IMPORTANCE Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes.OBJECTIVE To determine whether the combination of vasopressin and methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021.INTERVENTION Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses. MAIN OUTCOMES AND MEASURESThe primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2). RESULTS Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean [SD] age, 71 [13] years; 322 men [64%]). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference: −2.0% [95% CI, −7.5% to 3.5%]; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, −4.7% to 4.9%]; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively.CONCLUSIONS AND RELEVANCE Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival.
Endothelial activation is a pivotal event in the development and progression of inflammation. Central to endothelial activation is the up-regulation of cellular adhesion molecules (CAMs) including E-selectin (CD62E), ICAM-1 (CD54), VCAM-1 (CD106) and PECAM-1 (CD31). These CAMs are also found in soluble forms (sCAMs). In this in vitro study of endothelial activation, we examined whether the levels of sCAMs correlate with the endothelial surface expression of CAMs in a dosedependent and time-dependent manner. Such a correlation would support the use of sCAMs as surrogate markers for endothelial activation in inflammatory conditions. Human umbilical vein endothelial cells (HUVEC) were cultured with various concentrations of TNF-a for 8 hr and at a fixed concentration of TNF-a for various durations. The levels of soluble and surface-bound E-selectin, ICAM-1, VCAM-1 and PECAM-1 were quantified by flow cytometry. TNF-a stimulation increased CAM and sCAM expression in a dose-dependent and time-dependent manner. There was a significant positive correlation between the levels of ICAM-1 and sICAM-1 and between the levels of VCAM and sVCAM-1 in both the dose-response and time-response experiments. A positive correlation between the levels of E-selectin and sE-selectin was observed in the time-response experiment. This study supports the use of sCAMs as potential biomarkers of endothelial activation. In particular, the use of sICAM-1, sVCAM-1 and sE-selectin seems promising.
IntroductionSpondyloarthritis (SpA) comprises a group of diseases often associated with HLA-B27 and characterized by inflammation of the entheses and joints of the axial skeleton. The inflammatory process in SpA is presumably driven by innate immune cells but is still poorly understood. Thus, new tools for monitoring and treating inflammation are needed. The family of CD18 integrins is pivotal in guiding leukocytes to sites of inflammation, and CD18 hypomorphic mice develop a disease resembling SpA. Previously, we demonstrated that altered soluble CD18 (sCD18) complexes in the blood and synovial fluid of patients with arthritis have anti-inflammatory functions. Here, we study the mechanisms for these alterations and their association with SpA disease activity.MethodsPlasma levels of sCD18 in a study population with 84 patients with SpA and matched healthy controls were analyzed with a time-resolved immunoflourometric assay (TRIFMA). Binding of sCD18 to endothelial cells and fibroblast-like synoviocytes (FLSs) was studied with confocal microscopy. Shedding of CD18 from peripheral blood mononuclear cells (PBMCs) was studied with flow cytometry and TRIFMA.ResultsPlasma levels of sCD18 were decreased in patients with SpA compared with healthy volunteers (P <0.001), and the lowest levels were in the HLA-B27-positive subgroup (P <0.05). In a multiple regression model, the sCD18 levels exhibited an inverse correlation with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (P <0.05), the level of morning stiffness (P <0.05), the Bath Ankylosing Spondilitis Metrology Index (P <0.05), the physician global assessment score (P <0.01), and the sacroiliac magnetic resonance imaging activity score (P <0.05). The mechanisms for these changes could be simulated in vitro. First, sCD18 in plasma adhered to inflammation-induced intercellular adhesion molecule 1 (ICAM-1) on endothelial cells and FLS, indicating increased consumption. Second, CD18 shedding from SpA PBMCs correlated inversely with the BASDAI (P <0.05), suggesting insufficient generation. CD18 was shed primarily from intermediate CD14++ CD16+ monocytes, supporting the view that alterations in innate immunity can regulate the inflammatory processes in SpA.ConclusionsTaken together, the failure of patients with SpA to maintain adequate sCD18 levels may reflect insufficient CD18 shedding from monocytes to counterbalance the capture of sCD18 complexes to inflammation-induced ICAM-1. This could increase the availability of ICAM-1 molecules on the endothelium and in the synovium, facilitating leukocyte migration to the entheses and joints and aggregating disease activity.
BackgroundThe diagnosis of sepsis is challenging and there is an unmet need for sensitive and specific diagnostic and prognostic biomarkers. Following activation of macrophages and monocytes, the haptoglobin-haemoglobin receptor (CD163) and the mannose receptor (MR) are shed into the circulation (sCD163 and sMR).ObjectiveWe investigated monocyte expression of CD163 and MR, and levels of sCD163 and sMR in septic and non-septic patients, and in healthy controls. We hypothesised that these receptors are elevated during sepsis and can be used diagnostic and prognostic.MethodsTwenty-one patients with severe sepsis or septic shock and 15 critically ill non-septic patients were included in this prospective observational study at three ICUs at Aarhus University Hospital and Randers Regional Hospital, Denmark. Fifteen age- and gender-matched healthy volunteers served as controls. Levels of sCD163 and sMR were measured using a sandwich ELISA and monocyte expression of CD163 and MR was evaluated by flow cytometry during the first four days of ICU stay. The diagnostic and prognostic values of the receptors were assessed using AUROC curves.ResultsAt ICU admission and during the observation period, monocyte expression of CD163 and levels of sCD163 and sMR were significantly higher in septic patients compared with non-septic patients and healthy controls (p<0.01 for all comparisons). Monocytes did not express MR. The diagnostic values estimated by AUROC were 1.00 for sMR, 0.95 for sCD163, 0.87 for CRP, and 0.75 for monocyte-bound CD163. Among the septic patients, monocyte expression of CD163 was higher in non-survivors compared with survivors at ICU admission (p = 0.02) and during the observation period (p = 0.006). The prognostic value of monocyte-bound CD163 estimated by AUROC at ICU admission was 0.82.ConclusionThe macrophage-specific markers CD163, sCD163, and sMR are increased in septic patients. Particularly sMR is a promising new biomarker of sepsis.
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