What’s New in Shock? JUNE 2015

The current issue of Shock features a remarkable collection of research articles that together seem to cover the depth and breadth of shock research in a single issue. In highlighting the articles in this month’s issue, several themes emerge, which will be expanded on in greater detail below. First, our field has appropriately turned its attention to the role of the microcirculation as both a driver of the hemodynamic response and as a consequence of this response, and this is effectively reviewed in excellent articles by Saugel et al. (1) and D’Aragon et al. (2). In an excellent review article that explores an important driver of the systemic response leading to sepsis, Li et al. (3) explore the factors regulating intestinal immune homeostasis. The clinical science articles cover the entire spectrum of shock research, including an approach to consideration of the factors that may predict mortality in trauma patients by Liu et al. (4), and an evaluation of ADAMTS-13 in critically ill patients with sepsis by Aibar et al. (5). Jung et al. (6) provide an in-depth assessment on the link between glucagon levels and outcome in septic patients, whereas Chung et al. (7) explore the link between lymphopenia and mortality in septic patients, which places an important spotlight on the role of lymphocytes in inflammatory diseases. This issue also contains a series of excellent basic science articles, including a provocative evaluation of cyclosporine A as a cardioprotective and neuroprotective agent by Knapp et al. (8) and an innovative look at how delivery of the chaperone protein heat shock protein 70 (Hsp70) can modulate lung injury by Lyons et al. (9). In a series of elegant studies by Rani et al. (10), the role of gamma delta T cells in lung injury after trauma is examined, whereas Prat et al. (11) describe coagulation after blast injury in a highly intricate set of studies performed in a swine model. Finally, von Seth et al. (12) and Taddonio et al. (13) have performed very innovative studies to assess how to reverse the inflammatory effects of endotoxin in sepsis models. Taken together, this issue includes articles that cover the full spectrum of clinical and translational research in the field of shock and are sure to be of great interest to our readership. Saugel et al. (1) have written a very timely review article in which they ask, “Is it time for individual goal-directed hemodynamic therapy?” In seeking to address this question, the authors make the case that the presence and degree of microcirculatory failure that occurs in the setting of septic shock are in part independent of other variables that occur on the macrohemodynamic level and that microcirculatory failure and microcirculatory failure can both independently induce organ dysfunction. The authors go on to discuss the data on early goal-directed therapy for the resuscitation of the microcirculation, describe the concept of individualized goal-directed hemodynamic therapy, and describe the limitations in available technologies that remain critical barriers in the field. They also offer a way forward, provide a helpful schematic that integrates these new concepts, and describe avenues for future research into individual patient-centered treatment for shock that could significantly alter how we treat all patients with hemodynamic collapse. The article by Saugel et al. (1) is nicely complemented by a very thorough systematic review by D’Aragon et al. (2), which was conducted under the auspices of the Canadian Critical Care Trials Group and which assesses in detail the blood pressure targets for vasopressor therapy in patients with septic shock. The authors make the cogent argument that the evidence to inform practice on vasopressor dosing is actually very weak—an argument that is particularly important to make given the widespread use of vasopressor therapy in clinical medicine. After searching three online databases, the authors identified two randomized control trials and 10 crossover trials that led to the conclusion that there is in fact a paucity of clinical evidence to guide the administration of vasopressors in critically ill patients. This important study quite fairly discusses its own strengths and weaknesses and then provides an extremely strong rationale for further research to establish an evidence base for vasopressor administration in critically ill patients. Li et al. (3) present an outstanding review of the current literature regarding the mechanisms regulating intestine immune homeostasis after burns and trauma, with a focus on understanding how the addition of alcohol intoxication at the time of burn injury leads to an increase in infections. In doing so, they review how changes in the intestinal immune system after alcohol and burn injury lead to a relative immunosuppressed state because, in part, of deficits in T-cell populations resulting in impaired barrier integrity and translocation of gut bacteria from the intestinal lumen into the circulation. The authors nicely summarize the role of translocated bacteria in the stimulation of additional immune cells leading to a proinflammatory state and provide a comprehensive survey of the latest findings in the fields of innate and adaptive mucosal immunity. Four