IL-6 Inhibition for Modulating Inflammation After Cardiac Arrest

Resuscitated cardiac arrest is associated with a systemic inflammatory response that is directly associated with poor prognosis. Inhibition of the IL-6 mediated immune response may potentially inhibit the systemic inflammatory response, potentially improving the prognosis of these severely ill patients.

INTRODUCTION AND BACKGROUND:

The incidence of out-of-hospital cardiac arrest (OHCA) in Denmark is approximately 4,000 per year, and the mortality remains approximately 90%. Furthermore, in the approximately 30% of patients who are resuscitated and admitted to the intensive care unit (ICU), the mortality within the first month remains between 50% to 70%. Accordingly, an increasing emphasis on post-resuscitation care has been addressed by contemporary guidelines.

The high mortality after resuscitated OHCA has been attributed to a post-cardiac arrest syndrome (PCAS), which includes four mutually interacting components: a systemic inflammatory response (SIRS)-like syndrome, cerebral injury, myocardial dysfunction, and the persistent precipitating cause of the arrest. Despite repeated emphasis on post-resuscitation care, no specific therapies targeting PCAS have been implemented, with the exception of targeted temperature management (TTM), which has been recommended since 2003. Accordingly, research addressing mitigation of the PCAS seems intuitively beneficial.

During and after OHCA, exposure to whole-body ischemia and reperfusion injury triggers activation of inflammatory cascades leading to a sepsis-like syndrome. A multitude of inflammatory markers have been associated with unfavorable outcome after OHCA, including procalcitonin (PCT), c-reactive protein (CRP), interleukin (IL) 6, and IL-10.

Furthermore, the inflammatory markers interleukin 1β (IL-1β), IL-6, IL-10, and tumor necrosis factor α (TNF-α) have all been associated with the severity of PCAS, assessed by sequential organ failure assessment (SOFA) score. Importantly, levels of IL-6 have been shown to be independently associated with unfavorable outcome after adjustment for known risk markers. Further, the level of IL-6 was more strongly associated with PCAS severity compared to classical inflammatory markers such as CRP and PCT.

Interleukin-6 is a pro-inflammatory cytokine secreted by T cells and macrophages. IL-6 readily crosses the blood-brain-barrier and is a mediator of fever. Further, IL-6 is a mediator of the acute phase response and plays a role in activation of the coagulation system, increasing vascular permeability, and weakening papillary muscle contractions leading to myocardial dysfunction. As such, IL-6 is involved in pathological processes including tissue hypoxia, disseminated intravascular coagulation (DIC), and multiorgan failure, all of which represent parts of the SIRS response. IL-6 has been suggested to play a role in ischemia-reperfusion injury in myocardial infarction (MI), and higher levels of IL-6 have been associated both with the magnitude of myocardial injury, mortality and adverse events in this group.

Due to the role of IL-6 in many inflammatory diseases, IL-6 receptor antibodies (IL-6RA) have been developed. The first IL-6RA, tocilizumab, was approved for treatment of rheumatoid arthritis in 2009, and has later been approved for giant cell arthritis and chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome. In addition to the approved indications, tocilizumab has been suggested to have other beneficial immune modulating and organ protective effects.

In patients presenting with non-ST-elevation myocardial infarction (NSTEMI), a one-hour infusion of 280mg tocilizumab decreased the inflammatory response assessed by CRP levels, and further decreased myocardial injury assessed by TnT levels. Importantly, no increased risk of adverse events was observed in patients receiving tocilizumab. Animal data suggest that tocilizumab is safe and effective for treatment of severe acute pancreatitis and associated acute lung injury. Further, tocilizumab had neuroprotective effects in a model of Alzheimer disease. In humans, tocilizumab has been suggested to be effective against the autoimmune neurological disorders neuromyelitis optica and autoimmune encephalitis.

In summary, resuscitated OHCA is associated with a severe SIRS-like response, the magnitude of which has been associated with increased mortality and poor neurological outcome. Inhibiting the IL-6 mediated immune response may inhibit the SIRS-like response and may further inhibit ischemia-reperfusion injury leading to improved outcome.

HYPOTHESIS:

A one-hour infusion of the IL-6RA tocilizumab initiated as soon as possible after ROSC will reduce the SIRS-like response assessed by hsCRP levels after OHCA.

SAMPLE SIZE:

A total of 80 patients will be included, i.e. 40 being allocated to IL-6RA and placebo, respectively. Patients who die or become hemodynamically unstable immediately after randomization before the study drug has been prepared will be excluded from the modified intention to treat population and replaced by randomizing additional patients. Likewise, patients for whom the relatives refuse study participation when informed of the study and asked for consent (before the patients can be asked) will be excluded from the modified intention to treat population and replaced.

Eligibility Criteria:
Inclusion Criteria:

Each of the following criteria must be fulfilled for a subject to be eligible:

1. Age ≥ 18 years
2. OHCA of a presumed cardiac cause
3. Unconsciousness upon admission, i.e. a GCS \< 9
4. Sustained ROSC for more than 20 minutes

Exclusion Criteria:

None of the following criteria must be fulfilled for a subject to be eligible:

1. Consciousness upon admission, i.e. a GCS ≥ 9
2. Presumed non-cardiac cause of arrest
3. Unwitnessed asystole
4. Suspected or confirmed intracranial bleeding or stroke
5. Pregnancy, or females in fertile age, unless a negative serum HCG can rule out pregnancy within the inclusion window.
6. Temperature on admission \< 30 °C
7. Persistent cardiogenic shock\* that is not reversed within the inclusion window
8. Known disease making 180 day survival unlikely
9. Known limitations in therapy
10. Known pre-arrest Cerebral Performance Category of 3 to 4
11. \> 240 minutes from ROSC to randomization