Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial): A Double-Blinded, Placebo-Controlled, Single-Center, Randomized Clinical Trial

Background: Out-of-hospital cardiac arrest (OHCA) patients who remain comatose after initial resuscitation are at high risk of morbidity and mortality due to the ensuing post cardiac arrest syndrome (PCAS). Systemic inflammation constitutes a major component of PCAS, and interleukin-6 (IL-6) levels are associated with PCAS severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in PCAS. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after OHCA of presumed cardiac cause and thereby potentially mitigate organ injury. Methods: Eighty comatose OHCA patients were randomized 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72h. Primary endpoint: reduction in C-reactive protein (CRP) response from baseline till 72h in patients treated with tocilizumab evaluated by mixed model analysis for a treatment-by-time interaction. Secondary endpoints (main): marker of inflammation: leukocytes, markers of myocardial injury: Creatine Kinase Myocardial Band (CKMB), Troponin T (TnT), and N-terminal pro B-type natriuretic peptide (NT-proBNP); marker of brain injury: neuron-specific enolase (NSE); these secondary endpoints were analyzed by mixed model analysis. Results: The primary endpoint of reducing the CRP response by tocilizumab was achieved as there was a significant treatment-by-time interaction, p<0.0001, and a profound effect on CRP levels. Systemic inflammation was reduced by treatment with tocilizumab as both CRP and leukocyte levels were markedly reduced, tocilizumab vs placebo at 24h: -84% [-90%;-76%] and -34% [-46%;-19%] respectively, both p<0.001. Myocardial injury was also reduced documented by reductions in CKMB and TnT; active vs. placebo at 12h: -36% [-54%;-11%] and -38% [-53%;-19%], respectively, both p<0.01. NT-proBNP was similarly reduced by active treatment; tocilizumab vs placebo at 48h: -65% [-80%;-41%], p<0.001. There were no differences in survival or neurological outcome. Conclusions: Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose resuscitated OHCA patients. Clinical Trial Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT03863015

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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

Trials ◽

10.1186/s13063-020-04783-4 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Martin A. S. Meyer ◽

Sebastian Wiberg ◽

Johannes Grand ◽

Jesper Kjaergaard ◽

Christian Hassager

Keyword(s):

Clinical Trial ◽

Cardiac Arrest ◽

Inflammatory Response ◽

Randomized Clinical Trial ◽

Systemic Inflammation ◽

Interleukin 6 ◽

Single Center ◽

Secondary Endpoints ◽

Double Blinded ◽

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 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.

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

10.21203/rs.2.19360/v1 ◽

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.

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Abstract 202: Video Laryngoscopy for Out of Hospital Cardiac Arrest

Circulation ◽

10.1161/circ.142.suppl_4.202 ◽

2020 ◽

Vol 142 (Suppl_4) ◽

Author(s):

Ryan M Huebinger ◽

Hutch Stilgenbauer ◽

Jeffrey L Jarvis ◽

Daniel Ostermayer ◽

Kevin Schulz ◽

...

Keyword(s):

Cardiac Arrest ◽

Success Rate ◽

Mixed Model ◽

Model Analysis ◽

Video Laryngoscopy ◽

Mixed Model Analysis ◽

Shockable Rhythm ◽

First Pass ◽

Bystander Cpr ◽

Hospital Cardiac Arrest

Introduction: Intubation is an essential component of cardiac arrest resuscitation. While prior studies have evaluated video laryngoscopy (VL) to assist intubation for in hospital cardiac arrest, there is a paucity of research evaluating VL for out of hospital cardiac arrest (OHCA). We sought to evaluate the association of video laryngoscopy with first pass success and ROSC. Hypothesis: Video laryngoscopy improves first pass success rate and improves the rate of ROSC Methods: We analyzed the 2018 data from ESO Inc. (Austin, TX), a national prehospital electronic health record used by 1289 EMS agencies in the US. We included all adult (age >18 years), non-traumatic cardiac arrests that were intubated with an endotracheal device. We applied a chi2 test to evaluate the first pass success rate for VL vs direct laryngoscopy (DL). We then created a mixed model, fitting agency as a random intercept and adjusting for age, gender, race, location of arrest, witnessed arrest, initial shockable rhythm, and bystander CPR. We applied the mixed model to analyze the association between VL and first pass success rate, ROSC, and sustained ROSC (survival to ED or ROSC for greater than 20 minutes). Results: We included 22,097 patients cared for by 914 agencies. 5,674 (25.7%) patients were intubated with video laryngoscopy. The median age was 66 (IQR 55-77). 61.9% of patients were male and 73.0% were white. 71.9% of cardiac arrest happened at home, 56.8% of were witnessed, 37.4% had bystander CPR, and 20.6% had a shockable rhythm. Compared to DL, VL had a lower rate of bystander CPR (41.4% v 36.1%, p<.001), but other characteristics were similar between the groups. We found that VL had a higher first pass success rate than DL (75.1% v 69.5%, p<.001). Using a mixed model analysis, VL was associated with a higher rate of first pass success (OR 1.5, CI 1.3-1.6), but VL was not associated with improvement in ROSC (OR 1.1, CI 0.97-1.2) or sustained ROSC (OR 1.1, CI 0.9-1.2). Conclusion: VL had a higher first pass success rate than DL, and on adjusted, mixed-model analysis, VL use was associated with increased rate of first pass success. However, VL was not associated with increased rate of ROSC

