Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response after Out-of-Hospital Cardiac Arrest (IMICA): study protocol for a double-blinded, placebo-controlled, single-center, randomized clinical trial

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 interleukin-6 (IL-6), a pro-inflammatory cytokine, is associated with worse outcomes in OHCA patients, including higher vasopressor requirements and higher mortality rates. In this study, we aim to reduce systemic inflammation after OHCA by administering a single infusion of tocilizumab, an IL-6 receptor antibody approved for use for other indications. Methods Investigator-initiated, double-blinded, placebo-controlled, single-center, randomized clinical trial in comatose OHCA patients admitted to an intensive cardiac care unit. Brief inclusion criteria: OHCA of presumed cardiac cause, persistent unconsciousness, age ≥ 18 years. Intervention: 80 patients will be randomized in a 1:1 ratio to a single 1-h intravenous infusion of either tocilizumab or placebo (NaCl). During the study period, patients will receive standard of care, including sedation and targeted temperature management of 36 ° for at least 24 h, vasopressors and/or inotropes as/if needed, prophylactic antibiotics, and any additional treatment at the discretion of the treating physician. Blood samples are drawn for measurements of biomarkers included in the primary and secondary endpoints during the initial 72 h. Primary endpoint: reduction in C-reactive protein (CRP). Secondary endpoints (abbreviated): cytokine levels, markers of brain, cardiac, kidney and liver damage, hemodynamic and hemostatic function, adverse events, and follow-up assessment of cerebral function and mortality. Discussion We hypothesize 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 lessened vasopressor use, more normal hemodynamics, and better organ function. This will be assessed by primarily focusing on hemodynamics and biomarkers of organ damage during the initial 72 h. In addition, pro-inflammatory and anti-inflammatory cytokines will be measured to assess if cytokine patterns are modulated by IL-6 receptor blockage. Trial registration ClinicalTrials.gov Identifier: NCT03863015; submitted February 22, 2019, first posted March 5, 2019. EudraCT: 2018-002686-19; date study was authorized to proceed: November 7, 2018.

Cardiovascular disease and COVID-19: a consensus paper from the ESC Working Group on Coronary Pathophysiology & Microcirculation, ESC Working Group on Thrombosis and the Association for Acute CardioVascular Care (ACVC), in collaboration with the European Heart Rhythm Association (EHRA)

“…Further in a recent phase II trial, blocking of IL-6 signalling pathway with tocilizumab, reduced systemic inflammation after cardiac arrest and showed an apparent cardioprotective effect. 192 The same reasoning applies to LQTS and Torsades de Pointes. 174,180 Finally, in high prevalence areas it reasonable to encourage compression only resuscitation and public access defibrillation of adults with OHCA for lay people, as it has already been implemented in many first responder programmes in Europe.…”

High Oxygenation During Normothermic Regional Perfusion After Circulatory Death Is Beneficial on Donor Cardiac Function in a Porcine Model

“…Several compounds have been investigated in mitigating the inflammatory damage from cardiac arrest in both animal models and clinical trials. [25][26][27] These compounds may play an important role in the future for DCD HTX. Simple means to combat inflammatory damage in HTX has been investigated in porcine models comprising of hypertonic saline infusion to the donor and recipient 28,29 which showed promising results in attenuation inflammatory and ischemic damage from organ donation and transplantation; the method has, however, not been investigated in a DCD setting.…”

Single-cell transcriptomics reveal hyperacute cytokine and immune checkpoint axis in patients with poor neurological outcomes after cardiac arrest

“…Most clinical trials used untargeted treatments, such as corticosteroids and targeted temperature management, and have had mixed efficacy on outcomes (Donnino et al, 2016; Shah and Mitra, 2021). A recent clinical trial in cardiac arrest showed that the IL-6 receptor antagonist tocilizumab reduced plasma C reactive protein levels and myocardial injury, but tocilizumab did not improve survival or neurological outcomes (Meyer et al, 2021). We did identify an IL-6 response in monocytes associated with poor neurological outcome, but we also found a strong association between other inflammatory cytokines, such as IFNγ and TNFα, and neurological injury.…”