What's New in Shock, March 2018?

It is a great honor to be asked to write about the current issue of SHOCK. This task is really easy to do as it is not difficult to write about good science. But not only the quality of these publications is exceptional, it is also the broad topics that make this issue of SHOCK a great issue and fun to read. So, sit down, put on some good music, have a glass of your choice of beverage, find time and inspiration, and enjoy the articles. Trauma patients are often affected by a hypocoagulable condition referred to as trauma-induced coagulopathy (TIC) for which few therapeutic options exist. One available treatment is fresh platelets transfusion, although it is not efficacious enough and has a number of limitations. Lopez et al. conducted a literature review to propose and derive an alternative therapy based on platelet-derived microvesicles (1). The authors provide compelling detail on the role of platelet-derived microvesicles (PMVs) hypercoagulable and hypocoagulable conditions and the association with the underlying pathophysiology. Specifically, they describe PMVs and thrombosis, hemostasis, and their procoagulant effect. As a therapeutic agent, the authors provide strong support for the treatment of endotheliopathy of trauma (EoT) including on coagulation, modulating the inflammatory response (remains controversial), reestablishing endothelial barrier integrity, and modulating vascular tone. The authors provide a comprehensive and prospective view of this important area of trauma. Another interesting and very exciting area of research that is not well understood is the role of immune suppression and chronic critical illness (CCI) in sepsis survivors. As the 2017 New Investigator Award Recipient, Stortz et al. conducted a study to compare CCI with rapid recovery (RAP) in sepsis survivors to determine if there are differences in immunosuppressive biomarker profile and incidence of secondary infections (2). In this prospective observational study of 88 critically ill patients with sepsis and 20 healthy controls, the authors found that 40% of sepsis patients developed CCI relative to those that experienced RAP (57%). They concluded that CCI patients were characterized by higher incidence of overall number of infections, and reduced absolute lymphocyte counts (ALC) and monocytic human leukocyte antigen-DR (mHLA-DR) expression at the time of sepsis diagnosis, whereas plasma-soluble programmed death-ligand 1 (sPD-L1) was elevated. Interestingly, RAP patients had a restoration effect for the immunosuppression biomarkers, whereas CCI patients did not. Unfortunately, it was noted that there were no differences between the biomarkers between the groups before sepsis onset and thus makes it difficult to delineate susceptible patients. These findings suggest a persistent immunosuppression in subsets of critically ill patients and common biomarkers that reflect this aberrant expression. We think that this paper is one of its first to describe an area that moves into the focus of many researchers, which is long-term outcomes. Congratulations to the authors for a tremendous study and winning the award. Single-nucleotide polymorphisms (SNPs) and overall genomic differences between patients have been associated previously with sepsis and adverse outcomes after trauma (3). Presently, Schimunek et al. compared trauma survivors and nonsurvivors to determine whether specific SNP haplotypes could distinguish the groups (4). Comparing data between 397 blunt trauma patients (13 nonsurvivors and 384 survivors), the authors found that 7 SNPs distinguished survivors from nonsurvivors. Interestingly, the authors used computational modeling to demonstrate that severely injured blunt trauma patients that survived with the same 7 SNPs as nonsurvivors had unique inflammatory responses (altered Th17 cell phenotypes) relative to similarly injured survivors that did not have those SNPs. Thus, the authors present evidence for an interaction between genetic polymorphisms and inflammatory responses in trauma patients and the respective outcomes. It is worth mentioning that the authors reported an initial analysis conducted in 13 matched survivors and nonsurvivors, which yielded 126 SNPs. Thus, it would be interesting to know if a larger nonsurvivor group would yield more SNPs that are associated with poor outcomes and further if these differences can be translated in other critically ill patients. Renal ischemia–reperfusion (RIR) is a phenomenon that drives excessive tissue damage via the initiation of an inflammatory cascade that ultimately contributes to acute kidney injury, which results in rapid kidney dysfunction and higher mortality rates (5). Extending the recent work from Dr. Wang's group on cold-inducible RNA-binding protein (CIRP) and its induction of inflammation via TLR4, presently, McGinn et al. investigated the role of C23 (short peptide derived from CIRP that binds to myeloid differentiation factor 2) in reducing RIR injury by blocking CIRP (6). Consistent with other work from this group, the authors provide strong support for the C23's reduction of systemic inflammation (IL-6, TNF-α, IL-1β), inflammation in the kidneys, and less overall renal damage. Strikingly, a survival curve revealed that C23-treatment mice post RIR resulted in 70% survival rate relative to 37% in the vehicle group. The authors provide strong evidence for a therapeutic benefit of C23 in RIR, and it will be interesting to see if these improvements will translate to a potential clinical trial. Recent reports have brought Metformin back into the spotlight for its numerous therapeutic benefit extending well beyond glycemic control/metabolic regulation. Kim et al. conducted elegant studies to tease out the role of genetic deficiency (AMPKa1) worsening hemorrhage-induced multiple organ failure and whether treatment with metformin results in beneficial effects (7). Using a model of hemorrhagic shock characterized