Peptidylarginine Deiminase 2 Knockout Improves Survival in Hemorrhagic Shock Background: The peptidylarginine deiminase (PAD) family converts arginine into citrulline through protein citrullination. PAD2 and PAD4 inhibitors can improve survival in hemorrhagic shock (HS). However, the impact of isoform specific PAD inhibition in improving survival has not been studied. In this study, we utilize selective Pad2−/− knockout (KO) mice to elucidate loss of function of PAD2 leads to pro-survival effect in HS. Methods: HS: Pad2−/− and wild type (WT) mice (n = 5/group) were subjected to lethal HS (55% volume hemorrhage). Survival was monitored over seven days. Myocardial infarction (MI): Pad2−/− and WT mice (n = 9/group) were subjected to MI by permanent LAD ligation to examine the effect of ischemia on the heart. After 24 hours cardiac function and infarct size were measured. Results: HS: Pad2−/− mice demonstrated 100% survival compared to 0% for WT mice (p = 0.002). In a sub-lethal HS model, cardiac β-catenin levels were higher in Pad2−/− compared to WT after 24 hours. MI: WT mice demonstrated larger MI (75%) compared to Pad2−/− (60%) (p < 0.05). Pad2−/− had significantly higher ejection fraction and fractional shortening compared to WT (p < 0.05). Conclusions: Pad2−/− improves survival in lethal HS. Possible mechanisms by which loss of PAD2 function improve survival include the activation of cell survival pathways, improved tolerance of cardiac ischemia and improved cardiac function during ischemia. PAD2 is promising as a future therapeutic target for the treatment of HS and cardiac ischemia. Address reprint requests to Hasan B. Alam, MD, Norman Thompson Professor of Surgery, Head of General Surgery, University of Michigan, 2920 Taubman Center/5331, 1500 E Medical Center Dr, Ann Arbor, MI 48109-5331. E-mail: alamh@med.umich.edu Received 6 September, 2019 Revised 20 September, 2019 Accepted 15 November, 2019 Jing Zhou and Ben E. Biesterveld: Denotes authors contributed equally as co-first authors Disclosure of Funding: This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01GM084127 awarded to Dr. Alam and UMHS-PUHSC Joint Institute U050150 awarded to Dr. Alam. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. © 2019 by the Shock Society

Impaired B-Cell Maturation Contributes to Reduced B Cell Numbers and Poor Prognosis in Sepsis Background: Reduced B cell numbers plays a critical role in sepsis immunosuppression. The role of B-cell maturation regulated by T follicular helper (Tfh) cells in reduced B cell numbers during sepsis remains unclear. We tested the hypothesis that impaired B-cell maturation contributes to reduced B cell numbers. Design: Retrospective study and observational prospective cohort study. Settings: Critical care units. Methods: To identify the exact lymphocyte counts that affect the prognosis of sepsis, we firstly conducted a retrospective study. Then in the prospective cohort study, differences in B-cell maturation, B cell death and numbers of circulating Tfh (cTfh) cell were compared between 28-day survivors and 28-day non-survivors, mainly by flow cytometry and enzyme-linked immunosorbent assay. Main Results: In retrospective study (n = 123), we found patients with lymphocyte counts less than 0.4 × 109 cells/L had higher mortality than patients with lymphocyte counts above 0.4 × 109 cells/L. In observational prospective cohort study (n = 40), compared to survivors, non-survivors had fewer numbers of mature B cell and circulating Tfh (cTfh) cell (sepsis onset: memory B cells: 3.44% vs. 4.48%, antibody-secreting cells: 4.53% vs. 6.30%, cTfh cells: 3.57% vs. 4.49%; 24 h after sepsis onset: memory B cells: 4.05% vs. 7.20%, antibody-secreting cells: 5.25% vs. 8.78%, cTfh cells: 3.98% vs. 6.15%), while there were no differences in cell death of mature B cells between them. We further noticed the numbers of cTfh cell positively correlated with the numbers of mature B cell and immunoglobulin concentrations. Conclusions: Impaired B-cell maturation contributes to reduced B cell numbers, while the numbers of cTfh cell, acting as a warning indicator for sepsis prognosis, may be a new therapeutic target for treating sepsis. Address reprint requests to Weifeng Yu, PhD, Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 PuJian