Feasibility of Fluid Responsiveness Assessment in Patients at Risk for Increased Intracranial Pressure.

Background: Effective fluid management is important for patients at risk of increased intracranial pressure (ICP). Maintaining constant cerebral perfusion represents a challenge, as both hypovolemia and fluid overload can severely impact patient outcomes. Fluid responsiveness tests, commonly used in critical care settings, are often deemed potentially hazardous for these patients due to the risk of disrupting cerebral perfusion. Methods: This single-center, prospective, clinical observational study enrolled 40 patients at risk for increased ICP, including those with acute brain injury. Informed consent was obtained from each participant or their legal guardians before inclusion. The study focused on the dynamics of ICP and cerebral perfusion pressure (CPP) changes during the Passive Leg Raise Test (PLRT) and the End-Expiratory Occlusion Test (EEOT). Results: The results demonstrated that PLRT and EEOT caused minor and transient increases in ICP, while consistently maintaining stable CPP. EEOT induced significantly lower ICP elevations, making it particularly suitable for use in high-risk situations. Conclusions: PLRT and EEOT can be considered feasible and safe for assessing fluid responsiveness in patients at risk for increased ICP. Notably, EEOT stands out as a preferred method for high-risk patients, offering a dependable strategy for fluid management without compromising cerebral hemodynamics.

Non-Neuronal Acetylcholinesterase Activity Shows Limited Utility for Early Detection of Sepsis.

(1) Background: Sepsis is a severe systemic inflammatory condition characterized by rapid clinical deterioration and organ dysfunction. The cholinergic system has been implicated in modulating the inflammatory response. Acetylcholinesterase (AChE), an enzyme primarily responsible for the hydrolysis of acetylcholine, has been proposed as a potential early indicator of sepsis onset. However, the exact role of non-neuronal AChE activity in sepsis and its correlation with disease severity and patient outcomes remain unclear. This study aimed to investigate the involvement of AChE activity in sepsis and evaluate its association with disease severity and clinical outcomes. (2) Methods: A prospective study included 43 septic patients. AChE activity was measured at sepsis detection, as well as 7 and 28 days later. Inflammatory biomarkers, disease severity scores, and patient outcomes were evaluated. (3) Results: AChE activity remained stable for 7 days and decreased at 28 days. However, there was no correlation between initial AChE activity and inflammatory biomarkers, disease severity scores, ICU stay, or hospital stay. (4) Conclusions: Non-neuronal AChE activity may not reliably indicate early sepsis or predict disease severity.

Increased Enzymatic Activity of Acetylcholinesterase Indicates the Severity of the Sterile Inflammation and Predicts Patient Outcome following Traumatic Injury.

Traumatic injury induces sterile inflammation, an immune response often associated with severe organ dysfunction. The cholinergic system acts as an anti-inflammatory in injured patients. Acetylcholinesterase (AChE), an enzyme responsible for the hydrolysis of acetylcholine, plays an essential role in controlling cholinergic activity. We hypothesized that a change in the AChE activity might indicate the severity of the traumatic injury. This study included 82 injured patients with an Injury Severity Score (ISS) of 4 or above and 40 individuals without injuries. Bedside-measured AChE was obtained on hospital arrival, followed by a second measurement 4-12 h later. C-reactive protein (CRP), white blood cell count (WBCC), and Sequential Organ Failure Assessment (SOFA) score were simultaneously collected. Injured patients showed an early and sustained increase in AChE activity. CRP remained unaffected at hospital admission and increased subsequently. Initially elevated WBCC recovered 4-12 h later. AChE activity directly correlated with the ISS and SOFA scores and predicted the length of ICU stay when measured at hospital admission. An early and sustained increase in AChE activity correlated with the injury severity and could predict the length of ICU stay in injured patients, rendering this assay a complementary diagnostic and prognostic tool at the hand of the attending clinician in the emergency unit.

