Stem Cell Therapy and Hydrogen Sulfide: Conventional or Nonconventional Mechanisms of Action? Purpose: Hydrogen sulfide (H2S) has many beneficial biological properties, including the ability to promote vasodilation. It has been shown to be released from stem cells and increased by hypoxia. Therefore, H2S may be an important paracrine factor in stem cell mediated intestinal protection. We hypothesized that hydrogen sulfide created through conventional pathways would be a critical component of stem cell mediated intestinal protection following ischemic injury. Methods: Human bone marrow derived mesenchymal stem cells (BMSCs) were transfected with negative control siRNA (Scramble), or with siRNA to CBS, MPST, or CTH. Knockdown was confirmed with PCR and hydrogen sulfide gas assessed with AzMC fluorophore. Eight week old male mice then underwent intestinal ischemia for 60 mins, after which time, perfusion was restored. BMSCs from each of the above groups were then placed into the mouse abdominal cavity prior to final closure. After 24 hours, mice were reanesthetized and mesenteric perfusion was assessed by Laser Doppler Imaging (LDI). Animals were then sacrificed and intestines excised, placed in formalin, paraffin embedded, and stained with H & E. Intestines were then scored with a common mucosal injury grading scale. Results: PCR confirmed knockdown of conventional H2S producing enzymes (CBS, MPST, CTH). Hydrogen sulfide gas was decreased in MPST and CTH transfected cells in normoxic conditions but was not decreased compared to scramble in any of the transfected groups in hypoxic conditions. BMSCs promoted increased mesenteric perfusion at 24 hours post-ischemia compared to vehicle. Transfected stem cells provided equivalent protection. Histologic injury was improved with BMSCs compared to vehicle. CBS, MPST, and CTH knockdown cell lines did not have any worse histological injury compared to Scramble. Conclusion: Knocking down conventional H2S producing enzymes only impacted gas production in normoxic conditions. When cells were transfected in hypoxic conditions, as would be expected in the ischemic intestines, hydrogen sulfide gas was not depressed. These data, along with unchanged perfusion and histological injury parameters with conventional enzyme knockdown would indicate that alternative H2S production pathways may be initiated during hypoxic and/or ischemic events. Address reprint requests to Troy A. Markel, MD, Assistant Professor of Surgery, Indiana University School of Medicine, Riley Hospital for Children at IU Health, 705 Riley Hospital Dr., RI 2500, Indianapolis, IN 46202. E-mail: tmarkel@iupui.edu Received 17 June, 2019 Revised 8 July, 2019 Accepted 17 July, 2019 ARJ performed animal I/R experiments, protein isolation, histological grading and drafted the manuscript, NAD performed histological grading and statistical analysis, KRO performed hydrogen sulfide assays, TAM contributed critical ideas, assistance and manuscript advice. All authors provided critical revisions to the manuscript and assisted with its final preparation. Conflicts of Interest: TAM receives consultation fees from Scioto Biosciences and Onsite, LLC Funding: National Institutes of Health, NIDDK K08DK113226 (TAM) The Koret Foundation (TAM) Indiana University Biomedical Research Grant (KRO) The Department of Surgery at the Indiana University School of Medicine (TAM) © 2019 by the Shock Society

Direct Rivaroxaban-Induced Factor Xa Inhibition Proves to be Cardioprotective in Rats Background: Acute myocardial infarction is a leading cause of death worldwide. Though highly beneficial, reperfusion of myocardium is associated with reperfusion injury. While indirect inhibition of Factor Xa has been shown to attenuate myocardial ischemia-reperfusion (I/R) injury, the underlying mechanism remains unclear. Our study sought to evaluate the effect of rivaroxaban (RIV), a direct inhibitor of Factor Xa, on myocardial I/R injury and determine its cellular targets. Experimental Approach: We used a rat model of 40-minutes coronary ligation followed by reperfusion. RIV (3 mg/Kg) was given per os 1 hour before reperfusion. Infarct size and myocardial proteic expression of survival pathways were assessed at 120 and 30 minutes of reperfusion, respectively. Plasmatic levels