“Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA): Safety and efficacy of low-dose Iloprost, a prostacyclin analogue, in addition to standard therapy, as compared to standard therapy alone, in post-cardiac-arrest-syndrome patients.”

Meyer, Anna S.P.; Johansson, Pär I.; Kjærgaard, Jesper; Frydland, Martin; Meyer, Mechthild; Henriksen, H; Thomsen, Jakob Hartvig; Wiberg, Sebastian; Hassager, Christian; Ostrowski, Sisse Rye

doi:10.1016/j.ahj.2019.10.002

Cited by 17 publications

(9 citation statements)

References 44 publications

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“…No interaction between the prostacyclin and blood pressure intervention was seen regarding sTM ( p interaction bloodpressure*Iloprost =0.65), and norepinephrine doses were similar between patients receiving Iloprost and placebo (p=0.87, as published previously). 22…”

Section: Resultsmentioning

confidence: 99%

“…This study entitled ‘Endothelial Dysfunction in Resuscitated Cardiac Arrest’ (ENDO-RCA) had a 2×2 factorial design and all patients were randomised to both a blood pressure intervention and a 48-hour 1 ng/kg/min Iloprost infusion versus placebo. The protocol has previously been published 21 and so have the Iloprost trial results, 22 which showed no effect of Iloprost on either the primary endpoints nor haemodynamics at 48 h. This article describes the blood pressure target intervention only.…”

Section: Methodsmentioning

confidence: 99%

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A randomised double-blind pilot trial comparing a mean arterial pressure target of 65 mm Hg versus 72 mm Hg after out-of-hospital cardiac arrest

Grand

Meyer

Kjærgaard

et al. 2020

European Heart Journal. Acute Cardiovascular Care

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Background: After resuscitation from out-of-hospital cardiac arrest, mean arterial pressure below 65 mm Hg is avoided with vasopressors. A higher blood-pressure target could potentially improve outcome. The aim of this pilot trial was to investigate the effect of a higher mean arterial pressure target on biomarkers of organ injury. Methods: This was a single-centre, double-blind trial of 50 consecutive, comatose out-of-hospital cardiac arrest patients randomly assigned in a 1:1 ratio to a mean arterial pressure target of 65 mm Hg (MAP65) or 72 mm Hg (MAP72). Modified blood pressure modules with a –10% offset were used, enabling a double-blind study design. End-points were biomarkers of organ injury including markers of endothelial integrity (soluble trombomodulin) brain damage (neuron-specific enolase) and renal function (estimated glomerular filtration rate). Results: Mean arterial pressure was significantly higher in MAP72 with a mean difference of 5 mm Hg ( pgroup=0.03). After 48 h, soluble trombomodulin (median (interquartile range)) was 8.2 (6.7–12.9) ng/ml and 8.3 (6.0–10.8) ng/ml ( p=0.29), neuron-specific enolase was 20 (13–31 μg/l) and 18 (13–44 μg/l) p=0.79) and estimated glomerular filtration rate (mean (±standard deviation)) was 61±19 ml/min/1.73m2 and 48±22 ml/min/1.73 m2 ( p=0.08) for the MAP72 and MAP65 groups, respectively. Renal replacement therapy was needed in eight patients (31%) in MAP65 and three patients (13%) in MAP72 ( p=0.14). Conclusions: Double-blind allocation to different mean arterial pressure targets is feasible in comatose out-of-hospital cardiac arrest patients. A mean arterial pressure target of 72 mm Hg compared to 65 mm Hg did not result in improved biomarkers of organ injury. We observed a trend towards preserved renal function in the MAP72 group.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A randomised double-blind pilot trial comparing a mean arterial pressure target of 65 mm Hg versus 72 mm Hg after out-of-hospital cardiac arrest

Grand

Meyer

Kjærgaard

et al. 2020

European Heart Journal. Acute Cardiovascular Care

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“… 32 Also, in a recent study in a similar patient cohort from our cardiac ICU, the frequency of RRT in the active and placebo group was 24% and 23%, respectively, and thus of the same magnitude as seen in the tocilizumab group in the present study. 33 …”

Section: Discussionmentioning

confidence: 99%

Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial)

et al. 2021

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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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“…The time necessary for including the intended 80 patients is estimated to be 1 year from enrollment of the first patient. This estimate is based on inclusion rates of three previous studies in OHCA patients carried out at the Department of Cardiology, Rigshospitalet [8,26,27].…”

Section: Recruitment {15}mentioning

confidence: 99%

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

Meyer

Wiberg

Grand

et al. 2020

Trials

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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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“Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA): Safety and efficacy of low-dose Iloprost, a prostacyclin analogue, in addition to standard therapy, as compared to standard therapy alone, in post-cardiac-arrest-syndrome patients.”

Cited by 17 publications

References 44 publications

A randomised double-blind pilot trial comparing a mean arterial pressure target of 65 mm Hg versus 72 mm Hg after out-of-hospital cardiac arrest

A randomised double-blind pilot trial comparing a mean arterial pressure target of 65 mm Hg versus 72 mm Hg after out-of-hospital cardiac arrest

Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial)

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

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