The January 2018 issue of Shock: We start anew, filled with hopes for exciting science, improvements in care, new plans for collaboration! Allow me to expand this non-standard opening by adding some general reflections before delving into the purely scientific narrative. When reviewing the articles in this issue, I immediately noticed the widespread geographic origins of their authors. The papers are authored by scientists from 10 different countries on four continents. I was even happier to note that one-third of the papers are the fruit of international collaborations, such as those between researchers in China and the United States, and in Thailand and Indonesia. It is a very positive reflection on the scientific community that science is not contained by national borders, but rather—what is even more valuable—it connects people. In contrast to our sad (international) reality of rising walls and deep social divisions along national and political lines, science does connect people! I sincerely wish that all of us will promote and nourish this positive trend in 2018—and beyond.
The January melting pot of clinical and basic research offers two review articles, six of the former (clinical) and seven of the latter (basic) sort. The first review focuses on the most vulnerable patient groups including the aged and malnourished and those with severe systemic infections and trauma. Nomellini et al. (1) concentrate on the development of chronic illness phenomenon characterized by concurrent signs of persistent inflammation and immunosuppression. The article integrates the most recent concepts of chronic illness in the critical care patients. It analyzes the main triggers of chronic illness, its progression pathways as well as current definition deficits and knowledge gaps precluding its comprehension. The authors argue that the immune dysfunction in chronic critical illness shares many common denominators regardless by which specific “vulnerability pathway” progresses the decline in the affected patients. Thus, those common chronic illness blueprints, once clearly defined and standardized, could be potentially exploited for patient risk stratification and more efficient treatment strategies. The second review by the Chinese colleagues addresses hemodynamic monitoring in critically ill patients (2). The timing of this article is just right given the ongoing controversy on the early goal-directed therapy in septic shock patients after the recently published findings from the ProCESS, ARISE, and ProMISe trials. He et al. describe the concept of “critical hemodynamic therapy” as an appropriate balance between therapeutic target and therapeutic endpoint using targeting of the oxygen (delivery)—(blood) flow–(perfusion) pressure triad as an example. They also discuss the phenomenon of resuscitation incoherence (i.e., improved macrohemodynamics does not automatically translate into better microcirculation function) in the context of its early recognition and correction during resuscitation in critically ill patients— certainly an interesting read for all intensivists (and beyond).
The first paper of the Clinical Science Aspects is Chouihed et al. (3) tackled quite a different topic in their work: effective life support strategy for patients with refractory out of hospital cardiac arrested (ROHCA). They tested a new strategy (OSCAR-ECLS acronym) that optimizes access of ROHCA patients to extracorporeal life support (ECLS). Although the study has a preliminary character (46 patients; single center) its results are promising; OSCAR-ECLS strategy decreased time to ECLS implementation in ROHCA patients which translated to 18% improvement of survival. One can only hope that these findings will be reconfirmed in larger follow-up studies. The next paper by Gui et al. (4) remains in the general field of cardiovascular research. By using the collapsibility index measurement (by ultrasonography) in inferior vena cava (IVC), the authors investigated the early changes of intravascular volume triggered by passive leg rising in healthy volunteers. The underlying premise of this study was to establish whether this methodology is an acceptably sensitive and accurate predictor of fluid responsiveness in critically ill patients. The authors concluded that IVC collapsibility index data are strongly influenced by variables such as age and body mass index and appear inadequate for precise assessment of early (and subtle) intravascular volume change in the clinical setting. In their article (5), Karlin et al. examined the frequency and outcome of multiply organ dysfunction syndrome (MODS) in 157 trauma patients admitted to the intensive care unit of the University Medical Center in Utrecht (prospective cohort study). The Dutch colleagues made several interesting observations: only one patient died of MODS, kidney dysfunction was very rare, and MODS itself was characterized by an early onset, low severity, and a very short duration (median of 2 days). Based on those findings, the authors suggest that presentation and characteristics of “modern” MODS have assumed a new, less lethal shape. While this may be very true (pending further confirmations) in developed urban areas supported by effective logistics and sophisticated pre-and hospital critical care, it needs to be investigated whether the proposed paradigm shift has been occurring in less developed settings. In the next studies, we remain in the critical care field but shift from general characteristic to outcome prognostication. In the first study, Goag et al. (6) developed and tested a simplified mortality score (SMS) to predict 28-day outcome in adult critically ill patients. The approach is new in the sense that it sets together for the first time two parameters: delta neutrophil index and thrombotic microangiopathy (both easily obtainable from an automated blood cell analyzer). The results generated in this first examination indicate that SMS was not inferior compared with APACHE II and SOFA, while it was faster and simpler to obtain. The investigators aim to perform an external validation to reconfirm its clinical utility. The next study targeted pediatric patients with severe trauma. Russell et al. (7) measured histone-complexed DNA fragments (hcDNA) at admission (and after 24 h) and related their circulating concentration with outcome as well as markers of coagulation and endothelial damage; hcDNA increase positively correlated with all examined endpoints. Of note, this relationship was also true in patients presenting with a more severe (vs. milder) head injury. While not definitive, this is an important study given that it focuses on pediatric population and examines for the first time the relationship between hcDNA and coagulopathy in those patients.