of P-selectin and von Willebrand factor were measured at 60 minutes of reperfusion. Cellular RIV effects were assessed using hypoxia-reoxygenation (H/R) models on human umbilical vein endothelial cells and on rat cardiomyoblasts (H9c2 cell line). Key Results: RIV decreased infarct size by 21% (42.9% vs. 54.2% in RIV-treated rats and controls respectively, p < 0.05) at blood concentrations similar to human therapeutic (387.7 ± 152.3 ng/mL) levels. RIV had no effect on H/R-induced modulation of endothelial phenotype, nor did it alter myocardial activation of RISK and SAFE pathways at 30 min after reperfusion. However, RIV exerted a cytoprotective effect on H9c2 cells submitted to H/R. Conclusion: RIV decreased myocardial I/R injury in rats at concentrations similar to human therapeutic ones. This protection was not associated with endothelial phenotype modulation but rather with potential direct cytoprotection on cardiomyocytes. Address reprint requests to Laurent Macchi, MD, PhD, CHU Poitiers, Service d’hématologie biologique, 2, rue de la Milétrie, CS 90577, F-86021 POITIERS cedex. E-mail: laurent.macchi@chu-poitiers.fr Received 18 March, 2019 Revised 8 April, 2019 Accepted 10 July, 2019 This research was supported by a research grant from Bayer AG, Germany. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2019 by the Shock Society

Demographics, Treatments, and Outcomes of Acute Respiratory Distress Syndrome: The Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma (Forecast) Study Purpose: Acute respiratory distress syndrome (ARDS) remains a major cause of death. Epidemiology should be continually examined to refine therapeutic strategies for ARDS. We aimed to elucidate demographics, treatments, and outcomes of ARDS in Japan. Methods: This is a prospective cohort study for ARDS. We included adult patients admitted to intensive care units through emergency and critical care departments who satisfied the American–European Consensus Conference (AECC) acute lung injury (ALI) criteria. In addition, the fulfillment of the Berlin definition was assessed. Logistic regression analyses were used to examine the association of independent variables with outcomes Results: Our study included 166 patients with AECC ALI from 34 hospitals in Japan; among them, 157 (94.6%) fulfilled the Berlin definition. The proportion of patients with PaO2/FIO2 ≤100, patients under invasive positive pressure ventilation (IPPV), and in-hospital mortality was 39.2%, 92.2%, and 38.0% for patients with AECC ALI and 38.9%, 96.8%, and 37.6% for patients with Berlin ARDS, respectively. The area of lung infiltration was independently associated with outcomes of ARDS. Low-mid tidal volume ventilation was performed in 75% of patients under IPPV. Glucocorticoid use was observed in 54% patients, and it was positively associated with mortality. Conclusions: Our study included a greater percentage of patients with ARDS with high severity and found that the overall mortality was 38%. The management of ARDS in Japan was characterized by high the utilization rate of glucocorticoids, which was positively associated with mortality. Address reprint requests to Seitaro Fujishima, MD, Center for General Medicine Education, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: fujishim@keio.jp Received 13 April, 2019 Revised 11 July, 2019 Accepted 11 July, 2019 Funding source: This study was funded by the Japanese Association for Acute Medicine. Conflicts of interest: Dr. Fujishima reports grants and personal fees from Asahi Kasei Japan Co., personal fees from Thermofisher Diagnostics Co., grants from Chugai Pharmaceuticals Co. Ltd., grants from Daiichi-Sankyo Co., Ltd., grants from Pfizer, Inc., grants from Shionogi & Co., Ltd., outside the submitted work; Dr. Gando reports personal fees from Asahi Kasei America Cooperation, personal fees from Asahi Kasei Japan Cooperation, outside the submitted work; Dr. Abe reports grants from Grant-in-Aid for Challenging Exploratory Research JP 16K15388, personal fees from Asahi Kasei Pharma Co., personal fees from Japan Blood Products Organization, personal fees from Janssen Pharmaceutical K.K., outside the submitted work; Dr. Shiraishi reports personal fees from Nobelpharma Co., outside the submitted work; Dr. Okamoto reports personal fees from Asahi Kasei Japan Corporation, outside the submitted work; Dr. Sakamoto reports personal fees from Japan Blood Product Corporation, personal fees from Asahi Kasei Japan Corporation, outside the submitted work; Dr. Umemura reports personal fees from Asahi Kasei Pharma Corporation, personal fees from Japan blood products organization, outside the submitted work. The remaining authors have disclosed that they do not have any conflicts of interest. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2019 by the Shock Society

