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Editorial| Volume 184, 109715, March 2023

Targeting interleukin-6 after cardiac arrest—Let us not forget the brain

  • Patrick M. Kochanek
    Correspondence
    Corresponding author.
    Affiliations
    Critical Care Medicine, Anesthesiology, Pediatrics, and Clinical and Translational Science, Safar Center for Resuscitation Research, UPMC Children’s Hospital of Pittsburgh, Rangos Research Center – 6th floor, 4401 Penn Avenue, Pittsburgh, PA 15224, United States
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  • Dennis W. Simon
    Affiliations
    Departments of Critical Care Medicine and Pediatrics, University of Pittsburgh School of Medicine, Safar Center for Resuscitation Research, Children’s Neuroscience Institute, UPMC Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States
    Search for articles by this author
  • Amy K. Wagner
    Affiliations
    Neuroscience, Departments of Physical Medicine & Rehabilitation and Neuroscience, Center for Neuroscience, Safar Center for Resuscitation Research, Clinical and Translational Science Institute, University of Pittsburgh School of Medicine, 3471 Fifth Avenue, Suite 202, Pittsburgh, PA 15261, United States
    Search for articles by this author
Published:February 01, 2023DOI:https://doi.org/10.1016/j.resuscitation.2023.109715
Targeting interleukin-6 after cardiac arrest—Let us not forget the brain
Previous ArticleCan early blood biomarkers guide brain imaging strategy after cardiac arrest?
Next ArticleThe use of spectral Doppler to detect return of spontaneous circulation, a novel alternative to manual palpation
      The role of inflammation in mediating secondary injury after cardiac arrest was suggested twenty years ago by Adrie et al.,
      • Adrie C.
      • Adib-Conquy M.
      • Laurent I.
      • et al.
      Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome.
      Circulation. 2002; 106: 562-568
      in the description of post-resuscitation disease as a sepsis-like syndrome. Although inflammation was mentioned by Vladimir Negovsky et al.,
      • Negovsky V.A.
      • Gurvitch A.M.
      • Zolotokrylina E.S.
      Postresuscitation disease.
      Elsevier New York, Oxford1983: 84-85
      in his treatise on post-resuscitation disease in 1983, it was not highlighted. Similarly, early attempts to understand and/or modulate post-resuscitation disease in canine cardiac arrest models developed by Peter Safar revealed that sepsis-like sequelae such as disseminated intravascular coagulation and positive blood cultures were common, but outcomes were not improved with available interventions targeting those mechanisms such as hemabsorbtion using a charcoal filter.
      • Cerchiari E.L.
      • Safar P.
      • Klein E.
      • Diven W.
      Visceral, hematologic and bacteriologic changes and neurologic outcome after cardiac arrest in dogs. The visceral post-resuscitation syndrome.
      Resuscitation. 1993; 25: 119-136
      , 
      • Sterz F.
      • Safar P.
      • Diven W.
      • Leonov Y.
      • Radovsky A.
      • Oku K.
      Detoxification with hemabsorption after cardiac arrest does not improve neurologic recovery. Review and outcome study in dogs.
      Resuscitation. 1993; 25: 137-160
      In this issue of Resuscitation, Meyer et al.,
      • Meyer M.A.S.
      • Bjerre M.
      • Wiberg S.
      • et al.
      Modulation of inflammation by treatment with tocilizumab after out-of-hospital cardiac arrest and associations with clinical status, myocardial- and brain injury.
      Resuscitation. 2023; XX: XX-XXX
      report on blood levels of cytokines and other inflammatory markers in EDTA biobank samples and their correlations to organ injury in a secondary analysis of the Interleukin-6 (IL-6) receptor antibodies to modulate the systemic inflammatory response after out-of-hospital cardiac arrest (IMICA) trial. Recall that in that trial in adults with out-of-hospital cardiac arrest of a presumed cardiac cause, treatment with tocilizumab (8 mg/kg over 1 h vs placebo initiated by 240 min) significantly reduced systemic inflammation including decreasing circulating C-reactive protein (CRP) and leukocyte levels vs placebo, and tocilizumab decreased myocardial injury including reductions in serum levels of CPK MB, troponin T, and N-terminal pro B-type natriuretic peptide.
