Shock

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

Myocardial Edema: An Overlooked Mechanism of Septic Cardiomyopathy? No abstract available

Catecholamines Induce Endoplasmic Reticulum Stress via Both Alpha and Beta Receptors Severely burned patients suffer from a hypermetabolic syndrome that can last for years after the injury has resolved. The underlying cause of these metabolic alterations most likely involve the persistent elevated catecholamine levels that follow the surge induced by thermal injury. At the cellular level, endoplasmic reticulum (ER) stress in metabolic tissues is a hallmark observed in patients following burn injury and is associated with several detrimental effects. Therefore, ER stress could be the underlying cellular mechanism of persistent hypermetabolism in burned patients. Here, we show that catecholamines induce ER stress and that adreno-receptor blockers reduce stress responses in the HepG2 hepatocyte cell line. Our results also indicate that norepinephrine (NE) significantly induces ER stress in HepG2 cells and 3T3L1 mouse adipocytes. Furthermore, we demonstrate that the alpha-1 blocker, prazosin, and beta blocker, propranolol, block ER stress induced by NE. We also show that the effects of catecholamines in inducing ER stress are cell type-specific, as NE treatment failed to evoke ER stress in human fibroblasts. Thus, these findings reveal the mechanisms used by catecholamines to alter metabolism and suggest inhibition of the receptors utilized by these agents should be further explored as a potential target for the treatment of ER stress-mediated disease. Address reprint requests to Marc G. Jeschke, MD, PhD, Director Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre; Division of Plastic Surgery, Department of Surgery, Department of Immunology, University of Toronto; Sunnybrook Research Institute, 2075 Bayview Ave., Rm D704, Toronto, ON, CANADA, M4N 3M5. E-mail: marc.jeschke@sunnybrook.ca Received 18 March, 2019 Revised 5 April, 2019 Accepted 3 June, 2019 Disclosure statement: The authors have nothing to disclose. 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

TGF-β Pathway Inhibition Protectsthe Diaphragm From Sepsis-Induced Wasting and Weakness in Rat Sepsis is a frequent complication in patients in intensive care units (ICU). Diaphragm weakness,one of the most common symptoms observed, can lead to weaning problemsduring mechanical ventilation. Over the last couple of years, members of thetransforming growth factor (TGF) β family,such as myostatin, activin A and TGF-β1,have beenreported to strongly trigger the activation of protein breakdown involved in muscle wasting. The aim of this study was to investigate the effect of TGF-βinhibitorLY364947on the diaphragm during chronic sepsis. Rats were separated into four groups exposed to different experimental conditions: (i) Control group, (ii) Septic group, (iii) Septic group with inhibitor from day 0 (LY D0), and (iv) Septic group with inhibitor from day 1 (LY D1). Sepsis was induced in ratsby cecal ligation and puncture, and carried out for seven days. Chronic sepsis was responsible for a decrease inbody weight, food intake anddiaphragm's mass. The inhibitor was able to abolish diaphragm wasting only in the LY D1 group. Similarly, LY364947 had a beneficial effect on the diaphragm contraction only for the LY D1 group. SMAD3 was over-expressed and phosphorylated within rats in the Septic group;however this effect was reversed by LY364947. Calpain-1 and -2 as well as MAFbx were over-expressedwithin individuals in theSeptic group. Yet, calpain-1 and MAFbx expressions were decreased by LY364947 With this work, we demonstrate for the first time that the inhibition of TGF-β pathway during chronic sepsisprotects the diaphragm from wasting and weaknessas early asone day post infection. This could lead to more efficient treatment and care for septic patients in ICU. Address reprint requests to Jude Baptiste, PhD, Laboratoire de Physiologie – EA4324 ORPHY, Université de Bretagne Occidentale, 22 Avenue Camille Desmoulins 29238 Brest, Cedex 3 France; E-mail: bjude@outlook.fr Received 14 September, 2018 Revised 15 October, 2018 Accepted 29 May, 2019 Highlights: -Chronic sepsis of seven days is responsible for the decrease inthe diaphragm mass and its contractile force. -Sepsis induces the activation of TGF-β signaling and proteolytic pathway in the diaphragm. -The inhibition of TGF-β pathway prevents diaphragm dysfunction only if the inhibition starts 24 h after sepsis induction. -The early inhibition of the TGF-β pathway does not protect the diaphragm during sepsis. Conflict of interest: The authors declare that no conflict of interest exists. © 2019 by the Shock Society

The Use of Tranexamic acid (TXA) for The Management of Haemorrhage In Trauma Patients In The Prehospital Environment: Literature Review and Descriptive Analysis of Principal Themes Tranexamic acid (TXA) is an anti-fibrinolytic agent used to prevent traumatic exsanguination. It was first introduced to clinical practice for the management of patients with bleeding disorders, especially adapted to reduce bleeding in haemophiliacs undergoing oral surgical interventions. TXA exerts its action on the coagulation process by competitively inhibiting plasminogen activation, thereby reducing conversion of plasminogen into plasmin. This ultimately prevents fibrinolysis and reduces haemorrhage. Thus, TXA may be well suited for the management of traumatic haemorrhage in the pre-hospital setting. Despite multiplicity of studies on the use of TXA in clinical practice, there is no consensus regarding the use of TXA for the management of haemorrhage in trauma patients in the prehospital environment. Thus, a review on this topic was warranted. An extensive literature search yielded 14 full journal articles which met the inclusion criteria. These articles were thoroughly analysed and the and following themes were identified: "Dose of TXA administration", "Route of TXA administration", "Optimal window of TXA administration", "Safety of TXA use", "Clinical Effectiveness of TXA application" and the "Feasibility of TXA use in the prehospital setting". Overall, to achieve the best possible outcomes, literature supports the use of a loading dose of 1 gram of TXA, followed by 1 gram infusion over 8 hours, given by intravenous administration within a 3 hour window period of traumatic injury. TXA is very effective and safe to use in the pre-hospital setting, and its use is clinically and economically feasible. Address reprint requests to Dr Emmanuel Jesulola, Room 206, Building 1448, Charles Sturt University, Panorama Avenue, Bathurst, NSW 2795 Australia. E-mail: ejesulola@csu.edu.au Received 4 April, 2019 Revised 18 April, 2019 Accepted 14 May, 2019 Funding: No funding was required for this review article. Disclosure of interest: The authors report no conflict of interest. © 2019 by the Shock Society

Alexandros Sfakianakis
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