Critically Ill COVID-19 Patients Show Reduced Point of Care-Measured Butyrylcholinesterase Activity-A Prospective, Monocentric Observational Study.

A biomarker for risk stratification and disease severity assessment in SARS-CoV-2 infections has not yet been established. Point of care testing (POCT) of butyrylcholinesterase (BChE) enables early detection of systemic inflammatory responses and correlates with disease severity in sepsis and burns. In acute care or resource-limited settings, POCT facilitates rapid clinical decision making, a particularly beneficial aspect in the management of pandemic situations. In this prospective observational study, POCT-measured BChE activity was assessed in 52 critically ill COVID-19 patients within 24 h of ICU admission and on the third and seventh day after ICU admission. Forty (77%) of these patients required venovenous extracorporeal membrane oxygenation (vvECMO). In critically ill COVID-19 patients, BChE activity is significantly decreased compared with healthy subjects, but also compared with other inflammatory conditions such as sepsis, burns, or trauma. POCT BChE activity reflects the severity of organ dysfunction and allows prediction of 28-day mortality in critically ill COVID-19 patients. Implementing early POCT BChE measurement could facilitate risk stratification and support admission and transfer decisions in resource-limited settings.

Concurrent Change in Serum Cholinesterase Activity and Midregional-Proadrennomedullin Level Could Predict Patient Outcome following Liver Transplantation.

BACKGROUND: After liver transplantation (LTX), patients are susceptible to opportunistic infections resulting in reduced outcomes within the early post-transplantation period. The postoperative monitoring of LTX patients has gained much importance in recent years. However, reliable plasmatic markers predicting 90-day outcomes are still lacking. METHODS: In the post hoc analysis of a prospective, observational study, butyrylcholinesterase (BChE), mid-regional proadrenomedullin (MR-proADM), as well as conventional inflammatory markers (procalcitonin, C-reactive protein) were evaluated in 93 patients at seven consecutive timepoints within the first 28 days following LTX. RESULTS: Persistently reduced activity of BChE and elevated MR-proADM levels indicated reduced 90-day survival following LTX. Furthermore, reduced BChE and increased MR-proADM activity could indicate early post-transplantation bacterial infections, whereas conventional inflammatory biomarkers showed no diagnostic efficacy within the observation period. CONCLUSION: Concurrent assessment of BChE and MR-proADM activity might serve as a bedside diagnostic tool for early bacterial infections following liver transplantation. Thus, a combined utilization of the two biomarkers may be a useful tool in the risk evaluation of patients following liver transplantation.

Point-of-care measured serum cholinesterase activity predicts patient outcome following severe burns.

Risk stratification is of utmost importance in burn therapy. However, suitable bedside biomarkers to evaluate the emerging inflammatory response following burn injuries are missing. Serum cholinesterase (butyrylcholinesterase, BChE) has been shown to be a clinically relevant biomarker in acute inflammatory diseases including burns. In this observational cohort study BChE activity was measured by using point-of-care testing (POCT), a novel method in acute burn care. POCT measurements were performed at emergency room admission (ERA) of 35 patients and repeated 12, 24 and 48 h later. All patients or their legal designees gave informed consent. Patients with burn injuries showed sustained BChE activity reduction following hospital admission. BChE activity correlated negatively with burn injury severity, organ failure severity and intensive care unit resource requirements. BChE activity measured at ERA and 12 h later identified survivors and predicted 28-day patient outcome with noninferior efficacy compared to the abbreviated burn severity index (ABSI) scoring. Finally, POCT-measured BChE activity might complement ABSI scoring and possibly improve early risk stratification in acute burn care therapy.

Bedside-measurement of serum cholinesterase activity predicts patient morbidity and length of the intensive care unit stay following major traumatic injury.

