The Shock Society 2019–2021 Strategic Plan No abstract available

What's New in Shock, December 2019? No abstract available

Sparstolonin B: A Unique Anti-Inflammatory Agent Toll-like receptors are transmembrane proteins which sense and transmit infectious and inflammatory responses to the cells expressing them. Therapeutic strategies for the blockade of excessive Toll-like receptor signaling are being actively pursued for several diseases. Recently, Sparstolonin B, isolated from Chinese herb, which suppresses selectively Toll-like receptors has been studied in various inflammatory models. The objective of this review is to summarize the current literature regarding the use of Sparstolonin B in various in vitro and in vivo studies and to provide an overview regarding the potential use of this agent in different inflammatory diseases. Additionally, the current knowledge regarding the role of Toll-like receptors in inflammatory disease and the usage of various Toll-like receptor antagonists will be summarized. Based on our review, we believe Sparstolonin B could serve as a potential therapeutic agent for treatment of Toll-like receptor-mediated inflammatory disorders.

Left-Sided Ventricular–arterial Coupling and Volume Responsiveness in Septic Shock Patients Background: Suboptimal ventricular arterial coupling (VAC) is one of the pivotal determinants of inefficient heart performance despite appropriate administration of fluids or vasopressors in shocks. Here, we investigate the performance of VAC in patients who are unresponsive to fluid administration in septic shock. Methods: This is a retrospective observational study of septic shock patients (n = 35). VAC was evaluated by effective arterial elastance (EaI), left ventricular end-systolic elastance (EesI), and EaI/EesI. Septic shock patients successfully fluid resuscitated after pulse indicator continuous cardiac output (PiCCO) monitoring, defined as an increase in general end-diastolic ventricular volume (GEDVI) more than 10%, were divided into volume responsive (VVr), and volume unresponsive (VVur) groups based on a cardiac index increase above 10%. We hypothesize that two groups of patients will exhibit dissimilarities of VAC variation, defined as EaI/EesI variation (ΔEaI/EesI). Results: Variations of EaI (ΔEaI), and EaI/EesI (ΔEaI/EesI), and systemic vascular resistance index (ΔSVRI) were significantly lower in the VVr group than those in the VVur group (P < 0.05). Variations of cardiac index (ΔCI), stroke volume index (ΔSVI), and EesI (ΔEesI) were significantly higher in patients with ΔEaI/EesI ≤ 0. Concomitantly, ΔEaI and ΔSVRI were significantly diminished as compared with patients with ΔEaI/EesI > 0 (P < 0.05). ΔCI has an inverse relationship with both ΔEaI (r = −0.46, P = 0.006), ΔEaI/EesI (r = −0.65, P < 0.001), and ΔSVRI (r = −0.59, P < 0.001). We observed more patients who were fluid responsive in the ΔEaI/EesI ≤ 0 group than in the group with ΔEaI/EesI > 0 (88.89% vs. 26.92%, P = 0.01). Conclusions: Variation of VAC is often related to suboptimal ventricular volume responsiveness among patients with septic shock.