We now move to the territory dominated by animal and cell studies: the Basic Science Aspects section includes two sets of papers that utilized either rat or mouse sepsis models, one study featuring an ovine model of endotoxemia and two articles based on cell culture systems. The first in the lineup is a classic experimental treatment study; Chang et al. (8) hypothesized that fresh frozen plasma (FFP) is a superior resuscitation tool compared with normal saline. This was tested in the cecal ligation and puncture (CLP) rat model demonstrating a very favorable response of septic animals to FFP regarding survival rate, organ dysfunction, endothelial injury, and inflammation within the 48 h observation period (post-CLP). Interpretational caution is needed given that this is the first study of that kind and the authors rightfully point out to several important limitations in the design of their experiment. Nevertheless, considering the known benefits of FFP in the trauma/hemorrhage setting, this idea certainly deserves a follow-up testing in other animal model systems. Next comes an elegant collaborative study by colleagues from Thailand, Indonesia, and the United States (9). The team investigated the influence of intestinal Candida albicans on several endpoints such as outcome, inflammation, and fecal microbiome in a mouse CLP model. In several complementary experimental steps, they demonstrated that pre-CLP oral exposure to live C. albicans corresponded with worsened survival, elevation of circulating TNFα, and IL-6, general increase of pathogenic bacteria burden and rearrangements of fecal microbiome post-CLP. Interestingly, the magnitude of those changes was consistently higher in CLP mice that received daily oral antibiotic mixture (i.e., prior to CLP) underscoring the importance of prolonged (clinically relevant) exposure to antibiotics and heightened risk for worse outcomes once sepsis strikes. The next article by Flemming et al. (10) constitutes a warning shot across the bow of treatments that aim to augment sphingosine-1-phosphate (S1P) concentration in sepsis. In contrast to several previous positive studies, the authors showed futility of treatment that employed a specific S1P agonist SEW2871 and was tested in rats with colon ascendens stent peritonitis (CASP). Thanks to their sophisticated experimental setup enabling concurrent macro- and microhemodynamic monitoring, the investigators observed not only the lack of improvement regarding the CASP-induced microvascular barrier damage but also a strong deterioration of cardiovascular function. Interestingly, the latter side-effects are similar to the ones recorded in multiple sclerosis patients treated with an unspecific S1P agonist. While it remains to be established what specific mechanism(s) was responsible for the deleterious reactions, this negative study should be perceived very positively as it cautions against potential complications in this specific therapeutic paradigm. The twelfth paper in this SHOCK issue, namely the work of Chen et al. (11), investigated the toll-like receptor (TLR) signaling pathways and their interaction with CD14 receptor using a balanced mixture of vitro (i.e., peritoneal macrophages) and in vivo (mouse CLP sepsis) systems. The crux of those experiments reveals differential TLR activation patterns responsible for triggering the CD14 upregulation in a septic/inflammatory setting. This study markedly enhances understanding of the complex trigger-receptor signaling interactions in sepsis. The work by Zhang et al. (12) is the first one of the two that relied solely on in vitro testing. By using a culture of primary murine intestinal epithelial cells (IECS), the authors investigated the (LPS-induced) injury and apoptosis phenomenon with the specific focus on the beneficial effects of the surfactant proteins (and the related signaling pathways). This interesting study calls for more work to precisely establish the cell-saving mechanisms demonstrated by the surfactant proteins in IECS apoptosis and to verify utility of this effect in an inflammatory disease scenario. The next paper comes from afar, or rather from Down Under; the Australian colleagues add a new exciting modeling system to the existing repertoire of endotoxemia and shock models (13). Byrne et al. (13) developed a hyperdynamic, severe distributive shock by using a low-grade E. coli LPS infusion with a step-wise escalation in adult ewes (an intuitive choice of species in the context of geographical location). The key hemodynamic features of the new model include preserved cardiac index, substantial decline in the mean arterial pressure (below 60 mm Hg in all animals) with consequent increasing requirement for vasopressors (during the hemodynamic support phase), and only transient (and relatively mild) increase in the mean pulmonary artery pressure. Compared with the hypodynamic model established and used in many species, this new protocol better recapitulates the human septic shock and appears a suitable testing platform for new therapeutic approaches. The closing study of the January issue is authored by Wang et al. (14) and it relies on human microvascular endothelial cells (hMEC) used as simulation model of hypoxia/reoxygenation (H/R) injury for testing effects of endoplasmic reticulum protein, calreticulin. Exogenous calreticulin was shown to exert beneficial action in chronic wound healing, ischemic conditions, and the current authors recently demonstrated its anti-apoptotic role in hMECs exposed to radiation. In this work, autophagy was the chief intervention target. The authors demonstrated that pretreatment with calreticulin markedly attenuated the H/R-induced autophagy and that this effect was likely due to the suppression of autophagosome formation and Beclin-1 as well as to an increase in mTOR phosphorylation.
