Shock

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

X-Linked IRAK1 Polymorphism is Associated with Sex-Related Differences In Polymorphonuclear Granulocyte and Monocyte Activation and Response Variabilities Common X-linked genetic polymorphisms are expected to alter cellular responses affecting males and females differently through sex-linked inheritance pattern as well as X chromosome (ChrX) mosaicism and associated ChrX skewing, which is unique to females. We tested this hypothesis in ex vivo lipopolysaccharide and phorbol ester-stimulated polymorphonuclear granulocytes (PMNs) and monocytes from healthy volunteers (n = 51). Observations were analyzed after stratification by sex alone or the presence of variant IRAK1 haplotype a common X-linked polymorphism with previously demonstrated major clinical impacts. Upon cell activation, CD11b, CD45, CD66b, CD63 and CD14 expression was markedly and similarly elevated in healthy males and females. By contrast, PMN and monocyte activation measured by CD11b, CD66b and CD63 was increased in variant-IRAK1 subjects as compared to WT. Stratification by IRAK1 genotype and sex showed similar cell activation effect on variant-IRAK1 subjects and an intermediate degree of cell activation in heterozygous mosaic females. The increased membrane expression of these proteins in variant-IRAK1 subjects was associated with similar or increased inter-subject but uniformly decreased intra-subject cell response variabilities as compared to WT. We also tested white blood cell ChrX skewing in the healthy cohort as well as in a sample of female trauma patients (n = 201). ChrX inactivation ratios were similar in IRAK1 WT, variant and heterozygous healthy subjects. Trauma patients showed a trend of blunted ChrX skewing at admission in homozygous variant-IRAK1 and heterozygous mosaic-IRAK1 female subjects as compared to WT. Trauma-induced, de novo ChrX skewing was also depressed in variant-IRAK1 and mosaic-IRAK1 female trauma patients as compared to WT. Our study indicates that augmented PMN and monocyte activation in variant-IRAK1 subjects is accompanied by decreased intra-subject cellular variability and blunted de novo ChrX skewing in response to trauma. A more pronounced cell activation of PMNs and monocytes accompanied by decreased response variabilities in variant-IRAK1 subjects may be a contributing mechanism affecting the course of sepsis and trauma and may also impact sex-based outcome differences due to its X-linked inheritance pattern and high prevalence. Address reprint requests to Zoltan Spolarics, MD, PhD, Department of Surgery, Rutgers-New Jersey Medical School, 185 South Orange Ave., MSB G-578, Newark, NJ 07103. E-mail: spolaric@njms.rutgers.edu Received 13 May, 2019 Revised 28 June, 2019 Accepted 28 June, 2019 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

Beneficial Effects of Ivabradine on Post-Resuscitation Myocardial Dysfunction In A Porcine Model of Cardiac Arrest Background: Ivabradine selectively inhibits the If current, reducing the heart rate and protecting against myocardial ischemia/reperfusion injury. We investigated the effects of ivabradine on post-resuscitation myocardial function in a porcine model of cardiopulmonary resuscitation. Methods and Results: Ventricular fibrillation was induced and untreated for 8 minutes while defibrillation was attempted after 6 minutes of cardiopulmonary resuscitation in anesthetized domestic swine. Then the animals were randomized into ivabradine and placebo groups (n = 5 each). Ivabradine and saline were administered at the same volume 5 minutes after ROSC (Return of Spontaneous Circulation), followed by continuous intravenous infusion at 0.5 mg/kg for 480 minutes. Hemodynamic parameters were continuously recorded. Myocardial function was assessed by echocardiography at baseline and at 60, 120, 240, 480 minutes and 24 hours after resuscitation. The serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) were measured by commercial enzyme-linked immunosorbent assay kits. Animals were killed 24 hours after resuscitation, and all myocardial tissue was removed for histopathological analysis. The heart rate was significantly reduced from 1 hour after resuscitation in the ivabradine group (all p < 0.05). The post-resuscitation mitral E/A and E/e′ velocity ratios and left ventricular ejection fraction were significantly better in the ivabradine than placebo group (p < 0.05). The serum levels of myocardial injury biomarkers (NT-proBNP, cTnI) and the myocardial biopsy scores were significantly lower in the ivabradine than placebo group (p < 0.05). Neurological deficit scores were lower in the IVA group at PR 24 hours (p < 0.05). Conclusions: Ivabradine improved post-resuscitation myocardial dysfunction, myocardial injury and post-resuscitation cerebral function, and also slowed the heart rate in this porcine model. Address reprint requests to Min Yang, MD, PhD, The 2nd Department of Intensive Care Unit, No. 2 Hospital Affiliated to Anhui Medical University, Furong Road 678, Hefei, China, 230032. E-mail: 512130761@qq.com Received 4 April, 2019 Revised 25 April, 2019 Accepted 27 June, 2019 Source of funding: This study was supported by the National Natural Science Foundation of China (No. 81601661), Natural Science Foundation of Anhui Province of China (No. 1608085MH195), and Science Foundation for Post-doctoral Researchers in Anhui Province of China (No. 2016B140). Disclosure: The authors have no conflicts of interest to declare. 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