Road, Shanghai 200127, China. E-mail: ywf808@yeah.net; Zhenzhou He, Department of Anesthesiology and ICU, South Campus, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 2000 Jiang Yue Road, Shanghai 201114, China. E-mail: sandyhzz@126.com Received 17 September, 2019 Revised 3 October, 2019 Accepted 28 October, 2019 Shaoxia Duan, Yingfu Jiao and Jiemin Wang Contributed equally to this work. Declarations Ethical approval and consent to participate: Ethics committee approval was obtained prior to the start of recruitment (prospective clinical study and animal experiments: 2017–220; retrospective clinical study: 2018–118, Shanghai Jiaotong University School of Medicine, Renji Hospital Ethics Committee). Informed consent was obtained from patients or their legal designees if the patient was unconscious. Consent for publication: Not applicable. Availability of data and materials: Data are available on request. Conflicts of interest: The authors declare that they have no conflicts of interest. Funding: This research was supported by National Natural Science Foundation of China: 81801934, 81571048 and Shanghai Minhang Health and Family Planning Commission: 2017MW24. Authors’ contributions: Shaoxia Duan conceived the idea, did animal experiments and drafted the manuscript. Yingfu Jiao performed data analysis and edited manuscript. Jiemin Wang, as a clinical data manager, collected clinical data and samples. Dan Tang helped with flow cytometry. Saihong Xu and Ruoxi Wang helped data management and analysis. Tao Jiang and Jianlin Shao helped interpret the results and table preparation. Weifeng Yu and Zhenzhou He are the guarantor of the article, taking responsibility for the integrity of the work as a whole, from inception to published article. All authors read and approved the final 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

Dynamic Autoregulation is Impaired in Circulatory Shock Background: Circulatory shock is a life-threatening disorder that is associated with high mortality, with a state of systemic and tissue hypoperfusion that can lead to organ failure, including the brain, where altered mental state is often observed. We hypothesized that cerebral autoregulation (CA) is impaired in patients with circulatory shock. Methods: Adult patients with circulatory shock and healthy controls were included. Cerebral blood flow velocity (CBFV, transcranial Doppler ultrasound) and arterial blood pressure (BP, Finometer or intra-arterial line) were continuously recorded during 5-minutes in both groups. Autoregulation Index (ARI) was estimated from the CBFV response to a step change in BP, derived by transfer function analysis; ARI ≤ 4 was considered as impaired CA. The relationship between organ dysfunction, assessed with the Sequential Organ Failure Assessment (SOFA) score and the ARI was assessed with linear regression. Results: Twenty-five shock patients and 28 age-matched healthy volunteers were studied. The mean ± SD SOFA score was 10.8 ± 4.3. Shock patients compared to control subjects had lower ARI values (4.0 ± 2.1 vs. 5.9 ± 1.5, p = 0.001). Impaired CA was more common in shock patients (44.4% vs. 7.1%, p = 0.003). There was a significant inverse relationship between the ARI and the SOFA score (R = −0.63, p = 0.0008). Conclusions: These results suggest that circulatory shock is often associated with impaired CA and that the severity of CA alterations are correlated with the degree of multiple organ failure, reinforcing the need to monitor cerebral hemodynamics in patients with circulatory shock. Address reprint requests to Juliana R. Caldas, Critical Care Unit, Hospital São Rafael, Salvador, Brazil; E-mail: caldas.juliana@gmail.com Received 20 September, 2019 Revised 14 October, 2019 Accepted 11 November, 2019 The authors report 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