outstanding clinical science articles are included in this issue. Liu et al. (4) provide an important perspective on how analysis of heart rate variability and complexity can be used to predict mortality in a set of 108 prehospital trauma patients. The findings from this study suggested that the use of heart rate complexity and heart rate variability represent “new” vital signs that should be used simultaneously to improve the prediction of mortality. Given the relative ease with which these data points can be obtained in the field, the possibility exists that if confirmed in other data sets, these findings could become widely adopted in a manner that could rapidly impact clinical care. Aibar et al. (5) performed a study in 178 patients admitted to a Spanish ICU presenting with either septic syndromes or noninfections SIRS (systemic inflammatory response syndrome) to determine the levels of ADAMTS-13 in these patients and to determine the association with morbidity and mortality. ADAMTS-13 is the protease that cleaves ultralarge multimers of the von Willebrand factor and generates smaller forms that are then found in the circulation. The authors determined that patients with septic syndromes show significantly lower levels of ADAMTS-13 compared with those with noninfections SIRS, that levels of ADAMTS-13 are correlated with illness severity in septic syndromes, and, most remarkably, found that patients who died had significantly lower levels of ADAMTS-13 compared with survivors. These findings add to a growing list of potential biomarkers that may provide insights into the clinical course of a patient with sepsis and may eventually be used in point-of-care approaches for these patients to provide individualized care of the critically ill. Jung et al. (6) studied 112 patients who were admitted to an ICU in Seoul, Korea, to assess the clinical value of glucagon levels in comparison with clinical parameters and severity scores in patients with severe sepsis or septic shock. The authors determined that patients who died within 28 days had significantly higher glucagon levels on each day of examination, and that the area under the curve of glucagon levels could actually predict 28-day survival in a manner similar to disease severity scores APACHE II (Acute Physiology And Chronic Health Evaluation II) and SOFA (Sequential Organ Failure Assessment). The authors raise the intriguing concept that glucagon levels may not only predict outcome in septic patients but also provide some insights into pathophysiology and provide a strong rationale for the study of strategies to reverse glucagon elevation as a therapeutic approach for this population. These findings add to an increasing awareness that cellular metabolism likely plays an important role in determining the nature and extent of the host response to sepsis in critically ill patients. In an interesting set of studies, Chung et al. (7) prospectively enrolled 92 patients into an ICU in Taipei, Taiwan, to determine whether severe lymphocyte depletion at admission is associated with increased circulating cytokines and mortality. The authors determined that severe lymphopenia was present in 26% of patients and that these patients had significantly elevated cytokines and higher mortality. These studies not only indicate that the lymphocyte counts may provide information regarding the risk of death in septic patients but also suggest that additional studies are warranted to define the reasons behind a decrease in lymphocyte count to shed light on pathophysiology and offer novel treatment strategies for these patients. The current issue contains six excellent basic science articles that discuss various aspects of shock research. Each of which is highly translational, and each study uses animal models that have been carefully selected and well validated to provide important insights into the mechanisms of shock. Knapp et al. (8) evaluated cyclosporine A (CsA) in a rat model of cardiopulmonary resuscitation, with the aim of defining whether this immunosuppressant drug could have either neuroprotective or cardioprotective effects. The authors determined that rats treated with CsA had improved cardiac function and greater neuronal survival than untreated rats. The authors performed not only physiological studies but also used neurological tools and defined that CsA-treated animals performed better on a tape removal test than untreated counterparts. The authors conclude that pharmacological postconditioning with CsA after resuscitation from cardiac arrest may attenuate myocardial dysfunction and reduce neuronal damage. Although the mechanisms involved remain unclear, these findings shed light on a potential link between activation of the immune system and secondary organ injury and provide a rationale for the role for immunomodulatory strategies to decrease end-organ dysfunction after cardiac arrest. In an elegant and compelling series of studies, Lyons et al. (9) used a novel strategy of enhancing the expression of the chaperone protein Hsp70 by forming a fusion protein with the HIV-1 transactivator of transcription (TAT) to allow Hsp70 to enter cells. The authors then delivered the TAT-Hsp70 to septic rats intratracheally in a model of cecal ligation and puncture and found that TAT-Hsp70–treated