Early Maladaptive Cardiovascular Responses are Associated with Mortality In A Porcine Model of Hemorrhagic Shock Background: Hemorrhage is a leading cause of death on the battlefield. Current methods for predicting hemodynamic deterioration during hemorrhage are of limited accuracy and practicality. During a study of the effects of remote ischemic preconditioning in pigs that underwent hemorrhage, we noticed arrhythmias among all pigs that died before the end of the experiment but not among surviving pigs. The present study was designed to identify and characterize the early maladaptive hemodynamic responses (tachycardia in the presence of hypotension without a corresponding increase in cardiac index or mean arterial blood pressure) and their predictive power for early mortality in this experimental model. Methods: Controlled hemorrhagic shock was induced in 16 pigs. Hemodynamic parameters were monitored continuously for 7 h following bleeding. Changes in cardiovascular and laboratory parameters were analyzed and compared between those that had arrhythmia and those that did not. Results: All animals had similar changes in parameters until the end of the bleeding phase. Six animals developed arrhythmias and died early, while 10 had no arrhythmias and survived longer than 6 h or until euthanasia. Unlike survivors, those that died did not compensate for cardiac output (CO), diastolic blood pressure (DBP), and stroke volume (SV). Oxygen delivery (DO2) and mixed venous saturation (SvO2) remained low in animals that had arrhythmia, while achieving certain measures of recuperation in animals that did not. Serum lactate increased earlier and continued to rise in all animals that developed arrhythmias. No significant differences in hemoglobin concentrations were observed between groups. Conclusions: Despite similar initial changes in variables, we found that low CO, DBP, SV, DO2, SvO2, and high lactate are predictive of death in this animal model. The results of this experimental study suggest that maladaptive responses across a range of cardiovascular parameters that begin early after hemorrhage may be predictive of impending death, particularly in situations where early resuscitative treatment may be delayed. Address reprint requests to Dr Arik Eisenkraft, MD, MHA, Institute for Research in Military Medicine, Faculty of Medicine of the Hebrew University of Jerusalem, POB 12272, Jerusalem 91120, Israel. E-mail: aizenkra@gmail.com Received 16 December, 2018 Revised 17 January, 2019 Accepted 19 June, 2019 RS and LG have equal contributions. RS contributed to all aspects of the study including study design, data acquisition, analysis, interpretation of data, and drafting/critical revision. LG and AE contributed to all aspects of the study except data acquisition and analysis respectively. LW-A and GY contributed to study design, data acquisition, and drafting/critical revision. SDG and CW contributed to interpretation of the data and drafting/critical revision. JM, GS, BS-P, and AB contributed to the study design and data acquisition. This study was supported in part by the IDF Medical Corps Grant numbers 4440520303 and 4440622654 and The Alexander Grass Foundation Fund for Research in Military Medicine, The Institute for Research in Military Medicine (IRMM), Faculty of Medicine, The Hebrew University of Jerusalem, Israel. Prof SDG is the Director of the Military Track of Medicine and The Institute for Research in Military Medicine, and the Brandman Foundation Professor of Cardiac and Pulmonary Diseases of The Faculty of Medicine, The Hebrew University of Jerusalem. Part of this work was presented in the Euroanaesthesia 2016 Congress, May 28–30, London, UK, by Dr RS. This work was presented to the Scientific Council of The Israel Medical Association as part of the research component of Dr RS’ residency training in anesthesiology. The authors report no conflicts of interest. © 2019 by the Shock Society