by blood withdrawal followed by resuscitation with shed blood and Lactated Ringer's solution, it was shown that AMPKa1 knockout mice have more severe hypotension, higher lung and liver injury and neutrophil infiltration, and higher levels of plasma inflammatory cytokines relative to wildtypes. Surprisingly, metformin proved to be advantageous to both groups of mice by ameliorated organ injury and mean arterial blood pressure, reduced liver lipid peroxidation, and increased levels of complex II cosubstrate FAD and levels of ATP. Most importantly, it was associated with activation of liver kinase B1 and AMPKa2. Thus, the authors have shed light on a very important distinction in metformin's capacity for improvement after hemorrhagic shock and it would be interesting for future studies in other areas of trauma (sepsis and burn models) to determine if in fact the AMPKa2 activation is also the major source of activation for therapeutic advantage. Immunosenescence and alteration in immune responsiveness associated with aging are an ongoing battle when treating older and vulnerable populations in all forms of illness and trauma. With this in mind, Young et al. contributed to our understanding of this response by investigating the role of pulmonary endothelial cell activation to RBC-derived microparticles capacity to promote inflammation (8). Using cultured lung endothelial cells, the authors showed that microparticles from aged murine RBCs increased inflammation, expression of adhesion molecules, and endothelial endocytosis. The authors extended their analysis and used colocalization of microparticles with lysosomes for immunofluorescent staining to show endolysosomal trafficking and endocytosis. These studies enhance our understanding by proposing Rab5 as a possible mechanism for the observed effects. Knockdown of Rab5 results in impaired microparticle uptake and attenuation of the inflammatory response. Collectively, the authors suggest possible target for preventing the aberrant consequences of lung endothelial activation and inhibition may facilitate new targets for pulmonary dysfunction in specific populations. The authors are intrigued as to whether the knockdown of Rab5 would show the same benefit to pneumonia models in adult or elderly rodents. Hemorrhage is one of the most substantial causes of death after traumatic injury. One of the studies in this edition of clinical sciences aspects includes work by Johnson et al. presenting the Compensatory Reserve Index (CRI) (9). The CRI is a novel monitoring technology with the ability to assess physiologic reserve. Presently, the authors conducted a prospective observational study of 89 subjects at a single level I trauma center. The authors were able to predict hemorrhaging with 83% sensitivity, compared with standard methods (26%). It further detected significant hemorrhage requiring potentially life-saving therapy more reliably than SBP. The authors conclude that the CRI device demonstrated superior capacity over systolic blood pressure in predicting the need for posttraumatic hemorrhage intervention in the acute resuscitation phase after injury. Despite its sensitivity it would have been interesting for the authors to demonstrate temporal data for potentially the time saved of using this approach in patients rather than cumulative approach of traditional methods. As a by-product of cellular damage and injury, release of mitochondrial DNA (mtDNA) has been extensively studied in numerous models and critically ill populations (10, 11). The authors took an interesting perspective to understand the relationship between Systemic inflammatory response syndrome (SIRS) and the cross talk of mtDNA on the subsequent development or acute kidney injury (AKI) (12). Jansen et al. showed that in clinical SIRS patients that increased systemic mtDNA did not correlate with systemic inflammation or renal disease. They also showed in AKI patients that there is lack of additional effect on proportion of mtDNA. In murine studies, they showed that tubular epithelial cells and platelets respond to mtDNA resulting in increased expression of inflammatory cytokines. Thus, the data suggests that circulating mtDNA is most likely not important for the cross talk between SIRS and AKI. Rather, the authors propose that mtDNA accumulation may be having promoting intrarenal effects such as increased inflammation, coagulation, and overall dysfunction. mtDNA is a damage-associated molecular patterns (DAMP) and as such is most often associated with acute response to injury or trauma and it is difficult to relate acute phase mediators to pathophysiology of a renal dysfunction occurring later. This is consistent with the observed dysfunction remaining locally in the kidney and it will be interesting to observe subsequent studies by this group as to delineating the mechanism of mtDNAs malice. Diving right into the pulmonary mechanics and mortality of mechanistically ventilated patients, Fuller et al. conducted a secondary cohort study to identify patients at risk for acute respiratory distress syndrome ARDS (13). Driving pressure has been proposed as a major determinant of outcomes in ARDS. Using data from 1,705 mechanically ventilated patients, the authors examined mortality and outcomes associated with the use of early lung-protective ventilation. Using multivariable models the authors found that relative to survivors, nonsurvivors had higher driving and plateau pressures. Driving pressure was further shown to be independently associated with mortality. Using a subset of patients, the authors were able to demonstrate mechanical power was associated with ARDS development. Although this study introduced a novel approach and identified risk factors for ARDS, it would be interesting for the authors to extend their findings of driving pressure and plateau pressure in a prospective trial to truly determine the capacity of these measures to identify patients susceptible to