Leading off this issue is a tight review of therapeutic strategies against septic metabolism in children. Milica Bajčetić and coauthors from the University of Belgrade (1) contrast how flux along reactive oxygen species (ROS) and nuclear factor κB pathways is used differently from adults and outline strategy. Developing pediatric neurons and myocytes are most sensitive to ischemia because of their utter dependence on mitochondrial respiration (oxidative phosphorylation). But that involves reactive oxygen species and apoptosis (and could be gauged by lactate?). Neonatal cells apparently depend more on glutathione than catalase, to control H2O2, and children do suffer more from long-term effects of sepsis. This and many other articles in this issue relate to nuclear factor κB regulation. Practical pharmacological redox manipulations are suggested for pediatric sepsis. Intriguingly, the authors mention “negative” blood cultures in “septic” patients. Perhaps children’s different response to pathobiology provides clues to defects in adults. Find out.
The first entry in the Clinical Science aspects is evaluative. Shock readers are aware of the explosive growth in understanding the microbiome, the huge ecologies of bacteria that commensurably inhabit our skin, mouth, and gut. Most cannot be cultured as yet. Will you rejoice or despair with Stephen Davies and colleagues (2) from the University of Virginia, East Carolina University, University of Texas Southwestern, the Cleveland Clinic, and Mercy Clinic, Springfield, Mo, who find that “inappropriate” or “appropriate” antimicrobial therapy does not affect outcomes substantially. There is still 14% to 15% mortality in this cohort of septic surgical patients. Note the high P value of nocosomial infections (cultured?) in their Table 1. Shock has been wrestling with bacteremia and septic variants since inception.
Two basic science articles may relate to this clinical report. Focusing on the gut barrier side, Jordan Fishman and colleagues (3) contribute the latest finding from the surgical group at Rutgers University. Here they describe changes in the unstirred mucus layer caused by acute experimental pancreatitis. Reactive oxygen species at it again? If you don’t want to feel left out the next time gurus discuss the “inspissated” mucus, you should not miss this article.
I confess to being utterly pro-lymphology. Ed Deitch (3) and our Denver group probably represent a sizable fraction of all interest in proinflammatory lymph after shock. Why should YOU care about mesenteric lymph? Because it predates the blood circulation (Google hemolymph). Its genesis is around the same time that Toll-like receptors, innate immunity, and coagulation may have formed in jawed fishes about 500 million years ago. It seems conserved across species, grounds for solid comparative research.
Hong Jiang and coworkers (4) from the hospitals affiliated to Shanghai Jiao Tong University confirm that the multiligand Toll-like receptor 4 mediates acute lung inflammation after trauma/hemorrhagic shock (T/HS). This is a deceptively simple study until you realize that T/HS injury is being induced by the postshock lymph alone! Here the authors follow up on their previous finding that local inhibition of hypoxia-inducible factor 1α ameliorates lung injury induced by T/HS in rats. Read on.
Clinical Science’s second article hones in on ethanol and leukocytes. Shock researchers are always looking for applicable pharmacology, often preferring to repurpose known agents. Arnaud Gacouin and collaborators (5) from INSERM/Universite de Rennes report that in nontrauma but critically ill patients, acute alcohol exposure diminished inflammation and, remarkably, C-reactive protein (P < 0.001). Could wine alcohols (1 OH), or polyols (glycerol 3-OHs, mannitol 6-OHs), really be used imaginatively during resuscitation to regulate inflammation? Raise a toast to that.
The planar tetracyclines too are another early drug structure. Andaleb Kholmukhamedov and his international associates (6) at Medical University of South Carolina, including John Le Masters, who is also affiliated with J. W. Goethe University and the Institute of Theoretical & Experimental Biophysics of the Russian Academy of Sciences, Pushchino, find encouraging success with minocyline and doxycycline over tetracycline in squashing lung and kidney injury after HS and resuscitation. This topic is no longer about antibiotic actions but modulation of innate immunity during HS and resuscitation.
