What's New in Shock? November 2015

It is my great pleasure to once again take you on a grand tour of the latest issue of Shock, which has a distinctly international flavor with articles from researchers across Europe (France, The Netherlands, Italy, Portugal, Germany), Canada, Norway, China, and the UK, as well as multiple institutions across the United States. The variety also extends to topics covered in this month's articles, and as usual there is something for all Shock readers, no matter their research focus, with eight clinically based, and six basic science-based articles included in this month's issue. The review this month focuses on what is currently known about single-nucleotide polymorphisms (SNPs) on individual outcomes after trauma, including the propensity for infectious complications. Understanding individual variations in responses to trauma is obviously important if we are to move toward individualized or personalized medicine and to make use of specific immunotherapies, and understanding these genetic variations is one way to try to stratify patients to receive selected treatments. Bronkhorst et al. (1) found published information about trauma patients and the effects of SNPs on 36 proteins, as well as microRNA and mitochondrial DNA and this very comprehensive review focuses on SNPs in 28 genes that represent pattern recognition receptors and their signaling partners and inflammatory cytokines. Despite the numerous published studies, it is obvious that in most cases the number of patients included in each study is small, and variation in outcome measures between studies makes it hard to combine information across these small studies. This makes it hard to be definitive about the role of any of these SNPs in trauma patients, especially as everything is further confounded by potential ethnic/racial differences. The authors point out that a little more is known about some of the effects of similar SNPs in sepsis, but even there it is hard to know if this information will be able to impact treatment and outcomes in sepsis or trauma patients any time soon. The first research article in this month in the Clinical Aspects section is from Labros Sidossis and David Herndon's laboratory investigating skeletal muscle breakdown in pediatric burn patients (2). This group has developed a novel, less invasive way to measure muscle synthesis and breakdown rates using bolus injections of isotopically labeled phenylalanine tracers. The authors determine that the catabolic effects of burn trauma continue even after a year of recovery and occur despite high protein diets. Interestingly, both muscle synthesis and breakdown rates are increased, although breakdown is increased to a higher level ultimately leading to muscle loss. Previous studies have shown that trying to increase muscle synthesis is often ineffective, even when amino acids are provided at large doses intravenously. The authors speculate that determining new ways to decrease muscle breakdown may be beneficial, and represent a new avenue for investigation that may help shift the balance of breakdown/synthesis more toward overall synthesis. In a similar vein, Steve Wolf's laboratory is also interested in mechanisms of skeletal muscle loss after burn injury. Their article in the Basic Science Aspects section of the journal this month (3) details data using a mouse model of burn and looks at skeletal myogenesis and breakdown at time points up to 14 days after burn. The authors found that, at early time points after burn, increased levels of TNF led to increased muscle cell death and an overall decrease in myogenesis, which they conclude is also regulated by TNF. Both studies conclude that both synthesis and breakdown of muscle are increased after burns and that both sides of muscle homeostasis, which are also influenced by age and exercise, may need to be targeted in future therapies to improve outcomes in burn injured patients. Back in the clinical studies section, the next article also deals with an important topic in pediatrics: are corticosteroids beneficial in pediatric shock? The decision to prescribe corticosteroids in adults in septic shock is a little more defined, but no clinical trials have shown the benefit of these drugs in pediatric patients. Here, Menon et al. (4) performed a retrospective cohort study of pediatric ICU patients across four separate units in Canada to determine corticosteroid-prescribing practices and whether corticosteroids affected outcomes. The authors found that overall about one quarter of patients with shock (all types) were given corticosteroids, but that this level was much higher (about 60%) in sicker patients with treatment-resistant shock, with some suggestion that physicians are using steroids as something of a last-ditch effort to help their patients. Even when adjusted for illness severity, hydrocortisone (the most commonly prescribed corticosteroid) was, however, associated with increased time of vasopressin use, which the authors suggest may be a preliminary indication that steroids are actually detrimental. Obviously, the only way to more fully define which patients might benefit from steroids is, as the authors point out, to perform a clinical trial, and the authors also make a case for powering any such trial appropriately to find potential differences in endpoints other than mortality (e.g., time of vasopressin use). Rounding out the trio of pediatric studies in this month's Shock is a study investigating whether adding levels of neural damage marker, S100β, to already established clinical assessment criteria for minor head trauma can reduce unnecessary cranial CT scans. This is an important issue as repeated CT scans/XRAY exposure in children has