Urantide Improves Cardiac Function, Modulates Systemic Cytokine Response and Increases Survival in a Murine Model of Endotoxic Shock Introduction: Urotensin II (UII) is a potent vasoactive peptide activating the G protein-coupled receptor UT, and is involved in systemic inflammation and cardiovascular functions. The aim of our work was to study the impact of the UT antagonist urantide on survival, systemic inflammation and cardiac function during endotoxic shock. Methods: C57Bl/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) and then randomized to be injected either by urantide or NaCl 0.9% 3, 6 and 9 hours (H3, H6, H9) after LPS. The effect of urantide on the survival rate, the levels of cytokines in plasma at H6, H9, H12, the expression level of nuclear factor-kappa B (NF-κB-p65) in liver and kidney (at H12), and the cardiac function by trans-thoracic echocardiography from H0 to H9 was evaluated. Results: Urantide treatment improved survival (88.9% vs 30% on day 6, p < 0.05). This was associated with changes in cytokine expression: a decrease in IL-6 (2485 [2280–2751] pg/ml vs 3330 [3119–3680] pg/ml, p < 0.01) at H6, in IL-3 (1.0 [0.40–2.0] pg/ml vs 5.8 [3.0–7.7] pg/ml, p < 0.01), and IL-1β (651 [491–1135] pg/ml vs 1601 [906–3010] pg/ml, p < 0.05) at H12 after LPS administration. Urantide decreased the proportion of cytosolic NF-κB-p65 in liver (1.3 [0.9–1.9] vs 3.2 [2.3–4], p < 0.01) and kidney (0.3 [0.3–0.4] vs 0.6 [0.5–1.1], p < 0.01). Urantide improved cardiac function (left ventricular fractional shortening: 24.8 [21.5–38.9] vs 12.0 [8.7–17.6] %, p < 0.01 and cardiac output: 30.3 [25.9–39.8] vs 15.1 [13.0–16.9] ml/min, p < 0.0001). Conclusion: These results show a beneficial curative role of UT antagonism on cytokine response (especially IL-3), cardiac dysfunction and survival during endotoxic shock in mice, highlighting a potential new therapeutic target for septic patients. Address reprint requests to Hélène Castel, INSERM U1239, Laboratory of Neuronal and Neuroendocrine Cell Communication and Differentiation, University of Rouen Normandie, 25 Rue Tesnière, 76821 Mont-Saint-Aignan. E-mail: helene.castel@univ-rouen.fr Received 12 January, 2019 Revised 12 February, 2019 Accepted 6 September, 2019 Thomas Clavier and Emmanuel Besnier: These two authors contributed equally to this work. Hélène Castel and Vincent Compère: Co-last authors This work was supported by Normandie Rouen University and Inserm. Conflicts of Interest and Source of Funding: The authors have disclosed that they hold no financial interests related to the conduct or results of this research. 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

Austere Environments Consortium for Enhanced Sepsis Outcomes (ACESO) No abstract available

Comparative Early Haemodynamic Profiles in Patients Presenting to the Emergency Department With Septic and Non-Septic Acute Circulatory Failure Using Focused Echocardiography Study Objective: We evaluated the early haemodynamic profile of patients presenting with acute circulatory failure to the Emergency Department using focused echocardiography performed by emergency physicians after a dedicated training program. Methods: Patients presenting to the Emergency Department with an acute circulatory failure of any origin were successively examined by a recently trained emergency physician and by an expert in critical care echocardiography. Operators independently performed and interpreted on-line echocardiographic examinations to determine the leading mechanism of acute circulatory failure. Results: Focused echocardiography could be performed in 100 of 114 screened patients (55 with sepsis/septic shock and 45 with shock of other origin) after a median fluid loading of 500 mL (IQR: 187–1500 mL). A hypovolemic profile was predominantly observed whether the acute circulatory failure was of septic origin or not (33/55 [60%] vs. 23/45 [51%]: p = 0.37). Although a vasoplegic profile associated with a hyperkinetic left ventricle was most frequently identified in septic patients when compared to their counterparts (17/55 [31%] vs. 5/45 [11%]: p = 0.02), early left or right ventricular failure was observed in 31% of them. Haemodynamic profiles were adequately appraised by recently trained emergency physicians, as reflected by a good-to-excellent agreement with the expert's assessment (Κ: 0.61 to 0.85). Conclusions: Hypovolemia was predominantly identified in patients presenting to the Emergency Department with acute circulatory failure. Although vasoplegia was more frequently associated with sepsis, early ventricular dysfunction was also depicted in septic patients. Focused echocardiography appeared reliable when performed by recently trained emergency physicians without previous experience in ultrasound. Address reprint requests to Thomas Lafon, MD, Service d’Urgences, Centre Hospitalier Universitaire Dupuytren, 2, avenue Martin Luther King, 87042 Limoges cedex, France. E-mail: Thomas.LAFON@chu-limoges.fr Received 3 July, 2019 Revised 23 July, 2019 Accepted 10 September, 2019 Conflicts of Interest and Source of Funding: none to declare 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

