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Systemic inflammation can be triggered by infection, surgery, trauma or burns. During systemic inflammation, an overshooting immune response induces tissue damage resulting in organ dysfunction and mortality. Endothelial cells make up the inner lining of all blood vessels and are critically involved in maintaining organ integrity by regulating tissue perfusion. Permeability of the endothelial monolayer is strictly controlled and highly organ-specific, forming continuous, fenestrated and discontinuous capillaries that orchestrate the extravasation of fluids, proteins and solutes to maintain organ homeostasis. In the physiological state, the endothelial barrier is maintained by the glycocalyx, extracellular matrix and intercellular junctions including adherens and tight junctions. As endothelial cells are constantly sensing and responding to the extracellular environment, their activation by inflammatory stimuli promotes a loss of endothelial barrier function, which has been identified as a hallmark of systemic inflammation, leading to tissue edema formation and hypotension and thus, is a key contributor to lethal outcomes. In this review, we provide a comprehensive summary of the major players, such as the angiopoietin-Tie2 signaling axis, adrenomedullin and vascular endothelial (VE-) cadherin, that substantially contribute to the regulation and dysregulation of endothelial permeability during systemic inflammation and elucidate treatment strategies targeting the preservation of vascular integrity.

Background Loss of hemodynamic coherence is a phenomenon in critically ill patients. Due to inflammatory events and endothelial remodeling, macro- and microhemodynamics are decoupled from each other, resulting in microcirculatory disturbances and end organ ischemia despite adequate vital parameters. So far, quantification of perfusion of vessels with < 100 μm diameter on the intensive care unit (ICU) was regularly performed with incident darkfield (IDF) microscopy. Nailfold videocapillaroscopy (NVC), however, is an established and easy method for visualization of the microcirculation in chronic diseases. We here evaluated NVC in critically ill patients and compared its use with consensus microcirculatory assessment of IDF-microscopy. Methods A new score, the capillary microcirculation (CapMic) score summarizing the microcirculation of the nail fold at four regions of digitus III, IV and V in a number between 0 (= no microcirculation) and 1 (= completely preserved microcirculation) was first established in 10 healthy volunteers and compared to the Microangiopathy Evolution Score (MES) standardized for NVC in chronic diseases. Then, n = 60 critically ill patients were recruited from a surgical ICU. Consensus-defined IDF scores and NCV data were compared at a single time point. Results Evaluation of the CapMic score in 10 healthy volunteers at rest and under iatrogenic limb ischemia showed robust changes (0.80 ± 0.03 vs. 0.51 ± 0.12, p < 0.001). In critically ill patients, the IDF microscopy parameters “proportion of perfused vessels” (PPV) and “microvascular flow index” (MFI) inversely correlated with the MES (Spearman’s R = -0.590, p < 0.001; Spearman’s R = −0.585, p < 0.001). There was a positive correlation between PPV and the CapMic score (Spearman’s R = 0.714, p < 0.001) and between MFI and the CapMic score (Spearman’s R = 0.711, p < 0.001) and an inverse correlation between MES and the CapMic score (Spearman’s R = −0.610, p < 0.001). Both sublingual and nailfold microcirculation deteriorated under rising norepinephrine- and crystalloid volume-requirements. Conclusion NVC-imaging provides comparable information on the microcirculation in critically ill patients compared to sublingual IDF microscopy. NCV could represent a new, additional method for diagnosing microcirculatory parameters on the ICU.

Driveline infection (DLI) is a common complication in patients with left ventricular assist devices. This complication can seriously undermine quality of life while on left ventricular assist devices. Current diagnosis of a DLI in the outpatient setting is based on clinical examination and later bacteria isolation. The Moleculight i:XTM is a handheld fluorescence imaging device capable to visualize bacterial colonization in real-time. We here evaluated the performance of the Moleculight i:XTM for diagnosis of DLIs as this device may have the potential advantage to rapidly identify infection and therefore promptly influence therapy. A total of 107 examinations in patients with suspected DLIs were prospectively included in this study. All examinations took place in the outpatient setting. In addition to the standard treatment, Moleculight fluorescence images were captured and swabs were taken at the area of maximal luminosity. Wounds and pictures were reviewed and classified as positive or negative by a wound specialist and two heart surgeons independently from microbiological results. The Moleculight i:XTM showed positive results (red fluorescence) in 19 cases (17.76%), whereas microbiological examination was positive for microorganisms in 74 cases (69.16%). The most common bacteria was Staphylococcus aureus. The findings resulted in a sensitivity of 13.51% and a specificity of 72.73%. The positive predictive value was 52.63% and the negative predictive value was 27.27%. Sub-analyses of different wound dressings or previous antibiotic treatment did not show any relevant difference. The results of the Moleculight i:X show a low sensitivity and specificity when being used to detect DLIs in the outpatient setting. Clinical examination and swabs should remain the gold standard despite the delay for bacteria isolation and consequent antibiotic treatment. Sensitivity and specificity of the Moleculight i:X in open wounds after surgical revision of the driveline remain to be clarified.