      • Meyer M.A.S.
      • Wiberg S.
      • Grand J.
      • et al.
      Treatment effects of interleukin-6 receptor antibodies for modulating the systemic inflammatory response after out-of-hospital cardiac arrest (The IMICA trial).
      Circulation. 2021; 143: 1841-1851
      However, no differences in survival, neurological outcome, or circulating neuron specific enolase (NSE) levels were observed—arguing against a benefit on the brain.
      Tocilizumab is a humanized IL-6 receptor monoclonal antibody developed as an anti-rheumatic drug that is also used to treat COVID-19 and other autoimmune conditions. In this secondary analysis of the IMICA trial, we now see that treatment with tocilizumab early after cardiac arrest in adults, as anticipated, markedly increased IL-6 levels at 24, 48, and 72 h vs placebo, given that it blocks both soluble and cell surface IL-6 receptors.
      • Okuda Y.
      Review of tocilizumab in the treatment of rheumatoid arthritis.
      Biologics. 2008; 2: 75-82
      The IL-6 increases with treatment were marked reaching a mean level of 708.9 pg/mL at 24 h vs 106.4 pg/mL with placebo treatment. IL-5 levels were also increased vs placebo at 24 and 48 h, a marker often associated with allergic immunity and eosinophilic facilitation of IL-6 production.
      • Gomes I.
      • Mathur S.K.
      • Espenshade B.M.
      • Mori Y.
      • Varga J.
      • Ackerman S.J.
      Eosinophil-fibroblast interactions induce fibroblast IL-6 secretion and extracellular matrix gene expression: implications in fibrogenesis.
      J Allergy Clin Immunol. 2005; 116: 796-804
      Also, IL-17 levels were decreased vs placebo at 72 h, a reduction in key autoimmune associated inflammatory signaling of the JAK/STAT pathway and STAT3 transcription.
      • Benveniste E.N.
      • Liu Y.
      • McFarland B.C.
      • Qin H.J.
      Involvement of the janus kinase/signal transducer and activator of transcription signaling pathway in multiple sclerosis and the animal model of experimental autoimmune encephalomyelitis.
      Interferon Cytokine Res. 2014; 34: 577-588
      Neutrophil and monocyte levels were also reduced by treatment vs placebo at 24 and 48 h. Effects on these facets of systemic inflammation also appear to have been linked to the cardioprotection seen in patients treated with tocilizumab. Beyond what was previously reported, treatment significantly reduced the vasoactive inotrope score (by ∼50%) vs placebo further supporting a cardioprotective effect. Prior reports from the ASSAIL-MI trial suggested that tocilizumab improves myocardial salvage in ST-elevation myocardial infarction,
      • Broch K.
      • Anstensrud A.K.
      • Woxholt S.
      • et al.
      Randomized trial of interleukin-6 receptor inhibition in patients with acute ST-segment elevation myocardial infarction.
      J Am Coll Cardiol. 2021; 77: 1845-1855
      although modestly, and an effect on neutrophils was recently indicated to mediate that benefit.
      • Huse C.
      • Anstensrud A.K.
      • Michelsen A.E.
      • et al.
      Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.
      eBioMedicine. 2022; 80: 104013
      Detrimental effects of neutrophils in myocardial ischemia–reperfusion injury have been posited since the preclinical work in the laboratory of Benedict Lucchesi in the 1980s,
      • Romson J.L.
      • Hook B.G.
      • Kunkel S.L.
      • Abrams G.D.
      • Schork M.A.
      • Lucchesi B.R.
      Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog.
      Circulation. 1983; 67: 1016-1023
      although other effects of tocilizumab on IL-6 signaling may be involved.
      The IMICA trial, including the work of Meyer et al.,
      • Meyer M.A.S.
      • Bjerre M.
      • Wiberg S.
      • et al.
      Modulation of inflammation by treatment with tocilizumab after out-of-hospital cardiac arrest and associations with clinical status, myocardial- and brain injury.