Military Supplement: Reassessment of The Need for An Oxygen Carrier For The Treatment of Traumatic Hemorrhage When Blood is Not An Option Approximately 10 years ago, the development of hemoglobin-based oxygen carriers (HBOC) was largely stalled after two large phase 3 clinical trials failed to achieve licensure primarily because the safety profile was viewed as unsatisfactory when HBOCs were compared to red cells. Concerns were also raised that HBOCs, as a class, had inherent toxicities. Since then, clinical experience with HBOC in expanded access programs and under licensure in South Africa have demonstrated that HBOCs can be used safely and effectively. In recent years, clinical studies have demonstrated that pre-hospital blood transfusion improves survival in severely injured patients with hemorrhage, especially when transport times are longer than 20 to 30 minutes. Yet, logistical constraints still limit use of blood products in the prehospital setting. As the urgent need for oxygen carrying capacity for trauma patients for whom red cells are not available is becoming much more apparent, it is imperative that we re-examine the possibility of using HBOCs when RBC transfusion is not an option. Address reprint requests to Anthony E. Pusateri, PhD, Director of Research and Chief Science Officer, U.S. Army Institute of Surgical Research, Ft. Sam Houston, Texas 78234. E-mail: anthony.e.pusateri.civ@mail.mil Received 24 May, 2019 Revised 12 June, 2019 Accepted 12 July, 2019 Conflicts of interest: A.E. Pusateri: none; E. Glassberg: none; R. B. Weiskopf: consults for HbO2 Therapeutics Disclaimers: A.E. Pusateri: The opinions or assertions of the author are his own and do not represent the official position of the US Army or the US Department of Defense. E. Glassberg: None; R.B. Weiskopf: None © 2019 by the Shock Society

Lactic Acidosis and The Role of Sodium Bicarbonate: A Narrative Opinion Lactic acidosis occurs commonly and can be a marker of significant physiologic derangements. However what an elevated lactate level and acidemia connotes and what should be done about it is subject to inconsistent interpretations. This review examines the varied etiologies of lactic acidosis, the physiologic consequences, and the known effects of its treatment with sodium bicarbonate. Lactic acidosis is often assumed to be a marker of hypoperfusion, but it can also result from medications, organ dysfunction, and sepsis even in the absence of malperfusion. Acidemia causes deleterious effects in almost every organ system but it can also have positive effects, increasing localized blood flow and oxygen delivery, as well as providing protection against hypoxic cellular injury. The use of sodium bicarbonate to correct severe acidemia may be tempting to clinicians, but previous studies have failed to show improved patient outcomes following bicarbonate administration. Bicarbonate use is known to decrease vasomotor tone, decrease myocardial contractility, and induce intracellular acidosis. This suggests that mild to moderate acidemia does not require correction. Most recently, a randomized control trial found a survival benefit in a subgroup of critically ill patients with serum pH levels <7.2 with concomitant acute kidney injury. There is no known benefit of correcting serum pH levels ≥ 7.2, and sparse evidence supports bicarbonate use <7.2. If administered, bicarbonate is best given as a slow IV infusion in the setting of adequate ventilation and calcium replacement to mitigate its untoward effects. Address reprint requests to Mona R. Rudnick, 234 Los Gatos Blvd., Los Gatos, CA 95030. E-mail: Mlr47@georgetown.edu Received 15 April, 2019 Revised 6 May, 2019 Accepted 10 July, 2019 Conflicts of Interest: The authors have no relevant conflicts of interest to report. © 2019 by the Shock Society