Major traumatic injury (MTI), a life-threatening condition requiring prompt medical intervention, is associated with an extensive inflammatory response often resulting in multiple organ dysfunction. Early stratification of trauma severity and the corresponding inflammation may help optimize resources at the intensive care unit (ICU). The cholinergic system counters inflammation by quickly modulating the immune response. Serum cholinesterase (butyrylcholinesterase, BChE) is an enzyme that hydrolyses acetylcholine. We tested whether a change in the BChE activity correlates with the morbidity and the length of ICU stay. Blood samples from 10 healthy volunteers and 44 patients with MTI were gathered at hospital admission, followed by measurements 12, 24 and 48 hours later. Point-of-care approach was used to determine the BChE activity. Disease severity was assessed by clinical scoring performed within 24 hours following hospital admission. BChE activity, measured at hospital admission, showed a significant and sustained reduction and correlated with disease severity scores obtained 24 hours following admission. BChE activity, obtained at hospital admission, correlated with the length of ICU stay. Bedside measurement of BChE activity, as a complementary addition to established procedures, might prove useful in the primary assessment of the disease severity and might therefore optimize therapy in the ICU.

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.

GTS-21 reduces microvascular permeability during experimental endotoxemia.

INTRODUCTION: No effective pharmacological therapy is currently available to attenuate tissue edema formation due to increased microvascular permeability in sepsis. Cholinergic mediators have been demonstrated to exert anti-inflammatory effects via the α7 nicotinic acetylcholine receptor (α7nAChR) during inflammation. GTS-21, a partial α7nAChR agonist, is an appealing therapeutic substance for sepsis-induced microvascular inflammation due to its demonstrated cholinergic anti-inflammatory properties and its favorable safety profile in clinical trials. This study evaluated the effect of GTS-21 on microvascular permeability and leukocyte adhesion during experimental endotoxemia. METHODS: Male Wistar rats (n=60) were anesthetized and prepared for intravital microscopy (IVM). Sevoflurane inhalation combined with propofol (10mg/kg) and fentanyl (5µg/kg) was used for anesthesia induction, followed by continuous intravenous anesthesia with propofol (10-40mg/kg/h) and fentanyl (10µg/kg/h). The rat mesentery was prepared for evaluation of macromolecular leakage, leukocyte adhesion and venular wall shear rate in postcapillary venules using IVM. Following baseline IVM recording, GTS-21 (1mg/kg) was applied simultaneously with, 1h prior to and 1h after administration of lipopolysaccharide (LPS, 5mg/kg). Test substances (crystalloid solution, LPS, GTS-21) were administered as volume equivalent intravenous infusions over 5min in the respective treatment groups. The consecutive IVMs were performed at 60, 120 and 180min after the baseline IVM. The systemic inflammatory response was evaluated by measuring TNF-α levels after the 180min IVM. RESULTS: Microvascular permeability was significantly reduced in animals treated with GTS-21 simultaneously and 1h after induction of endotoxemia. Leukocyte adhesion, venular wall shear rate and TNF-α levels were not affected by GTS-21 treatment compared to the untreated endotoxemic animals. CONCLUSION: GTS-21 has a protective effect on microvascular barrier function during endotoxemia. Considering its anti-inflammatory efficacy and safety profile, its clinical use might prove beneficial for the treatment of capillary leakage in sepsis therapy.

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.

Data on microcirculatory parameters of GTS- 21 treated rats assessed by intravital microscopy.

This article contains animal experimental data associated with the research article entitled "GTS-21 reduces microvascular permeability during experimental endotoxemia" (Schmidt et al., 2017) [1] (supplementary datasets of baseline intravital microscopic measurements, baseline TNF-α levels and vital parameters of the evaluated experimental groups are provided). Beneficial anti-inflammatory effects of cholinergic mediators on microvascular inflammation have been demonstrated by intravital microscopic investigations (Schmidt et al., 2015) [2], therefore we evaluated the effect of the cholinergic mediator GTS-21 on microcirculatory alterations during endotoxemia [1]. The data regarding microcirculatory effects of GTS-21 treatment ((3-(2,4-Dimethoxybenzylidene)-anabaseine dihydrochloride; 1 mg/kg; i.v.) in non-endotoxemic animals are presented in this article.