High Central Venous-to-Arterial CO2 Difference is Associated With Poor Outcomes in Patients After Cardiac Surgery: A Propensity Score Analysis Purpose: In contrast to arterial lactate, previous studies have proposed central venous-to-arterial CO2 difference (P (v-a)CO2) as a more useful guide for categorizing patients at risk of developing septic shock. It is worthwhile studying P (v-a)CO2 in determining whether it could serve as a useful predictor for poor postoperative outcomes in patients undergoing cardiac surgery. We investigated the ability of P(v-a)CO2 to predict poor outcomes of patients with postoperative cardiogenic shock. Methods: In total, 1,672 patients were enrolled in this study from January 1, 2014 to June 1, 2017. Of these patients, 143 exhibited complicated and poor outcomes. To address any bias, we derived a propensity score predicting the functions of P(v-a)CO2 on poor outcomes and matched 114 cases to 114 controls with a similar risk profile. In this cohort study, poor outcomes were defined as the occurrence of any adverse complications, including sudden death, cardiac arrest, extracorporeal membrane oxygenation, oliguria, and the administration of a large amount of vasoactive-inotropic drugs. Results: In propensity-matched patients, significant differences in P(v-a)CO2 (6.11 ± 2.94 mm Hg vs. 11.21 ± 5.22 mm Hg, P < 0.001) were noted between the control group and poor outcome group. The area under the receiver operating characteristic curve of P(v-a)CO2 (AUC: 0.837, 95% CI: 0.782–0.892) for the detection of poor outcomes was significantly better compared to that of the central venous oxygen saturation and arterial lactate. Additionally, there was a negative correlation between cardiac index and P(v-a)CO2 (R= −0.68, P < 0.001). Conclusion: We have shown a correlation between P(v-a)CO2 to cardiac output which may be used as an alternative metric to predict the poor outcomes of patients with postoperative cardiogenic shock.

Lipopolysaccharide Stress Induces Cryptic Exon Splice Variants of the Human Glucocorticoid Receptor Glucocorticoids are widely used in the treatment of numerous inflammatory conditions, including sepsis. Unfortunately, patient response to glucocorticoid therapy can be inconsistent. Variations in the human glucocorticoid receptor (hGR) may contribute to the differential patient response. We screened for hGR variants in the buffy coats of burn patients and peripheral blood mononuclear cells (PBMCs) treated with lipopolysaccharide. Three novel splice variants containing cryptic exons were upregulated in the PBMCs after lipopolysaccharide exposure at 3 and 13 h with the greatest observed expression at 3 h. Luciferase assays revealed that two of the isoforms had no significant activity in comparison with the reference hGR when stimulated with hydrocortisone. The third isoform had an augmented response that was greater than the reference hGR at a high cortisol dose. This shows that PBMCs are able to produce variant hGR isoforms in response to stress. Furthermore, lipopolysaccharide stress appears to induce these hGR variants, potentially by influencing mRNA splicing. In the future, identifying hGR expression profiles may be a key component in individually tailoring a patient's treatment to sepsis and injury.

Predictive Factors of Duration of Continuous Renal Replacement Therapy in Acute Kidney Injury Survivors The factors influencing continuous renal replacement therapy (CRRT) duration for critically ill patients with acute kidney injury (AKI) are unclear. Therefore, we investigated the clinical factors that could influence the duration of CRRT for AKI survivors. In this retrospective observational study, the medical records of all hospital survivors who required CRRT for AKI in intensive care units were analyzed. The CRRT duration (median, 6 days) was categorized as short-duration CRRT (≤ 6 days, n = 65) and long-duration CRRT (> 6 days, n = 59), according to the median CRRT duration. A urine output of less than 0.5 mL/kg/h (adjusted odds ratio [OR], 3.4; P = 0.010), mechanical ventilation use (adjusted OR, 7.9; P = 0.001), and extracorporeal membrane oxygenation (ECMO) use (adjusted OR, 6.5; P = 0.010) were independent predictors of long-duration CRRT, whereas serum creatinine and neutrophil gelatinase-associated lipocalin were not significant predictors. A clinical model demonstrated a good discriminatory ability to predict long-duration CRRT (area under the curve, 0.84; 95% confidence interval, 0.76–0.90). The urine output immediately before CRRT initiation and factors associated with disease severity significantly affected the duration of CRRT. Simultaneously considering the urine output, mechanical ventilation use, and ECMO use predicted CRRT duration in AKI survivors.

