The Selective NLRP3-inflammasome inhibitor MCC950 Mitigates Post-resuscitation Myocardial Dysfunction and Improves Survival in a Rat Model of Cardiac Arrest and Resuscitation

Purpose To investigate the effects of the selective NLRP3 inflammasome inhibitor MCC950 on post-resuscitation myocardial function and survival in a rat model of cardiopulmonary resuscitation (CPR). Methods Thirty-six Sprague Dawley rats were randomized into three groups: (1) MCC950, (2) control, and (3) sham. Each group consisted of a 6 h non-survival subgroup (n = 6) and a 48 h survival subgroup (n = 6). Ventricular fibrillation (VF) was induced and untreated for 6 min. CPR was initiated and continued for 8 min. Resuscitation was attempted with a 4 J defibrillation. MCC950 (10 mg/kg) or vehicle was administered via intraperitoneal injection immediately after the return of spontaneous circulation (ROSC). Myocardial function and sublingual microcirculation were measured after ROSC in the non-survival subgroups. Plasma levels of interleukin Iβ (IL-1β) and cardiac troponin I (cTnI) were measured at baseline and 6 h in the non-survival subgroups. Heart tissue was harvested to measure the NLRP3 inflammasome constituents, including NLRP3, apoptosis-associated speck-like protein (ASC), Caspase-1, and IL-1β. Survival duration and neurologic deficit score (NDS) were recorded and evaluated among survival groups. Results Post-resuscitation myocardial function and sublingual microcirculation were improved in MCC950 compared with control (p < 0.05). IL-1β and cTnI were decreased in MCC950 compared to control (p < 0.01). The MCC950 treated groups showed significantly reduced ASC, caspase-1, and IL-1β compared with the control group (p < 0.05). Survival at 48 h after ROSC was greater in MCC950 (p < 0.05) with improved NDS (p < 0.05). Conclusion Administration of MCC950 following ROSC mitigates post-resuscitation myocardial dysfunction and improves survival.

Mid-Regional Proadrenomedullin (MR-proADM) and Microcirculation in Monitoring Organ Dysfunction of Critical Care Patients With Infection: A Prospective Observational Pilot Study

Introduction: Microvascular alterations are involved in the development of organ injury in critical care patients. Mid-regional proadrenomedullin (MR-proADM) may predict organ damage and its evolution. The main objective of this study was to assess the correlation between MR-proADM and microvascular flow index (MFI) in a small cohort of 20 adult critical care patients diagnosed with infection, sepsis, or septic shock. Further objectives were to evaluate the correlation between the clearance of MR-proADM and the variables of microcirculation and between MR-proADM and the Sequential Organ Failure Assessment (SOFA) score.Materials and Methods: This is a prospective observational pilot study. Inclusion criteria: consecutive adult patients admitted to intensive care unit (ICU) for or with infection-related illness. Daily measurement of MR-proADM and calculation of the SOFA score from admission in ICU to day 5. Repeated evaluations of sublingual microcirculation, collection of clinical data, and laboratory tests.Results: Primary outcome: MR-proADM was not significantly correlated to the MFI at admission in ICU. A clearance of MR-proADM of 20% or more in the first 24 h was related to the improvement of the MFIs and MFIt [percentual variation of the MFIs + 12.35 (6.01–14.59)% vs. +2.23 (−4.45–6.01)%, p = 0.005; MFIt +9.09 (4.53–16.26)% vs. −1.43 (−4.36–3.12)%, p = 0.002].Conclusion: This study did not support a direct correlation of MR-proADM with the MFI at admission in ICU; however, it showed a good correlation between the clearance of MR-proADM, MFI, and other microvascular variables. This study also supported the prognostic value of the marker. Adequately powered studies should be performed to confirm the findings.

Links between Endothelial Glycocalyx Changes and Microcirculatory Parameters in Septic Patients

The glycocalyx is an endothelial surface layer that is essential for maintaining microvascular homeostasis. Impaired integrity of the endothelial glycocalyx may be directly related to the development of microvascular dysfunction. To explore this hypothesis, we conducted a prospective observational study on adult patients diagnosed with sepsis. The study aimed to evaluate the degree of damage to the glycocalyx and to identify correlations between microcirculatory parameters and glycocalyx thickness based on capillary diameter. Sublingual microcirculation was examined using a handheld Cytocam-incident dark field video microscope. A sidestream dark field video microscope attached to a GlycoCheck monitor was used to determine the perfused boundary regions (PBRs) of sublingual blood vessels grouped by diameter (5–9 μm, 10–19 μm, and 20–25 μm). We identified significant damage to the glycocalyx in sublingual blood vessels of all the aforementioned diameters in septic patients compared to healthy age-matched controls. Furthermore, we found that the PBRs of the smallest capillaries (diameter class 5–9µm) correlated moderately and inversely with both total and perfused blood vessel densities. Collectively, our data suggest that there may be a functional relationship between damage to the endothelial glycocalyx of the smallest capillaries and alterations in the microcirculation observed in response to sepsis.