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

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.

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.

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.

Cytidine-5-diphosphocholine reduces microvascular permeability during experimental endotoxemia.

BACKGROUND: Microvascular permeability and leukocyte adhesion are pivotal mechanisms in sepsis pathophysiology contributing to the development of shock and mortality. No effective pharmacological therapy is currently available to restore microvascular barrier function in sepsis. Cholinergic mediators have been demonstrated to exert anti-inflammatory effects during inflammation. Cytidine-5-diphosphocholine (CDP-choline) is an extensively studied cholinergic drug due to its brain protective characteristics in cerebrovascular diseases. This study evaluated the effect of CDP-choline 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) (4 mg/kg/h) or equivalent volumes of saline were continuously infused following baseline IVM at 0 min. IVM was repeated after 60 and 120 min in endotoxemic and nonendotoxemic animals. CDP-choline (100 mg/kg) was applied as an i.v. bolus. Animals received either saline alone, CDP-choline alone, CDP-choline 10 min before or 30 min after LPS administration, or LPS alone. Due to nonparametric data distribution, Wilcoxon test and Dunn's multiple comparisons test were used for data analysis. Data were considered statistically significant at p < 0.05. RESULTS: Treatment with LPS alone significantly increased microvascular permeability and leukocyte adhesion and decreased venular wall shear rate. CDP-choline significantly reduced microvascular permeability in animals treated with LPS. Leukocyte adhesion and venular wall shear rate were not affected by CDP-choline during endotoxemia. CONCLUSION: CDP-choline has a protective effect on microvascular barrier function during endotoxemia. Considering the excellent pharmacologic safety profile of CDP-choline, its use could be an approach for the treatment of capillary leakage in sepsis.

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 Dunn's 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 serum butyrylcholinesterase activity indicates severe systemic inflammation in critically ill patients.

Systemic inflammation is an immune response to a nonspecific insult of either infectious or noninfectious origin and remains a challenge in the intensive care units with high mortality rate. Cholinergic neurotransmission plays an important role in the regulation of the immune response during inflammation. We hypothesized that the activity of butyrylcholinesterase (BChE) might serve as a marker to identify and prognose systemic inflammation. By using a point-of-care-testing (POCT) approach we measured BChE activity in patients with severe systemic inflammation and healthy volunteers. We observed a decreased BChE activity in patients with systemic inflammation, as compared to that of healthy individuals. Furthermore, BChE activity showed an inverse correlation with the severity of the disease. Although hepatic function has previously been found essential for BChE production, we show here that the reduced BChE activity associated with systemic inflammation occurs independently of and is thus not caused by any deficit in liver function in these patients. A POCT approach, used to assess butyrylcholinesterase activity, might further improve the therapy of the critically ill patients by minimizing time delays between the clinical assessment and treatment of the inflammatory process. Hence, assessing butyrylcholinesterase activity might help in early detection of inflammation.

Recruitment of oriens-lacunosum-moleculare interneurons during hippocampal ripples.

Sharp wave-associated ∼200-Hz ripple oscillations in the hippocampus have been implicated in the consolidation of memories. However, knowledge on mechanisms underlying ripples is still scarce, in particular with respect to synaptic involvement of specific cell types. Here, we used cell-attached and whole-cell recordings in vitro to study activity of pyramidal cells and oriens-lacunosum-moleculare (O-LM) interneurons during ripples. O-LM cells received ripple-associated synaptic input that arrived delayed (3.3 ± 0.3 ms) with respect to the maximum amplitude of field ripples and was locked to the ascending phase of field oscillations (mean phase: 209 ± 6°). In line, O-LM cells episodically discharged late during ripples (∼6.5 ms after the ripple maximum), and firing was phase-locked to field oscillations (mean phase: 219 ± 9°). Our data unveil recruitment of O-LM neurons during ripples, suggesting a previously uncharacterized role of this cell type during sharp wave-associated activity.