Assessment of the Left Ventricular-Arterial Coupling: A More Reasonable Method No abstract available

Golden Method is a Perfect but not Clinically Applicable No abstract available

Early Axonal Injury and Delayed Cytotoxic Cerebral Edema are Associated With Microglial Activation in a Mouse Model of Sepsis Sepsis-induced brain injury is associated with an acute deterioration of mental status resulting in cognitive impairment and acquisition of new functional limitations in sepsis survivors. However, the exact nature of brain injury in this setting is often subtle and remains to be fully characterized both in pre-clinical studies and at the bedside. Given the translation potential for the use of magnetic resonance imaging (MRI)1 to define sepsis-induced brain injury, we sought to determine and correlate the cellular changes with neuroradiographic presentations in a classic murine model of sepsis induced by cecal ligation and puncture (CLP)2. Sepsis was induced in 6–10-week-old male C57/BL6 mice by CLP. We used immunohistochemistry (IHC)3 to define neuropathology in a mouse model of sepsis along with parallel studies using MRI, focusing on cerebral edema, blood-brain barrier (BBB)4 disruption, and microglial activation on days 1 and 4 days after CLP. We demonstrate that septic mice had evidence of early axonal injury, inflammation and robust microglial activation on day 1 followed by cytotoxic edema on day 4 in the cortex, thalamus, and hippocampus in the absence of BBB disruption. We note the superiority of the MRI to detect subtle brain injury and cytotoxic cerebral edema in comparison to the traditional gold standard assessment, i.e., percent brain water (wet-dry weight method). We conclude that inflammatory changes in the septic brain can be detected in real-time, and further studies are needed to understand axonal injury and the impact of inhibition of microglial activation on the development of cerebral edema. Address reprint requests to Rajesh K. Aneja, MD, University of Pittsburgh, Pittsburgh, PA, United States. E-mail: anejar@upmc.edu Received 16 May, 2019 Revised 5 June, 2019 Accepted 30 August, 2019 This study was supported by: Shock Society Research Investigator Award for Early Scientists (DP) NICHD T32 training grant 5T32HD040686 (DP, AMA, PMK) NIGMS R01GM098474 (RKA) NINDS NS 087978 (PMK) Department of Defense (DoD) W81XWH1810070 (YLW) American Heart Association (AHA) 18CDA34140024 (YLW) This work was presented at the Shock Society 39th Annual Conference on Shock; June 11-14, 2016; Austin, TX. 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

