What's New in Shock, February 2019?

It is still the middle of winter, and for most of the readers of Shock, these are depressing times characterized by cold weather, dark skies, and snow, or even worse, my great nemesis, mud. It is the perfect time to enjoy the proverbial fire with a good journal, a glass of your favorite drink, and await the inevitable coming of Spring. If you are as fortunate as I, my reading material this week is the current issue of Shock. As I have commented frequently in the past, the age of electronic search engines, pdf files, and the now ubiquitous PMID or PMCID, the opportunity to peruse a journal is rapidly disappearing. I personally will find it a great loss because having a journal in one's hands is like going into a candy store, never really knowing what you will find, exploring new subjects and revisiting old ones. This month, I decided rather than looking first for those articles directly relevant to my own field, I would read the journal cover to cover, and enjoy the delight of finding one article and then the next. Anytime, “magnetic levitation” is in the title of an article in Shock, my curiosity is piqued and this is an excellent first read. Dr Andersen et al. (1) from the Beth Israel Hospital in Boston and Odense University in Denmark have used a novel technique combining magnetic levitation of blood leukocytes and microscopic phenotyping to distinguish dramatic differences between blood from healthy controls and septic individuals. Although the authors acknowledge the small sample sizes and the homogeneity of the patient population, this proof-of-principle report demonstrates that they might be on to something. Early stages of research are always full of optimism, but the findings are consistent with what we know regarding leukocyte morphology in the septic host. The option of having it bedside with rapid turnaround gives it a distinct advantage over flow cytometry, although alternative newer bedside technologies are being rapidly developed. Clearly, this is a rich environment that will require both validation and further technological development. Kudos to the research team. Soussi et al. (2) from Paris and the PRONOBURN collaboration have provided an interesting and clinically important observation about the risk of mesenteric insufficiency in burn patients. Using a retrospective, case-control study design, the investigators demonstrate that low cardiac outputs and the presence of multiple organ failure are independent predictors of mesenteric ischemia, a deadly consequence of severe burns. There are two interesting take-home points: the mesenteric ischemia was nonocclusive suggesting that its etiology was primarily redistribution of blood flow and inadequate perfusion of the bowel, and secondary, acute mesenteric insufficiency was nearly uniformly lethal in burn patients. An excellent retrospective analysis suggesting that acute mesenteric insufficiency is a life-threatening complication of burn and should be closely monitored in patients with multiple organ dysfunction and low cardiac outputs. Easier to prevent than to treat, surely. I am a big fan of using retrospective analyses in a discovery mode, obtaining preliminary data for a prospective trial. Clinical studies and randomized clinical trials in particular are a vast treasure of unplumbed observational data. Understanding their limitations still provides the opportunity to extract novel findings that can be tested moving forward. Here, Li et al. (3) from Chengdu, China, have conducted a retrospective cohort analysis of the neutrophil to lymphocyte ratio (NLR) in patients with acute respiratory distress syndrome (ARDS). NLR takes advantage of both the lymphopenia and granulocytosis associated with adaptive immune suppression and inflammation in ARDS patients. The results from 224 patients showed a clear relation between the NLR ratio at 24 h with mortality. NLR ratios at days 2 and 3 were also different between survivors and nonsurvivors, although the results were not as dramatic. Clearly, the studies demonstrate the value of an early NLR measurement, which importantly can be obtained routinely from a total and differential white blood cell count. Elevated NLRs at day 1 should be a clear warning signal to intensivists. My only wish had been that the authors had compared the predictive ability of NLR to other markers of both the severity of the ARDS, and the magnitude of the adaptive and innate immune systems. I am still unsure whether NLR is going to be more predictive than simply absolute lymphocyte count, procalcitonin, interleukin 6 (IL-6), or a plethora of other biomarkers. Along the same lines, Laurikkala and the FINNRESCUI investigators conducted a retrospective analysis of 458 out of hospital cardiac arrest patients and used time-weighted lactate values as prognostic markers for subsequent outcome (4). Using regression models, the investigators demonstrated that both the time-weighted lactate values during