Volatile anesthetics are used more commonly for sedation in the intensive-care-unit (ICU). However, evidence for long-term use remains low. We therefore conducted a randomized-controlled trial comparing sevoflurane with intravenous sedation with particular focus on efficacy and safety. In this prospective, randomized-controlled phase-IIb monocentric clinical-trial ICU patients requiring at least 48 h of sedation were randomized to receive sevoflurane (S) or propofol/midazolam (P). Sedation quality was monitored using the Richmond-Agitation-Sedation-Scale. Following termination of sedation, the time to spontaneous breathing and extubation, opioid consumption, hemodynamics, ICU and hospital length of stay (LOS) and adverse events were recorded. 79 patients were eligible to randomization. Sedation quality was comparable between sevoflurane (n = 39) and propofol (n = 40). However, the use of sevoflurane lead to a reduction in time to spontaneous breathing (26 min vs. 375 min, P < 0.001). Patients sedated with propofol had lower opioid requirements (remifentanil:400 μg/h vs. 500 μg/h, P = 0.007; sufentanil:40 μg/h vs. 30 μg/h, P = 0.007) while hemodynamics, LOS or the occurrence of adverse events did not differ. ICU patients sedated with sevoflurane >48 h may return to spontaneous breathing faster, while the quality of sedation is comparable to a propofol-based sedation regime. Sevoflurane might be considered to be safe for long-term sedation in this patient population, while being non-inferior compared to propofol. •Apart from intravenous sedation, volatile anesthetics are becoming more used in ICU.•Long term inhalative sedation of critically ill patients showed shorter weaning times.•Patients sedated with propofol had lower opioid requirements.•Hemodynamics, length of stay or the occurrence of adverse events did not differ.

Background Systemic inflammation is a critical clinical condition regularly observed in the context of surgery-induced trauma or infection. Systemic inflammation induces an ubiquitous activation of the vasculature and vascular dysfunction related to organ damage and adverse outcomes. The dipeptidyl peptidase-4 (DPP4) modulates the receptor preferences and activity of a multitude of humoral substrates mediating the systemic inflammatory response. We here determined whether DPP4 inhibition is a means to beneficially modulate systemic inflammatory responses affecting vascular and organ integrity. Methods In cardiac surgery patients medicated with DPP4 inhibitors, we used a systems biology approach for in-depth characterization of the perioperative immune response and assessment of macro- and microvascular dynamics compared to control patients. In parallel, we mechanistically evaluated the efficacy of DPP4 inhibition on modulating immune responses, capillary leakage, vasoplegia and endothelial transcriptomic profiles in mice with severe systemic inflammation. Results Preoperative oral intake of the DPP4 inhibitor sitagliptin modulated innate and adaptive immune phenotypes and was associated with augmented microvascluar integrity, reduced vasoplegia and improved clinical parameters of capillary leakage in patients undergoing cardiac surgery. In mice, DPP4 inhibition curbed the inflammatory response to a polymicrobial sepsis resulting in a massive reduction in endothelial gene activation assoicated with preserved vascular barrier function, augmented vasopressor responses and organ integrity. Conclusions We conclude that DPP4 inhibition may be a safe and potent means to curb immune responses to surgery or infection, resulting in a preservation of vascular integrity that translates into organ protection and improved clinical outcomes. Trial registration https://www.clinicaltrials.gov ; Unique identifier: NCT05725798, study start: 2022-02-01. Graphical abstract

