Admission interleukin-6 is associated with post resuscitation organ dysfunction and predicts long-term neurological outcome after out-of-hospital ventricular fibrillation

Vaahersalo, Jukka; Skrifvars, Markus B.; Pulkki, Kari; Stridsberg, Mats; Røsjø, Helge; Hovilehto, Seppo; Tiainen, Marjaana; Varpula, Tero; Pettilä, Ville; Ruokonen, Esko

doi:10.1016/j.resuscitation.2014.08.036

Cited by 60 publications

(53 citation statements)

References 32 publications

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“…However, level of inflammation has been associated with both endothelial disturbances, microcirculatory impairment and mortality (17,20,21). The magnitude of an early inflammatory response assessed by IL-6 associates with greater severity of organ dysfunction and adverse outcome, whereas procalcitonin and CRP are not elevated in the early time course after OHCA (12,22). The dynamic process of the inflammatory response is important to acknowledge when evaluating serial measurements of inflammatory markers as demonstrated by previous studies (23,24).…”

Section: Discussionmentioning

confidence: 96%

Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest

Bro-Jeppesen

Kjærgaard

Wanscher

et al. 2015

Critical Care Medicine

144

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Section: Discussionmentioning

confidence: 96%

Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest

Bro-Jeppesen

Kjærgaard

Wanscher

et al. 2015

Critical Care Medicine

144

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“…following elective surgery or in patients with pneumonia . Furthermore, IL‐6 levels are associated with organ failure and impaired (functional) outcome following severe injury, cardiac surgery, cardiac arrest, stroke and sepsis . With respect to renal function, IL‐6 plays a critical role in the development of AKI, independently predicting mortality in patients starting dialysis and predicting AKI following cardiac surgery .…”

Section: Discussionmentioning

confidence: 99%

A randomized double‐blind, placebo‐controlled clinical phase IIa trial on safety, immunomodulatory effects and pharmacokinetics of EA‐230 during experimental human endotoxaemia

Groenendael

Kox

Leijte

et al. 2019

Brit J Clinical Pharma

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Aims EA‐230 is a human chorionic gonadotropin hormone‐derived linear tetrapeptide, developed for the treatment of systemic inflammation‐related disorders. EA‐230 has shown promising immunomodulatory and tissue‐protective effects in animals and an excellent safety profile in human phase I studies that we performed. The present phase IIa study follows‐up on these results by investigating the safety, efficacy and pharmacokinetics of EA‐230 under systemic inflammatory conditions induced by experimental human endotoxaemia. Methods In this randomized, double blind, placebo‐controlled phase IIa study, systemic inflammation was induced by intravenous administration of Escherichia coli‐derived lipopolysaccharide (LPS). At t = 0 hours, 36 healthy male volunteers received 2 ng/kg LPS, followed by a 2‐hour continuous infusion of EA‐230 (15, 45 and 90 mg/kg/h, n = 8 per group) or placebo (n = 12). Results EA‐230 was well tolerated and showed a favourable safety profile. Treatment with the highest dose of EA‐230 resulted in a significant attenuation of the LPS‐induced increase in plasma levels of inflammatory mediators interleukin (IL)‐6, IL‐8, IL‐1 receptor antagonist, monocyte chemoattractant protein‐1, macrophage inflammatory proteins‐1α and ‐1β, and vascular cell adhesion protein‐1 (% reduction of 48, 28, 33, 28, 14, 16 and 19 respectively, p < .01), and reduced fever (peak decrease from 1.8 ± 0.1°C to 1.3 ± 0.2°C, P < .05) and symptom scores (peak decrease from 7.4 ± 1.0 to 4.0 ± 1.2 points, P < .05). EA‐230 exhibited a very short elimination half‐life and a large volume of distribution in the highest dosage group (geometric mean and 95% confidence interval: 0.17 [0.12–0.24] hours and 2.2 [1.3–3.8] L/kg, respectively). Conclusion Administration of EA‐230 is safe and results in attenuation of the systemic inflammatory response in humans.

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“…At the bedside, changes on the clinical exam, brain imaging, and increased levels of neuron-specific enolase all reflect the evolution of such pathological cascades (Calderon, et al 2014). The role of systemic inflammation in post-ischemic neurodegeneration is also well recognized (Samborska-Sablik, et al 2011, Vaahersalo, et al 2014). For example, serum levels of IL-6 and other cytokines correlate with poor neurologic recovery after cardiac arrest and in-hospital death following ischemic stroke (Rallidis, et al 2006, Vaahersalo, et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…The role of systemic inflammation in post-ischemic neurodegeneration is also well recognized (Samborska-Sablik, et al 2011, Vaahersalo, et al 2014). For example, serum levels of IL-6 and other cytokines correlate with poor neurologic recovery after cardiac arrest and in-hospital death following ischemic stroke (Rallidis, et al 2006, Vaahersalo, et al 2014). And in the case of prolonged cardiac arrest, the induced cytokine storm produces endothelial dysfunction, coagulation defects, and multi-organ failure mimicking septic shock (Adrie, et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion

Mai

Prifti

Rininger

et al. 2017

Experimental Neurology

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Post-ischemic neurodegeneration remains the principal cause of mortality following cardiac resuscitation. Recent studies have implicated gastrointestinal ischemia in the sepsis-like response associated with the post-cardiac arrest syndrome (PCAS). However, the extent to which the resulting low-grade endotoxemia present in up to 86% of resuscitated patients affects cerebral ischemia-reperfusion injury has not been investigated. Here we report that a single injection of low-dose lipopolysaccharide (50 μg/kg, IP) delivered after global cerebral ischemia (GCI) induces blood-brain barrier permeability, microglial activation, cortical injury, and functional decline in vivo, compared to ischemia alone. And while GCI was sufficient to induce neutrophil (PMN) activation and recruitment to the post-ischemic CNS, minimal endotoxemia exhibited synergistic effects on markers of systemic inflammation including PMN priming, lung damage, and PMN burden within the lung and other non-ischemic organs including the kidney and liver. Our findings predict that acute interventions geared towards blocking the effects of serologically occult endotoxemia in survivors of cardiac arrest will limit delayed neurodegeneration, multi-organ dysfunction and potentially other features of PCAS. This work also introduces lung-brain coupling as a novel therapeutic target with broad effects on innate immune priming and post-ischemic neurodegeneration following cardiac arrest and related cerebrovascular conditions.

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Admission interleukin-6 is associated with post resuscitation organ dysfunction and predicts long-term neurological outcome after out-of-hospital ventricular fibrillation

Cited by 60 publications

References 32 publications

Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest

Systemic Inflammatory Response and Potential Prognostic Implications After Out-of-Hospital Cardiac Arrest

A randomized double‐blind, placebo‐controlled clinical phase IIa trial on safety, immunomodulatory effects and pharmacokinetics of EA‐230 during experimental human endotoxaemia

Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion

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