Effects of The Poly(ADP-ribose) Polymerase Inhibitor Olaparib in Cerulein-Induced Pancreatitis Objective: Activation of the constitutive nuclear and mitochondrial enzyme poly(ADP-ribose) polymerase (PARP) has been implicated in the pathogenesis of cell dysfunction, inflammation and organ failure in various forms of critical illness. The objective of our study was to evaluate the efficacy and safety of the clinically approved PARP inhibitor olaparib in an experimental model of pancreatitis in vivo and in a pancreatic cell line subjected to oxidative stress in vitro. The preclinical studies were complemented with analysis of clinical samples to detect PARP activation in pancreatitis. Methods: Mice were subjected to cerulein-induced pancreatitis; circulating mediators and circulating organ injury markers; pancreatic myeloperoxidase and malondialdehyde levels were measured and histology of the pancreas was assessed. In human pancreatic duct epithelial cells (HPDE) subjected to oxidative stress, PARP activation was measured by PAR Western blotting and cell viability and DNA integrity were quantified. In clinical samples, PARP activation was assessed by PAR (the enzymatic product of PARP) immunohistochemistry. Results: In male mice subjected to pancreatitis, olaparib (3 mg/kg i.p.) improved pancreatic function: it reduced pancreatic myeloperoxidase and malondialdehyde levels, attenuated the plasma amylase levels, and improved the histological picture of the pancreas. It also attenuated the plasma levels of pro-inflammatory mediators (TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-12, IP-10, KC) but not MCP-1, RANTES or the anti-inflammatory cytokine IL-10. Finally, it prevented the slight, but significant increase in plasma blood urea nitrogen level, suggesting improved renal function. The protective effect of olaparib was also confirmed in female mice. In HPDE cells subjected to oxidative stress olaparib (1 μM) inhibited PARP activity, protected against the loss of cell viability and prevented the loss of cellular NAD+ levels. Olaparib, at 1–30 μM did not have any adverse effects on DNA integrity. In human pancreatic samples from patients who died of pancreatitis, increased accumulation of PAR was demonstrated. Conclusion: Olaparib improves organ function and tempers the hyperinflammatory response in pancreatitis. It also protects against pancreatic cell injury in vitro without adversely affecting DNA integrity. Repurposing and eventual clinical introduction of this clinically approved PARP inhibitor may be warranted for the experimental therapy of pancreatitis. Address reprint requests to Csaba Szabo, MD, PhD, Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, Fribourg 1700, Switzerland. E-mail: csaba.szabo@unifr.ch. Received 22 May, 2019 Revised 18 June, 2019 Accepted 26 June, 2019 Ethics approval and consent to participate: The current report does not contain human interventional studies. (The human pancreatic tissue samples were obtained from a commercial biobank which obtained them under informed consent and in compliance with all applicable rules and regulations.) Consent for publication: The current report does not contain human studies or studies that would require consenting. Availability of data and material: The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request. Competing interests: The authors declare no competing interests. Funding: This work was supported by grants from the National Institutes of Health (R01GM107876) and the Swiss National Foundation (to C.S.), and by the FAPESP (to R.S. and F.G.S.) Authors’ contributions: AA conducted in vivo and in vitro experiments; BS, GT, ND, and MM conducted in vitro studies, CS, LL, FGS and RS conceived the overall study design; AA, ST, LL, FGS and RS contributed to various parts of the study design, method development, data interpretation and writing of the manuscript. CS was responsible for the coordination of the project. CS drafted the first version of the manuscript and finalized the manuscript. 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). The authors declare that they have no competing interests. © 2019 by the Shock Society

Activation of hypoxia-inducible factor -1α via succinate dehydrogenase pathway during acute lung injury induced by trauma/hemorrhagic shock Hypoxia-inducible factor (HIF)-1α is a transcription factor that is critical for tissue adaption to hypoxia and inflammation. Previous studies had indicated that normoxic activation of HIF-1α in cancer involves inhibition or mutation of the metabolic enzyme succinate dehydrogenase (SDH). We have found that local inhibition of HIF-1α ameliorates acute lung injury (ALI) induced by trauma/hemorrhagic shock (T/HS) in rats. In this study, we found pulmonary activation of HIF-1α and inhibition of SDH during THS-Induced ALI in rats and transcriptional activation of HIF-1α during ALI induced by T/HS lymph via SDH pathway in vitro. Furthermore, pharmacologic inhibition of HIF-1α attenuates lung inflammation and pulmonary edema during ALI by T/HS. Activation of HIF-1α is detrimental to ALI induced by T/HS. Thus, our data suggest that HIF-1α activation by T/HS is necessary for T/HS-induced lung injury and a critical role for SDH in the initiation of acute inflammatory response following ALI. Nevertheless, this is a preclinical work and several limitations impede translation of the findings to patients, such as uncontrolled bleeding and simultaneous treatment, and prolonged course of clinical shock on the outcome of the work, which needs to be addressed in future. Address reprint requests to Qifang Li, Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, NO.2 Ruijin Road, Shanghai, 200025, China. E-mail: psoriasisbreak@163.com. Received 25 December, 2018 Revised 23 January, 2019 Accepted 14 March, 2019 There is no relevant conflict of interest. © 2019 by the Shock Society