      Resuscitation. 2023; XX: XX-XXX
      published in this issue of Resuscitation represents a valuable advance in the field and begins to modulate the potential role of the inflammatory response to cardiac arrest using a targeted anti-inflammatory tool. Reducing myocardial damage and improving hemodynamics are of course highly desirable. Several other facets of this work, however, merit discussion.
      In this study, treatment with tocilizumab did not affect elevated blood levels of the contemporary brain injury biomarker neurofilament light chain over 72 h. This mirrors the findings previously reported in this same sample with the classical biomarker NSE and is consistent with the lack of effect of tocilizumab on neurological outcome in the trial. IMICA was a phase 2 trial with blood levels of CRP the primary outcome, and thus, was not powered to assess neurological outcome or blood-based biomarkers of brain injury. Nevertheless, tocilizumab has a molecular weight of 145 kDa, and blood brain barrier (BBB) disruption, particularly to large molecules, is extremely variable both in magnitude and temporal course after cardiac arrest in humans.
      • Park J.S.
      • You Y.
      • Min J.H.
      • et al.
      Study on the timing of severe blood-brain barrier disruption using cerebrospinal fluid-serum albumin quotient in post cardiac arrest patients treated with targeted temperature management.
      Resuscitation. 2019; 135: 118-123
      , 
      • Jeon G.R.
      • Ahn H.J.
      • Park J.S.
      • et al.
      The association between neurological prognosis and the degree of blood-brain barrier disruption in cardiac arrest survivors who underwent target temperature management.
      Neurocrit Care. 2021; 35: 815-824
      Thus, delivery of tocilizumab to brain was probably low with IV administration. Consistent with that premise, in rhesus macaques treated with the human equivalent of 8 mg/kg IV, cerebrospinal fluid (CSF) levels of tocilizumab do not increase until ∼24 h later and are low, reaching values of only ∼0.1 µg/mL-well below the reported ∼4 µg/mL required to effectively inhibit the IL-6 receptor.
      • Nellan A.
      • McCully C.M.L.
      • Cruz Garcia R.
      • et al.
      Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques.
      Blood. 2018; 132: 662-666
      Additional insight on brain penetration of tocilizumab stems from its use to treat cytokine release syndrome (CRS) that can be encountered in the treatment of refractory B-cell malignancies. In CRS, IL-6 is a central mediator.
      • Lee D.W.
      • Gardner R.
      • Porter D.L.
      • et al.
      Current concepts in the diagnosis and management of cytokine release syndrome.
      Blood. 2014; 124: 188-195
      Most CRS symptoms respond rapidly after treatment with tocilizumab except for the neurotoxicities. It has also been suggested that sometimes, these neurotoxicities worsen with treatment related to the rise in serum IL-6 linked to receptor blockade
      • Nellan A.
      • McCully C.M.L.
      • Cruz Garcia R.
      • et al.
      Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques.
      Blood. 2018; 132: 662-666
      —an effect seen here after treatment of patients with cardiac arrest.
      • Meyer M.A.S.
      • Bjerre M.
      • Wiberg S.
      • et al.
      Modulation of inflammation by treatment with tocilizumab after out-of-hospital cardiac arrest and associations with clinical status, myocardial- and brain injury.
      Resuscitation. 2023; XX: XX-XXX
      Fortunately, detrimental effects on acute readouts of brain injury in patients treated after cardiac arrest were not observed. However, longer-term outcome assessments will be important in follow-up and in future trials.
      Existing data suggest that IL-6 is a potential target to mitigate secondary brain injury after cardiac arrest. IL-6 levels have been long known to be markedly increased in various forms of acute brain injury
      • Ott L.
      • McClain C.J.
      • Gillespie M.
      • Young B.
      Cytokines and metabolic dysfunction after severe head injury.
      J Neurotrauma. 1994; 11: 447-472
      with CSF levels in patients with traumatic brain injury (TBI) like those seen in the serum of patients with sepsis.
      • Bell M.J.
      • Kochanek P.M.
      • Doughty L.A.
      • et al.
