What's New in Shock, December 2016?

Discovery consists of seeing what everybody has seen, and thinking what nobody has thought. Albert Szent-Györgyi (Winner of Nobel Prize in Physiology or Medicine 1937 for “for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid”) It is that time of the year when the nights are long and cold, and the days too short, holiday planning is in full swing, and newspapers are full of “Best of the Year” lists and touching tributes to those who passed away. This atmosphere compels many to take stock of the year that is coming to an end, personally and professionally. As a researcher, it is natural to tally our “wins” and “losses,” papers published or rejected, grants secured or missed, and discoveries made or not. I think it is also a good time to remind ourselves that scientific discovery is hardly ever a coincidence. Not only chance favors the prepared mind (Dans les champs de l’observation le hasard ne favorise que les esprits préparés. Louis Pasteur. Lecture, University of Lille; December 7, 1854), but an observation is not enough by itself. Most of the observations are rather mundane, and the difference lies really in how we react to them. It typically requires many years, often decades, of logical, incremental, and meticulous work to prove a new scientific concept, and to change an established clinical practice. I think we must also acknowledge that investigators need communities that inspire, challenge, and support them to deliver their best. SHOCK Society is a prime example of such an international community where clinicians and basic scientists can come together for scientific discourse, collaboration, inspiration, encouragement, and comradery. I was, therefore, thrilled to be invited to write a summary for the December issue of SHOCK. Not only did it serve as a great reminder about the high caliber research that is being published by our journal, but these 16 manuscripts (eight basic science, six clinical, and two review articles) highlight how an everyday phenomenon such as shock continues to challenge us to ask novel questions, and to propose bold solutions. The first review is by Drs VanEpps and Younger (1) from my home institution, the University of Michigan. They not only bring expertise in emergency medicine and basic/translational research to the table, but also an entrepreneurial spirit. Their review addresses the issue of implantable-device-related infections, which is a major and increasing health care problem. In fact, of the nearly two million healthcare-associated infections reported by the Centers for Disease Control, 50% to 70% can be attributed to indwelling medical devices. This number is also highly likely to increase over time due to the increasing rates and types of device utilization, the aging of the population, and the increasing frequency of comorbidities in our patients. After defining the problem and the challenges faced by clinicians in diagnosing and treating these infections, the authors provide a superb review of the pathogenesis of device infection. They focus specifically on biofilm formation and the role of host immune and coagulation systems. Using this framework, they describe how current and future preventative and therapeutic strategies can target these specific processes. Understanding the underlying mechanisms clarifies how new materials could be made more resistant, how more effective antimicrobial substances/strategies should be developed, and how new technologies could be designed to treat infections in situ. The second article by Naumann et al. (2) is a systematic review of the preclinical studies in an effort to identify the “optimal fluid to restore microcirculatory dynamics” after hemorrhagic shock. They found 3,103 potential studies of interest, of which 71 studies fulfilled all eligibility criteria (62 rodent, five canine, and four porcine studies). As with most such reviews, the heterogeneity in the models, species, degree of shock, associated insults, and the endpoints studied in various experiments makes it impossible to come up with one perfect resuscitation fluid. They do identify some features that are highly desirable and conclude that “the ideal resuscitation fluid for restoration of the microcirculation following hemorrhagic shock is likely to contain a preparation of hemoglobin, favor higher oncotic/osmotic potential and viscosity, protect and reconstitute the endothelium, and attenuate inflammation.” I, like most trauma surgeons, believe that the ideal replacement for lost blood is actually fresh whole blood (FWB). As FWB is not a clinical reality except in certain battlefield conditions, early component therapy with transfusion of plasma, red cells, and platelets is the next best strategy. Their review conceptually supports this approach, which is also the foundation of the “Damage Control Resuscitation” strategy where crystalloid resuscitation is minimized and blood components are given early. Many clinical trials are now reporting their results (such as the PROPPR Trial) which validate the conclusions of these preclinical studies. In the clinical studies section, Hayakawa et al. (3) from Japan have published the results of a multicenter retrospective observational study of antithrombin (AT) supplementation in septic patients with disseminated intravascular coagulation (DIC). Data from 3,195 consecutive adult patients admitted to 42 intensive care units for severe sepsis treatment were retrospectively analyzed; 1,784 patients were diagnosed with DIC (n = 715, AT group; n = 1,069, control group). Propensity score analysis indicated a statistically significant (P = 0.034) association between AT supplementation and lower in hospital all-cause mortality. To put the findings in a proper context, KyberSept trial, which was a large-scale randomized controlled trial, did not find any benefits to high-dose AT administration (total 30,000 IU over 4 days) in patients with severe sepsis. Furthermore, a meta-analysis of 20 randomized trials concluded that AT treatments should not be recommended for critically ill patients; notably, the patients in this analysis were