Pharmacokinetics, Pharmacodynamics and Safety of Nivolumab in Patients With Sepsis-induced immunosuppression: A multicenter, open-label phase 1/2 study Background: Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers. Methods: In this multicenter, open-label phase 1/2 study, a single 480 or 960 mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis. Doses were selected to mimic the exposure achieved with the approved dosage for cancer patients (3 mg/kg every 2 weeks [Q2W]). Results: Single 480 and 960 mg nivolumab doses were intravenously infused into five and eight patients, respectively. The maximum concentration after 480 mg (132 μg/mL) was similar to the predicted concentration at the end of infusion with 3 mg/kg Q2W (117 μg/mL). The concentration on Day 28 after 960 mg (33.1 μg/mL) was within the predicted trough concentration range for 3 mg/kg Q2W (90% prediction interval 19.0 to 163 μg/mL). Absolute lymphocyte counts and monocyte human leukocyte antigen-DR subtype expression levels appeared to increase over time. The incidences of adverse events (AEs) were 80% and 50% in the 480 and 960 mg groups, respectively. Drug-related AEs were observed in only one patient in the 480 mg group. No deaths related to nivolumab occurred. Conclusions: A single dose of 960 mg nivolumab appeared to be well-tolerated and sufficient to maintain nivolumab blood concentrations. Both 480 and 960 mg nivolumab seemed to improve immune system indices over time. Trial registration: JAPIC, JapicCTI-173600 Address reprint requests to Eizo Watanabe, MD, PhD, Department of General Medical Science, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo, Chiba 260-8670, Japan. E-mail: watanabee@faculty.chiba-u.jp Received 28 May, 2019 Revised 14 June, 2019 Accepted 23 August, 2019 Conflicts of interest and source of funding: This study was funded by Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb. Ono Pharmaceutical Co., Ltd. was involved in the design of the study; collection, analysis, and interpretation of data; and in drafting the manuscript. Bristol-Myers Squibb did not have a role in the study design; data collection, analysis and interpretation; nor writing of the manuscript. EW received personal fees and non-financial support from Ono Pharmaceutical Co., Ltd., during the conduct of the study; and grants, personal fees and non-financial support from Asahi Kasei Pharma, and personal fees from Alexion Pharma, outside the submitted work. ON received grants and personal fees from Ono Pharmaceutical Co., Ltd., during the conduct of the study; and grants from Maruishi Pharmaceutical Co., Ltd., Fuso Pharmaceutical Industries, Ltd., Asahi Kasei Pharma, and Japan Blood Products Organization, outside the submitted work. YK received personal fees from Ono Pharmaceutical Co., Ltd., during the conduct of the study; and grants and personal fees from Ono Pharmaceutical Co., Ltd., grants from Japan Blood Products Organization, and grants from Asahi Kasei Pharma, outside the submitted work. MO, TO and TH received personal fees from Ono Pharmaceutical Co., Ltd., during the conduct of the study. SO received personal fees from Ono Pharmaceutical Co., Ltd., during the conduct of the study; and personal fees from Ono Pharmaceutical Co., Ltd., outside the submitted work. 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

Critical Role of Mortalin/GRP75 In Endothelial Cell Dysfunction Associated With Acute Lung Injury Mortalin/GRP75 (glucose regulated protein 75), a member of heat shock protein 70 (Hsp70) family of chaperones, is involved in several cellular processes including proliferation and signaling, and plays a pivotal role in cancer and neurodegenerative disorders. In this study, we sought to determine the role of mortalin/GRP75 in mediating vascular inflammation and permeability linked to the pathogenesis of acute lung injury (ALI). In an aerosolized bacterial lipopolysaccharide (LPS) inhalation mouse model of ALI, we found that administration of mortalin/GRP75 inhibitor MKT-077, both prophylactically and therapeutically, protected against PMN influx into alveolar airspaces, microvascular leakage and expression of pro-inflammatory mediators such as IL-1β, E-selectin and TNFα. Consistent with this, thrombin-induced inflammation in cultured human endothelial cells (EC) was also protected upon before and after treatment with MKT-077. Similar to pharmacological inhibition of mortalin/GRP75, siRNA-mediated depletion of mortalin/GRP75 also blocked thrombin-induced expression of proinflammatory mediators such as ICAM-1 and VCAM-1. Mechanistic analysis in EC revealed that inactivation of mortalin/GRP75 interfered with the binding of the liberated NF-κB to the DNA, thereby leading to inhibition of downstream expression of adhesion molecules, cytokines and chemokines. Importantly, thrombin-induced Ca2+ signaling and EC permeability were also prevented upon mortalin/GRP75 inactivation/depletion. Thus, this study provides evidence for a novel role of mortalin/GRP75 in mediating EC inflammation and permeability associated with ALI. Address reprint requests to Fabeha Fazal, PhD, Department of Pediatrics, Box 850, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642. E-mail: Fabeha_Fazal@URMC.Rochester.edu Received 8 May, 2019 Revised 24 May, 2019 Accepted 29 August, 2019 Author contributions: F.F, A.L. and A.R. conceived and designed the experiments. A.L and P.S performed the experiments (equal contribution). F.F analyzed the data and drafted the manuscript. F.F, D.Y and A.R edited and approved the final version of the manuscript. Conflict of interest: No conflict of interest, financial or otherwise, are declared by the authors The authors declare that they have no competing interests. © 2019 by the Shock Society