The next 2 Clinical Science presentations concern lactate. Impaired energy metabolism during shock causes substantive changes in pH and general anion cation balance. Detailed accounting of major cations minus common anions can quantify the “strong anion gap,” which can predict postshock outcome very well. So does “base deficit,” which assumes equilibrium between HCO3 and pH. However, this requires extensive blood chemistry, and furthermore, the anion-cation balance shifts as patients are resuscitated. In contrast, the measurement of glycolytically produced lactate anions is quick and easy and provides a first approximation of inadequate mitochondrial function. Thus, the initial venous L-lactate presents an estimation of the trauma/shock/sepis insult (like global injury severity scores or arterial pressure) but from a metabolic point of view reflecting the depth of hypoxic/hypoperfused conditions suffered by the patient. Seeking emergency applicability, Afshin Parsikia and colleagues (7) from Einstein Healthcare Network examine the not inconsiderable predictive power of the initial lactate, in a cohort of 1,297 level I trauma patients. As they did not have arterial samples, relative comparison with base deficit and precise strong ion gap was not available. Could the mixed results with the ROC for lactate and mortality be due to other anions contributing to postshock acidosis (including D-lactate, metabolites)?
In a similar vein (no pun intended), Sung Yeon Hwang et al. (8) from Samsung University show that initial lactate also predicts patients transiting from cryptic shock to overt shock with high mortality. How could physicians utilize this easily comprehended metabolic index to improve resuscitation therapy?
The fascinating discovery of ischemic preconditioning against subsequent ischemia-reperfusion has provoked interesting insights, involving signaling by lipid and/or calcium-regulated PKC isoforms, conferred states of adaptation against ischemia, and sequelae from opening of mitochondrial KATP channels. Originally discovered in myocardium in the early 1990s, this protective phenomenon has been replicated in other tissue beds as well. Interestingly, remote precondition of at least the brain and heart can be accomplished by causing ischemia-reperfusion at some distal bed (usually limb tourniquet), although the mechanisms here are less certain. Many members of Shock study these phenomena avidly, but feel stymied by an apparent lack of relevance causally linking myocardial dysfunction to postshock deaths. In fact, the role of indirect myocardial injury after trauma has been hitherto neglected, because other problems, such as coagulative defects or lung injury, dominate acute mortality.
But, in the final clinical science article, Ninad Gawande and associates (9) from Punjabrao Deshmukh Medical College & Hospital, Amravati, Government Medical College & Hospital, Nagpur, and Vasantrao Naik Government Medical College & Hospital, analyze myocardial medicolegal autopsies revealing clear symptoms of early ischemic/anoxic lesions. If so, what do trauma victims really die of? Well, the heart stopped! Why? Find out.
Even as neuroscientists forge ahead trying remote preconditioning for acute cerebral ischemia, we are delighted and relieved to learn from Xianwen Hu et al. (10), at the Weil Institute of Critical Care Medicine, University of Southern California, and Anhui Medical University, that four cycles of limb ischemia (5 min off, 5 min on) protect against myocardial and cerebral dysfunction, spanning 2 to 72 h. Their measures of echocardiographic dysfunction and neurological deficits induced by HS will appeal to readers. For this sepsis/shock model, the authors support the glibenclamide-sensitive KATP mechanism (one of many hypotheses afloat for remote preconditioning).
Only one article published recently considers the role of miRNA-1, a most abundant cardiac species, in preconditioned rat heart. Timo Brandenburger et al. (11), from University Hospital Duesseldorf and Hebrew University of Jerusalem, now link the expression of miRNA-1 to a well-defined target gene, the brain-derived neurotrophic factor Surprisingly, despite initial downregulation of miRNA-1, brain-derived neurotrophic factor expression did not change. Why? Go figure. Read on.
And speaking of the families of PKC, did you know that PKCe activates rodent vascular rho kinases after HS? Read how Tao Li (12) from the State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, decrypt the problem with crisscrossing agonists and antagonists. Figure 2 depicts the changes after shock.
Two daring reports in this issue tackle the challenging cytokine milieu after trauma-hemorrhage or sepsis. Yong Zhang (13) and colleagues at University of Pittsburgh and Huazhong University of Science and Technology collaborate to examine the iconic interleukin 6 (IL-6) in polytrauma. Few Shock readers will have missed how early levels of this pluripotent cytokine are a profound predictor of outcome. We all have puzzled about its pro-anti and other unexpected effects on early inflammation and thereafter. Using an anti–IL-6 antibody within the context of C57/Bl polytrauma, the authors illustrate the manifold faces of IL-6 in promoting inflammation with an impressive set of figures, including one on the noticeable effects on STATs and SOCs.
