Interleukin 6 blockage alters the plasma metabolome in out-of-hospital cardiac arrest

Abstract

Background: Comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) exhibit a systemic inflammatory response, as indicated by elevated interleukin-6 (IL-6) levels, which is associated with increased mortality. Tocilizumab, an IL-6 receptor antagonist that reduced C-reactive protein response and markers of myocardial injury in a phase II OHCA trial.

Aim: To describe the early effects of tocilizumab on circulating levels of metabolites in comatose patients resuscitated from OHCA.

Method: Patients from the phase-II double-blinded randomized trial (NCT: 03863015) were included in this substudy. A total of 85 comatose patients resuscitated from OHCA were randomized at the time of arrival to the hospital to either tocilizumab 8 mg/kg or placebo, of which 80 received the intervention and did not later withdraw from the study. Plasma samples before randomization and 48 h later were analyzed by a targeted metabolomics approach quantifying 60 circulating metabolites.

Results: Of 80 enrolled patients (median age 62 years (IQR: 54-72), men 66 (83 %)), 39 were randomized to tocilizumab group and 41 to placebo. Comorbidities and cardiac arrest characteristics were overall well-balanced. At hospital arrival, levels of metabolites from the tricarboxylic acid (TCA) cycle were associated with time to return of spontaneous circulation and independently with early levels of IL-6 (all p < 0.05). The early levels of medium-chain acylcarnitines were associated with age, NT-proBNP, estimated glomerular filtration rate, and marker of neurological injury (neurofilament light chain) (all p < 0.01). At 48 h, tocilizumab increased the levels of plasma amino acids, especially threonine, glycine, and serine, by more than a factor of 1.5 (p < 0.01). Two eicosanoids 15(S)-HETE and 12(S)-HETE were 1.9 times higher (p < 0.01).

Conclusion: Blocking the IL-6 receptor with tocilizumab early after OHCA impacts circulating metabolites, particularly those within the glycine, serine, and threonine pathways, highlighting the connection between acute systemic inflammation and metabolism. Further, early levels of TCA metabolites are independently associated with early inflammatory response and early medium-chain acylcarnitine with later markers of neurological injury.

Keywords: Inflammation; Interleukin-6; Metabolomics; Out-of-hospital cardiac arrest; Tocilizumab.