ICU admission and the last lactate measurement from the ICU were independent predictors of 1-year survival. Surprisingly, neither admission lactate nor admission lactate clearance rates were good independent predictors of survival. Although this is not my strong area of knowledge, it is reassuring to know that admission lactates are not as important as the successful correction of tissue perfusion during ICU stay, and the degree of normality at discharge which are more important indicators of long-term success. Congratulation to the investigators on a potentially important observation, undoubtedly affected by the excellent ICU care provided in Finland. Another example of important data extracted retrospectively from large data bases is the study of Yoshihiro et al. (5) in Hiroshima, Japan. Here, the investigators have extracted data from 1,180 patients at 42 academic institutions with severe sepsis and respiratory failure receiving recombinant human thrombomodulin (rhTM). Propensity score analyses were used to adjust the 356 subjects receiving rhTM and 824 subjects not receiving rhTM. Mortality was significantly reduced in the subjects receiving rhTM in patients with severe sepsis and respiratory failure, compared with subjects not receiving drug. The authors conclude that rhTM improves survival in this select cohort. Retrospective studies like this in which subpopulations are culled from larger databases runs the risk of over-fitting data. There are a large number of past experiences where retrospective subgroup analyses have demonstrated efficacy only to have prospective trials fail to replicate the findings. One of the challenges with retrospective analyses is getting access to the data with sufficient granularity. For example, in this study, the amount of rhTM and the timing of the dosing were not known. Furthermore, there was no follow-up after hospital discharge. Although such data must be evaluated with a fair degree of skepticism, the findings here are large enough and significant enough to encourage a prospective, double blind, randomized controlled trial to answer the question definitively. Only through such rigorous study designs can these important questions be answered. Dr Wade et al. in Houston have led the field for many years exploring the role of damaged glycocalyx and endothelial vesicles as endogenous alarmins and markers of endothelial injury. In this case-control study of trauma patients, Wade et al. (6) have examined a number of endothelial markers in 12 severely injured and 12 less severely injured trauma patients. A wide variety of analytes were compared between the two groups. There are a number of very interesting findings. Despite rather similar injury severity scores between the two groups, syndecan-1 concentrations differed 10-fold between subjects defined as having the endotheliopathy of trauma (EOT) and those that did not. Despite these dramatic differences in syndecan-1 concentrations, there were no differences in endothelial microvesicles irrespective of the antibody used. Plasma norepinephrine, sEselectin, sVE-cadherin, and histone-complexed DNA fragments levels were also similar. Only thrombomodulin, reductions in clot initiation, amplification, propagation and strength, and a greater frequency of transfusion, 92% versus 33% were seen in patients with EOT. The authors conclude that endothelial cellular damage or apoptosis does not differ, and, thus, endothelial glycocalyx disruption is the underlying primary cause of EOT. The subjects were initially categorized by their baseline syndecan-1 levels and not the severity of the injury per se, so it may be prudent to limit the conclusions to trauma patients with this degree of injury severity. In these patients, it seems reasonable to conclude that damage to the glycocalyx leads to EOT, but the role of microvesicles and cfDNA in severe trauma and EOT is still unresolved in patients with other injury severity. Multiplex technologies for inflammatory cytokines and other mediators have revolutionized how we look at cytokine networks. These technologies generally use less sample and the reduced cost of analyte/sample has essentially eliminated the older ELISA technologies that measure one analyte at a time. Cytokine measurements have now become discovery tools with arrays reaching 40 to 50 cytokines measured simultaneously. In this report, Matsuura et al. (7) from Osaka have measured 11-cytokine panels in 38 burned subjects (>20 total body surface area) over periods of 1 month, and 12 healthy subjects. Not surprisingly, plasma IL-6, IL-8, IL-10, and MCP-1 concentrations were most predictive of survival, and these values were predictive early in the hospital course. The investigators argue that combining clinical markers with cytokine concentrations could be used to identify subjects at high risk of dying from their burn injuries. Although these findings replicate a large number of earlier studies looking at cytokine concentrations in