Neuromuscular electrical stimulation (NMES) is a potential strategy to counteract skeletal muscle atrophy in critically ill patients unable to engage in early mobilization. However, it is difficult to confirm whether the exercise load applied by NMES is sufficient to elicit a physiological effect in patients under sedation or with impaired consciousness, as the appropriate stimulus intensity and exercise load of NMES are generally assessed using subjective responses. This study aimed to evaluate changes in energy expenditure during NMES in sedated, mechanically ventilated patients using indirect calorimetry. This single-center observational study included 22 mechanically ventilated patients under deep sedation in the intensive care unit (ICU). Energy expenditure was measured using indirect calorimetry during NMES sessions. The primary outcome was the difference in energy expenditure before and during NMES. Multivariable linear regression analysis was performed to calculate the adjusted mean difference in energy expenditure. A clinically meaningful increase in energy expenditure attributable to NMES was predefined as 150 kcal/day, which was assumed based on an increase in energy expenditure when sitting on the edge of the bed. In total, 26 NMES sessions involving 22 participants were included in the analysis. The mean energy expenditure was 1,137 ± 170 kcal/day pre-NMES and 1,350 ± 228 kcal/day during NMES. The adjusted increase in energy expenditure during NMES was 213.8 kcal/day (95
Abstract Background Sepsis, a leading cause of death worldwide, is characterized by dysregulated host immune responses and multi-organ dysfunction. Neutrophil extracellular traps (NETs) are extracellular fibers from activated neutrophils that contribute to the immune response. However, excessive NETs formation during sepsis may exacerbate inflammation, thrombosis, and tissue injury, potentially affecting sepsis prognosis. We examined whether NETs-modulating interventions are beneficial in experimental sepsis models. Methods Following PRISMA guidelines, this review analyzed studies from PubMed and Scopus that reported NETs-targeting therapies and included outcome measures. A meta-analysis of random-effects models using a restricted maximum likelihood estimation was performed with a priori moderators including NETs quantification tier, intervention timing relative to insult, and intervention class. Results In 33 included studies, the therapies significantly reduced NETs levels, while three studies increased NETs following treatment. The a priori moderators, NETs tier and treatment timing, were not significant, whereas intervention class significantly modified treatment effects. The treated groups had a lower risk of death and reduced IL-6, IL-1β, TNF-ɑ levels when compared to the control group. The treatments reduced tissue injury with considerable heterogeneity (I 2 =68.4%) and should be cautiously interpreted due to small study numbers. NETs modulation was significantly associated with a decrease in cytokine concentration and tissue injury. The heterogeneity of protocols, diverse outcome measures, publication bias, and overall poor reporting quality of the studies warranted conservative effect estimates and cautious interpretation of findings. Conclusion Our meta-analysis suggests NETs modulation is associated with reduced mortality risk, attenuated organ injury, and decreased inflammation, based primarily on LPS endotoxemia rodent models. Notably, experimental protocols and model limitations impede the translatability of these therapies for clinical care at this stage of research. Trial registration In accordance with the guidelines, our systematic review protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO) registration number CRD420251124339 and was published with INPLASY on 20 August 2025
Abstract Background Direct, cell-resolved quantification of NLRP3 inflammasome activation in clinical patients has not been feasible. Previous studies have relied on indirect surrogates such as downstream cytokines, which are influenced by inflammasome-independent pathways and systemic clearance kinetics, potentially explaining the inconsistent prognostic findings reported in the literature. We applied a proximity ligation assay (PLA) to directly visualise NLRP3-caspase-1 complex formation in peripheral blood mononuclear cells of septic patients, providing a cell-specific, in situ readout of inflammasome assembly at the single-cell level. Methods In this prospective, multicentre proof-of-concept pilot study, 78 patients fulfilling Sepsis-3 criteria were enrolled across three university hospitals. The PLA was validated in THP-1-derived macrophages against established readouts of canonical inflammasome activation prior to clinical application. Patients were stratified into low (n = 28), intermediate (n = 23), and high (n = 27) NLRP3 inflammasome activity groups. Results Median age was 64 years (IQR: 56-78), 63% were male, and median Sequential Organ Failure Assessment score was 8 (IQR: 4-12). Baseline characteristics, disease severity scores, and routine inflammatory biomarkers did not differ across activity groups. Kaplan-Meier analysis revealed a non-linear pattern of 30-day survival, with the most favourable outcomes in the intermediate activity group. Both low and high activity were associated with increased mortality (log-rank p = 0.003). In adjusted Cox regression, low inflammasome activity (HR 7.88, 95% CI 1.79-34.65; p = 0.006) and high inflammasome activity (HR 4.35, 95% CI 1.01-19.88; p = 0.048) remained associated with 30-day mortality. Modelling PLA activity as a continuous variable using restricted cubic splines confirmed a significant non-linear association with 30-day mortality, independent of the tertile-based categorisation (p for non-linearity = 0.015). Conclusions This proof-of-concept pilot study demonstrates that direct in situ quantification of NLRP3–caspase-1 complex assembly is feasible in septic patients and reveals a non-linear association with 30-day survival. These findings indicate that PLA-based profiling captures immune heterogeneity beyond routine inflammatory biomarkers. Larger independent cohorts are needed to validate these findings before clinical application or patient stratification can be considered.
Abstract Background Septic shock due to streptococcal infection (SRSS) carries a high mortality and is in part driven by toxin-mediated inflammation. Therapeutic plasma exchange (TPE) may modulate the septic host responses by removing injurious mediators while replenishing protective plasma factors, but data specific to SRSS is lacking. We performed a retrospective, multicenter, cohort study of adults with SRSS between 2012–2024. Methods Patients from three tertiary care ECMO centers in Germany and Switzerland were included requiring (i) streptococcal spp. detected in blood or primary focus and (ii) septic shock according to sepsis-3 definition. Adjunctive TPE with fresh frozen plasma at the intensivists` discretion was compared with standard of care (SOC). The primary outcome was 90-day-hospital mortality. Key exploratory outcomes included 24-h kinetics of vasoactive-inotropic score(VIS) and lactate, as well as SRSS-related complications. Results were validated in a 1:1 propensity score–matched (PSM) cohort. Results Of 149 patients, 31 (20.8%) received TPE and 118 (79.2%) SOC. TPE patients were more severely ill at baseline: SOFA 14 (IQR 13.5–15) vs 11 (IQR 8–14) (p<0.001); lactate 6.4 vs 2.8 mmol/L (p<0.001); Vasoactive-Inotropic-Score (VIS) 70.7 vs 23.3 (p<0.001); more frequent invasive ventilation (87% vs 65%), VV-ECMO (36% vs 19%), and renal replacement therapy (96.8% vs 52.5%). Overall, 90-day hospital mortality was 27.5% (TPE 29.0%, SOC 27.1%). Following SOFA-score adjustment, TPE was associated with lower mortality risk (aHR 0.67 [95% CI 0.5–0.9]; p=0.009). This was validated in the PSM cohort, with an aHR for TPE of 0.44 (95% CI 0.3–0.8); p=0.002. Mixed-effects modeling demonstrated a significant VIS reduction only with TPE (fixed effect 24-h change, p=0.027) and improved lactate decrease versus SOC. Conclusion In SRSS, adjunctive TPE was associated with rapid hemodynamic stabilization and improved lactate kinetics. Exploratory adjusted survival analyses support prospective evaluation of TPE in SRSS.