The Consequences of Aging on the Response to Injury and Critical Illness Changing demographic trends have led to an increase in the overall geriatric trauma patient volume. Furthermore, the intersection of aging and injury can be problematic because geriatric patients have multiple comorbidities, geriatric-specific syndromes, and reduced physiological reserve. Despite mounting evidence that frail geriatric patients have inferior outcomes following trauma, very few studies have examined the effect of aging on the biological response to injury. In the present article, we review the current literature and explore the pathophysiological rationale underlying observed data, available evidence, and future directions on this topic. Address reprint requests to Bellal Joseph, MD, University of Arizona, Department of Surgery, Division of Trauma, Critical Care, Burn and Emergency Surgery, 1501 N. Campbell Ave, Room.5411, P.O. Box 245063, Tucson, AZ 85727. E-mail: bjoseph@surgery.arizona.edu Received 31 August, 2019 Revised 17 September, 2019 Accepted 18 November, 2019 There are no identifiable conflicts of interests to report. This study did not have financial support. The authors have no financial or proprietary interest in the subject matter or materials discussed in the manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors © 2019 by the Shock Society

Neutrophil Elastase Inhibition Ameliorates Endotoxin-Induced Myocardial Injury Accompanying Degradation of Cardiac Capillary Glycocalyx Myocardial injury in sepsis may be caused by a burst of several inflammatory mediators, leading to vascular endothelial injuries. However, the contribution of neutrophil elastase (NE) to myocardial injury in sepsis is still unknown. We aimed to evaluate whether endotoxaemia-induced myocardial injury is associated with NE. Lipopolysaccharide (LPS) was injected intraperitoneally at a dose of 20 mg/kg into granulocyte-colony-stimulating-factor knockout mice (G-CSF-KO), which have few neutrophils, and littermate control mice. The survival rate of G-CSF-KO mice 48 h after LPS injection was significantly greater than that of control mice. The serum level of troponin I in G-CSF-KO mice was significantly lower than that in control mice. In addition, the concentration of inflammatory cytokine interleukin-6 (IL-6) was significantly decreased 6 and 12 h after LPS administration compared with that in control mice. Ultrastructural analysis revealed that vascular endothelial structures and the endothelial glycocalyx in G-CSF-KO mice were clearly preserved. Next, mice were injected with 0.2 mg/kg sivelestat (an NE inhibitor) after LPS administration. The survival rate was significantly higher and the serum level of troponin I was lower in sivelestat-injected mice than in control mice, respectively. Furthermore, IL-6 levels were significantly decreased 6 and 12 h after LPS administration compared with those in control mice. Vascular endothelial structures and the endothelial glycocalyx in sivelestat-treated mice were clearly preserved at the ultrastructural level. In conclusion, NE is significantly associated with myocardial injury in endotoxaemia. Inhibition of NE may be a useful tool for the management of endotoxaemia. (245 words; 250 word limit) Address reprint requests to Hideshi Okada, MD, PhD, Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. E-mail: hideshi@gifu-u.ac.jp Received 22 August, 2019 Revised 14 September, 2019 Accepted 1 November, 2019 Tetsuya Fukuta and Hideshi Okada: These authors contributed equally to this article. Conflicts of Interest and Source of Funding: The authors declare that they have no competing interests. This work was supported in part by grants-in-aid for scientific research [19H03756, 19K18347, 19K08499, 19K09410, 18K16511, 18K08914, 18K08884, 17K11569, 16H05497, 16K09509, 16K20381, and 15K10973] from the Ministry of Education, Science and Culture of Japan. 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). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 © 2019 by the Shock Society

Tenascin C Plasma Levels in Critically Ill Patients with or Without Sepsis: A Multicentre Observational Study Tenascin C (TNC) is an extracellular matrix protein able to modulate the immune response. Knowledge regarding its role during sepsis and general critical illness is still limited. We here assessed the temporal dynamics of plasma TNC during sepsis and non-septic critical illness, its capacity to predict patient outcome, and its specificity towards infection. TNC plasma concentrations were measured in 895 consecutive sepsis patients on ICU-admission, day 2 and 4 thereafter, and, in a subset, before ICU-discharge. To assess TNC diagnostic value, we compared patients with abdominal sepsis (n = 143) to non-infectious