What's New in Shock, June 2018? (2018)

This month brings another excellent and diverse crop of articles to the readers of Shock. This issue leads off with an excellent review article by Du et al. (1) on antiplatelet therapy for sepsis, and makes the case for yet another benefit of aspirin. The focus on sepsis continues with the work of Dargent et al. (2), who carried out a clinical sub-study involving 370 patients from the epidemiology of septic shock in French intensive care units trial in septic shock, aiming to assess whether the cumulative dose of vasopressors (CDV) is a predictor of death within 72 h after admission due to refractory septic shock. A strategy in two steps based on CDV was able to predict these early deaths with a low sensitivity but high specificity, supporting a possible role for CDV as a prognostic marker which may be aimed at better patient stratification for clinical trials in sepsis (2). Continuing with the sepsis theme, Lu et al. (3) performed a prospective observational study on patients with community-acquired, pneumonia-associated severe sepsis to characterize the expression and clinical correlations of costimulatory molecules on peripheral T lymphocyte subsets. Their results showed that the expression of key costimulatory molecules on various peripheral T-cell subsets is activated in early-stage severe sepsis. In addition, their results showed an imbalance in cell surface expression of other molecules on Tregs and Tconvs which may contribute to a functional imbalance of these two regulatory T-cell populations. These findings could have potential clinical implications, wherein a single flow cytometric measurement of defined T-cell populations could facilitate the rapid assessment of organ dysfunction in the setting of severe sepsis. Remaining on the sepsis theme with a focus on sepsis-associated thrombocytopenia, Bedet et al. (4) have prospectively evaluated factors associated with thrombocytopenia during septic shock, with an emphasis on endogenous sepsis mediators using multiplex cluster analysis. Unbiased hierarchical clustering analysis identified five different clusters of sepsis mediators that were associated with thrombocytopenia. These findings provide granular insights into the complex biological mechanisms associated with thrombocytopenia in the setting of sepsis, which could aid in future studies to test specific therapeutic strategies. Moving in a different direction, Kong et al. (5) examined the clinical utility of the delta neutrophil index (DNI, which reflects the fraction of circulating immature granulocytes) as a marker of severity in patients with acute pulmonary embolism (PE) admitted to the emergency department (ED). Based on a retrospective analysis of a large cohort of patients diagnosed with acute PE from a single center ED, higher DNI values upon ED admission were significantly associated with short-term mortality. The authors concluded that the DNI value, which could be obtained as part of the complete blood count analysis, might serve as useful as a marker to predict 28-day mortality in patients with acute PE. Yaroustovsky et al. (6) examined the antisepsis strategy of endotoxin adsorption in a single-center clinical study. They observed improvement in hemodynamic and respiratory parameters, decreased procalcitonin and endotoxin activity, a normalization of body temperature, and improved survival in the treatment group versus historical controls, giving further credence to the potential therapeutic value of this time-tested strategy. The nitric oxide system has been hypothesized to be important in the pathophysiology of necrotizing soft tissue infection (NSTI). Hansen et al. (7) investigated the association between admission circulating levels of the nitric oxide metabolites nitrite and asymmetric dimethylarginine (ADMA), as well as the nitric oxide synthase substrate L-arginine and the L-arginine/ADMA ratio versus presence of septic shock in patients with NSTI. They found that ADMA level was higher in patients in need of renal replacement therapy as well as correlating positively with multiple organ dysfunction scores. Also, patients with a low baseline L-arginine/ADMA ratio were at higher risk of dying (7). Switching gears, Dr Thiemermann's group extend their prior work on the role of artesunate, an antimalarial drug, to define novel effects in experimental ischemic heart disease (8). Khan et al. (8) investigated the effects of artesunate or its active metabolite dihydroartemisinin (DHA) in a model of transient myocardial ischemia/reperfusion (I/R) injury and evaluated the mechanism of action of the observed cardioprotective effects of artesunate and DHA, demonstrating beneficial effects and suggesting potential mechanisms associated with this beneficial effect. It would be interesting to see if these mechanisms also play a role in the clinical setting of trauma/hemorrhage in which this drug is currently being trialed. Returning to the sepsis theme, e Silva Castanheira et al. (9) examined the role of atypical chemokine receptor 2 (ACKR2) receptor (which can remove and degrade CC chemokines) in the setting of a murine sepsis model. The authors hypothesized that although chemokines play a key role in recruiting neutrophils to the primary site of infection and thereby helping combat eliminate bacteria, chemokines in sepsis could lead to multiple organ failure through exacerbated neutrophil infiltration to vital