and a goal-directed therapy. Various inflammation biomarkers have been used in clinical and experimental practice. However, a definitive diagnostic tool for an early detection of systemic inflammation remains to be identified. Acetylcholine (Ach) has been shown to play an important role in the inflammatory response. Serum cholinesterase (butyrylcholinesterase [BChE]) is the major Ach hydrolyzing enzyme in blood. The role of this enzyme during inflammation has not yet been fully understood. This study tests whether a reduction in the BChE activity could indicate the onset of the systemic inflammatory response upon traumatic injury. Patients and methods This observational study measured BChE activity in patients with traumatic injury admitted to the emergency room by using point-of-care-test system (POCT). In addition, the levels of routine inflammation biomarkers during the initial treatment period were measured. Injury Severity Score was used to assess the trauma severity. Results Altered BChE activity was correlated with trauma severity, resulting in systemic inflammation. Reduction in the BChE activity was detected significantly earlier compared to those of routinely measured inflammatory biomarkers. Conclusion This study suggests that the BChE activity reduction might serve as an early indicator of acute systemic inflammation. Furthermore, BChE activity, measured using a POCT system, might play an important role in the early diagnosis of the trauma-induced systemic inflammation.

Reduced serum cholinesterase activity indicates splenic modulation of the sterile inflammation

BACKGROUND Sterile inflammation is an immediate and well-coordinated immune response to surgical injury. The cholinergic system plays a pivotal role in the inflammatory response. Induced inflammation stimulates the vagus nerve, which in turn activates anti-inflammatory nonneuronal processes. Serum cholinesterase (butyrylcholinesterase [BChE]) is an enzyme that hydrolyzes acetylcholine. Measuring the activity of the BChE in blood might indicate the level of the nonneuronal cholinergic activity. The spleen is a major organ of the immune system playing an important role during inflammation. A functional connection of the neuroimmune reflex has thus far been described only in experimental settings. MATERIALS AND METHODS In 48 patients receiving major pancreatic surgery, BChE activity was measured by applying point-of-care-testing, in addition to standard laboratory tests. RESULTS The BChE activity decreased in patients receiving surgery. This reduction emerged much earlier than changes in C-reactive protein concentration, an inflammatory biomarker broadly used in the clinical environment. A milder reduction in the BChE activity was observed in patients subjected to surgery with splenectomy than in those with a preserved spleen. CONCLUSIONS The use of the point-of-care-testing system for quick bedside diagnostics and the rapid effects of inflammation on BChE levels provide a method and a marker to facilitate the early detection of systemic inflammation. Furthermore, this study provides evidence that the experimentally documented neuroimmune interaction is part of the physiological response to surgery-induced sterile inflammation. Splenic function plays an essential role in modulating the cholinergic anti-inflammatory response.

Muscarinic M1 receptors modulate endotoxemia-induced loss of synaptic plasticity.

Septic encephalopathy is associated with rapid deterioration of cortical functions. Using magnetic resonance imaging (MRI) we detected functional abnormalities in the hippocampal formation of patients with septic delirium. Hippocampal dysfunction was further investigated in an animal model for sepsis using lipopolysaccharide (LPS) injections to induce endotoxemia in rats, followed by electrophysiological recordings in brain slices. Endotoxemia induced a deficit in long term potentiation which was completely reversed by apamin, a blocker of small conductance calcium-activated potassium (SK) channels, and partly restored by treatment with physostigmine (eserine), an acetylcholinesterase inhibitor, or TBPB, a selective M1 muscarinic acetylcholine receptor agonist. These results suggest a novel role for SK channels in the etiology of endotoxemia and explain why boosting cholinergic function restores deficits in synaptic plasticity. Drugs which enhance cholinergic or M1 activity in the brain may prove beneficial in treatment of septic delirium in the intensive care unit.

A Sustained Reduction in Serum Cholinesterase Enzyme Activity Predicts Patient Outcome following Sepsis

Early sepsis identification is of paramount importance for an effective therapy and the patient outcome; however, a suitable prognostic biomarker is lacking. Anti-inflammatory nonneuronal cholinergic signaling modulates the magnitude of an immune response. Serum cholinesterase (BChE), an enzyme that hydrolyzes acetylcholine, plays an important role during inflammatory response and serves as an accurate index of cholinergic activity. BChE activity was measured in septic patients using a point-of-care system, and levels of conventional inflammatory markers and the disease severity scores were obtained. We observed a strong, sustained reduction in BChE activity in patients who died within a 90-day observation period, as compared to survivors. Reduced BChE activity when measured at the ICU admission effectively differentiated between the 90-day survivor and the nonsurvivor patient groups. We estimated a critical BChE level of 1.661 kU/L (CI 0.5–0.8, 94% sensitivity, 48% specificity, AUC 0.7) to best predict patient outcome providing a benchmark criterion for early detection of potentially fatal sepsis measured at the admission. This finding suggests that the BChE activity, used in combination with the laboratory tests, clinical examination, and the disease severity scoring, could serve to identify high-risk patients at the ICU admission, the most critical time point in the sepsis treatment.