ARDS. Contrast-induced nephropathy (CIN) is among the most serious complications in ST-elevation myocardial infarction and is associated with increased mortality and morbidity, predisposing patients to renal dysfunction. Kong et al. conducted a retrospective analysis of adult patients admitted to the emergency department with ST-elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI) to determine the usefulness of the delta neutrophil index (DNI) (14). The DNI can be described as a measure of immature granulocytes and can further identify risk for developing contrast-induced nephropathy (CIN). The authors were able to demonstrate that both independent factors (DNI within 2h after PCI and 24 h after emergency department admission) were able to predict CNI among patients with STEMI who underwent PCI. This crude yet powerful prospective index is able to delineate at-risk patient populations of CNI and should pave the way for subsequent interventional studies. Another basic science paper this edition investigating sepsis and oxygenation of the intestinal mucosa was conducted by Schulz and colleagues (15). Septic patients generally have insufficient microvascular oxygenation, and hypercapnia is one of the strategies to ameliorate the negative consequences. Considering that blockade of the sympathetic nervous system (SNS) eliminates the protective effect of hypercapnia, the authors aimed to determine if these same results were consistent under septic conditions. Septic mice showed decreased oxygenation in normocapnia and increased during hypercapnia. Administration of a SNS blocker did not have an effect on these results with oxygenation increasing in septic mice under conditions of hypercapnia both with and without treatment. Although the authors had a well-defined study and clear hypothesis, the conclusion that hypercapnia improves microcapillary perfusion independent of SNS in sepsis mice, it leaves the reader slightly unfulfilled. It would have been interesting if the authors were able to shed more light on why. Continuing the exploratory journey through the intestinal tissue during sepsis, Ribeiro et al.'s study included the association between inflammation and the tight junction (TJ) (16). Presently, the authors performed a pretreatment with low-dose dexamethasone (DEX) and the capacity to modulate the inflammatory response and TJ expression and arrangement in endotoxemic rats. Unlike the endotoxemic control rats, pretreatment with DEX resulted in an attenuation of the systemic and mucosal production of inflammatory mediators and also reverted the injurious effect of LPS on the ileum. This study did, indeed, support the benefit of early DEX treatment “breaking the vicious cycle of local gut inflammation and barrier dysfunction.” However, for argument sake, it would have been interesting if the authors were able to further demonstrate using a more representative model (treatment after endotoxemic sepsis) that these beneficial effects were abolished or more importantly that significantly greater doses are required to achieve the same outcome as early low-dose pretreatment. In the final basic research manuscript, Daniels et al. investigated the critical role of oxidative stress and specifically, the redox potential and critical injury (17). They hypothesized that redox potential (a reflection of oxidative stress) quantification will correlate with the accumulation of O2 debt produced by hemorrhaging over time. Using a polytrauma swine model of hemorrhage over time, they were able to demonstrate that redox potential changes throughout O2 debt accumulation was significant relative to baseline and at the end of resuscitation. Furthermore, whole blood redox potential also correlated with oxygen extraction ratio. Interestingly plasma redox potential did not correlate with O2 debt. The author concluded that considering redox potential in plasma was not as representative, measures should be made in whole blood versus plasma. Further analysis determining the cause of the discrepancy between whole blood and plasma would have added to the story. For example, do these findings extend to sera? Finally, in a letter to the Editor, Drs. Martin and Thiemermann in response to the paper published by Jansen et al. propose some interesting considerations for the study authors (18). After a comprehensive background, Martin and Thiemermann found that although Jansen et al. concluded that neither the systemic administration of mtDNA nor purified mitochondrial ligands resulted in AKI so elevation in systemic mtDNA cannot be regarded as a key factor in the pathophysiology of the AKI associated with SIRS; however, it remains unclear whether the increase in mtDNA in the urine is the cause (driver) or the consequence (biomarker) of renal injury and inflammation. In other words, the “chicken or the egg” predicament. An excellent comment and suggestion was the potential for a time-course to address some of the disparity. Taking into consideration that mtDNA have a very short half-life time in circulation, they propose that it would have been useful to use a time-course study for changes in creatinine and signs of lung inflammation in response to mtDNA in vivo. We would like to thank SHOCK for allowing us the opportunity to highlight and critique this journal issue. The manuscripts submitted in this edition have not only provided pivot knowledge for both basic sciences and clinical studies, but they reflect the ongoing mechanistic insight that is targeting numerous topics that burden critically ill patients. We are confident the readers will enjoy dissecting these interesting studies and at times controversial will allow their curiosity to drive subsequent discoveries and contradictions. We are confident the readers will enjoy dissecting these interesting and at times controversial studies, allowing their curiosity to drive subsequent discoveries and contradictions.

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