organs. To test this hypothesis, and using a cecal ligation and puncture murine model, they demonstrated that ACKR2-deficient mice exhibited a significant reduction in the survival rate compared with similarly treated wild-type (WT) mice. In addition, ACKR2-deficient mice showed increased neutrophil infiltration and elevated CC chemokine levels in multiple organs with concomitantly severe anatomical lesions when compared with the WT mice. To validate these findings, lung samples from patients who died of sepsis were examined for ACKR2+ cells and compared with control individuals who died of other causes. The lung samples from septic patients showed an increased number of ACKR2+ cells compared with those of control patients. The authors conclude that ACKR2 may have a protective role during sepsis, and that the absence of ACKR2 may lead to exacerbated chemokine accumulation which in turn leads to increased neutrophil infiltration and hence damage to vital organs. Though further studies are clearly warranted, ACKR2 represents a novel potential therapeutic target in sepsis. An interesting study by Langgartner et al. (10) examined the effects of psychosocial stress exposure following thoracic trauma and its association with complications such as acute lung injury, acute respiratory distress syndrome, and multiple organ failure. The authors used the chronic subordinate colony housing (CSC) paradigm to induce “psychosocial traumatic preload” and systemic low-grade immune activation in male mice, which was accompanied with systemic inflammation. Their results showed that CSC exposure aggravated the early immune response as well as elevated markers of inflammation and injury in thorax trauma-exposed CSC versus thorax trauma-exposed single-housed control mice. These results suggest that repeated psychosocial traumatization during adulthood can slightly aggravate the local immune response toward an isolated thorax trauma, though overall these changes may be considered a minor risk factor in terms of thorax trauma-associated complications. Vagus nerve stimulation (VNS) is a medical treatment that involves delivering electrical impulses to the vagus nerve which is used as an adjunctive therapy for certain types of intractable epilepsy and treatment-resistant depression. Prior studies in murine models have demonstrated the benefits of VNS treatment in reducing ischemia/reperfusion injury. In the current issue, Sun et al. (11) examined the protective effects of VNS in murine model of cardiopulmonary resuscitation (CPR) and whether VNS is dependent on the alpha 7 nicotinic acetylcholine receptor (α7nAChR) or not. The authors showed improved post-resuscitation myocardial and cerebral functions with longer duration of survival in the VNS-treated animals. Importantly, VNS decreased the number of electrical shocks and the duration of CPR required, and these protective effects were abolished by α7nAChR inhibitors. The study concluded that VNS improves the outcomes after CPR and that the cholinergic anti-inflammatory pathway, via α7nAChR, plays an important role during CPR. Along the same lines, Wang et al. (12) examined the effects of dichloroacetate (DCA, a pyruvate dehydrogenase kinase inhibitor) on post-resuscitation neurological injury in an asphyxia cardiac arrest animal model in rats. Their result showed that DCA treatment increased survival time and reduced neurologic deficit scores after return of spontaneous circulation, concomitant with attenuated cerebral pathology, reduced cerebral expression of inflammatory markers, and improved cellular energetics. These interesting studies suggest the potential utility of DCA as a therapeutic agent via its neuroprotective effects on brain tissue following cardiac arrest. Chronic kidney disease (CKD) is known to exacerbate myocardial ischemia reperfusion (IR) injury. Guo et al. (13) focused their study on the potential role of endoplasmic reticulum (ER) stress-mediated apoptosis in myocardial I/R injury in a mouse model of CKD + I/R. The expression of ER stress-mediated apoptotic proteins was markedly upregulated—and that of anti-apoptotic protein downregulated—after I/R injury. Treatment with a chemical ER chaperone pretreatment ameliorated this damage, suggesting that excessive activation of ER stress-mediated apoptosis pathways is involved in CKD-induced myocardial susceptibility to I/R injury, and suggesting a possible therapeutic efficacy of chemical ER chaperones in this setting (13). Hundeshagen et al. focus their study on the role of Fms-like tyrosine kinase-3 ligand (Flt3L) in the setting of a mouse model of burn injury, which induces immunosuppression and promotes infection with opportunistic pathogens. They examined the effects of post-burn prophylactic Flt3L treatment on local and systemic infection and inflammation, demonstrating significantly reduced bacterial burden in the lung and spleen, reduced pulmonary and systemic inflammation, and lower incidences of bacteremia and septic distant organ manifestation, and delayed mortality. These studies raise the possible therapeutic utility of prophylactic treatment with Flt3L (14). Taken together, this month's issue of Shock presents a smorgasbord of translational and pretranslational studies spanning the gamut of shock states. We hope you will enjoy reading these articles as much as we did, and hope that they will stimulate novel directions for research and clinical translation.