Association of preoperative plasma suPAR levels with intraoperative sublingual microvascular perfusion in patients undergoing major non-cardiac surgery

Introduction: The plasma suPAR level has previously been associated with postoperative complications and has been shown to be an independent predictor of coronary microvascular function and flow reserve. We investigated the association between preoperative suPAR levels and intraoperative sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery. Methods: This study included 100 patients undergoing major non-cardiac surgery between February 2019 and September 2020. The primary objective was to investigate the association between preoperative suPAR and intraoperative sublingual De Backer score, Consensus Proportion of Perfused Vessels (Consensus PPV), and Consensus PPV (small). Secondary objectives were to investigate the associations between these sublingual microcirculatory variables and (1) complications and (2) mean arterial pressure. EDTA blood was collected before induction of anesthesia and plasma suPAR levels were determined using the suPARnostic quick triage lateral flow assay. Sublingual microcirculation was monitored with Sidestream DarkField (SDF+) imaging technique at 20 minutes after induction of anesthesia before surgical incision (baseline) and then every 30 minutes until emergence from anesthesia. Results: A decrease of 0.7 mm-1 in the De Backer score, 2.5% in the Consensus PPV, and 2.8% in the Consensus PPV (small) from baseline measurement was observed for every 1 ng/ml increase of suPAR or 1 additional minute of intraoperative time. De Baker score did not change significantly from baseline (p=0.404), while Consensus PPV and Consensus PPV (small) decreased significantly from baseline (p<0.001 in both cases). The De Backer score, the Consensus PPV, and the Consensus PPV (small) correlated with postoperative complications. Mean arterial pressure correlated with De Backer score (p=0.487) but not with Consensus PPV (p=0.506) or Consensus PPV (small) (p=0.697) during the intraoperative period. Conclusion: Preoperative suPAR levels and prolonged operative duration were associated with intraoperative impairment of sublingual microvascular perfusion in patients undergoing elective major non-cardiac surgery.

Efficacy of CytoSorb in a Pediatric Case of Severe Multisystem Infammatory Syndrome (MIS-C): A Clinical Case Report

Background: Multisystem inflammatory syndrome in children (MIS-C) has emerged during the COVID-19 pandemic as a new SARS-CoV-2-related entity, potentially responsible for a life-threatening clinical condition associated with myocardial dysfunction and refractory shock.Case: We describe for the first time in a 14-year-old girl with severe MIS-C the potential benefit of an adjuvant therapy based on CytoSorb hemoperfusion and continuous renal replacement therapy with immunomodulatory drugs.Conclusions: We show in our case that, from the start of extracorporeal blood purification, there was a rapid and progressive restoration in cardiac function and hemodynamic parameters in association with a reduction in the most important inflammatory biomarkers (interleukin 6, interleukin 10, C-reactive protein, ferritin, and D-dimers). Additionally, for the first time, we were able to show with analysis of the sublingual microcirculation a delayed improvement in most of the important microcirculation parameters in this clinical case of MIS-C.

Combined Therapy With Polyethylene Glycol‐20k and MCC950 Preserves Post‐Resuscitated Myocardial Function in a Rat Model of Cardiac Arrest and Cardiopulmonary Resuscitation

Background To investigate the therapeutic potential of combined therapy with polyethylene glycol‐20k (PEG‐20k) and MCC950 on post‐resuscitation myocardial function in a rat model of cardiac arrest. Methods and Results Thirty rats were randomized into 5 groups: Sham, Control, PEG‐20k, MCC950, PEG‐20k+ MCC950. Except for sham, animals were subjected to 6 minutes of ventricular fibrillation followed by 8 minutes cardiopulmonary resuscitation. Two milliliters PEG‐20k was administered by intravenous injection coincident with the start of cardiopulmonary resuscitation; MCC950 (10 mg/kg), a highly selective NLRP3 inflammasome inhibitor, was delivered immediately after restoration of spontaneous circulation. Myocardial function, sublingual microcirculation, mitochondrial function, plasma cardiac troponin I, and interleukin‐1β, expression of proteins in SIRT1 (sirtuin 1)/PGC‐1α (peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha) and NLRP3 (the NOD‐like receptor family protein 3) inflammasome pathways were evaluated. Following cardiopulmonary resuscitation, myocardial function was compromised with a significantly decreased cardiac output, ejection fraction, and increased myocardial performance index, cardiac troponin I. Sublingual microcirculation was disturbed with impaired perfused vessel density and microvascular flow index. Cardiac arrest reduced mitochondrial routine respiration, Complex I‐linked respiration, respiratory control rates and oxidative phosphorylation coupling efficiency. PEG‐20k or MCC950 alone restored mitochondrial respiratory function, restituted sublingual microcirculation, and preserved myocardial function, whereas a combination of PEG‐20k and MCC950 further improved these aspects. PEG‐20k restored the expression of SIRT1 and PGC‐1α, and blunted activation of NLRP3 inflammasomes. MCC950 suppressed expression of cleaved‐caspase‐1/pro‐caspase‐1, ASC (apoptosis‐associated speck‐like protein), GSDMD [gasdermin d], and interleukin‐1β. Conclusions Combined therapy with PEG‐20k and MCC950 is superior to either therapy alone for preserving post‐resuscitated myocardial function, restituting sublingual microcirculation at restoration of spontaneous circulation at 6 hours. The responsible mechanisms involve upregulated expression of SIRT1/PGC1‐α in tandem with inhibition of NLRP3 inflammasomes.