abdominal surgery controls (n = 98), and patients with severe community-acquired pneumonia (CAP, n = 227) to patients whose CAP diagnosis was retrospectively refuted (no-CAP controls, n = 70). Plasma TNC levels were persistently elevated in sepsis patients compared to healthy volunteers throughout the ICU stay. TNC levels varied by site of infection and increased with the number of organs failing. Association of TNC levels with 30-day mortality could be wholly attributed to differences in disease severity. Non-infectious ICU patients also showed elevated TNC levels, albeit with different temporal dynamics. Although admission TNC was higher in CAP than in no-CAP patients, it performed poorly in distinguishing the two groups. TNC plasma levels are persistently elevated during sepsis and non-septic critical illness. In sepsis patients they are reflective of disease severity more than independent predictors of mortality. Despite higher levels in patients with infection compared with non-infectious controls, TNC does not perform sufficiently to be used as a standalone biomarker discriminating sepsis from non-infectious critical illness. Address reprint requests to Mariska T. Meijer, Amsterdam UMC, location Academic Medical Center, Meibergdreef 9, Room G2-130, 1105 AZ Amsterdam, the Netherlands. E-mail: m.t.meijer@amsterdamumc.nl. Received 15 August, 2019 Revised 5 September, 2019 Accepted 31 October, 2019 The authors report 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). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 © 2019 by the Shock Society

MITOCHONDRIAL DYSFUNCTION IS ASSOCIATED WITH AN IMMUNE PARALYSIS PHENOTYPE IN PEDIATRIC SEPSIS Objective: Immune dysregulation is a defining feature of sepsis, but the role for mitochondria in the development of immunoparalysis in pediatric sepsis is not known. We sought to determine if mitochondrial dysfunction measured in peripheral blood mononuclear cells (PBMCs) is associated with immunoparalysis and systemic inflammation in children with sepsis. Design: Prospective observational study Setting: Single academic pediatric intensive care unit (PICU) Patients: 161 children with sepsis/septic shock and 18 non-infected PICU controls Measurements and Main Results: Mitochondrial respiration in PBMCs, markers of immune function, and plasma cytokines were measured on days 1-2 (T1), 3-5 (T2), and 8-14 (T3) after sepsis recognition, and once for controls. Immunoparalysis was defined as whole-blood ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-α) ≤200 pg/mL or monocyte human leukocyte antigen (mHLA)-DR ≤30%. Mitochondrial respiration was lower in children with versus without immunoparalysis measured at the same timepoint. Mitochondrial respiration measured early (at T1 and T2) was also lower in those with immunoparalysis at T2 and T3, respectively. Although most patients with immunoparalysis exhibited low mitochondrial respiration, this metabolic finding was not specific to the immunoparalysis phenotype. Plasma cytokines, including IL-8, IL-10, TNF-α, and MCP-1 were highest in the subset of sepsis patients with immune paralysis or low mitochondrial respiration at T1. Conclusions: Children with sepsis had lower PBMC mitochondrial respiration when immunoparalysis was present compared to those without immunoparalysis. The subsets with immune paralysis and low mitochondrial respiration exhibited the highest levels of systemic inflammation. Address reprint requests to Scott L. Weiss, Assistant Professor of Critical Care and Pediatrics, Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 3401 Civic Center Blvd, Wood Building 6th Floor, Suite 6026A, Philadelphia, PA 19104. E-mail: WeissS@email.chop.edu Received 28 August, 2019 Revised 23 September, 2019 Accepted 7 November, 2019 The authors declare that they have no competing interests. This study was performed at The Children's Hospital of Philadelphia. Financial Support: Financial support was provided by NICHD K12HD047349 (SLW), NIGMS K23GM110496 (SLW), and the Center for Mitochondrial and Epigenomic Medicine (though grants awarded to DCW including NIH NS021328, MH108592, OD010944 and US Department of Defense grant W81XWH-16-1-0401) and Department of Anesthesiology and Critical Care at the Children's Hospital of Philadelphia. 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

