Abstract 10169: Changes in Cytokine Responses by Treatment with Tocilizumab After Out-of-Hospital Cardiac Arrest - A Sub Study of the IMICA Trial

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Martin A Meyer ◽  
Mette Bjerre ◽  
Sebastian Wiberg ◽  
Johannes Grand ◽  
Anna Sina P Meyer ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Systemic Inflammation ◽  
Gm Csf ◽  
Cytokine Responses ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Trial Treatment ◽  
Interleukin 6 Receptor ◽  
Post Cardiac Arrest Syndrome ◽  
Hospital Cardiac Arrest

Background: Out-of-hospital cardiac arrest (OHCA) patients are at high risk of morbidity and mortality attributable to the post-cardiac arrest syndrome, in which systemic inflammation is a major component. Cytokines are involved in many processes, including inflammation. In the IMICA trial, treatment with the interleukin 6 receptor (IL-6R) antagonist tocilizumab in resuscitated comatose OHCA patients reduced systemic inflammation as characterized by a greatly reduced CRP response and lower levels of leukocytes as compared to placebo. Markers of myocardial injury were also reduced by treatment. Aim: To investigate changes in cytokine levels induced by blocking the IL-6-mediated signaling with tocilizumab after OHCA by employing a broad cytokine panel. Methods: We randomized 80 patients to a single infusion of tocilizumab 8 mg/kg or placebo after admission. Blood samples were drawn at 0, 24, 48, and 72 hours. Cytokines were measured using a 17-plex cytokine assay: G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1β, TNF-α, IL- 1β, 2, 4-8, 10, 12, 13, and 17. Data were log2 transformed and analyzed by constrained linear mixed models. Results: Most cytokines had temporal changes after OHCA. However, only for IL- 5, 6 (Figure) and 17 were the treatment-by-time interactions significant, all p<0.05. Circulating IL-5 and in particular IL-6 was markedly increased by inhibition of the IL-6R with tocilizumab as compared to the placebo group. For IL-17 the changes were less pronounced and only differed between groups at 72 hours. Conclusions: Treatment with the IL-6R antagonist, tocilizumab, did not alter the cytokine responses in general, however, IL-5 and IL-6 were markedly increased. Experimental data suggests that IL-5 may play a role in cardiac recovery after ischemia. Blockage of the IL-6R greatly increased the IL-6 levels, and as the CRP response was greatly reduced by tocilizumab, a response strongly associated with IL-6, it can be demonstrated that the function of IL-6 was blunted.

scholarly journals Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response after Out-of-Hospital Cardiac Arrest (IMICA): study protocol for a randomized clinical trial

2019 ◽  
Author(s):  
Martin A. S. Meyer ◽  
Sebastian Wiberg ◽  
Johannes Grand ◽  
Jesper Kjaergaard ◽  
Christian Hassager
Keyword(s):  
Clinical Trial ◽  
Cardiac Arrest ◽  
Inflammatory Response ◽  
Systemic Inflammation ◽  
Interleukin 6 ◽  
Systemic Inflammatory Response ◽  
Receptor Antibody ◽  
Cytokine Levels ◽  
Interleukin 6 Receptor ◽  
Hospital Cardiac Arrest