Effects of remote ischemic conditioning on microcirculatory alterations in patients with sepsis: a single-arm clinical trial

Background Remote ischemic conditioning (RIC) is a promising technique that may protect organs and tissues from the effects of additional ischemic episodes. However, the therapeutic efficacy of RIC in humans with sepsis remains unknown. We hypothesized that RIC might improve sublingual microcirculation in patients with sepsis. Methods This prospective single-arm trial was performed in a mixed ICU at a tertiary teaching hospital. We included patients with sepsis or septic shock within 24 h of ICU admission. The RIC procedure comprised 3 cycles of brachial cuff inflation to 200 mmHg for 5 min followed by deflation to 0 mmHg for another 5 min. The procedure took 30 min. RIC was performed at the time of study inclusion and repeated after 12 and 24 h. Sublingual microcirculatory measurements were obtained before and after each RIC procedure using a Cytocam®-incident dark-field (IDF) device (Braedius Medical, Huizen, The Netherlands). The microcirculatory data were compared with a historical control. Data are reported as the medians along with the 25th and 75th percentiles. Results Twenty-six septic patients with a median age of 65 (57–81) years were enrolled in this study. The median Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores at admission were 20 (13–23) and 10 (9–12), respectively. All patients were receiving vasopressors. After the 1st RIC procedure, the microvascular flow index (MFI) and the proportion of perfused vessels (PPV) among small vessels were significantly higher than before the procedure, with pre- and post-treatment values of 2.17 (1.81–2.69) and 2.59 (2.21–2.83), respectively, for MFI (p = 0.003) and 87.9 (82.4–93.8) and 92.5 (87.9–96.1) %, respectively, for PPV (p = 0.026). This result was confirmed by comparison with a historical control group. We found no change in microcirculatory flow or density parameters during repeated RIC after 12 h and 24 h. Conclusion In patients with sepsis, the first remote ischemic conditioning procedure improved microcirculatory flow, whereas later procedures did not affect sublingual microcirculation. Trial registration NCT04644926, http://www.clinicaltrials.gov. Date of registration: 25 November 2020. Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04644926.

Microcirculatory Response to Changes in Venoarterial Extracorporeal Membrane Oxygenation Pump Flow: A Prospective Observational Study

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) pump flow is crucial for maintaining organ perfusion in patients with cardiogenic shock, but VA-ECMO pump flow optimization remains as a clinical challenge. This study aimed to investigate the response of sublingual microcirculation to changes in VA-ECMO pump flow.Methods: Sublingual microcirculation was measured before and after changing VA-ECMO pump flow according to the treatment plan of ECMO team within 24 h and at 24-48 h after VA-ECMO placement. In clinical events of increasing VA-ECMO pump flow, those events with increased perfused vessel density (PVD) were grouped into group A, and the others were grouped into group B. In clinical events of decreasing VA-ECMO pump flow, those events with increased PVD were grouped into group C, and the others were grouped into group D.Results: Increased PVD was observed in 60% (95% CI, 38.5–81.5%) of the events with increasing VA-ECMO pump flow. The probability of increasing PVD after increasing VA-ECMO pump flow were higher in the events with a PVD &lt; 15 mm/mm2 at baseline than those with a PVD ≥ 15 mm/mm2 [100% (95% CI, 54.1–100%) vs. 42.9% (95% CI, 17.7–71.1%), P = 0.042]. Other microcirculatory and hemodynamic parameters at baseline did not differ significantly between group A and B or between group C and D.Conclusion: This study revealed contradictory and non-contradictory responses of sublingual microcirculation to changes in VA-ECMO pump flow. Tandem measurements of microcirculation before and after changing VA-ECMO pump flow may help to ensure a good microcirculation.