Identification of Fibrinogen as a Key Anti-Apoptotic Factor in Human Fresh Frozen Plasma for Protecting Endothelial Cells In Vitro Resuscitation with human fresh frozen plasma (FFP) in hemorrhagic shock (HS) patients is associated with improved clinical outcomes. Our group has demonstrated that the beneficial effect of FFP is due to its blockade on endothelial hyperpermeability, thereby improving vascular barrier function. The current study aimed to investigate HS-induced endothelial cell apoptosis, a potential major contributor to the endothelial hyperpermeability, and to determine the effect and the key components/factors of FFP on protecting endothelial cells from apoptosis. We first measured and demonstrated an increase in apoptotic endothelial microparticles (CD146+AnnexinV+) in patients in shock compared to normal subjects, indicating the induction of endothelial cell activation and apoptosis in shock patients. We then transfused HS rats with FFP and showed that FFP blocked HS-induced endothelial cell apoptosis in gut tissue. To identify the anti-apoptotic factors in FFP, we utilized high-performance liquid chromatography, fractionated FFP, and screened the fractions in vitro for the anti-apoptotic effects. We selected the most effective fractions, performed mass spectrometry, and identified fibrinogen as a potent anti-apoptotic factor. Taken together, our findings suggest that HS-induced endothelial apoptosis may constitute a major mechanism underlying the vascular hyperpermeability. Furthermore, the identified anti-apoptotic factor fibrinogen may contribute to the beneficial effects of FFP resuscitation, and therefore, may have therapeutic potential for HS. Address reprint requests to Yanna Cao, MD, Department of Surgery, The University of Texas Health Science Center at Houston, 6431 Fannin St., MSB4.608, Houston, TX 77030. E-mail: Yanna.Cao@uth.tmc.edu, Tien C. Ko, MD, Department of Surgery, The University of Texas Health Science Center at Houston, 5656 Kelly, 30S62008, Houston, TX 77026. E-mail: Tien.C.Ko@uth.tmc.edu. Received 9 May, 2019 Revised 28 May, 2019 Accepted 14 June, 2019 This study was supported by the National Institute of General Medical Sciences P50 grant GM038529 (T.C.K. and J.B.H.), Jack H Mayfield M.D. Distinguished Professorship in Surgery (T.C.K), the William Stamps Farish Fund, the Howell Family Foundation, and the James H. “Red” Duke Professorship Chair fund (C.E.W), and Dean's fund for Summer Research Program (J.M.D.). The authors report no conflicts of interest. © 2019 by the Shock Society

First-Days Reduction of Plasma and Skin Advanced Glycation End Products is Related to Outcome in Septic Patients Background: Advanced glycation end products (AGEs) are a result of non-enzymatic glycation of proteins and lipids, which can attach to either their cell surface receptor (RAGE) or its soluble form (sRAGE). Evidence exists for the implication of AGE-RAGE axis in sepsis, but data are still insufficient and conflicting. We aimed to analyse the kinetics of plasma and skin AGEs and sRAGE during sepsis, and their association with outcome in septic patients. Methods: We performed a prospective observational study. We enrolled 90 consecutive patients with severe sepsis or septic shock, within the first 24 hours of Intensive Care Unit admission. During the first 5 days of sepsis, we measured plasma autofluorescence (PAF) and skin autofluorescence (SAF) as surrogates of circulating and skin AGEs, respectively. sRAGE was measured on days 1, 3 and 5. Delta values were defined as the difference between the PAF, SAF or sRAGE on a specific day and the value on day 1. Results: 28-day mortality was 18%. Bivariate analysis found that ΔPAF3-1, ΔPAF4-1, ΔPAF5-1 and ΔSAF5-1 were significantly associated with 28-day mortality. Additionally, sRAGE1 was inversely correlated to ΔPAF4-1 (r = -0.250, p = 0.019) and ΔPAF5-1 (r = -0.246, p = 0.024), and significantly associated with 28-day mortality. In an adjusted multivariate logistic regression analysis, ΔPAF2-1, ΔPAF3-1, ΔPAF4-1, ΔPAF5-1 and ΔSAF5-1 were associated with 28-day mortality. Conclusions: Kinetics of plasma and skin AGEs during the first days of sepsis are independently associated with mortality, where a decrease of plasma and skin AGEs are related to higher mortality. Address reprint requests to Emilio Rodriguez-Ruiz, MD, Intensive Care Medicine Department, Complexo Hospitalario Universitario de Santiago (CHUS). C/Choupana s/n, 15706 Santiago de Compostela, A Coruña, Spain. E-mail: r.ruizemilio@gmail.com Received 27 March, 2019 Revised 10 June, 2019 Accepted 10 June, 2019 Conflicts of interest and Source of Funding: The authors have no conflicts of interest to declare regarding this article. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 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