Shock

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

LncRNA-Ang362 Promotes Pulmonary Arterial Hypertension by Regulating miR-221 and miR-222 Background: Pulmonary arterial hypertension is a life-threatening cardiopulmonary disorder. LncRNA-Ang362 (lnc-Ang362) regulates miR-221 and miR-222 in vascular smooth muscle cell proliferation, which can lead to pulmonary arterial hypertension. The present study was design to investigate the function and underlying mechanisms of lnc-Ang362 in pulmonary arterial hypertension (PAH). Methods: The expression of lnc-Ang362, miR-221 and miR-222 in 15 PAH patients and 10 healthy controls were measured by qRT-PCR. Lnc-Ang362 overexpression vector and siRNA were transfected into human pulmonary arterial smooth muscle cells (HPASMCs), and cell proliferation, migration, apoptosis rate were assessed. The protein expression of p-p65 and p-IκBα were measured by western blot. MiR-221 or miR-222 inhibitor were co-transfected with lnc-Ang362 overexpression vector into HPASMCs. Results: Data from the present study showed significantly increased lnc-Ang362, miR-221, and miR-222 expression in the lung tissues of patients with pulmonary arterial hypertension and in hypoxic human pulmonary arterial smooth muscle cells. Whereas overexpression of lnc-Ang362 promoted proliferation and migration of human pulmonary arterial smooth muscle cells, inhibition of lnc-Ang362 had the opposite effect. Additionally, apoptosis of human pulmonary arterial smooth muscle cells significantly decreased after lnc-Ang362 overexpression and increased after lnc-Ang362 inhibition. Meanwhile, lnc-Ang362 upregulated miR-221 and miR-222 expression and activated the NFκB signaling pathway in human pulmonary arterial smooth muscle cells. Moreover, miR-221 and the miR-222 inhibitor both attenuated the proliferation and migration effects of lnc-Ang362 and elevated apoptosis in these cells. Conclusion: Lnc-Ang362 played an important role in regulating the biological function of human pulmonary arterial smooth muscle cells by promoting miR-221 and miR-222. Lnc-Ang362 thus may be a novel therapeutic lncRNA candidate for treating pulmonary arterial hypertension. Address reprint requests to Ruiling Qin, Department of respiratory and critical care medicine, The Second Affiliated Hospital of Zhengzhou, No.2 Jingba Road, Zhengzhou 450003, Henan, China. E-mail: ruilg_qin@163.com Received 12 April, 2019 Revised 6 May, 2019 Accepted 9 July, 2019 Conflicts of interest: The authors declare that they have no conflict of interest. © 2019 by the Shock Society

Blockade of PD-1 Attenuated Post-Sepsis Aspergillosis via The Activation Of IFN-γ and The Dampening of IL-10 Background: Nosocomial aspergillosis in patients with sepsis have emerged in the past few years. Blockade of PD-1/PD-L pathway has tended to become a promising therapeutic strategy as it improved the outcome of bacterial sepsis and post-sepsis secondary fungal infection. Recently, the controversial effects of PD-1 blockade on infectious diseases, including aspergillosis, have been demonstrated, therefore, the efficacy of anti-PD-1 drug still remains to be elucidated. Methods: Cecal ligation and puncture (CLP) was conducted as a mouse sepsis model. Aspergillus fumigatus spores were intravenously inoculated on day 5 post-CLP, when the immune cells succumbed to exhaustion. Amphotericin B was medicated together with or without anti-PD-1 treatment after Aspergillus infection. Results: Amphotericin B alone was not effective to treat the CLP-mice with secondary aspergillosis. In contrast, anti-fungal medication with the adjunctive anti-PD-1 treatment attenuated the fungal burdens in blood and internal organs, and improved the survival rate of the mice with secondary aspergillosis. These outcomes of PD-1 blockade were concurring with the enhanced CD86 expression on splenocytes, the augmented serum IFN-γ and the dampened IL-10. Activated T cells from anti-PD-1 treated mice also highly increased IFN-γ and diminished IL-10 production. Conclusion: The blockade of PD-1 on post-sepsis aspergillosis presumably reinvigorated exhausted antigen-presenting cells and T cells by upregulating CD86 expression and IFN-γ production, and dampened IL-10 production, which consequently leaded to the attenuation of secondary aspergillosis. The adjunctive anti-PD-1 therapy may become a promising strategy for the advanced immunotherapy against lethal fungal infection. Address reprint requests to Asada Leelahavanichkul, MD, PhD, Assistant Professor., Immunology Unit, Department of Microbiology, Faculty of Medicine Chulalongkorn University, Bangkok 10330, Thailand. E-mail: aleelahavanit@gmail.com; Patcharee Ritprajak, DDS, PhD, Assistant Professor, Department of Microbiology, Faculty of Dentistry, Chulalongkorn University, Pathumwan, Bangkok 10330, Thailand. E-mail: Patcharee.R@chula.ac.th. Received 5 April, 2019 Revised 24 April, 2019 Accepted 29 May, 2019 Funding: This project was supported by Thailand Government Fund (RSA-6080023), Thailand Research Fund (RES_61_202_30_022), Ratchadaphiseksomphot Endowment Fund 2017 (76001-HR) and the Chulalongkorn Academic Advancement into Its 2nd Century Project. Chau Tran Bao Vu was supported by The 100th Anniversary Chulalongkorn University Fund for Doctoral Scholarship. Conflict of interest: All authors have none to declare. © 2019 by the Shock Society