burn subjects, there are two novelties here. The first is that the large number of cytokines measured simultaneous focuses us on those that may be helpful, which are generally known, but also those that are not informative in terms of outcome. Second, they give us measures of relative value among the four cytokines of greatest predictive ability. Clearly, if the intent is to move this into the clinic with an Food and Drug Administration-cleared diagnostic, it would be important to identify the single cytokine that provides the most information. It would have been helpful if the authors had actually given us the area under the curves for the individual cytokines, and had conducted deLong's test to determine whether there were statistical differences among area under the receiver-operator curves. This latter point may not be necessary given the relatively small sample size and the need to validate these findings in larger cohorts, as discussed by the authors. IL-33 is a member of the IL-1 superfamily and is thought to play a significant role in the polarization of the TH2 signaling pathway. ST2 is the presumed receptor. Much is known about IL-33's role in asthma, allergies, and contact dermatitis, but its role in T-cell polarization in burns is relatively unknown. Ruiz-Castilla et al. (8) in Barcelona studied 69 patients with burns ranging from 13% to 30% total body surface area and measured in the plasma a number of IL-33 superfamily members. Thirteen patients died of their burn injury. Surprisingly, neither IL-6, IL-8, nor IL-33 differed on day 1 after burn injury between survivors and nonsurvivors, while only sST2 differed. This difference held up at day 3. Using predictive modeling, the investigators report area under the receiver-operator curves of 0.73 and 0.85 for sST2, at days 1 and 3 post-burn. At day 3, elevated sST2 could best predict outcome even with cofounders. There are a couple of issues that the authors need to consider. First, as they already discuss, the sample size is small and heterogenous. Those subjects that died were generally older with more severe burns. In this same issue of Shock, investigators from Japan have shown a significant value of IL-6 and IL-8 in predicting outcome in burns; yet here, the differences are minimal for IL-6 and IL-8. This suggests a difference in the two populations which only emphasizes the need for larger studies with well-defined burn populations. Clearly, the findings are evocative and require further study. Congratulations to the investigators for their work and their findings. The role of the kidney in multiorgan failure secondary to septic or hemorrhagic shock has emphasized its importance in recovery or death. Acute kidney injury is one of the best predictors of outcome from severe sepsis or trauma. And yet, unless we are nephrologists, we think of the kidney as a homogenous organ whose response to shock is uniform. In this issue of Shock, Yan et al. (9) from the Netherlands investigated the inflammatory responses of three different renal microvascular segments, i.e., arterioles, glomeruli, and postcapillary venules, to hemorrhagic shock (HS) and resuscitation (HS/R) in mice, and to explore the effects of intervention with a nuclear factor-kappaB (NF-κB) inhibitor on these responses. Surprisingly, activation of the TIE-angiotensin network, and the cytokine cascade by HS/R affected different regions of the kidney, and blockade of NF-κB during the resuscitation phase only partly influenced the inflammatory response. This paper deserves a close read because it is a technological tour de force and its effort to focus on specific structural regions of the kidney. Although NF-κB blockade was not as effective as may have been desirable, the importance of the angiotensin and cytokine networks on different kidney regions is an outstanding observation in itself. Moving from the kidney to the lung, Safavian et al. (10) from Toronto, Canada have examined the mechanisms driving M1 expansion in the lungs of mice subjected to HS/R. Their straightforward hypothesis is that HS/R increases the lung responsiveness to secondary injury by increasing the M1/M2 ratio and increasing the inflammatory response. Here, they phenotyped lavage fluid from mice undergoing HS/R with or without intratracheal endotoxin challenge 2 hours after resuscitation. Some animals received intratracheal administration of M2 polarized macrophages. The findings are somewhat surprising in that the increased M1/M2 ratio was predominantly due to a loss of M2 cells rather than expansion of M1 subgroups. Readministration of M2 macrophages attenuated the inflammatory response in the lung to lipopolysaccharide. The novelty here is the observation that therapies should be perhaps targeting expansion of the M2 population after hemorrhagic shock and resuscitation, rather than attenuating M1 phenotypes. Another outstanding and evocative paper from the Toronto group. Sticking with the lung for a few minutes, Gugliandolo