Abstract Background: Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose at admission are at high risk of morbidity and mortality. This has been attributed to the post-cardiac arrest syndrome (PCAS) which encompasses multiple interacting components, including systemic inflammation. Elevated levels of circulating interlukin-6 (IL-6), a pro-inflammatory cytokine, is associated with worse outcomes in OHCA patients, including, higher vasopressor requirements and higher mortality rates. For other indications, an IL-6 receptor antibody, tocilizumab has been approved. In this study we aim to reduce systemic inflammation after OHCA by administering a single infusion of tocilizumab. Methods: Investigator-initiated, randomized, double blind, placebo-controlled clinical trial in OHCA patients remaining unconscious after hospital admission. Intervention: Intravenous administration of an interleukin-6 receptor antibody (IL-6RA), tocilizumab, or placebo after admission. Primary endpoint: reduction in C-reactive protein (CRP). Secondary endpoints (abbreviated): cytokine levels, markers of brain, cardiac, kidney and liver damage, and hemodynamic and haemostatic function, adverse events, as well as follow-up assessment of cerebral function and mortality. Discussion: We hypothesise that reducing the effect of circulating IL-6 by administering an IL-6 receptor antibody will mitigate the systemic inflammatory response and thereby modify the severity of PCAS, in turn leading to decreased need of vasopressor support, more normal hemodynamics, as well as better organ function. A previous trial of IL6-RA in patients with non-ST elevation myocardial infarction showed a reduction in CRP and troponin levels, as well as a change in cytokine levels. Following these findings, we will be measuring a range of both pro-inflammatory and anti-inflammatory cytokines to possibly reveal a change in cytokine patterns following blockage of the IL-6 receptor, as well as investigate whether IL-6RA leads to reduced organ damage. Infection after OHCA is not uncommon and IL6-RA has previously been shown to increase the frequency of infections. Accordingly, we will monitor for infections, and patients will be treated with prophylactic antibiotics. Trial registration: ClinicalTrials.gov Identifier: NCT03863015; submitted February 22 2019, first posted March 5, 2019. EudraCT: 2018-002686-19; First entered August 10 2019.

Effects of Targeted Temperature Management in Patients with Post-Cardiac Arrest Syndrome after an Out-Of-Hospital Cardiac Arrest Caused by Hanging: A Prospective Observational Cohort Study in Japan

2021 ◽  
Author(s):  
Ryuichiro Kakizaki ◽  
Naofumi Bunya ◽  
Shuji Uemura ◽  
Takehiko Kasai ◽  
Keigo Sawamoto ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Cardiac Arrest ◽  
Propensity Score ◽  
Multivariate Logistic Regression Analysis ◽  
Targeted Temperature Management ◽  
Temperature Management ◽  
Matched Cohort ◽  
Neurological Outcomes ◽  
Post Cardiac Arrest Syndrome ◽  
Hospital Cardiac Arrest

Abstract Background: Targeted temperature management (TTM) is recommended for unconscious patients after a cardiac arrest. However, its effectiveness in patients with post-cardiac arrest syndrome (PCAS) by hanging remains unclear. Therefore, this study aimed to investigate the relationship between TTM and favorable neurological outcomes in patients with PCAS by hanging.Methods: This study was a retrospective analysis of the Japanese Association for Acute Medicine out-of-hospital cardiac arrest (OHCA) registry between June 2014 and December 2017 among patients with PCAS admitted to the hospitals after an OHCA caused by hanging. A multivariate logistic regression analysis was performed to estimate the propensity score and to predict whether patients with PCAS by hanging receive TTM. We compared patients with PCAS by hanging who received TTM (TTM group) and those who did not (non-TTM group) using propensity score analysis.Results: A total of 199 patients with PCAS by hanging were enrolled in this study. Among them, 43 were assigned to the TTM group and 156 to the non-TTM group. Logistic regression model adjusted for propensity score revealed that TTM was not associated with favorable neurological outcome at 1-month (adjusted odds ratio [OR]: 1.38, 95% confidence interval [CI]: 0.27–6.96). Moreover, no difference was observed in the propensity score-matched cohort (adjusted OR: 0, 73, 95% CI: 0.10–4.71) and in the inverse probability of treatment weighting-matched cohort (adjusted OR: 0.63, 95% CI: 0.15–2.69).Conclusions: TTM was not associated with increased favorable neurological outcomes at 1-month in patients with PCAS after OHCA by hanging.

scholarly journals Cytokine dysregulation persists in childhood post Neonatal Encephalopathy

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zunera Zareen ◽  
Tammy Strickland ◽  
Victoria Mc Eneaney ◽  
Lynne A. Kelly ◽  
Denise McDonald ◽  
...  
Keyword(s):  
School Age Children ◽  
Therapeutic Window ◽  
School Age ◽  
Neonatal Encephalopathy ◽  
Gm Csf ◽  
Cytokine Responses ◽  
Tnf Α ◽  
Cytokine Dysregulation ◽  
Macrophage Colony

