Modulating interleukin-6 pathways to understand the effect of systemic inflammation on detrimental neuroinflammation following Traumatic Brain Injury

Traumatic Brain Injury (TBI; brain injury resulting from a physical force) is the most common cause of death in young adults, leads to more disability in our society than diseases like stroke or Alzheimer's, and costs the UK around £15 billion per year. Although there is little that can reduce the initial damage caused by the physical blow, we know that other factors occurring after the initial injury can cause extra brain damage, worsening people's recovery. This additional brain damage is called "secondary injury". A significant cause of this secondary injury is excessive inflammation in the brain. In the same way that other body parts become red and swollen when injured (inflammation), so does the brain. No medications to reduce inflammation are currently used in TBI, even though this cause of secondary injury could (in principle) be treated by anti-inflammatory drugs used in other diseases. A big hurdle in treating brain inflammation is that many medicines cannot get into the brain, as they are too large to pass through the barrier which protects the brain (the blood-brain barrier [BBB]), significantly reducing the number of potential treatment options. However, we know that inflammation occurring elsewhere in the body, happening for example as the result of injuries to other body parts or infections (which are common in patients with TBI), can indirectly cause brain inflammation. This happens because some inflammation chemicals are small enough to cross the BBB from the body and into the brain. So, if we reduce inflammation elsewhere in the body, we can prevent this flow of inflammation chemicals into the brain, reducing brain inflammation and in turn preventing secondary brain injury. In this study, we will treat patients admitted with TBI to our intensive care unit (ICU) with a medicine called Tocilizumab (tocilizumab), a powerful anti-inflammatory which is usually used in rheumatoid arthritis. Tocilizumab has also recently been shown to be effective in treating severe COVID-19 by reducing the bad effects of inflammation, showing that it can be used safely in critically ill patients. We will begin by giving tocilizumab to five patients who have tubes which drain cerebrospinal fluid from their brain (a treatment used for some TBI patients); this will give us preliminary information on the effects on inflammation in the body in the context of TBI and whether tocilizumab enters the brain directly (which we think it will not given the size of the molecule). Then, so that we can better understand the effects of tocilizumab in patients TBI, we will recruit 50 participants and give either tocilizumab or a salt-water placebo, so that we can compare the two groups. The main effect we are looking for is a reduction of brain inflammation in patients treated with tocilizumab. As part of normal care in our ICU, patients have brain monitors which measure whether their brains have enough blood and nutrients, and we can use these same monitors to measure inflammation. We will also take blood samples to see whether tocilizumab reduces brain injury by using blood tests which can detect the level of ongoing brain injury.