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Faculty Opinions recommendation of Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718040347.793485413 ◽

2013 ◽

Author(s):

Thomas Slaughter

Keyword(s):

Clinical Trial ◽

Cardiac Arrest ◽

Randomized Clinical Trial ◽

Hospital Cardiac Arrest

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Faculty Opinions recommendation of Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718040347.793482197 ◽

2013 ◽

Author(s):

David Gaieski

Keyword(s):

Clinical Trial ◽

Cardiac Arrest ◽

Randomized Clinical Trial ◽

Hospital Cardiac Arrest

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ReTEECA Trial. Rescue TransEsophageal Echocardiography for In-Hospital Cardiac Arrest.

10.21203/rs.3.rs-1233317/v1 ◽

2022 ◽

Author(s):

Asad Ali Usman ◽

Samantha Stein ◽

Audrey Spelde ◽

Felipe Teran-merino ◽

John Augoustides ◽

...

Keyword(s):

Clinical Trial ◽

Cardiac Arrest ◽

Transesophageal Echocardiography ◽

Hospital Discharge ◽

Phase Ii ◽

Point Of Care ◽

Phase Ii Clinical Trial ◽

Image Guided ◽

Hospital Cardiac Arrest

Abstract This trial is aimed at studying the utility and interventional outcomes of rescue transesophageal echocardiography (RescueTEE) to aid in diagnosis, change in management, and outcomes during CPR by using a point of care RescueTEE protocol in the evaluation of in-hospital cardiac arrest (IHCA). This is an interventional prospective convenience sampled partially blinded phase II clinical trial with primary outcomes of survival to hospital discharge (SHD) with RescueTEE image guided ACLS versus conventional ACLS.

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Abstract 26: Prevalence and Pattern of Myocardial Injury in Patients With Cardiac vs Non-Cardiac Cause of Out-Of-Hospital Cardiac Arrest: A One-Year Multicenter Clinical Experience With the High-Sensitivity Troponin T Assay

Circulation ◽

10.1161/circ.140.suppl_2.26 ◽

2019 ◽

Vol 140 (Suppl_2) ◽

Author(s):

David E Hamilton ◽

Bradley J Petek ◽

Lindsay G Panah ◽

Sean R Mendez ◽

Philip E Dormish ◽

...

Keyword(s):

Cardiac Arrest ◽

Myocardial Injury ◽

Troponin T ◽

Clinical Care ◽

High Sensitivity ◽

Severity Of Injury ◽

High Sensitivity Troponin T ◽

One Year ◽

Hospital Cardiac Arrest

Introduction: Myocardial injury is common after out-of-hospital-cardiac arrest (OHCA). However, little is known about the role of early serial hs-TnT in patients with OHCA for identifying myocardial injury, and whether the prevalence and severity of injury differs according to cardiac (CV) vs noncardiac (non-CV) cause of OHCA. Hypothesis: Early hs-TnT will demonstrate high rates of myocardial injury after OHCA regardless of etiology. However, in the first 6 hours after OHCA the extent of hs-TnT elevation and rate of rise will be higher in patients with CV vs non-CV etiology. Methods: Multicenter retrospective study including OHCA patients presenting from 4/1/2018 to 4/1/2019. Hs-TnT was drawn as part of routine clinical care. Results: Baseline hs-TnT was measured in 120 patients after OHCA due to CV (n=51) and non-CV (n=69) etiologies, with subsequent serial hs-TnT values at 1hr, 3hrs, and 6hrs. Hs-TnT was greater than the 99 th percentile in 97% (115/120) of patients and myocardial injury (hs-TnT> 52ng/L) was detected in 88% (105/120) of patients (no difference between CV vs non-CV etiology). Median hs-TnT values were compared between CV and non-CV etiologies of OHCA identifying no difference in hs-TnT at baseline (Figure: 54 [IQR 18-134] vs. 41 [IQR 19-100]; p=0.357) but significantly higher hs-TnT in patients with CV etiology at 1hr (159 [IQR 80-392] vs 93 [IQR 42-247]; p=0.049), 3hrs (400 [IQR 168-1005] vs 151 [IQR 75-401] p=0.009), and 6hrs (746 [IQR 248-1965] vs 251 [IQR 75-580]; p=0.001). Additionally, hs-TnT rise from baseline was present in both CV and non-CV etiologies but was significantly higher in patients with CV etiology (p = 0.005). Conclusions: As identified by hs-TnT, myocardial injury was prevalent in patients with both CV and non-CV cause of OHCA. Baseline hs-TnT was no different in patients with CV vs non-CV cause, however, over the first 6 hours both absolute value and rate of hs-TnT rise were significantly higher for patients with CV vs non-CV etiology of OHCA.

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