Sepsis is associated with hypotension, vascular leakage, vasoplegia and microvascular dysfunction. Therefore, the endothelium is a target for sepsis therapies. Since truncated procalcitonin exerts vascular activity, we here evaluated the efficacy of targeting procalcitonin for vascular integrity and sepsis outcomes. Sepsis up-regulated >2000 genes involved in pro-inflammatory responses while similar numbers of genes involving cell growth and maintenance were down-regulated. Transcriptomic changes in endothelial cells diminished by >50% by anti-procalcitonin antibodies and this was functionally associated with preserved vascular barrier integrity in lungs and intestines, reduced sepsis-induced vasoplegia, preserved endothelial nitric oxide bioavailability, improved organ integrity and reduced sepsis severity in mice. Mechanistically, procalcitonin neutralization was associated with reduced signaling of the interleukin-17 pathway. We here show sepsis induces substantial changes to the endothelial transcriptome and vascular integrity and neutralizing procalcitonin is a suitable means to preserve endothelial homeostasis at a transcriptomic and functional level that could translate into organ protection during sepsis. Sepsis causes endothelial dysfunction that drives vascular failure and organ injury. Here the authors show that neutralizing truncated procalcitonin reduced pro-inflammatory activation and leakage in the endothelium, resulting in preserved organ integrity, improved clinical outcomes and predicted survival in septic mice.

Pain signals are relayed to the brain via a nociceptive system, and in rare cases, this nociceptive system contains genetic variants that can limit the pain response. Here, we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and, further, whether we could target this region with a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N-knockin mouse using CRISPR/Cas9, we discovered that the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral responses to noxious chemical stimuli and less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Furthermore, blocking this K710 region in WT rodents using a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels. These findings identify K710 TRPV1 as a discrete site that is crucial for the control of nociception and provide insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options.

Patients experiencing cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) often die or suffer from severe neurological impairment. Post resuscitation syndrome is characterized by a systemic inflammatory response. Toll-like receptor 4 (TLR4) is a major mediator of inflammation and TLR4 has been implicated in the pathogenesis of post-resuscitation encephalopathy. The aim of this study was to evaluate whether TLR4 deficiency or inhibition can modulate survival and neurofunctional outcome after CA/CPR. Following intubation and central venous cannulation, CA was induced in wild type (C57Bl/6J, n = 38), TLR4 deficient (TLR4-/-, n = 37) and TLR4 antibody treated mice (5mg/kg MTS510, n = 15) by high potassium. After 10min, CPR was performed using a modified sewing machine until return of spontaneous circulation (ROSC). Cytokines and cerebral TNFalpha levels were measured 8h after CA/CPR. Survival, early neurological recovery, locomotion, spatial learning and memory were assessed over a period of 28 days. Following CA/CPR, all mice exhibited ROSC and 31.5% of wild type mice survived until day 28. Compared to wild type mice, neither TLR4-/- nor MTS510 treated wild type mice had statistically significant altered survival following CA/CPR (51.3 and 26.7%, P = 0.104 and P = 0.423 vs. WT, respectively). Antibody-treated but not TLR4-/- mice had higher IL-1β and IL-6 levels and TLR4-/- mice had higher IL-10 and cerebral TNFalpha levels. No differences existed between mice of all groups in early neurological recovery, locomotion, spatial learning ability or remembrance. Therapeutic strategies targeting TLR4 may not be suitable for the reduction of mortality or neurofunctional impairment after CA/CPR.

Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0.01–50 ng/mL procalcitonin for 2×72 h and evaluated for proliferation, necrosis, metabolic activity, cellular integrity, microalbumin synthesis, and detoxification capacity. Acetaminophen served as positive control. For further standardization, procalcitonin effects were confirmed in a cellular toxicology assay panel employing L929 fibroblasts. Data were analyzed using ANOVA/Tukey’s test. Results. Already at concentrations as low as 0.25 ng/mL, procalcitonin induced HepG2/C3A necrosis (P<0.05) and reduced metabolic activity, cellular integrity, synthesis, and detoxification capacity (all P<0.001). Comparable effects were obtained employing L929 fibroblasts. Conclusion. We provide evidence for procalcitonin to directly impair function and viability of human hepatocytes and exert general cytotoxicity in vitro. Therapeutical targeting of procalcitonin could thus display a novel approach to reduce incidence of liver dysfunction and failure during sepsis and lower morbidity and mortality of septic patients.