Abstract Background Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls. Method Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF β, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin). Results GM-CSF, TNF-β, IL-2 IL-6 and IL-8 were significantly elevated at school age following NE (n = 40) compared to controls (n = 37). A rise in GM-CSF, IL-8, TNF-α, IL-1β, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-β. Elevated TNF-β was associated with low gross motor scores on assessment at school age. Conclusion School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-β was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for neuroprotection therapies.

scholarly journals The post-cardiac arrest syndrome: A case for lung–brain coupling and opportunities for neuroprotection

2019 ◽  
Vol 39 (6) ◽  
pp. 939-958 ◽  
Author(s):  
Nguyen Mai ◽  
Kathleen Miller-Rhodes ◽  
Sara Knowlden ◽  
Marc W Halterman
Keyword(s):  
Cardiac Arrest ◽  
Reperfusion Injury ◽  
Systemic Inflammation ◽  
Short Circuit ◽  
Spontaneous Circulation ◽  
Innate Immune ◽  
Neurological Injury ◽  
Temperature Management ◽  
Immune Priming ◽  
Post Cardiac Arrest Syndrome

Systemic inflammation and multi-organ failure represent hallmarks of the post-cardiac arrest syndrome (PCAS) and predict severe neurological injury and often fatal outcomes. Current interventions for cardiac arrest focus on the reversal of precipitating cardiac pathologies and the implementation of supportive measures with the goal of limiting damage to at-risk tissue. Despite the widespread use of targeted temperature management, there remain no proven approaches to manage reperfusion injury in the period following the return of spontaneous circulation. Recent evidence has implicated the lung as a moderator of systemic inflammation following remote somatic injury in part through effects on innate immune priming. In this review, we explore concepts related to lung-dependent innate immune priming and its potential role in PCAS. Specifically, we propose and investigate the conceptual model of lung–brain coupling drawing from the broader literature connecting tissue damage and acute lung injury with cerebral reperfusion injury. Subsequently, we consider the role that interventions designed to short-circuit lung-dependent immune priming might play in improving patient outcomes following cardiac arrest and possibly other acute neurological injuries.

scholarly journals Post-cardiac arrest syndrome in adult hospitalized patients

2021 ◽  
Author(s):  
Estivalis G. Acosta-Gutiérrez ◽  
Andrés M. Alba-Amaya ◽  
Santiago Roncancio-Rodríguez ◽  
José Ricardo Navarro-Vargas
Keyword(s):  
Cardiac Arrest ◽  
Latin American ◽  
Myocardial Dysfunction ◽  
Spontaneous Circulation ◽  
Neurologic Recovery ◽  
One Year ◽  
Meta Analyses ◽  
Post Cardiac Arrest Syndrome ◽  
Hospital Cardiac Arrest

Adult In-hospital Cardiac Arrest (IHCA) is defined as the loss of circulation of an in-patient. Following high-quality cardiopulmonary resuscitation (CPR), if the return of spontaneous circulation (ROSC) is achieved, the post-cardiac arrest syndrome develops (PCAS). This review is intended to discuss the current diagnosis and treatment of PCAS. To approach this topic, a bibliography search was conducted through direct digital access to the scientific literature published in English and Spanish between 2014 and 2020, in MedLine, SciELO, Embase and Cochrane. This search resulted in 248 articles from which original articles, systematic reviews, meta-analyses and clinical practice guidelines were selected for a total of 56 documents. The etiologies may be divided into 56% of in-hospital cardiac, and 44% of non-cardiac arrests. The incidence of this physiological collapse is up to 1.6 cases/1,000 patients admitted, and its frequency is higher in the intensive care units (ICU), with an overall survival rate of 13% at one year. The primary components of PCAS are brain injury, myocardial dysfunction and the persistence of the precipitating pathology. The mainstays for managing PCAS are the prevention of cardiac arrest, ventilation support, control of peri-cardiac arrest arrythmias, and interventions to optimize neurologic recovery. A knowledgeable healthcare staff in PCAS results in improved patient survival and future quality of life. Finally, there is clear need to do further research in the Latin American Population.