not limited to those with sepsis. These reports also indicated that AT treatment, particularly with heparin increased bleeding complications. The current study focuses on the subset of septic patients with DIC, and AT was administered without heparin. I think that their findings are intriguing but are unlikely to change clinical practice. These results should, however, serve as a foundation for doing a more robust prospective trial in this specific patient population. The study by Drs Wong and Lindsell (4) from the University of Cincinnati talks a very interesting approach toward how we should enroll patients in a clinical trial. Patient selection is always critical but this is especially true in sepsis where numerous trials over the last few decades have failed to show benefits of specific pharmacological treatments. Essentially, the ideal patients must be sick enough to demonstrate a benefit from the treatment but not too sick where the treatment is likely to be futile. The authors used Adult Septic Shock Information and Stratification (ASSIST), which is a tool for estimating mortality risk that incorporates a panel of biomarkers, age, lactate, and chronic health status, and performed a post hoc analysis of a recently completed clinical trial that failed to establish the efficacy of a polyclonal antitumor necrosis factor—a fragment antibody (AZD9773) in adults with severe sepsis or septic shock. They discovered that in that study, a beneficial effect of AZD9773 might have been observed if the trial had selected low to intermediate-risk patients using ASSIST as an enrichment tool. I think using adaptive trial designs strategies or sophisticated enrichment tools to increase our chances of success is the wave of the future. We simply cannot afford to enroll a highly heterogeneous patient population simply based on a few rudimentary physiological criteria, as this has proven itself to be a recipe for failure in the past. Dr Morton et al. (5) from the Liverpool School of Tropical Medicine have tested the concept of augmented passive immunotherapy with P4 peptide (which increases phagocytic activity) by determining ex vivo P4 activity in a target population of patients with severe infection. They prospectively recruited patients with severe sepsis and blood samples were taken in the early (≤48 h post-diagnosis, n = 54), latent (7 days post-diagnosis, n = 39), and convalescent (3–6 months post-diagnosis, n = 18) phases of the disease. The primary outcome measure was killing of opsonized Streptococcus pneumoniae by neutrophils, with and without P4 peptide stimulation. They discovered that the P4 peptide increased neutrophil killing of opsonized pneumococci by 8.6% (CI 6.35–10.76, P <0.001) in all phases of sepsis, independent of infection source and microbiological status. Hopefully, these results will serve as the foundation for more robust in vivo studies. Dr Hayase et al. (6) at the University of Tokyo have contributed a paper describing an association between heart rates and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in septic patients. In this prospective observational cohort study (95 septic patients), they noted that tachycardia was significantly and independently associated with NTproBNP elevation and lower survival rate in septic patients, although no association was observed in non-septic patients. This led them to conclude that increased NT-proBNP in septic and tachycardic patients might predict poor outcomes in intensive care unit (ICU). However, as the vast majority of patients in both groups survived, I am not entirely sure how their findings will help the clinician take better care of their patients. It would be much more meaningful if they follow up with additional studies, showing that modulation of these variables (e.g., control of tachycardia) could improve the outcomes. Dr Yeh (7) from the University of Pittsburg and his coauthors have published a paper that focuses on a very rapidly evolving area of research. The aim of their study was to characterize spatial and temporal variation in the microbiota of critically ill patients. Trauma and acute surgery patients admitted to the ICU were sampled at five body sites (stool, tongue, skin, trachea, urine) every 3 to 4 days. Their results demonstrate that the microbiome of critically ill patients undergoes a loss of diversity, loss of site specificity, and a shift toward dominant pathogens. The challenge for researchers in this arena is to take it to the next step by figuring out how we could precisely modulate the microbiome of these critically ill patients to change the outcomes. The last clinical paper is by the Canadian Critical Care Translational Biology Group (8) that examined plasma samples obtained from septic patients and concluded that increased levels of extracellular histones found in sepsis contribute to dysregulated coagulation by increasing the tissue factor activity of monocytes. Furthermore, they discovered that these procoagulant effects can be partially ameliorated by heparin. The finding that histones are released into the circulation by dying/activated cells, and that they contribute to septic pathology by creating additional inflammation is already fairly well established. The new contribution here is that they have elucidated the influence of histones on the hemostatic functions of circulating monocytes in septic patients. This adds to the growing body of literature supporting research efforts to find novel pharmacological treatments to neutralize the circulating histones and/or to block their downstream effects. Many labs are currently working in this area of investigation. The basic science papers are all top-notch. Su et al. (9) have compared the effects of hypertonic sodium lactate (HTL), hypertonic saline, 0.9% (“normal”) saline, and Ringer lactate on hemodynamics, sublingual and renal microcirculation, renal, mesenteric and brain perfusion, renal and cerebral metabolism, and survival in anesthetized, mechanically ventilated, adult female sheep. They discovered that administration of HTL was associated with earlier onset impaired tissue perfusion and shorter