been associated with an increased risk of cancer, and one of the most common reasons for emergency room admission of children is because of head trauma, most of which is clinically insignificant. The current study by Simon-Pimmel et al. (5) is a retrospective analysis from a single institution in France and suggests that using S100β levels together with the clinical criteria is a safe way to identify clinically significant head trauma and may reduce unnecessary CT scans by nearly 30%. Next up on the clinical side is a article by Rahbar et al. (6) on behalf of the Early Whole Blood Investigators which reanalyzes data from the recent Early Whole Blood trial and seeks to determine if modified whole blood or components are better at improving coagulation profiles in trauma patients. Recent research efforts have tried to determine optimal resuscitation strategies for severely injured trauma patients to try to prevent (or reduce) trauma-induced coagulopathy. Trauma-induced coagulopathy occurs in about one quarter of severely injured patients and is thought to result from reduced clotting factors, decreased platelet numbers, and increased platelet dysfunction. The current study uses some sophisticated statistical analysis of what the authors admit is pilot data to show that modified whole blood improves platelet function, but platelet transfusions were more beneficial at improving coagulation profiles. Importantly, the authors confirm that timing of resuscitation is an independent factor in outcome, as much as the type of blood product or the mix of blood products used. There is more to come from this group so watch this space! The next two clinical articles investigate the effects of fluid resuscitation on critically ill patients. The first by Wang et al. (7) retrospectively assessed whether CVP readings were associated with outcome in septic shock patients monitored in the ICU. A CVP between 8 and 12 mmHg is currently recommended to indicate appropriate fluid resuscitation in septic shock patients. However, in this study the authors conclude that patients in whom the CVP dipped lower than 8 mmHg over a 7-day period of monitoring did better than patients with consistently maintained higher CVP. Interestingly, higher CVP level was associated with increased signs of multiple organ failure, as well as decreased survival. This begs the question of whether restricting fluid resuscitation to some degree, or working to reduce CVP to below 8 mmHg, would help reduce mortality and morbidity in these patients. Similarly, the study from Raimundo et al. (8) investigated whether increased fluid treatment in patients with early acute kidney injury (AKI) was detrimental. This was also a retrospective analysis that aimed to determine whether increased fluid intake rather than decreased urine output in AKI patients resulted in progression of AKI to severe disease and reduced recovery. The data suggest that increased fluid intake is indeed an independent variable for AKI progression, although the authors admit that optimal fluid therapy is challenging and difficult to assess accurately, especially given that it is dynamic. In order to follow the tenet of “do no harm” in medicine, the authors also suggest daily fluid balance assessments to try to ensure adequate hydration without overload. Both these studies suggest that fluid restriction, to some degree, may be beneficial in patients and this probably warrants further investigation. Another interesting clinical study detailed in this month is the study by Piton et al. (9) that seeks to assess whether there is small bowel ischemia during cardiac arrest that may contribute to post-cardiac arrest syndrome. In this study, the authors measured markers of enterocyte damage (intestinal fatty acid binding protein and citrulline) and associated levels of these markers with outcome post-cardiac arrest. They found that low citrulline and increased intestinal fatty acid binding protein is associated with an increased risk of poor neurological outcome, and the authors speculate that this is in part in response to gut ischemia that provides a sensitive marker of overall ischemic damage and higher risk of bacterial translocation from the gut that contributes to ongoing inflammation of post-cardiac arrest syndrome. None of the biomarkers used in this study can currently be measured by automated systems, but the authors suggest that these markers may be useful in patient management in the future. The final clinical aspects article by Ma et al. (10) investigates the efficacy of continuous venovenous hemofiltration (CVVH) in reducing sodium levels in critically ill patients with acute severe hypernatremia of any cause. This is a potentially important therapy as although the number of patients with acute severe hypernatremia is small, the condition has a very high mortality rate with current treatment strategies. CVVH has been used effectively in small numbers of patients reported as case series in the literature, although the authors point out that no large study has been done to confirm the usefulness of CVVH in this situation. The authors were able to carry out a retrospective study of CVVH effectiveness as the procedure was taken up as standard of care at their institution in early 2011 after a small successful case series of CVVH treatment for hypernatremia. They, therefore, compared outcomes of matched hypernatremia patients before and after March 2011 and found that there was a dramatic increase in both 7-day and 28-day survival rates with the use of CVVH, supporting its potential usefulness in this small group of patients in the ICU. Moving back to Basic Science Aspects articles, the first listed article is from Rosemary Kozar's laboratory (11). This