Title: Early intravenous beta-blockade with esmolol in adults with isolated severe traumatic brain injury: a phase 2a intervention design study.
Funder: Department of Health and Social Care

Abstract: Secondary damage after severe traumatic brain injury is a significant contributor to death and disability. Processes triggered by impact are amenable to medical intervention but no therapy has yet been proven to reduce secondary injury. One probable driver of secondary injury is the uncontrolled sympathetic surge in response to trauma. High levels of sympathetic activation produces endothelial injury and increases cerebral metabolic rate. Cerebral oedema and ischaemia may follow resulting in secondary brain injury. It is open to modulation with beta-blockade. Observational data indicates an association between beta-blockade after severe traumatic brain injury and reduction in mortality and poor outcome (death, vegetative state, dependence). There are potential adverse effects - like prolonged ICU length of stay - reported. Crucially beta-blockers may produce hypotension resulting in low cerebral perfusion pressure that, in the context of severe traumatic brain injury, increases secondary brain damage. There is are no multi-centre prospective interventional trials to confirm or refute the hypothesis that modulation of the sympathetic response to traumatic brain injury with beta-blockade reduces morbidity and mortality. The right drug, dose, timing and therapeutic end-points are not known. We propose a single centre open label intervention design study using esmolol. The main advantage of esmolol is rapid onset and offset, making titration to specific individualised physiological end-points feasible. It is also familiar to UK clinicians in the context of control of tachycardia and hypertension, and may have a role in management of septic shock. Our primary objective is to define a dose schedule for esmolol started within 24 hours of severe traumatic brain injury in adults that provides control of the sympathetic response without compromising cerebral perfusion pressure. The criterion for control of the sympathetic response will be a sustained reduction of 15% in baseline heart rate. The criterion for dose limiting toxicity will be failure to maintain the cerebral perfusion pressure above the minimum recommended by Brain Trauma Foundation guidelines (60 mmHg). We will use a sequential design to find the maximum tolerated dose of esmolol in this context (continual reassessment method with a cohort size of three and sample size of twenty-four). The primary output of this research is a dose schedule suitable for use as the intervention in subsequent feasibility and substantive randomised controlled trials with extended Glasgow Outcome Scale at one year as the primary outcome.

Lay abstract: Damage to the brain following an accident has two forms. Primary injury happens at the moment of impact and cannot be altered. Secondary injury happens in the minutes, hours and days after the event. It can be improved by medical treatment. Less secondary injury means patients are more likely to survive, and to survive with less disability. One cause of secondary injury is adrenaline. Adrenaline is a hormone with many functions in the body. It is released in massive amounts at the time of the accident and remains high for days. Adrenaline supports blood pressure to help deliver oxygen to the brain, but the high levels damage the lining of blood vessels. This makes blood vessels leaky. Fluid and cells leak from the bloodstream into the brain. This produces swelling and inflammation which reduces blood and oxygen supply to damaged areas of the brain. This leads to a vicious cycle of more swelling and inflammation. The result is secondary brain injury. Blocking adrenaline may break the cycle. This is done with drugs called beta-blockers. Clinical databases suggest that patients taking or given beta-blockers do better after traumatic brain injury. The databases cannot say which beta-blocker is best, or how it should be given. Randomised trials are needed to see if beta-blockers do actually work. Beta-blockers have side effects like reducing blood pressure that may be harmful. Before starting randomised trials it is essential to know that the drug and doses to be tested are safe for patients soon after brain injury. We aim to design a course of beta-blocker treatment that can be given to adults soon after having a serious head injury. We will use a beta-blocker called esmolol. Esmolol is quick to act and to wear off. It blocks the effects of adrenaline thought to be important in secondary injury to the brain. It is already used to control heart rate and blood pressure in patients during anaesthesia or in the intensive care unit. In one study esmolol was given to patients with shock from infection (sepsis). The patients with sepsis, like patients after a bad brain injury, were on a life support machine and getting drugs to support blood pressure. Esmolol actually increased blood pressure and patients on esmolol were more likely to survive. Our research is based on similar esmolol doses to the sepsis study. After each group of 3 patients we will consider changing the doses. At the end of the study we will have a safe course of treatment for patients soon after brain injury.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INJURIES AND ACCIDENTS