Endothelin A and B Receptors: Potential Targets for Microcirculatory-Mitochondrial Therapy in Experimental Sepsis The hypoxia-sensitive endothelin (ET) system plays an important role in circulatory regulation through vasoconstrictor ETA and ETB2 and vasodilator ETB1 receptors. Sepsis progression is associated with microcirculatory and mitochondrial disturbances along with tissue hypoxia. Our aim was to investigate the consequences of treatments with the ETA receptor (ETA-R) antagonist, ETB1 receptor (ETB1-R) agonist, or their combination on oxygen dynamics, mesenteric microcirculation and mitochondrial respiration in a rodent model of sepsis. Sprague Dawley rats were subjected to fecal peritonitis (0.6 g kg−1 ip) or a sham operation. Septic animals were treated with saline or the ETA-R antagonist ETR-p1/fl peptide (100 nmol kg−1 iv), the ETB1-R agonist IRL-1620 (0.55 nmol kg−1 iv), or a combination therapy 22 h after induction. Invasive hemodynamic monitoring and blood gas analysis were performed during a 90-min observation, plasma ET-1 levels were determined, and intestinal capillary perfusion (CPR) was detected by intravital videomicroscopy. Mitochondrial Complex I (CI)- and CII-linked oxidative phosphorylation (OXPHOS) was evaluated by high-resolution respirometry in liver biopsies. Septic animals were hypotensive with elevated plasma ET-1. The ileal CPR, oxygen extraction (ExO2), and CI–CII-linked OXPHOS capacities decreased. ETR-p1/fl treatment increased ExO2 (by >45%), CPR, and CII-linked OXPHOS capacity. The administration of IRL-1620 countervailed the sepsis-induced hypotension (by >30%), normalized ExO2, and increased CPR. The combined ETA-R antagonist–ETB1-R agonist therapy reduced the plasma ET-1 level, significantly improved the intestinal microcirculation (by >41%), and reversed mitochondrial dysfunction. The additive effects of a combined ETA-R–ETB1-R-targeted therapy may offer a tool for a novel microcirculatory and mitochondrial resuscitation strategy in experimental sepsis. Address reprint requests to József Kaszaki, PhD, Institute of Surgical Research, University of Szeged, H-6724 Szeged, Pulz u. 1., Hungary. E-mail: kaszaki.jozsef@med.u-szeged.hu Received 28 April, 2019 Revised 20 May, 2019 Accepted 10 July, 2019 Attila Rutai and Roland Fejes contributed equally to this article. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). Conflict of interest: none declared © 2019 by the Shock Society

sEH Inhibitor TPPU Ameliorates Cecal Ligation and Puncture-Induced Sepsis by Regulating Macrophage Functions Background: Sepsis is a life-threatening organ dysfunction initiated by a dysregulated response to infection, with imbalanced inflammation and immune homeostasis. Macrophages play a pivotal role in sepsis. N-[1-(1-oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy)phenyl)-urea (TPPU) is an inhibitor of soluble epoxide hydrolase (sEH), which can rapidly hydrolyze epoxyeicosatrienoic acids (EETs) to the bio-inactive dihydroxyeicosatrienoic acids (DHETs). TPPU was linked with the regulation of macrophages and inflammation. Here, we hypothesized that sEH inhibitor TPPU ameliorates cecal ligation and puncture (CLP)-induced sepsis by regulating macrophage functions. Methods: A polymicrobial sepsis model induced by CLP was used in our study. C57BL/6 mice were divided into four groups: (1) sham+PBS, (2) sham+TPPU, (3) CLP+PBS, (4) CLP+TPPU. Mice were observed 48 hours after surgery to assess the survival rate. For other histological examinations, mice were sacrificed 6 hours after surgery. Macrophage cell line RAW264.7 was used for in vitro studies. Results: TPPU treatment, accompanied with increased EETs levels, markedly improved the survival of septic mice induced by CLP surgery, which was associated with alleviated organ damage and dysfunction triggered by systemic inflammatory response. Moreover, TPPU treatment significantly inhibited systemic inflammatory response via EETs-induced inactivation of MAPK signaling due to enhanced macrophage phagocytic ability and subsequently reduced bacterial proliferation and dissemination, and decreased inflammatory factors release. Conclusions: sEH inhibitor TPPU ameliorates cecal ligation and puncture-induced sepsis