      Comparison of the interleukin-6 and interleukin-10 response in children after severe traumatic brain injury or septic shock.
      Acta Neurochir Suppl. 1997; 70: 96-97
      , 
      • Kumar R.G.
      • Diamond M.L.
      • Boles J.A.
      • et al.
      Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.
      Brain Behav Immun. 2015; 45: 253-262
      In cardiac arrest, Oda et al.,
      • Oda Y.
      • Tsuruta R.
      • Kasaoka S.
      • Inoue T.
      • Maekawa T.
      The cutoff values of intrathecal interleukin 8 and 6 for predicting the neurological outcome in cardiac arrest victims.
      Resuscitation. 2009; 80: 189-193
      reported that CSF levels of IL-6 were elevated >2000-fold vs control (median of 2040 vs 1 pg/mL, respectively) in resuscitated adults and a level of 2708 pg/mL was associated with unfavorable outcome. Similar to TBI,
      • Kumar R.G.
      • Diamond M.L.
      • Boles J.A.
      • et al.
      Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.
      Brain Behav Immun. 2015; 45: 253-262
      CSF levels were even higher than serum levels in cardiac arrest patients post resuscitation. Thus, there is a robust IL-6 response in brain after cardiac arrest, but it remains unclear if IL-6 mediates key secondary injury mechanisms such as neuronal death, cerebral edema, or BBB injury. Recently, IV administration of tocilizumab reduced CRP levels in CSF in patients with amyotrophic lateral sclerosis, but three treatments were given, and CSF was assessed at 8 weeks—reflecting delayed effects of IV administration.
      • Milligan C.
      • Atassi N.
      • Babu S.
      • et al.
      Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients.
      Muscle Nerve. 2021; 64: 309-320
      In pre-clinical studies, administration of tocilizumab into CSF could achieve therapeutic levels, but the intranasal route could not.
      • Lee D.W.
      • Gardner R.
      • Porter D.L.
      • et al.
      Current concepts in the diagnosis and management of cytokine release syndrome.
      Blood. 2014; 124: 188-195
      Pre-clinical studies of early IV plus CSF administration of tocilizumab are thus warranted in models of cardiac arrest.
      The IMICA trial included almost exclusively adults with a shockable rhythm
      • Adrie C.
      • Adib-Conquy M.
      • Laurent I.
      • et al.
      Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome.
      Circulation. 2002; 106: 562-568
      and thus patients that experienced arrests of a cardiac rather than asphyxial etiology. Given the cardiac rather than neurological protection afforded by toclilzumab, and an increase in circulating IL-6 levels, it is unclear that it would produce benefit or raise concerns for risks in adults who experience arrests of asphyxial phenotype, such as with opioid overdose, where brain injury predominates.
      • Uray T.
      • Lamade A.
      • Elmer J.
      • et al.
      Phenotyping cardiac arrest: Bench and bedside characterization of brain and heart injury based on etiology.
      Crit Care Med. 2018; 46: e508-e515
      A similar concern might be raised in children suffering out-of-hospital cardiac arrest, given that they generally result from a respiratory event, and post-arrest myocardial dysfunction is less of a therapeutic target.
      • Du Pont-Thibodeau G.
      • Fry M.
      • Kirschen M.
      • et al.
      Timing and modes of death after pediatric out-of-hospital cardiac arrest resuscitation.
      Resuscitation. 2018; 133: 160-166
      Despite the promise of these new tocilizumab studies in cardiac arrest, there may be more effective ways to target IL-6 signaling. Trans IL-6 signaling mediates pro-inflammatory effects such as leukocyte recruitment, while classical signaling has anti-inflammatory effects.
      • Scheller J.
      • Rose-John S.
      Interleukin-6 and its receptor: From bench to bedside.
      Med Microbiol Immunol. 2006; 195: 173-183
      Unlike tocilizumab, which blocks both pathways, newer agents such as recombinant sgp130, which selectively block trans-signaling, may be more effective, with less risk for immunocompromise. George et al.,
      • George M.J.
      • Jasmin N.H.
      • Cummings V.T.
      • et al.