scholarly journals Cytokine Dysregulation Persists in Childhood Post Neonatal Encephalopathy

2019 ◽  
Author(s):  
Zunera Zareen ◽  
Tammy Strickland ◽  
Victoria Mc Eneaney ◽  
Lynne A. Kelly ◽  
Denise McDonald ◽  
...  
Keyword(s):  
Significant Rise ◽  
School Age Children ◽  
Therapeutic Window ◽  
School Age ◽  
Neonatal Encephalopathy ◽  
Gm Csf ◽  
Cytokine Responses ◽  
Tnf Α ◽  
Cytokine Dysregulation

Abstract Objective: Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls. Method: Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF β, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin). Results: GM­-CSF, TNF-β, IL-2 IL-6, IL-8, IL-10, and IL-18 were significantly elevated at school age following NE (n=40) compared to controls (n=37). A significant rise in GM-CSF, IL-8, TNF-α, IL-1β, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-β. Elevated TNF-β was associated with low gross motor scores on assessment at school age. Conclusion: School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-β was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for immunomodulatory adjunctive therapies.

scholarly journals Cytokine Analysis in 154 Patients with Transient Abnormal Myelopoiesis: Jccg JPLSG TAM-10 Clinical Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2362-2362
Author(s):  
Genki Yamato ◽  
Myoung-Ja Park ◽  
Akira Shimada ◽  
Norio Shiba ◽  
Yoshiyuki Yamada ◽  
...  
Keyword(s):  
Growth Factor ◽  
Early Death ◽  
Therapeutic Interventions ◽  
P Value ◽  
Gm Csf ◽  
Transient Abnormal Myelopoiesis ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Wbc Count ◽  
Stimulating Factor

Abstract Introduction: Transient abnormal myelopoiesis (TAM), also known as transient leukemia or transient myeloproliferative disorder, is a unique clonal myeloproliferation characterized by immature megakaryoblasts occurring in 10% of neonates with Down syndrome. Although most patients show spontaneously resolution of TAM without therapeutic interventions, approximately 20% of TAM cases result in early deaths, i.e., within 9 months, and approximately 20% of the survivors develop acute megakaryoblastic leukemia (AMKL) within 4 years. A somatic GATA1 gene mutation that leads to the exclusive expression of a truncated GATA1 protein is shared by both TAM and AMKL cells. According to previous reports, cytokine levels are associated with liver failure, which is a cause of early death. Here, we analyzed 154 DS patients with TAM enrolled in the TAM-10 prospective observational study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group to determine the association between clinical characteristics and cytokine levels in such patients. Patients and Methods: A total of 167 neonates (89 boys and 78 girls) diagnosed with TAM were prospectively registered in the TAM-10 study between May 2011 and February 2014. We analyzed cytokine levels in 154 of the 167 enrolled patients whose samples were available. Somatic GATA1 gene mutations were confirmed in 151 (98%) of 154 patients using Sanger and/or next-generation sequencing. Using the Bio-Prex cytokine assay, serum concentrations of the following 27 cytokines were measured: interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins alpha and beta (MIP-1α and MIP-1β), eotaxin, interferon gamma-induced protein (IP-10), regulated upon activation, normal T-cell expressed and secreted, interleukin I receptor agonist (IL-RA), and 13 different interleukins (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, and IL-17). For all analyses, P values were two-tailed and a P value of &lt;0.05 was considered statistically significant. Mann-Whitney test were used as appropriate for comparisons between groups. Moreover, the cumulative incidence for competing events was compared with the Gray test. Results: The median (range) white blood cell (WBC) count at diagnosis was 37.2 (2.4-478.7) × 10 9 cells/L. Forty-seven (31%) of 154 patients received low-dose cytarabine. When we compared 29 patients with a high WBC count (≥100 × 10 9 cells/L, known as a poor prognostic factor in TAM patients) to 125 patients without a high WBC count for 27 cytokine levels, the levels of 16 cytokines (IL-1b, IL-1ra, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, Eotaxin, PDGF-bb, basic FGF, G-CSF, GM-CSF, MCP-1b, and VEGF) were significantly higher in patients with a high WBC group. Early death occurred in 14 (9%) of 154 patients. Cytokine levels were compared between the early death group (n = 14) and remaining patients (n = 140) and it was observed that the levels of 10 cytokines (IL-1b [p = 0.016], IL-1ra [p &lt; 0.001], IL-6 [p &lt; 0.001], IL-7 [p = 0.009], IL-8 [p &lt; 0.001], IL-10 [p = 0.014], IL-13 [p = 0.002], MCP-1 [p = 0.030], MIP-1b [p = 0.024], and TNF-α [p = 0.008]) were significantly higher in the early death group. When the patients were divided in two groups according to the median IL-1β concentration showing the lowest p-value, the early death rate in the IL-1β high group was significantly higher than that in the IL-1β low group (16% vs. 3%, p &lt; 0.001). IL-1, IL-6, IL-8, and TNF-α are proinflammatory cytokines induced by MCP-1 and MIP1-b. Early death was strongly associated with hypercytokinemia, suggesting that therapeutic interventions (e.g., systemic steroid therapy) may be effective in patients with hypercytokinemia. However, there was no relation between the levels of 27 cytokines and leukemia development. Conclusion: Our findings suggested that measurement of cytokine levels may be a useful marker for predicting early death and an indicator of therapeutic interventions required in TAM patients. Disclosures No relevant conflicts of interest to declare.