by regulating macrophage functions, including improved phagocytosis and reduced inflammatory response. Our data indicate that sEH inhibition has potential therapeutic effects on polymicrobial-induced sepsis. Address reprint requests to Dr. Xizhen Xu, MD, PhD or Dr. Ling Tu, MD, PhD, Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. E-mail: xzxu@tjh.tjmu.edu.cn or lingtu@tjh.tjmu.edu.cn Received 5 April, 2019 Revised 29 April, 2019 Accepted 5 July, 2019 This work was partially supported by the funding from National Natural Science Foundation of China (NO. 81471021) and Hu Bei Health and Family Planning Commission (WJ2015MB006). Conflicts of Interest and Source of Funding: The authors declare they have no conflicts of interest. © 2019 by the Shock Society

Right ventricular function and long-term outcome in sepsis: a retrospective cohort study Background: Sepsis-related myocardial dysfunction is associated with impaired outcome. Traditionally, in this setting the main focus has been on left ventricular performance. Currently, specific knowledge on the prognostic importance of right ventricular dysfunction is scarce. The aim of this study was to determine whether right ventricular ejection fraction (RVEF) is predictive of long-term mortality in sepsis. Methods: Single-centre retrospective cohort study in adult patients admitted to the ICU with severe sepsis and septic shock, and equipped with a pulmonary artery catheter within the first day following admission. RVEF was recorded as an average over the first 24 hours (sample rate of 1 per minute). Patients were separated a priori into subgroups according to their RVEF: RVEF < 20% (A), RVEF 20–30% (B), and RVEF>30% (C). The primary endpoint was one-year all-cause mortality. Results: In a 7-year period, 101 patients fulfilled all entry criteria and 98 were included in the study. One-year all-cause mortality was significantly different between groups: 57% in group A (n = 21), 18% in group B (n = 55), and 23% in group C (n = 22); p = 0.003. Kaplan-Meier survival analysis revealed a clear separation between group A and B/C (X2 = 14.00, p = 0.001). In a multivariate logistic regression analysis RVEF, both as a categorical variable (RVEF < 20%) and as a continuous variable, remained independently associated with the primary endpoint (OR 4.1; 95% CI 1.3–13.4; p = 0.018 and OR 0.92; 95% CI 0.85–0.99; p = 0.018 respectively). Conclusion: RVEF was independently associated with one-year all-cause mortality in a highly selected group of patients with severe sepsis and septic shock. Address reprint requests to Jurgen C. Winkelhorst, Department of Intensive Care, Medical Centre Leeuwarden, Henri Dunantweg 2, P.O. Box 888, 8901 BR Leeuwarden, The Netherlands. E-mail: jurgenwinkelhorst@gmail.com Received 8 May, 2019 Revised 10 July, 2019 Accepted 10 July, 2019 Funding: Not applicable. Conflict of interest: The authors have no conflicts of interest. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2019 by the Shock Society

An Aging-Related Single-Nucleotide Polymorphism is Associated with Altered Clinical Outcomes and Distinct Inflammatory Profiles in Aged Blunt Trauma Patients The contribution of individual genetic determinants of aging to the adverse clinical outcomes and altered inflammation mediator networks characteristic of aged trauma patients is unknown. The AA genotype of the aging-related single-nucleotide polymorphism (SNP) rs2075650 in TOMM40 has been associated with longevity, while the AG and GG genotypes are associated with an increased risk of Alzheimer's disease. Here, we studied the effect of rs2075650 on clinical outcomes and dynamic biomarker patterns after traumatic injury. Genomic DNA was obtained from blunt trauma patients admitted to the ICU and examined for 551,839 SNPs using an Illumina microarray kit. Plasma was sampled from each patient three times within the first 24 hours and daily from day 1 to 7 then assayed for 31 biomarkers using Luminex. Aged patients (65–90 years) were segregated into AA (n = 77) and AG/GG (n = 17) genotypes. Additional comparisons were made with matched groups of young patients (18–30 years), controlling for injury severity score (ISS) and sex ratio, and also segregated into AA (n = 56) and AG/GG (n = 19) genotypes. Aged patients with the AA