      Selective interleukin-6 trans-signaling blockade is more effective than panantagonism in reperfused myocardial infarction.
      JACC Basic Transl Sci. 2021; 6: 431-443
      in a pre-clinical model of myocardial ischemia–reperfusion, reported enhanced efficacy of recombinant sgp130Fc vs an anti-IL-6 antibody in attenuating neutrophil infiltration, infarct size, and myocardial dysfunction. Trans IL-6 signaling is also believed to represent the dominant mechanism for pathogenic actions of IL-6 in brain.
      • Campbell I.L.
      • Erta M.
      • Lim S.L.
      • et al.
      Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain.
      J Neurosci. 2014; 34: 2503-2513
      Acute and post-acute IL-6 signaling is associated with poor outcomes clinically after TBI
      • Kumar R.G.
      • Diamond M.L.
      • Boles J.A.
      • et al.
      Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.
      Brain Behav Immun. 2015; 45: 253-262
      and has been linked to both autoimmune and neurodegenerative diseases involving the CNS,
      • Brunello A.G.
      • Weissenberger J.
      • Kappeler A.
      • et al.
      Astrocytic alterations in interleukin-6/Soluble interleukin-6 receptor alpha double-transgenic mice.
      Am J Pathol. 2000; 157: 1485-1493
      , 
      • Escrig A.
      • Canal C.
      • Sanchis P.
      • et al.
      IL-6 trans-signaling in the brain influences the behavioral and physio-pathological phenotype of the Tg2576 and 3xTgAD mouse models of Alzheimer's disease.
      Brain Behav Immun. 2019; 82: 145-159
      , 
      • Kimura A.
      • Kishimoto T.
      IL-6: regulator of Treg/Th17 balance.
      Eur J Immunol. 2010; 40: 1830-1835
      although some beneficial effects of trans signaling have recently been suggested on microglial repopulation that supports neurogenesis.
      • Willis E.F.
      • MacDonald K.P.A.
      • Nguyen Q.H.
      • et al.
      Repopulating microglia promote brain repair in an il-6-dependent manner.
      Cell. 2020; 180: 833-846.e16
      Thus, pre-clinical studies evaluating sgp130 are warranted in models of cardiac arrest. However, systemic administration of sgp130 which is also a large molecule, may likely require modification to enhance BBB delivery to achieve sufficient brain levels to block trans IL-6 signaling. Again, CSF delivery might be required. Given the robust IL-6 target after cardiac arrest, BBB permeable selective small molecule IL-6 inhibitors should also be developed and tested. They would have the additional potential benefit over monoclonal antibodies of a shorter half-life and a more titratable effect.
      Less selective approaches have been recently shown in pre-clinical studies to reduce circulating IL-6 after cardiac arrest, including novel lipase and protease inhibitors and hemofiltration, among other therapies.
      • Xu J.
      • Zheng G.
      • Hu J.
      • et al.
      The monoacylglycerol lipase inhibitor, JZL184, has comparable effects to therapeutic hypothermia, attenuating global cerebral injury in a rat model of cardiac arrest.
      Biomed Pharmacother. 2022; 156113847
      , 
      • Jiang X.M.
      • Hu J.H.
      • Wang L.L.
      • Ma C.
      • Wang X.
      • Liu X.L.
      Effects of ulinastatin on global ischemia via brain pro-inflammation signal.
      Transl Neurosci. 2016; 7: 158-163
      , 
      • Shinozaki K.
      • Lampe J.W.
      • Kim J.
      • et al.
      The effects of early high-volume hemofiltration on prolonged cardiac arrest in rats with reperfusion by cardiopulmonary bypass: a randomized controlled animal study.
      Intensive Care Med Exp. 2016; 4: 25
      Given the findings here, selective approaches targeting IL-6 may represent a favored approach. Surprisingly, targeted temperature management (TTM) at 32 vs 36 °C did not impact circulating IL-6 levels in patients post arrest
      • Bro-Jeppesen J.
      • Kjaergaard J.
      • Wanscher M.
      • et al.
      The inflammatory response after out-of-hospital cardiac arrest is not modified by targeted temperature management at 33°C or 36°C.