et al. (11) from Messina, Italy, have examined the role of the TLR4 signaling pathways and the inflammasome, and particularly, PPARα in the host response to Pseudomonas pneumonia. Here, the investigators used a genetic approach, employing TLR4 and PPARα null mice. Not surprisingly, Pseudomonas pneumonia was more lethal in both TLR4 and PPARα null mice, indicating an essential role for both these proteins in host protective immunity. Interestingly, both pathways are critical for the magnitude of the inflammatory response either directly through NF-κB or through processing of IL-1β, IL-18. In both cases, NF-κB translocation to the nucleus was increased in all of the knockout mice, and although this may appear superficially contradictory, it is more consistent with the increased pathogenicity, lung damage, and death in the null mice. My take from these important studies is that TLR4 and the inflammasome signaling pathways both activate NF-κB-dependent early response genes essential for host protective immunity, and loss of either increases mortality to Pseudomonas pneumonia. Mortality is secondary to an exaggerated inflammatory response even in the absence of TLR4 and PPARα. Probably one of the most exciting focus of sepsis research in 2018 to 2019 has been on how sepsis influences the brain. Neuroinflammation in sepsis is now being reported and is being observed for months after resolution of the initial inflammatory event. Long-term cognitive and behavioral changes are being recognized much more frequently. Yet, little is still known about how the brain responds to septic insults. Here, Kurtz et al. (12) from Rio De Janeiro conducted brain microdialysis in pigs subjected to the hyperdynamic phase of sepsis. In this porcine model of resuscitated sepsis, the investigators found increased oxidative stress, exacerbated activity of the glutamate/glutamine cycle and increased glucose utilization by the brain, however without any evidence of decompensated energy metabolism. Whether this increased oxidative stress is responsible for astrocyte and glial cell activation, commonly seen in sepsis survivors needs to further elucidated. Back to the lung and therapeutic interventions aimed at reducing lung injury, Wang et al. (13) from Shanghai examined the role of tissue factor pathway inhibitor (TFPI) on endotoxin induced lung injury produced by endotoxin administration. I have to disclose my bias as I participated in both the preclinical baboon studies with recombinant TFPI as well as the clinical trials in sepsis. Here, the investigators took the alternative approach by TFPI from endothelial by using mice. The findings seen with this genetic were how the importance of TFPI is in the inflammatory response to These endothelial TFPI null mice were to into the TFPI exacerbated changes in lung, and changes in and fluid cytokines IL-1β, and IL-6 in lavage fluid in lung in response to The number and of white blood cells from lavage fluid and lung tissue of TFPI null mice with acute lung injury was increased compared with mice with Clearly, endogenous TFPI an essential role in lung injury. I only wish that levels of TFPI could have had the same magnitude of response in patients with sepsis, with either or TFPI This demonstrates the of collaboration and the use of from and have conducted a study of specific and in an model of shock and model of septic shock These are both excellent randomized one on the other The of this approach is the ability to both potentially and effects of versus specific of in shock with specific without effects on in septic shock in the showed effects in both models, and survival time. these findings could not have been by on a single research on in shock to be et al. from and their from and have a novel observation regarding a role for the TLR4 from other of the signaling in that for the TLR4 can signal both through pathways directly to NF-κB activation, and through pathways at I Here, the authors demonstrate that vesicles can to TLR4 and be by and their is both the of I and the Interestingly, the investigators a by which in can activate both plasma TLR4 and it also provides an for both the importance of and an for the exaggerated inflammatory response by both signaling and the It also the somewhat observation that inflammasome activation is increased by a this will be a read and It deserves as much for the novelty of the observation and the of the data. one would be a significant if they did not read the to the by and and the response by et al. The is an important one and is on the role of and nuclear DNA as from cell injury and death. In this particular the the role of DNA in the kidney injury associated with sepsis. In the is more DNA recognized by alarmins through signaling pathways by and they the tissue and organ injury that we in sepsis, injury. are they the magnitude of endogenous tissue injury. It is a no is and the results will require

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.