Venous-To-Arterial Carbon Dioxide Partial Pressure Difference: Predictor of Septic Patient Prognosis Depending on Central Venous Oxygen Saturation This study aimed to assess the viability of using the venous-to-arterial carbon dioxide partial pressure difference (P(v–a)CO2) to predict clinical worsening of septic shock, depending on central venous oxygen saturation (ScvO2). The prospective, observational, multicentric study conducted in three intensive care units (ICU) included all patients with a septic shock episode during the first six hours, with 122 patients assessed. Clinical worsening was defined as an increase of sequential organ failure assessment (SOFA) scores ≥1 (ΔSOFA ≥1) within two days. To assess the ability of P(v–a)CO2 to predict clinical worsening, univariate and multivariate analyses were performed according to ΔSOFA. A receiver operating characteristic (ROC) analysis was used to confirm model predictions. Associations between P(v–a)CO2 and mortality were explored using correlations. Using multivariate analyses, two independent factors associated with ΔSOFA ≥1 were identified: an averaged six-hour value of lactate concentration (Lac [1–6]) (odds ratios [OR], 2.43 [95% confidence interval (CI), 1.20–4.89]; p = 0.013) and an averaged six-hour value of P(v–a)CO2 (P(v–a)CO2 [1–6]) (OR, 1.49 [95% CI, 1.04–2.15]; p = 0.029). ROC analysis confirmed that Lac [1–6] and P(v–a)CO2 [1–6] were significantly associated with ΔSOFA ≥1, while ScvO2 [1–6] was not. Finally, ΔSOFA ≥1 was associated with higher 28-day (76% vs. 10%, p = 0.001) and ICU (83% vs. 12%, p = 0.001) mortality rates, which were higher in patients with P(v–a)CO2 [1–6] > 5.8 mmHg (57% vs. 33%; p = 0.012). In conclusion, P(v–a)CO2 may help predict outcomes for septic shock patients regardless of ScvO2 values. Address reprint requests to Marc Leone, MD, PhD, Service d’Anesthésie et de Réanimation, Hôpital Nord, Chemin des Bourrely, 13015 Marseille, France. E-mail: marc.leone@ap-hm.fr Received 4 June, 2019 Revised 26 June, 2019 Accepted 23 August, 2019 Conflicts of interest and source of funding: No conflict of interest in relation to the submitted study. Funding: Assistance Publique Hôpitaux de Marseille This paper contains sufficient information to comply with the ARRIVE guidelines. 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

Association of Vitamin D Deficiency with Profound Cardiogenic Shock In Patients Resuscitated from Sudden Cardiac Arrest Background: Vitamin D deficiency is associated with various cardiovascular diseases, including sudden cardiac arrest (SCA). Profound cardiogenic shock is associated with morbidity and mortality in patients with SCA. This study investigated the association of vitamin D deficiency with profound cardiogenic shock in patients resuscitated from SCA. Materials and Methods: We enrolled patients who were successfully resuscitated from out-of-hospital cardiac arrests of a presumed cardiac cause. Profound cardiogenic shock was defined as refractory hypotension requiring high-dose vasopressor infusion (norepinephrine >0.5 mcg/kg/min) despite adequate intravascular volume replacement. Vitamin D levels were measured as plasma 25(OH)D concentrations and severe vitamin D deficiency was defined as 25(OH)D <10 ng/mL. Results: A total of 237 subjects (179 men (76%), mean age 56.5 ± 16.5 years) were included in this study. The first monitored rhythm was shockable in 160 subjects (68%). Mean arrest time and CPR times were 25.6 ± 15.7 and 22.8 ± 15.0 minutes, respectively. Profound cardiogenic shock was observed in 100 subjects (42%). The mean vitamin D level was 12.3 ± 6.7 ng/mL, and vitamin D deficiency was diagnosed in 109 subjects (46%). In profound cardiogenic shock subjects, vitamin D levels were significantly lower (10.7 ± 7.0 vs. 13.4 ± 6.2 ng/mL, p = 0.002) and severe vitamin D deficiency was observed more frequently (63% vs. 34%, p < 0.001). Subjects with profound cardiogenic shock were likely to have longer arrest times (29.5 ± 17.0 vs. 22.7 ± 14.0 minutes, p = 0.001), left ventricular systolic dysfunction (LVEF < 40%, 73% vs. 38%, p < 0.001), and baseline renal dysfunction (65% vs. 37%, p < 0.001). Multivariate logistic analysis indicated that vitamin D deficiency was significantly associated with profound cardiogenic shock after SCA (OR 2.71, 95% CI 1.42–5.18, p = 0.003) after adjusting for confounding variables. Conclusions: Severe vitamin D deficiency was strongly associated with profound cardiogenic shock and mortality in patients resuscitated from SCA. Address reprint requests to Jin Wi, MD, PhD, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon, Korea 21565. E-mail: caesar@gilhospital.com Received 10 July, 2019 Revised 4 August, 2019 Accepted 23 August, 2019 Conflict of interest: The authors have no financial conflicts of interest. © 2019 by the Shock Society