      Resuscitation. 2014; 85: 1480-1487
      —consistent with CSF findings of the effect of hypothermia on IL-6 in randomized controlled trials of patients with TBI.
      • Buttram S.D.
      • Wisniewski S.R.
      • Jackson E.K.
      • et al.
      Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: Effects of moderate hypothermia.
      J Neurotrauma. 2007; 24: 1707-1717
      How therapies selectively targeting IL-6, and their interaction with TTM at various levels, also merits exploration.
      The IMICA trial, and this valuable secondary analysis, have begun to reveal the potential role of inflammation in secondary injury after cardiac arrest. Even without direct effects on brain, targeting IL-6 with tocilizumab might confer benefit in some patients. However, if there is potential to produce breakthrough effects in the treatment of cardiac arrest, it is highly likely that therapies targeting IL-6, or other aspects of inflammation, will also require brain targeting in order to yield measurable improvement in neurological outcomes.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgement

      Drs. Wagner and Kochanek are supported by W81XWH-22-2-0056 from the U.S. Department of Defense. Dr. Simon is supported by R01NS127372-01A1.

      References

        • Adrie C.
        • Adib-Conquy M.
        • Laurent I.
        • et al.
        Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome.
        Circulation. 2002; 106: 562-568
        View in Article
        • Negovsky V.A.
        • Gurvitch A.M.
        • Zolotokrylina E.S.
        Postresuscitation disease.
        Elsevier New York, Oxford1983: 84-85
        View in Article
        • Cerchiari E.L.
        • Safar P.
        • Klein E.
        • Diven W.
        Visceral, hematologic and bacteriologic changes and neurologic outcome after cardiac arrest in dogs. The visceral post-resuscitation syndrome.
        Resuscitation. 1993; 25: 119-136
        View in Article
        • Sterz F.
        • Safar P.
        • Diven W.
        • Leonov Y.
        • Radovsky A.
        • Oku K.
        Detoxification with hemabsorption after cardiac arrest does not improve neurologic recovery. Review and outcome study in dogs.
        Resuscitation. 1993; 25: 137-160
        View in Article
        • Meyer M.A.S.
        • Bjerre M.
        • Wiberg S.
        • et al.
        Modulation of inflammation by treatment with tocilizumab after out-of-hospital cardiac arrest and associations with clinical status, myocardial- and brain injury.
        Resuscitation. 2023; XX: XX-XXX
        View in Article
        • Meyer M.A.S.
        • Wiberg S.
        • Grand J.
        • et al.
        Treatment effects of interleukin-6 receptor antibodies for modulating the systemic inflammatory response after out-of-hospital cardiac arrest (The IMICA trial).
        Circulation. 2021; 143: 1841-1851
        View in Article
        • Okuda Y.
        Review of tocilizumab in the treatment of rheumatoid arthritis.
        Biologics. 2008; 2: 75-82
        View in Article
        • Gomes I.
        • Mathur S.K.
        • Espenshade B.M.
        • Mori Y.
        • Varga J.
        • Ackerman S.J.
        Eosinophil-fibroblast interactions induce fibroblast IL-6 secretion and extracellular matrix gene expression: implications in fibrogenesis.
        J Allergy Clin Immunol. 2005; 116: 796-804
        View in Article
        • Benveniste E.N.
        • Liu Y.
        • McFarland B.C.
        • Qin H.J.
        Involvement of the janus kinase/signal transducer and activator of transcription signaling pathway in multiple sclerosis and the animal model of experimental autoimmune encephalomyelitis.
        Interferon Cytokine Res. 2014; 34: 577-588
        View in Article
        • Broch K.
        • Anstensrud A.K.
        • Woxholt S.
        • et al.
        Randomized trial of interleukin-6 receptor inhibition in patients with acute ST-segment elevation myocardial infarction.
        J Am Coll Cardiol. 2021; 77: 1845-1855
        View in Article
        • Huse C.
        • Anstensrud A.K.
        • Michelsen A.E.
        • et al.
        Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.
        eBioMedicine. 2022; 80: 104013
        View in Article
        • Romson J.L.