rats demonstrated decreased lung macrophage and neutrophil chemokine response, reduce myeloperoxidase abundance, and, most importantly, showed attenuated histological evidence of inflammation at both 24 and 48 h. The addition of TAT-Hsp70 also increased survival in the animal model. These results not only support the hypothesis that decreased Hsp70 renders organs at increased risk of secondary injury in the setting of sepsis but also extend these findings through the description of a novel organ-protective strategy. These findings also raise the possibility that other organs could be similarly protected in sepsis via a strategy that restores cellular Hsp70 levels either through upregulation of endogenous production or through the exogenous administration of Hsp70 using the current approach. Rani et al. (10) describe an extremely well-conducted set of experiments in which they provide compelling evidence that γδ T cells can regulate the inflammatory cell infiltration of the lungs after trauma/hemorrhage. To do so, the authors studied either wild-type or δ TCR−/− mice that were subjected to trauma/hemorrhage or sham treatment. The authors determined that the lung was injured at 2 h and showed a marked increase in T cells, including both αβ and γδ T cells. Interestingly, δ TCR−/− mice showed reduced T-cell infiltration of the lung after trauma/hemorrhage, whereas other inflammatory cells were increased. The authors conclude that γδ T cells may regulate the infiltration of the lung with inflammatory cells after injury. These studies provide a rationale for understanding how this population of T cells can regulate the infiltration of other cell types in the determination of lung injury after trauma and raise the possibility that these findings may also apply to other epithelial surfaces that may be injured in the setting of remote injury, such as the gastrointestinal or the urogenital tracts. Two articles are included in this issue in which swine models of injury or sepsis have been explored to gain insights into the mechanisms leading to critical illness in humans. Prat et al. (11) subjected pigs to severe open-field blast injury to gain insights into the severe and acute coagulopathy that has been noted to occur in soldiers who sustain injury from improvised explosive devices. The authors determined that, after 1 h, although the mortality was 33%, coagulation dysfunction was not observed, suggesting that isolated primary injury is not responsible for acute coagulopathy of trauma in victims of explosion. The authors discuss that their findings are consistent with similar studies that have been performed in small animal models and provide a highly convincing platform for further investigations on this important mechanism of injury. In a second porcine study, von Seth et al. (12) studied the anti-inflammatory and hemodynamic effects of the novel antibiotic tigecycline in comparison with the antibiotic doxycycline in a 6-h model of endotoxemia. The authors determined that tigecycline ad ministration resulted in a higher mean arterial pressure but had no effect on cytokine levels. The fact that minimal anti-inflammatory effects of tigecycline were observed may be a result of the sample size that was studied, the dose of endotoxin that was selected, or the chosen time at which cytokines were measured, but, from a practical purpose, because these findings were obtained in a large animal model of endotoxemia, they certainly merit attention and further investigation. In the final article in this issue, Taddonio et al. (13) seek to test the hypothesis that lipopolysaccharide-binding protein (LBP) is essential to bacterial clearance from the lung and, furthermore, that the absence of LBP leads to alteration of the pulmonary inflammatory response to pneumonia. This hypothesis was tested in adult wild-type and LBP−/− mice, in which Klebsiella pneumonia was administered intratracheally, and the degree of lung inflammation was assessed. The authors determined that LBP−/− mice showed significantly elevated levels of bacteria in the lung, greater proinflammatory cytokines, and higher neutrophils compared with wild-type mice, suggesting that LBP plays a role in clearance of this bacteria from the lung. The authors concluded that LBP not only has a protective role in the lung but also that it is necessary for proper coordination of the immune response after invasion of K. pneumonia. Given the importance of pneumonia as a common cause of morbidity and mortality in septic patients, these studies suggest a potential unifying set of mechanisms based perhaps on the expression of LBP at baseline in determining the development of pneumonia and/or its resolution. The articles that are included in this issue cover a range of important studies that shed light on some of the essential questions that face researchers in the field of shock. These articles describe studies that are all highly translational in nature and that are likely to be widely generalizable to other populations or other systems. The studies were each a distinct pleasure to summarize, and the authors are to be congratulated for their scientific efforts and creativity. I hope our readers will enjoy them as much as I did.

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