genotype had a significantly lower requirement for ventilation and fewer days on mechanical ventilation, as well as significantly higher levels of one mediator and lower levels of two mediators. Dynamic Bayesian Network inference revealed IL-23 as a central node in each network regardless of age or genotype, with MIG and IP-10 also as key mediators in the networks of the aged patients. These findings suggest that an aging-related SNP, rs2075650, may influence clinical outcomes and inflammation networks in aged patients following blunt trauma, and thus may serve as a predictive outcome biomarker in the setting of polytrauma. Address reprint requests to Yoram Vodovotz, MD, Department of Surgery, University of Pittsburgh, W944 Starzl Biomedical Sciences Tower, 200 Lothrop St., Pittsburgh, PA 15213. E-mail: vodovotzy@upmc.edu; Ashley Lamparello, MD, University of Pittsburgh, Pittsburgh, PA UNITED STATES. E-mail: lamparelloa@upmc.edu Received 10 May, 2019 Revised 10 June, 2019 Accepted 10 July, 2019 This work was supported by National Institutes of Health grant P50-GM-53789. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). The authors report no conflicts of interest. © 2019 by the Shock Society

Cardiac Glucose and Fatty Acid Transport After Experimental Mono- and Polytrauma Objective: The aim of this study was to define the influence of trauma on cardiac glucose and fatty acid transport. The effects were investigated in vivo in a porcine mono- and polytrauma model and in vitro in human cardiomyocytes, which were treated simultaneously with different inflammatory substances, mimicking post-traumatic inflammatory conditions. Methods and Results: In the porcine fracture- and polytrauma model, blood glucose concentrations were measured by blood gas analysis during an observation period of 72 h. The expression of cardiac glucose and fatty acid transporters in the left ventricle was determined by RT-qPCR and immunofluorescence. Cardiac and hepatic glycogen storage was examined. Furthermore, human cardiomyocytes were exposed to a defined trauma-cocktail and the expression levels of glucose- and fatty acid transporters were determined. Early after polytrauma, hyperglycaemia was observed. After 48 h and 72 h, pigs with fracture- and polytrauma developed hypoglycaemia. The propofol demand significantly increased post trauma. The hepatic glycogen concentration was reduced 72 h after trauma. Cardiac glucose and fatty acid transporters changed in both trauma models in vivo as well as in vitro in human cardiomyocytes in presence of proinflammatory mediators. Conclusions: Monotrauma as well as polytrauma changed the cardiac energy transport by altering the expression of glucose and fatty acid transporters. In vitro data suggest that human cardiomyocytes shift to a state alike myocardial hibernation preferring glucose as primary energy source in order to maintain cardiac function. Address reprint requests to Miriam Kalbitz, MD, University of Ulm Medical School, Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, Center of Surgery, Albert-Einstein-Allee 23, 89081 Ulm, Germany. E-mail: miriam.kalbitz@uniklinik-ulm.de Received 18 April, 2019 Revised 6 May, 2019 Accepted 24 June, 2019 Ina Lackner and Birte Weber these authors are equally contributed first authors. Authors’ contributions: Regarding contributions of the authors I.L., B.W. and D.K performed the experiments including animal studies, cell culture experiments, microscopic studies and ELISAs. I.L. primarily wrote the paper K.H., B.R., F.G., H.C.P., M.H.L, F.H. and M.K. contributed to experimental design and data analysis and coordinated the study and supervised financial support for the studies. All authors made substantial contributions to conception and design of the study and participated in drafting the article. All authors gave final approval of the version to be published. Conflicts of Interest and Source of Funding: This work was conducted in the framework of the CRC 1149 funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project number 251293561. This work was also supported by the AO Foundation project number S-14–14P. For the authors none conflicts of interest were declared. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.shockjournal.com). © 2019 by the Shock Society