Therapeutic and Adverse Effects of Thrombomodulin Alfa to Treat Sepsis-Induced Disseminated Intravascular Coagulation In the treatment of disseminated intravascular coagulation (DIC), which is a complication of underlying diseases such as infections and malignant tumors, effective plasma concentrations of thrombomodulin (TM) alfa range from 300–900 ng/mL; however, appropriate concentrations when treating sepsis-induced DIC are unknown. Thus, our aim was to determine the relationship between plasma concentrations of TM alfa and its therapeutic effects, and hemorrhagic adverse events. First, we calculated the plasma trough concentrations of TM alfa in septic DIC patients. Next, we divided patients into two groups according to their plasma concentrations into a low- and high-concentration group based on a cut-off value of 600 ng/mL. Fourteen and 35 patients were included in the low- and high-concentration groups, respectively. The Japanese Association for Acute Medicine DIC diagnostic criteria score 4 days after TM alfa administration decreased significantly by 2.06 points from baseline in the high-concentration group compared with 0.71 points in the low-concentration group. The 90-day survival rate was significantly higher in the high-concentration group (85.4%) than in the low-concentration group (49.0%) (hazard ratio, 0.27; 95% confidence interval: 0.09–0.86). In contrast, the incidence of serious hemorrhage was not significantly different between the groups. The recommended plasma concentration of TM alfa in the treatment of septic DIC was determined to be higher than 600 ng/mL, and a dose of 380 U/kg (0.06 mg/kg) was necessary to achieve this concentration. Address reprint requests to Fumihiko Katagiri, PhD, Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail: katagiri@toyaku.ac.jp Received 29 August, 2019 Revised 25 September, 2019 Accepted 25 October, 2019 Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest statement: The authors declare no conflict of interest. © 2019 by the Shock Society

The Reproducibility of the Point of care Microcirculation (Poem) Score when used to Assess Critically Ill Patients: A Multicenter Prospective Observational Study Background: The current standard of analyzing microcirculatory video microscopy is time-consuming and occurs away from the patient, limiting its clinical utility. Point-of-care assessment with incident dark field (IDF) microscopy, however, may offer greater clinical applicability. We aimed to determine the reproducibility of the Point of Care Microcirculation (POEM) tool when used at the bedside in critically ill patients. Methods: A multinational, multicenter, prospective observational study of adult intubated patients was undertaken during a 9-month period in Germany, the United Kingdom, and the United States. A user recorded a batch of four standardized video clips from each patient, calculated a POEM score and recorded the time for image acquisition. A second user blinded to the first repeated this process. Patients with video clips of poor quality were excluded. At a later date, the two users again blinded themselves to reassess both their own clips and those of the other user. Basic demographic information was recorded. Intra-user reliability (an individual user rescoring the same batch of videos after blinding), inter-user reliability (a second user rescoring the other user's video batch after blinding) and test-retest reliability (two users individually capturing videos and recording POEM scores) were assessed using a linearly weighted kappa statistic for ordinal data. Results: Sixty-five patients were included in the final analysis. Observer agreement was substantial for all tests. Intra-user agreement was 0.73 (0.95 CI 0.64–0.81), inter-user agreement 0.71 (0.95 CI 0.63 – 0.79), and test-retest agreement 0.75 (0.95 CI 0.65 – 0.86). Average time to record videos and assess POEM scores 7:34 +/- 3:37 minutes. Conclusions: Point-of-care assessment of the microcirculation using IDF video microscopy and POEM scoring appears to be both a feasible and reproducible approach to microcirculatory assessment. Testing of the score in critically ill patients showed substantial agreement within and between investigators, but further studies should validate