Influence of Hyperglycemia During Different Phases of Ischemic Preconditioning on Cardioprotection—A Focus On Apoptosis and Aggregation of Granulocytes Background: Ischemic preconditioning (IPC) protects the myocardium against ischemia/reperfusion injury. Evidence suggests that hyperglycemia inhibits IPC-induced cardioprotection. The effects of hyperglycemia initiated during different phases of IPC on myocardial injury were characterized with emphasis on apoptosis and aggregation of polymorphonuclear granulocytes (PMN). Methods: Male Wistar rats were subjected to 35 min of myocardial ischemia and 2 h of reperfusion. Control animals were not further treated. IPC was induced by three cycles of 3 min ischemia and 5 min of reperfusion before major ischemia. Hyperglycemia (blood glucose more than 22.2 mmol/L) was induced by glucose administration with or without IPC during different phases (trigger- (before ischemia), mediator-(during ischemia), early reperfusion-phase). One additional group received an anti-PMN-antibody before ischemia. Infarct size was quantified by triphenyltetrazolium chloride staining. Cytochrome C release and B-cell lymphoma two (Bcl-2) expression were assessed by western blot analysis. Poly-ADP-Ribose staining and PMN accumulation were quantified with immunohistochemistry and histochemistry. Results: IPC reduced infarct size compared with control. Hyperglycemia completely abolished IPC-induced cardioprotection independent of the time point of initiation. Hyperglycemia before and during major ischemia but without IPC also slightly reduced infarct size. IPC reduced the accumulation of PMNs. This effect was reversed by hyperglycemia during trigger- and mediator-phase but not by hyperglycemia during reperfusion. Hyperglycemia alone had no effect on PMN accumulation. In all treatment groups, signs of myocardial apoptosis were reduced compared with control. IPC alone, combined with hyperglycemia and anti-PMN treatment, reduced apoptosis by a Bcl-2-associated mechanism. Hyperglycemia alone reduced apoptosis by a Bcl-2-independent pathway. Conclusion: Hyperglycemia inhibits IPC-induced cardioprotection independent of its onset. Furthermore, hyperglycemia prevents apoptosis and IPC-induced reduction of PMN aggregation. Address reprint requests to Ragnar Huhn, MD, PhD, Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. E-mail: Ragnar.Huhn@med.uni-duesseldorf.de Received 16 May, 2019 Revised 11 June, 2019 Accepted 3 July, 2019 In partial fulfillment of the requirements for a MD thesis of JZ. The study was supported by the Research Commission of the Medical Faculty of the Heinrich-Heine-University Duesseldorf, Germany, and by the Else Kröner-Fresenius-Foundation, Bad Homburg, Germany. The authors report no conflicts of interest. © 2019 by the Shock Society

The Prognostic Usefulness of The Lactate/Albumin Ratio For Predicting Clinical Outcomes In Out-Of-Hospital Cardiac Arrest: A Prospective, Multicentre Observational Study (KoCARC Study) Background and Purpose: We aimed to evaluate the lactate/albumin ratio (LAR) to identify its significance as a prognostic marker for favourable neurologic outcome and survival in patients with return of spontaneous circulation after out-of-hospital cardiac arrest (OHCA). Based on the LAR and multiple parameters, we developed new nomograms and externally validated the tools. Methods: We conducted an observational study using a prospective, multicentre registry of out-of-cardiac arrest resuscitation provided by the Korean Cardiac Arrest Research Consortium registry from October 2015 to June 2017. Results: A total of 524 patients were included in this study. An increased LAR was significantly associated with decreased favourable neurologic outcomes (odds ratio [OR] 0.787; 95% confidence interval [CI] 0.630–0.983; P = 0.035) and survival at discharge (OR 0.744; 95% CI 0.638–0.867; P < 0.001). The areas under the curve (AUCs) for predicting neurologic outcome and survival to discharge using the LAR were 0.824 (P < 0.001) and 0.781 (P < 0.001), respectively. A LAR value of more than the optimal cut-off values of 2.82 and 3.62 could significantly improve prediction of decreased favourable neurologic outcome and survival to discharge, respectively. We constructed nomograms based on the multivariate logistic model. The model for predicting favourable neurologic outcomes and survival discharge had AUCs of 0.927 (P < 0.001) and 0.872 (P < 0.001), respectively. Conclusion: The prognostic performance of the LAR was superior to a single measurement of lactate for predicting favourable neurologic outcomes and survival to discharge after OHCA. The newly developed nomograms can provide rapid prediction of probability of clinical outcomes. Address reprint requests to Je Sung You, MD, PhD, Department of Emergency Medicine, Yonsei University College of Medicine, 211 Eonju-Ro, Gangnam-Gu, Seoul 06273, Republic of Korea. E-mail: youjsmd@yuhs.ac Received 13 May, 2019 Revised 28 June, 2019 Accepted 28 June, 2019 Declaration of interest: The authors declare no conflicts of interest. Source of funding: J.S.Y. was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2018R1C1B6006159). S.P.C. and T.K. were supported by a Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT, and Future Planning (NRF-2017R1A2B4012378). The funding bodies had no role in the design, collection, analysis, or interpretation of this study. J.S.Y. is an investigator on unrelated studies sponsored by Siemens Health Care, which provide research funding to the Yonsei University College of Medicine, Gangnam Severance Hospital. None of the other authors have potential financial conflicts of interest to disclose. Author Contributions: TK, SPC, and JSY conceived and planned the study. They were mainly responsible for the design of the study. TK, YSP, SDS, KCC, SOH, and SPC collected the data. TK, SK, HSL, and JSY were mainly responsible for analysing the data. TK and JSY wrote the first draft of the manuscript. All authors contributed to the interpretation of finding and reviewed the manuscript. All authors reviewed the statistical analyses and made changes to the content of the manuscript. All authors have also provided intellectual contribution to the manuscript. 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