laboratory continues their investigation of mechanisms of injury associated with hemorrhagic shock and resuscitation. Their previous work showed that resuscitation with fresh frozen plasma (FFP) after shock results in attenuated lung injury and inflammation and is able to normalize levels of syndecan-1. In this current study, the authors investigate whether FFP is also protective in the gut, as well as further investigating the role of syndecan-1 in protection of epithelia. The authors found that FFP was indeed gut protective in wild-type mice, but that FFP was unable to protect syndecan-1 knockout mice. They also show data to suggest that a possible mechanism for FFP protection is via reduced levels of TNF and ADAM17 (TACE) in the gut, both of which are important in shedding of syndecan-1. Syndecan levels are best known to indicate endothelial damage, but given data in this article and the authors’ previous lung-based study the authors suggest that syndecan-1 is an important protector of epithelia as well, and shedding of syndecan from the cells leaves them exposed to harmful inflammatory cytokines. The next article moves from hemorrhagic shock to sepsis, and investigates local organ damage and inflammation in Neisseria meningitidis sepsis. The severity of meningitis sepsis has been shown to be correlated with bacterial numbers in blood, as well as circulating levels of inflammatory mediators that are thought to be the cause of systemic inflammatory responses and organ failure/damage. In this current article, Hellerud et al. (12) show that in fact organs are also loaded with bacteria and have very high local levels of inflammatory cytokines in post-mortem samples from patients who died from meningitis sepsis, and in a porcine model of meningitis bacteremia. Interestingly, other bacteria such as Streptococci pneumoniae do not seem to cause similar local cytokine production and organ infiltration despite causing sepsis and septic shock. The authors also show that lipopolysaccharide initiates many, but not all, of the inflammatory cytokines and taken together the data suggest that it may be necessary to consider new ways of treating this disease. Blast injury from shock waves produced during explosions is common among combat casualties, and according to Spear et al. (13), authors of the next basic science article, blast injury accounts for 70% of extremity injuries in combat, many of which have a poor functional outcome even if the limb can be salvaged. The current article focuses on the effects of blast waves on blood vessels, microcirculation, and muscle in the hind limbs of rabbits exposed to different severities of compressed air shock waves. High-blast injury caused the release of endothelial cells into the circulation, together with increased histological damage to the muscle as blast severity increased. Interestingly, there was also necrosis within the muscle by 6 h after injury, and increased indicators of tissue hypoxia. The authors conclude that blast injury may exacerbate more systemic blast effects, and may explain to some degree the difficulties in recovery of extremity function and limb salvage success in these patients. Our discussion now moves back to burn and smoke inhalation injury, which are known to induce large systemic inflammatory responses (and large amounts of inflammatory cytokines) leading to multiple organ failure and death with subsequent disproportionate anti-inflammatory responses that can lead to increased risk of infections, multiple organ failure, and also death. Here, Linden et al. (14) investigate the efficacy of hemoadsorption of cytokines and myoglobin by Cytosorb™ in a pig model of burn and smoke injury. Cytosorb™ is a non-specific remover of 10 to 50 kDa proteins from blood, has been previously shown to be effective at reducing plasma levels of cytokines in rodents after burn. In this pig model, the authors show that the column successfully removed cytokines from the blood, but that this was insufficient to reduce the plasma levels of inflammatory cytokines. The authors speculate that they need a larger column or to use something with larger capacity for cytokine removal to see plasma level reductions in this large animal model. Additionally, the pigs getting the hemadsorption treatment appeared to have increased mortality, although the reasons for this are not clear. The final manuscript in this issue of Shock investigates mechanisms of lung fibrosis. Wang et al. (15) used maresin-1 (MaR1), a proresolving lipid mediator, in an attempt to inhibit TGFβ1-induced epithelial to mesenchymal cell transitions known to be important in lung fibrosis pathogenesis. They tested MaR1 in vitro in alveolar epithelial cells, and in vivo in a bleomycin-induced fibrosis model in mice. MaR1 successfully prevented TGFβ1-induced fibronectin and alpha-smooth muscle actin expression in alveolar epithelial cells, and prolonged survival and prevented lung collagen deposition and lung destruction in vivo. The authors also show that one possible mechanism for these effects is through regulation of the PI3K/AKT pathway. Pulmonary fibrosis is a serious disease that is very hard to treat and these data presented in this article suggest that MaR1 could help prevent disease progression, which would be valuable if shown to work in human disease. So I hope you now have a flavor of the interesting and thought-provoking research contained in this month's Shock journal, particularly for those involved in patient care. I continue to be impressed by the breadth of research included in the journal, and how relevant each article is to my own interests. I cannot wait to see what is in store for next month!

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