Multimodality Monitoring Directed Management of Patients Suffering From Traumatic Brain Injury

Background:

Traumatic brain injury (TBI, "head injury) is a major cause of morbidity and mortality worldwide (Hyder et al., 2007). During the first four decades of life, trauma is the leading cause of death and TBI is involved in at least half the number of cases (Jennett, 1996). In the UK, 1,500 per 100,000 of the population (total 1 million) attend Accident and Emergency Departments with a head injury per year. Of these, around 135,000 people are admitted each year and there are an estimated 500,000 people (aged 16 - 74) with long term disabilities as a direct result of TBI (Headway, 2016). Approximately 10 per 100,000 per year die from head injury (Jennett and MacMillan, 1981, Hutchinson et al., 1998).

The major determinant of outcome from TBI is the severity of the primary injury, which is irreversible. However, primary injury invariably leads to the activation of cellular and molecular cascades which mediate further secondary injury that evolve over the ensuing hours and days (Masel and DeWitt, 2010) and are therefore amenable to therapeutic intervention. These molecular cascades can lead to brain swelling within the confines of a fixed intracranial compartment, leading to increased intracranial pressure (ICP) and compromising cerebral perfusion pressure (CPP) (Werner and Engelhard, 2007). The control of ICP and maintenance of CPP has been the bedrock of neurointensive care management of TBI for several decades, however, a recent multicenter randomised clinical trial could not show a long-term favorable outcome with ICP guided therapy (Carney et al., 2012).

The Neuro Critical Care Unit (NCCU) in Cambridge is a world leader in TBI monitoring and routinely employs multi-modal monitoring comprising of ICP, brain tissue oxygen and microdialysis monitoring, in every TBI patient. Conceptually, microdialysis monitoring is an attractive method of assessing tissue biochemistry as it provides a direct measure of metabolic substrates at the cellular level at which energy failure occurs. Specifically, the microdialysis derived measure Lactate/Pyruvate Ratio (LPR) is a measure of cellular redox state and therefore the balance between aerobic and anaerobic metabolism. To date, studies in the literature have focused on demonstrating that individual monitoring parameters e.g. microdialysis derived LPR>25 correlate with an unfavorable outcome in multivariate analyses (Sarrafzadeh et al., 2000, Timofeev et al., 2011).

One reason that an ICP monitoring trial has not been proven to deliver improved outcome is that there are several alternative routes to neuronal injury include insufficient oxygen delivery (Nortje and Gupta, 2006), diffusion barrier within tissues (Smielewski et al., 2002), tissue hypoglycaemia (Vespa et al., 2003) and mitochondrial dysfunction (Verweij et al., 2000). Our understanding of these pathophysiological mechanisms has been greatly advanced by the use of multi-modality monitoring including direct measurement of brain tissue oxygen and cerebral microdialysis. In theory, these pathophysiological states could be treated using treatment of ICP lowering therapy, augmenting cerebral perfusion pressure (CPP), increasing oxygen delivery and augmenting glucose delivery. Though, we currently don't know the best way to combine these treatments and they are often used together making independent analysis difficult. Moreover, there is currently no approved therapy for mitochondrial dysfunction, and while some claim that mitochondrial dysfunction is imminent in increased LPR (Nordstrom et al., 2016), the reality is more complex as there will be conditions that are treatable with an increased LPR, but these states need to be better established for clinicians in order to accurately guide treatment (Lazaridis and Robertson, 2016). Previous implementations of guidelines in TBI have shown to improve care and reduce health related cost, something we hope to achieve with our established clinical protocol (Faul et al., 2007).