Background:
Out-of-hospital cardiac arrest (OHCA) patients are at high risk of morbidity and mortality attributable to the post-cardiac arrest syndrome, in which systemic inflammation is a major component. Cytokines are involved in many processes, including inflammation. In the IMICA trial, treatment with the interleukin 6 receptor (IL-6R) antagonist tocilizumab in resuscitated comatose OHCA patients reduced systemic inflammation as characterized by a greatly reduced CRP response and lower levels of leukocytes as compared to placebo. Markers of myocardial injury were also reduced by treatment.
Aim:
To investigate changes in cytokine levels induced by blocking the IL-6-mediated signaling with tocilizumab after OHCA by employing a broad cytokine panel.
Methods:
We randomized 80 patients to a single infusion of tocilizumab 8 mg/kg or placebo after admission. Blood samples were drawn at 0, 24, 48, and 72 hours. Cytokines were measured using a 17-plex cytokine assay: G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1β, TNF-α, IL- 1β, 2, 4-8, 10, 12, 13, and 17. Data were log2 transformed and analyzed by constrained linear mixed models.
Results:
Most cytokines had temporal changes after OHCA. However, only for IL- 5, 6 (Figure) and 17 were the treatment-by-time interactions significant, all p<0.05. Circulating IL-5 and in particular IL-6 was markedly increased by inhibition of the IL-6R with tocilizumab as compared to the placebo group. For IL-17 the changes were less pronounced and only differed between groups at 72 hours.
Conclusions:
Treatment with the IL-6R antagonist, tocilizumab, did not alter the cytokine responses in general, however, IL-5 and IL-6 were markedly increased. Experimental data suggests that IL-5 may play a role in cardiac recovery after ischemia. Blockage of the IL-6R greatly increased the IL-6 levels, and as the CRP response was greatly reduced by tocilizumab, a response strongly associated with IL-6, it can be demonstrated that the function of IL-6 was blunted.