The Contribution of the Omentum to the Outcome From Sepsis: An Experimental Animal Study The omentum is a large mesenchymal fibro-fatty tissue with remarkable healing capability. It is also rich in immune cells, including macrophages and lymphocytes, within particular structures named milky spots. Clinical observations indicate a high incidence of peritonitis after the removal of the omentum suggesting that it may play a role in sepsis. To test this possibility, male CD-1 mice underwent simultaneous omentectomy and cecal ligation and puncture (CLP), omentectomy-sham operation and CLP alone, and mortality was documented within 72 h post the insults. A significant increase in mortality was observed in mice subjected to omentectomy and CLP in comparison with CLP alone. Mortality was correlated with an increase in cytokine gene expression within the lung after omentectomy and CLP as opposed to CLP alone. However, no differences in bacterial load were observed within the peritoneum or blood between groups. To test the long-term effect of omentectomy, mice were subjected to omentum removal or sham operation, allowed to recover from surgery for 14 or 28 days, and then both were subjected to CLP. In these cases, no differences in mortality were observed between the groups suggesting that the lack of omentum triggers a compensatory mechanism. Finally, omentectomy and sham operation altered the composition of peritoneal immune cells with the disappearance of F4/80high macrophages and the appearance of a new population of F4/80low macrophages within 1 or 14 days post-surgery. The F4/80high positive cells reappeared after 28 days following the procedures. All of these observations suggest that the omentum plays an early role in the outcome from sepsis.

Hypoxia-Inducible Factor (HIF)-1α Promotes Inflammation and Injury Following Aspiration-Induced Lung Injury in Mice Acid aspiration-induced lung injury is a common disease in the intensive care unit (ICU) and acute respiratory distress syndrome (ARDS). Hypoxia-inducible factor (HIF)-1α is a major transcription factor responsible for regulating the cellular response to changes in oxygen tension. A clear understanding of the function of HIF-1α in lung inflammatory response is currently lacking. Here, we sought to determine the role of HIF-1α in type 2 alveolar epithelial cells (AEC) in the generation of the acute inflammatory response following gastric aspiration (GA). GA led to profound hypoxia at very early time points following GA. This correlated to a robust increase in HIF-1α, tissue albumin and pro-inflammatory mediators following GA in AECs. The extent of lung injury and the release of pro/anti-inflammatory cytokines were significantly reduced in HIF-1α (−/−) mice. Finally, we report that HIF-1α upregulation of the acute inflammatory response is dependent on NF-κB following GA.

N-Acetylcysteine Ameliorates Gentamicin-Induced Nephrotoxicity by Enhancing Autophagy and Reducing Oxidative Damage in Miniature Pigs The clinical use of gentamicin over prolonged periods is limited because of dose and time-dependent nephrotoxicity, in which intracellular oxidative stress and heightened inflammation have been implicated. Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. The aim of this study was to determine changes in autophagy in response to the antioxidant N-acetylcysteine (NAC), via its effects on oxidative stress, inflammation, apoptosis, and renal function, following treatment with gentamicin in mini pigs. Adult mini pigs were divided into isotonic saline solution, gentamicin, and gentamicin plus NAC combination treatment groups. Gentamicin-induced histopathological changes, including inflammatory cell infiltration and tubular necrosis, were attenuated by NAC. NAC ameliorated the gentamicin-induced decreases in the levels of autophagy-related proteins, such as LC3 (microtubule-associated protein 1 light chain 3), PINK1 (phosphatase and tensin homologue deleted on chromosome10-induced kinase 1), phospho-parkin, AMBRA1 (activatingmolecule in Beclin 1-regulated autophagy), p62/SQSTM1 (sequestosome protein 1), and polyubiquitinated protein aggregates. NAC also caused a significant reduction in oxidative damage markers, including 4-hydroxy-2-nonenal, protein carbonyls, γ-H2AX (gamma histone variant H2AX), and 8-hydroxy-2′-deoxyguanosine, in gentamicin-treated animals. These data show that the protective effects of NAC might be related, at least in part, to a reduced inflammatory response, as observed in animals treated with both gentamicin and NAC. These results suggest that autophagy could be a new therapeutic target for preventing gentamicin-induced kidney injury, and that NAC might ameliorate gentamicin-induced nephrotoxicity by autophagy.