David Cauvi et al. (14) from University of California San Diego, La Jolla, report their comparisons of the iconic IL-23/IL-17 axis, in C57NL/6J versus A/J mice. The former strain is known to be resistant to lipopolysaccharide and lacks sPLA2. Paradoxically, the authors say the C57/Bl mice had increased IL-17 and more neutrophils in the lung after cecal ligation and puncture! Could the higher interferon γ produced by the A/J mice really have been protective? Check it out.
A salute to the all authors, technicians, reviewers, and journal staff who served up this fine scientific smorgasbord!
1. Bajčetić M, Spasić S, Spasojević I: Redox therapy in neonatal sepsis: reasons, targets, strategy, and agents. Shock 42: 179–184, 2014.
2. Davies SW, Efird JT, Guidry CA, Hranjec T, Metzger R, Swenson BR, Sawyer RG: Does it matter if we get it right? Impact of appropriateness of empiric antimicrobial therapy among surgical patients. Shock 42: 185–191, 2014.
3. Fishman JE, Levy G, Alli V, Zheng X, Mole DJ, Deitch EA: The intestinal mucous layer is a critical component of the gut barrier that is damaged during acute pancreatitis. Shock 42: 264–270, 2014.
4. Jiang H, Hu R, Sun L, Chai D, Cao Z, Li Q: Critical role of toll like receptor 4 in hypoxia inducible factor-1α activation during trauma/hemorrhagic shock induced acute lung injury after lymph infusion in mice. Shock 42: 271–278, 2014.
5. Gacouin A, Roussel M, Le Priol J, Azzaoui I, Uhel F, Fest T, Le Tulzo Y, Tadie JM: Acute alcohol exposure has an independent impact on C-reactive protein levels, neutrophil CD64 expression and subsets of circulating white blood cells differentiated by flow cytometry in nontrauma patients. Shock 42: 192–198, 2014.
6. Kholmukhamedov A, Czerny C, Hu J, Schwartz J, Zhong Z, Lemasters JL: Minocycline and doxycycline, but not tetracycline, mitigate liver and kidney injury after hemorrhagic shock/resuscitation. Shock 42: 256–263, 2014.
7. Parsikia A, Bones K, Kaplan M, Strain J, Leung PS, Ortiz J, Joshi ART: The predictive value of initial serum lactate in trauma patients. Shock 42: 199–204, 2014.
8. Hwang SY, Shin TG, Jo IJ, Jeon K, Suh GY, Lee TR, Cha WC, Sim MS, Song KJ, Jeong YK: Association between hemodynamic presentation and outcome in sepsis patients. Shock 42: 205–210, 2014.
9. Gawande NB, Tumram NK, Dongre AP: Cardiac changes in hospitalized patients of trauma. Shock 42: 211–217, 2014.
10. Hu X, Yang Z, Yang M, Qian J, Cahoon J, Xu J, Sun S, Tang W: Remote ischemic preconditioning mitigates myocardial and neurological dysfunction via KATP channel activation in a rat model of hemorrhagic shock. Shock 42: 228–233, 2014.
11. Brandenburger T, Grievink H, Heinen N, Barthel F, Huhn R, Stachuletz F, Kohns M, Pannen B, Bauer I: Effects of remote ischemic preconditioning and myocardial ischemiaon microRNA-1 expression in the rat heart in vivo. Shock 42: 234–238, 2014.
12. Li T, Zhu Y, Zang J-T, Peng X-Y, Lan D, Yang G-M, Xu J, Liu L-M: Rho kinase acts as a downstream molecule to participate in PKC ε regulation of vascular reactivity after hemorrhagic shock in rats. Shock 42: 239–245, 2014.
13. Zhang Y, Zhang J, Korff S, Ayoob F, Vodovotz Y, Billiar TR: Delayed neutralization of IL-6 reduces organ injury, selectively suppresses inflammatory mediator and partially normalizes immune dysfunction following trauma and hemorrhagic shock. Shock 42: 218–227, 2014.
14. Cauvi DM, Williams MR, Bermudez JA, Armijo G, De Maio A: Elevated expression of IL-23/IL-17 pathway-related mediators correlates with exacerbation of pulmonary inflammation during polymicrobial sepsis. Shock 42: 246–255, 2014.