Thank you very much for devoting your time to reading this commentary. My writing work is done now; your reading work begins here. Hopefully the above synopsis will help you to narrow down your reading choices. Bear in mind that reading papers authored by other scientists is also a way to connect with them. Thus, keep connecting and Happy New Year!
1. Nomellini V, Kaplan LJ, Sims CA, Caldwell CC. Chronic critical illness and persistent inflammation: what can we learn from the elderly, injured, septic, and malnourished? Shock
2. He H, Long Y, Zhou X, Wang X, Zhang H, Chai W, Cui N, Wang H, Liu D. Oxygen–flow–pressure targets for resuscitation in critical hemodynamic therapy. Shock
3. Chouihed T, Kimmoun A, Lauvray A, Laithier F-X, Jaeger D, Lemoine S, Maureira JP, Nace L, Duarte K, Albizzati S, et al. Improving patient selection for refractory out of hospital cardiac arrest treated with extracorporeal life support. Shock
4. Gui J, Yang Z, Ou B, Xu A, Yang F, Chen Q, Jiang L, Tang W. Is the collapsibility index of the inferior vena cava an accurate predictor for the early detection of intravascular volume change? Shock
5. van Wessem KJP, Leenen LPH. Reduction in mortality rates of postinjury multiple organ dysfunction syndrome: a shifting paradigm? A prospective population-based cohort study. Shock
6. Goag EK, Lee JW, Roh YH, Leem AY, Kim SY, Song JH, Kim EY, Jung JY, Park MS, Kim YS, et al. A simplified mortality score using delta neutrophil index and the thrombotic microangiopathy score for prognostication in critically ill patients. Shock
7. Russell RT, Christiaans SC, Nice TR, Banks M, Mortellaro VE, Morgan C, Duhachek-Stapelman A, Lisco SJ, Kerby JD, Wagener BM, et al. Histone-complexed DNA fragments levels are associated with coagulopathy, endothelial cell damage, and increased mortality after severe pediatric trauma. Shock
8. Chang R, Holcomb JB, Johansson PI, Pati S, Schreiber MA, Wade CE. Plasma resuscitation improved survival in a cecal ligation and puncture rat model of sepsis. Shock
9. Panpetch W, Somboonna N, Bulan DE, Issara-Amphorn J, Worasilchai N, Finkelman M, Chindamporn A, Palaga T, Tumwasorn S, Leelahavanichkul A. Gastrointestinal colonization of candida albicans
increases serum (1→3)-β-D-glucan, without candidemia, and worsens cecal ligation and puncture sepsis in murine model. Shock
10. Flemming S, Burkard N, Meir M, Schick MA, Germer C-T, Schlegel N. Sphingosine-1-phosphate receptor-1 agonist SEW2871 causes severe cardiac side effects and does not improve microvascular barrier breakdown in sepsis. Shock
11. Chen Z, Shao Z, Mei S, Yan Z, Ding X, Billiar T, Li Q. Sepsis upregulates CD14 expression in a MyD88-dependent and TRIF-independent pathway. Shock
12. Zhang L, Meng Q, Yepuri N, Wang G, Xi X, Cooney RN. Surfactant proteins-A and –D attenuate LPS-induced apoptosis in primary intestinal epithelial cells (IECS). Shock
13. Byrne L, Obonyo NG, Diab S, Dunster K, Passore M, Boon AC, Hoe LS, Hay K, Van Haren F, Tung J-P, et al. An ovine model of hyperdynamic endotoxemia and vital organ metabolism. Shock
14. Wang Y, Tao T-Q, Song D-D, Liu X-H. Calreticulin ameliorates hypoxia/reoxygenation-induced human microvascular endothelial cell injury by inhibiting autophagy. Shock