SHOCK, Vol. 40, No. 6, pp. 441Y443, 2013

Commentary WHAT’S NEW IN SHOCK? DECEMBER 2013 Saeid Amini-Nik, MD, PhD and Marc G. Jeschke, MD, PhD Division of Plastic Surgery, Department of Surgery, and Department of Immunology, University of Toronto; Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre; and Sunnybrook Research Institute, Toronto, Ontario, Canada

This volume of Shock is special as it includes excellent and outstanding articles, but furthermore, this edition of Shock includes the articles of the five finalists for the 2013 new investigator award competition. It is our pleasure to write a commentary for this issue of Shock as it not only brings the latest aspects of shock science on a clinical level but also contains several basic articles that can potentially change our clinical practice. The reports in this issue range from review articles briefing the clinical rationale behind the use of freezedried plasma (FDP) at the point of injury, to review on lipid A analogs as an attractive family of immune modulators, and to therapeutic potential of inhibiting neutrophil mobilization in the improvement of local and remote tissue damage following ischemia-reperfusion injury (IRI). In the clinical research area, we have reports on the diagnostic value of endotoxin scattering photometry (ESP) for differentiation between sepsis and septic shock, the advantage of using activated protein C (APC) for improving vascular reactivity, and the dynamic of lipid and protein metabolism in regulating the response to systemic inflammation and a report on the advantage of monitoring femoral arterial pressure in septic shock patients who receive high-dose norepinephrine therapy. In our new investigator award completion, all the five reports used animal models to address some of the features of shock. The reports range from a work showing modulation of the degree of neuroinflammation by systemic interleukin 6 (IL-6) to usefulness of peripheral blood mononuclear cell (PBMC) mitochondrial function as a proxy for kidney mitochondrial function during hemorrhagic shock, to a report on benefit of using growth arrestYspecific protein 6 (Gas6) in treatment sepsis and acute lung injury, to beneficial effect of antiYhigh-mobility group box 1 (HMGB1) monoclonal antibody therapy in sepsis survivors, and finally a report on the possible role of regulatory T cells in improving the outcome of Pseudomonas aeruginosa pneumonia when treated with Lactobacillus rhamnosus GG (LGG). The elegant review written by Schofield et al. (1) at the Institute for Molecular Bioscience, The University of Queensland, Australia, is emphasizing the importance of neutrophils as a significant contributor to the progression of IRI. Ischemiareperfusion injury still remains a common incidence in coronary bypass surgery, stroke, organ transplantation, and gut hypoperfusion. The complex pathophysiology of IRI continues to elude treatment. As inflammatory response is an essential mediator of IRI, this review highlights the role of neutrophils in progression of IRI and explains the mechanism of this contribution. The authors summarize studies that show neutrophils are

exacerbating ischemia through blockage of capillaries (noreflow phenomenon) and escalate the inflammatory response by releasing cytokines, damage cells unaffected by ischemia through release of reactive oxygen species, and by disrupting the endothelial and epithelial barriers, which leads to multiple organ failure. As such, they argue that an ideal therapeutic approach would reduce the inflammatory signals that mobilize and recruit neutrophils. This review is very fascinating as it indicates the future therapeutic potential in IRI, an area that still troubles clinicians from a variety of specialties. The fascinating review article by Glassberg et al. (2) describes the clinical rationale behind the use of FDP at the point of injury. While the authors designed an administration protocol and explained the process of procurement and distribution of FDP, they present preliminary data describing the first casualties treated with FDP at the point of injury. This is important because dried plasma enables early treatment in out-of-hospital settings, being as close as possible to the point of injury, which can potentially provide an important contribution to the care given to hemorrhaging patients. The last excellent review by Bohannon et al. (3) explains the advantages of using lipid A analogs as a family of immune modulators that could have clinical application in patients at high risk for developing infections. Although it is known that lipid A is an activator of innate immune response and provides attractive immunological characteristics, it is furthermore associated with inflammatory responses, which limits its use as a clinical immune modulator. The authors describe various aspects of the synthetic lipid A, which possess attenuated proinflammatory activity but retain essential properties as immune adjuvants. In the section of the new investigator award competition, we find incredible high-quality publications. Using a murine model of mild traumatic brain injury (TBI), Yang et al. (4) base their investigation on prior studies, in which they showed that IL-6 is a mediator of mild TBI. They now examine whether IL-6 plays a role in the neuroinflammatory and functional deficits after injury. They present data that suggest systemic IL-6 modulates the degree of neuroinflammation and contributes to reduced motor coordination after mild TBI. Moreover, the authors evaluate the effects of brief hypoxia on mild TBI and show that brief exposure to hypoxia after TBI exacerbates systemic and brain inflammation, an observation that abrogates by IL-6 blockade. Their animal study suggests that IL-6 represents a target cytokine for the management of patients with mild TBI reducing the degree of neuroinflammation after TBI. Karamercan et al. (5) present an animal study aimed to address whether PBMCs and their mitochondrial dysfunction can 441

Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.