Abstract 140: Effects of ω-3 Polyunsaturated Fatty Acids on Systemic Inflammation and Post-resuscitation Myocardial Function in a Rat Model of Cardiac Arrest and Cardiopulmonary Resuscitation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_4) ◽  
Author(s):  
Cheng Cheng ◽  
Hui Li ◽  
Tao Jin ◽  
Lian Liang ◽  
Guozhen Zhang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cardiac Arrest ◽  
Polyunsaturated Fatty Acids ◽  
Systemic Inflammation ◽  
Rat Model ◽  
Myocardial Function ◽  
Myocardial Dysfunction ◽  
Spontaneous Circulation ◽  
Sprague Dawley ◽  
Tnf Α

Introduction: Massive systemic inflammation is a primary cause of myocardial dysfunction following cardiac arrest (CA) and resuscitation (CPR). We investigated the effects of ω-3 polyunsaturated fatty acids (ω-3 PUFA) on systemic inflammation and myocardial function after CA and CPR. Hypothesis: Administration of ω-3 PUFA at the start of CPR will alleviate post CPR inflammation and improve cardiac function in a rat model of CA and CPR. Methods: 18 male Sprague-Dawley rats weighing between 450g-550g were randomized into three groups: Sham, Control, and ω-3 PUFA. Ventricular fibrillation (VF) was induced and untreated for 6 min. 4J defibrillation was attempted after 8 min of CPR. Saline placebo or ω-3 PUFA (5mL/kg) was infused at the start of CPR and continued for 4h. Ejection fraction (EF), cardiac output (CO) and myocardial performance index (MPI) were measured by echocardiography at baseline, 1, 3 and 6h after return of spontaneous circulation (ROSC). Inflammatory cytokines (IL-6 and TNF-α) and cardiac biomarker (cTnI) levels in plasma were detected at baseline and 6 hrs after ROSC. Results: A decrease in EF and CO and an increase in MPI occurred after resuscitation. Significant improvement was noted in ω-3 PUFA compared to control animals (p<0.05) (Fig. 1). ELISA analysis showed increased plasma IL-6, TNF-α, and cTnI in post-resuscitated rats. Administration of ω-3 PUFA attenuated the rise in these plasma biomarkers (p<0.05) (Fig. 2). Conclusion: Administration of ω-3 PUFA attenuates post-resuscitation systemic inflammation and improves myocardial function in a rat model of CA and CPR.

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