        • Hook B.G.
        • Kunkel S.L.
        • Abrams G.D.
        • Schork M.A.
        • Lucchesi B.R.
        Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog.
        Circulation. 1983; 67: 1016-1023
        View in Article
        • Park J.S.
        • You Y.
        • Min J.H.
        • et al.
        Study on the timing of severe blood-brain barrier disruption using cerebrospinal fluid-serum albumin quotient in post cardiac arrest patients treated with targeted temperature management.
        Resuscitation. 2019; 135: 118-123
        View in Article
        • Jeon G.R.
        • Ahn H.J.
        • Park J.S.
        • et al.
        The association between neurological prognosis and the degree of blood-brain barrier disruption in cardiac arrest survivors who underwent target temperature management.
        Neurocrit Care. 2021; 35: 815-824
        View in Article
        • Nellan A.
        • McCully C.M.L.
        • Cruz Garcia R.
        • et al.
        Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques.
        Blood. 2018; 132: 662-666
        View in Article
        • Lee D.W.
        • Gardner R.
        • Porter D.L.
        • et al.
        Current concepts in the diagnosis and management of cytokine release syndrome.
        Blood. 2014; 124: 188-195
        View in Article
        • Ott L.
        • McClain C.J.
        • Gillespie M.
        • Young B.
        Cytokines and metabolic dysfunction after severe head injury.
        J Neurotrauma. 1994; 11: 447-472
        View in Article
        • Bell M.J.
        • Kochanek P.M.
        • Doughty L.A.
        • et al.
        Comparison of the interleukin-6 and interleukin-10 response in children after severe traumatic brain injury or septic shock.
        Acta Neurochir Suppl. 1997; 70: 96-97
        View in Article
        • Kumar R.G.
        • Diamond M.L.
        • Boles J.A.
        • et al.
        Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.
        Brain Behav Immun. 2015; 45: 253-262
        View in Article
        • Oda Y.
        • Tsuruta R.
        • Kasaoka S.
        • Inoue T.
        • Maekawa T.
        The cutoff values of intrathecal interleukin 8 and 6 for predicting the neurological outcome in cardiac arrest victims.
        Resuscitation. 2009; 80: 189-193
        View in Article
        • Milligan C.
        • Atassi N.
        • Babu S.
        • et al.
        Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients.
        Muscle Nerve. 2021; 64: 309-320
        View in Article
        • Uray T.
        • Lamade A.
        • Elmer J.
        • et al.
        Phenotyping cardiac arrest: Bench and bedside characterization of brain and heart injury based on etiology.
        Crit Care Med. 2018; 46: e508-e515
        View in Article
        • Du Pont-Thibodeau G.
        • Fry M.
        • Kirschen M.
        • et al.
        Timing and modes of death after pediatric out-of-hospital cardiac arrest resuscitation.
        Resuscitation. 2018; 133: 160-166
        View in Article
        • Scheller J.
        • Rose-John S.
        Interleukin-6 and its receptor: From bench to bedside.
        Med Microbiol Immunol. 2006; 195: 173-183
        View in Article
        • George M.J.
        • Jasmin N.H.
        • Cummings V.T.
        • et al.
        Selective interleukin-6 trans-signaling blockade is more effective than panantagonism in reperfused myocardial infarction.
        JACC Basic Transl Sci. 2021; 6: 431-443
        View in Article
        • Campbell I.L.
        • Erta M.
        • Lim S.L.
        • et al.
        Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain.
        J Neurosci. 2014; 34: 2503-2513
        View in Article
        • Brunello A.G.
        • Weissenberger J.
        • Kappeler A.
        • et al.
        Astrocytic alterations in interleukin-6/Soluble interleukin-6 receptor alpha double-transgenic mice.
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      Article info

      Publication history

      Published online: February 01, 2023
      Accepted: January 24, 2023
      Received: January 20, 2023

      Identification

      DOI: https://doi.org/10.1016/j.resuscitation.2023.109715

      Copyright

      © 2023 Elsevier B.V. All rights reserved.

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