SHOCK VOL. 40, NO. 6

be used as a surrogate readout of mitochondrial dysfunction in vital tissues such as kidney, liver, and heart. Mitochondrial dysfunction is contributing to the development of posttraumatic organ failure. As such, evaluation of mitochondrial dysfunction in vital organs is important but clinically impractical. Using a fixed-pressure hemorrhagic shock model in rats, the authors show some degree of association between mitochondrial dysfunction in PBMCs and other tissues. However, lack of linear correlation over the spectrum of shock and resuscitation limits the practicality of using PBMCs as a proxy for tissue-specific mitochondrial function in the acute setting. Giangola et al. (6) subjected mice to sepsis by cecal ligation and puncture and asked the question whether Gas6 can attenuate the severity of acute lung injury and sepsis. They present strong supporting evidence suggesting Gas6 weakens some of the characteristics of lung injury and sepsis but more importantly increases the 10-day survival rate of the mice. The authors suggest that Gas6 administration soon after infection may delay the development of sepsis. The authors conclude that GAS6 has potential to be developed as a novel therapeutic agent to treat patients with sepsis and acute lung injury. This is an intriguing and fascinating outcome of this study. Of course, the main question remains whether these findings will hold up in a clinical trial. In another article from a new investigator, Valdes-Ferrer et al. (7) asked whether HMGB1 plays a role in mediating the immune dysfunction of splenocytes in sepsis survivors. They show that while splenocytes were exposed to HMGB1 and subsequently challenged with cognate ligands to Toll-like receptor 2 (TLR2), TLR4, TLR9, and RAGE receptors had enhanced cytokine release. Administration of anti-HMGB1 antibody to the splenocytes of the mice (which survived cecal ligation and punctureYinduced sepsis) reversed the priming of splenocytes. The authors conclude that targeting HMGB1 may weaken proinflammatory state of splenocytes, which is a source of inflammatory cytokines in sepsis survivors. In the last report of this section, Khailova et al. (8) try to elucidate the mechanism of beneficial effect of LGG administration in critical illness. They show LGG significantly improved 7-day survival of mice subjected to intratracheal injection of P. aeruginosa. This is in association with an increase in the number of T regulatory cell as demonstrated with flow cytometry analysis using Foxp3 and CD4 as markers, as well as reduced bacterial counts in bronchoalveolar lavage and with markers of systemic inflammatory response. The authors suggest using probiotic bacteria in critically ill patients in combination with traditional antibiotic therapies would be an ideal and cost-effective approach in preventing hospital-acquired infections. Lactobacillus have been studied intensively and showed mixed results. The investigators used a different strain of Lactobacillus, and clinical data will demonstrate whether this strain is associated with beneficial outcomes in patients. In addition, the question comes up why different strains of lactobacilli have different effects, leading to the investigation of variation in signaling pathways. In a clinical report, Shimizu et al. (9) evaluate the predictive power of ESP assay in comparison with standard turbidimetric LAL assay and procalcitonin assay for diagnosing sepsis. The


authors present data that demonstrate ESP detects plasma endotoxin with higher sensitivity compared with turbidimetric LAL assay. Moreover, endotoxin level detected by ESP assay correlates with the degree of sepsis after emergency gastrointestinal surgery. This report is important as clinicians still fail to predict sepsis and infections accurately, and various trials showed mixed results with the use of conventional markers such as CRP and procalcitonin. Activated protein C is a vitamin KYdependent serine protease that is shown to have a positive impact on global hemodynamics. Favory et al. (10) hypothesized that APC may have a positive effect on vascular reactivity to !1 agonists in humans and that it could have an influence on vascular reactivity at the microcirculatory level. They assess vascular effects of APC during the first hour of treatment in 12 patients both at macrocirculatory (measuring arterial pressure in response to !1 adrenergic agonist titration) and microcirculatory (studying microvascular blood flow using cutaneous laser Doppler at rest and with post occlusive reactive hyperaemia [PORH]) level. The authors show that APC improves vascular reactivity both at macrocirculatory and microcirculatory levels very quickly. Despite the failure of APC in a clinical setting, it appears that APC has some effect that may be used in different entities, and this study is an excellent endeavor in this direction. Kamisoglu et al. (11) attempted to outline the global metabolic responses during endotoxemia in humans. Endotoxemia was induced by injecting intravenous endotoxin, and the authors profiled 366 plasma metabolites at different time points. They report an opposite direction of lipid and protein metabolism in response to endotoxemia and systemic inflammation. Metabolites associated with lipid metabolism were upregulated within the first 6 h, whereas amino acids or their derivatives were initially downregulated up to 6 h after injection, but then upregulated. The authors report that within 24 h after injection, the dysbalance of metabolites is mostly reaching their equilibrium again. This wonderful study is an extension of previous studies from this group and not only clearly demonstrated the effects of endotoxemia on metabolism, but also indicated how fast metabolic changes occur. In addition, it clearly shows that endotoxemia is a quick pathophysiology because we know from studies in burn and trauma patients that metabolites can be altered for years. This indicates the metabolic and genomic differences between entities. Given the importance of arterial blood pressure monitoring in management of septic shock patients, Kim et al. (12) investigate the difference between radial (peripheral) and femoral (central) arterial blood pressure in septic shock patients receiving highdose norepinephrine. They report an average of +4.9-mmHg difference between radial and femoral, which was higher (+6.2 mmHg) during high-dose norepinephrine therapy, a significant underestimation of central pressure when radial artery is monitored in septic shock patients, in particular when receiving high-dose norepinephrine. The authors suggest obtaining femoral arterial pressure monitoring when high-dose norepinephrine is administered. This is very important information for clinicians as catecholamines are administered and targeted to certain blood pressure ranges, and if the radial artery pressure is lower than the femoral, one would have to adjust for this difference in our target range.

Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.

SHOCK DECEMBER 2013 On a personal note, we would like to thank Shock for the honor to write this commentary. It was a pleasure to have had the opportunity to review this month’s issue of Shock. It is fascinating and wonderful to see the diversity and incredible quality of articles published in this Shock volume. REFERENCES 1. Schofield ZV, Woodruff TM, Halai R, Wu MC-L, Cooper MA: NeutrophilsVa key component of ischemia-reperfusion injury. Shock 40:463Y470, 2013. 2. Glassberg E, Nadler R, Gendler S, Abramovich A, Spinella PC, Gerhardt TR, Holcomb JB, Kreiss Y: Freeze dried plasma at the point of injuryVfrom concept to doctrine. Shock 40:444Y450, 2013. 3. Bohannon JK, Hernandez A, Enkhbaatar P, Adams WL, Sherwood ER: The immunobiology of Toll-like receptor 4 agonists: from endotoxin tolerance to immunoadjuvants. Shock 40:451Y462, 2013. 4. Yang SH, Gangidine M, Pritts TA, Goodman MD, Lentsch AB: Interleukin 6 mediates neuroinflammation and motor coordination deficits after mild traumatic brain injury and brief hypoxia in mice. Shock 40:471Y475, 2013. 5. Karamercan MA, Weiss SL, Villarroel JPP, Guan Y, Werlin E, Figueredo R, Becker LB, Sims C: Can peripheral blood mononuclear cells be used as a proxy for mitochondrial dysfunction in vital organs during hemorrhagic shock and resuscitation? Shock 40:476Y484, 2013.



6. Giangola MD, Yang W-L, Rajayer SR, Nicastro J, Coop GF, Wang P: Growth arrest-specific protein 6 attenuates neutrophil migration and acute lung injury in sepsis. Shock 40:485Y491, 2013. 7. Valdes-Ferrer SI, Rosas-Ballina M, Olofsson PS, Lu B, Dancho ME, Li JH, Yang H, Pavlov VA, Chavan SS, Tracey KJ: HMGB1 mediates persistent splenocyte priming in sepsis survivors: evidence from a murine model. Shock 40:492Y495, 2013. 8. Khailova L, Baird CH, Rush AA, McNamee EN, Wiuschmeyer PE: Lactobacilllus rhamnosus GG improves outcome in experimental pseudomonas aeruginosa pneumonia: potential role of regulatory T cells. Shock 40: 496Y503, 2013. 9. Shimizu T, Obata T, Sonoda H, Akabori H, Miyake T, Yamamoto H, Tabata T, Eguchi Y, Tani T: Diagnostic potential of endotoxin scattering photometry for sepsis and septic shock. Shock 40:504Y511, 2013. 10. Favory R, Julien P, Alves I, Guerry M-J, Lemyze M, Parmentier-Decrucq, E, Duburcq T, Mathiew D: Activated protein C improves macro and microvascular reactivity in human severe sepsis and septic shock. Shock 40: 512Y518, 2013. 11. Kamisoglu K, Sleight KE, Calvano SE, Coyle SM, Corbett SA, Androulakis IP: Temporal metabolic profiling of plasma during endotoxemia in humans. Shock 40:519Y526, 2013. 12. Kim WY, Jun JH, Huh JW, Hong SB, Lim C-M, Koh Y: Radial to femoral arterial blood pressure differences in septic shock patients receiving high-dose norepinephrine therapy. Shock 40:527Y531, 2013.

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What's new in Shock? December 2013.

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