survival time. What limits the applicability of this study for US audience is the fact that HTL is not a fluid that is in clinical use here. However, their data highlights that not all hypertonic fluids are the same, especially when it comes to tissue and cellular injury. In my opinion, resuscitation fluids must be considered drugs rather than simply volume expanders. Dwivedi et al. (10) from Canada have published an elegant study focusing on proprotein convertase subtilisin/kexin type 9 (PCSK9), which targets lipoprotein receptors for degradation, thereby reducing hepatic lipid clearance. PCSK9 inhibition reduces mortality in septic mice, presumably through increased hepatic clearance of pathogen lipids due to increased lipoprotein receptor concentrations. They decided to evaluate the effects of differential PCSK9 expression on systemic infection, inflammation, and coagulation using wild-type, PCSK9 knockout, and transgenic mice that overexpress PCSK9 that were subjected to cecal ligation and puncture. These findings demonstrate that PCSK9 deficiency confers protection against systemic bacterial dissemination, organ pathology, and tissue inflammation, particularly in the lungs and liver, while PCSK9 overexpression exacerbates multi-organ pathology as well as the hypercoagulable and pro-inflammatory states in early sepsis. This is exciting because PCSK9 inhibitors are clinically approved for managing hypercholesterolemia, and I hope that the authors will follow these mechanistic studies with large animal translational experiments as a bridge to clinical testing. Nakagawa et al. (11) used a rat model to test a novel treatment for crush syndrome. It is a rather rare, but devastating condition that can lead to multiple organ failure due to ischemia-reperfusion of crushed (ischemic) limbs. They tested ETS-GS, which is a novel water-soluble, stable anti-oxidative agent composed of vitamin E derivative in a rat model where bilateral hindlimbs were compressed for 6 h (ischemia) followed by release of compression (reperfusion). They concluded that administration of ETS-GS could suppress ROS generation, systemic inflammation, and the subsequent organ damage, thus improving survival in a rat model of crush injury. I think this study is very interesting but the findings would have been more compelling if they had included other anti-oxidant agents as well to provide a more robust comparison. Jin et al. (12) from China have contributed a paper looking at the protective role of antioxidants in a rodent model of heatstroke. Rats were pretreated with superoxide dismutase or saline and then subjected to heatstroke. They discovered that microcirculatory disturbances could be detected early and well before the systemic hemodynamic manifestations. Also, they noted that superoxide dismutase pretreatment attenuated changes in pulmonary permeability, normalized tissue blood flow rates, maintained blood pressure, and improved survival. This is one of many studies showing the benefits of antioxidants, but the heatstroke model is rather rare. I do wonder whether they would see the same benefits with post-treatment, especially late in the course of the illness? Another excellent paper from China by Tong et al. (13) explores the role of mesenteric lymph on lung injury in heatstroke. Clearly, this clinical entity is getting more attention in China compared with the United States, where not much research focuses on heatstroke (HS)-related shock. Vascular endothelium injury biomarkers (circulating endothelial cell as well as von Willebrand factor [vWF] and thrombomodulin), proinflammatory factors, and coagulant markers were tested in HS and HS with mesenteric lymph duct ligation (LDL) rats. In addition, lung histopathology, arterial blood gas, Evans Blue dye and protein lung permeability, pulmonary inflammatory parameters, myeloperoxidase activity, and vWF immune staining were analyzed. LDL appeared to protect against many of the systemic and organ-specific injury parameters in this HS model. These findings are supported by numerous previous studies that have established the role of gut-derived lymph as a driver of systemic inflammation in various other models of shock. A study from Vienna by Warenits et al. (14) looks at extracorporeal life support that is being used ever more frequently for selected patients in refractory cardiogenic shock and severe pulmonary failure. The authors describe in detail the rat model of extracorporeal life support, and the numerous pitfalls that had to overcome. This is an excellent reference for any team that is interested in establishing animal models of cardiac arrest and extracorporeal support. Hobai et al. (15) have published results from an lipopolysaccharide (LPS) injection study in mice that suggest that LPS-induced cardiomyopathy develops through distinct sex-specific myocardial mechanisms. While in males LPS induces sGC-independent decrease in Ca2+ transients, in female mice LPS acts downstream possibly via sGC-dependent myofilament dysfunction. Although gender dimorphism in shock has a robust background, this is the first head-to-head comparison of female versus male C57Bl/6J mice from the of of after challenge with I hope that the authors will their studies to whether these also to then it is that male and female patients therapeutic as the authors with cardiomyopathy benefit from therapeutic strategies that increase myofilament male patients benefit from drugs that or These are very intriguing and for future research. The basic science paper is by et al. that cardiac to in mice and the role of and in these in a model. They conclude that both and mechanisms are and although treatment of this effect not have a major role in the systemic to This in with research as most researchers now believe that do not need bacterial to systemic inflammation and organ injury. and a of and are of these in the of bacterial the in this is a great issue of and I hope have these that have been by research from the and best for the next I hope that all be to follow lead and find exciting new discoveries in

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