its utility as a tool to guide shock resuscitation. Address reprint requests to James C. Watchorn, MBBS, Critical Care Department, King's College Hospital, Denmark Hill, London, UK, London, UK, United Kingdom. E-mail: J.watchorn@nhs.net Received 29 August, 2019 Revised 24 October, 2019 Accepted 25 October, 2019 Competing interests: The authors declare that they have no competing interests Funding: Funding for this study was provided by the UK Ministry of Defence and supported by the UK National Institute for Health Research. Consent for publication: Not applicable Availability of data and material: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Authors’ contributions: James Watchorn collected data in the UK in conjunction with others and was responsible for data analysis and drafting the manuscript. Ulrich Goebel and Jakob Wollborn gathered data in Germany and contributed to manuscript editing. Michael T. McCurdy, Hithem Fargaly, Muhammad Gilani, Jordan Assadi, and Andrew R. Deitchman collected data in the USA and contributed to writing and editing the manuscript. David Naumann collected data in the UK and contributed to editing the manuscript. Sam Hutchings devised the study, wrote the protocol and oversaw the study in its entirety. All authors read and approved the final 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

Removal of Circulating Neutrophil Extracellular Trap Components With An Immobilized Polymyxin B Filter: A Preliminary Study Components of neutrophil extracellular traps (NETs) are released into the circulation by neutrophils and contribute to microcirculatory disturbance in sepsis. Removing NET components (DNA, histones, and proteases) from the circulation could be a new strategy for counteracting NET-dependent tissue damage. We evaluated the effect of hemoperfusion with a polymyxin B (PMX) cartridge, which was originally developed for treating gram negative infection, on circulating NET components in patients with septic shock, as well as the effect on phorbol myristate acetate (PMA)-stimulated neutrophils obtained from healthy volunteers. Ex vivo closed loop hemoperfusion was performed through PMX filters in a laboratory circuit. Whole blood from healthy volunteers (incubated with or without PMA) or from septic shock patients was perfused through the circuit. For in vivo experiment blood samples were collected before and immediately after hemoperfusion with PMX to measure the plasma levels of cell-free NETs. The level of cell-free NETs was assessed by measuring myeloperoxidase-associated DNA (MPO-DNA), neutrophil elastase-associated DNA (NE-DNA), and cell-free DNA (cf-DNA). Plasma levels of MPO-DNA, NE-DNA, and cf-DNA were significantly increased after 2 hours of PMA stimulation. When the circuit was perfused with blood from septic shock patients or PMA-stimulated neutrophils from healthy volunteers, circulating levels of MPO-DNA, NE-DNA, and cf-DNA were significantly reduced after 1 and 2 hr of perfusion with a PMX filter compared to perfusion without a PMX filter. In 10 patients with sepsis, direct hemoperfusion through filters with immobilized PMX significantly reduced plasma levels of MPO-DNA and NE-DNA. These ex vivo and in vivo findings demonstrated that hemoperfusion with PMX removes circulating NET components. Selective removal of circulating NET components from the blood could be effective for prevention/treatment of NET-related inappropriate inflammation and thrombogenesis in patients with sepsis. Address reprint requests to Naoshi Takeyama, Department of Emergency and Critical Care Medicine, Aichi Medical University, Aichi, 480-1195, Japan. E-mail: takeyama@aichi-med-u.ac.jp Received 22 July, 2019 Revised 9 August, 2019 Accepted 25 October, 2019 Conflicts of Interest and Source of Funding: The authors report no conflicts of interest. Statement of Ethics: Written informed consent was obtained from each patient included in the study, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected a priori by the individual institutions’ Medical Ethics Committees. Disclosure Statement: All data generated and/or analyzed during this study are included in this published article. The authors declare that they have no competing interests. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 © 2019 by the Shock Society