Discussion
axonal injury, critically ill, paroxysmal sympathetic hyperactivity, hyperactivity, TBI, PSH, CFS
CRITICALLY ILL, PAROXYSMAL SYMPATHETIC HYPERACTIVITY
This study is the only prospective double-blinded, placebo-controlled randomized trial of sympathetic blockade using propranolol and clonidine in patients with severe TBI. We found that it is safe and feasible to administer combined adrenergic blockade in these critically ill patients. However, we identified no significant differences in our primary outcome of ventilator-free days. The mean ventilator-free days were 13.6 in the placebo group and 13.4 in the intervention, whereas study drug administration only ran from up to 7 to 9 days (starting between 0 and 48 h after injury). This discrepancy may have resulted in a rebound effect of sympathetic hyperactivity that may have resulted in an inability to detect a difference. Although we did not identify significant differences in our primary clinical endpoint, we did find that despite this small sample, the treatment group receiving adrenergic blockade had improved scores on the Clinical Features Scale (CFS), a scale designed to assess symptoms of paroxysmal sympathetic hyperactivity (PSH), also known as “neurostorming”, “sympathetic storming”, and by other synonyms [In contrast to the lack of clinical benefit demonstrated in this study, several translational animal-model, retrospective, prospective and non-placebo-controlled trials support a link between adrenergic blockade with survival and even long-term cognitive benefit in severe TBI [Limitations of our study include small sample size and single-center design. Despite being the largest double-blinded placebo-controlled randomized trial to date of sympathetic blockade in patients with severe TBI, the power of the study was limited due to it being a small single-center pilot. Demographic and injury diversity was limited, with most patients being very young (< 30 years of age), male, white, and with enrollment criteria of severe TBI defined as GCS < 8. Marshall CT Class does not account for diffuse axonal injury (DAI), a characteristic seen on advanced neuroimaging, however, not usually typical in the acute phase of injury, and with an unclear relationship to the intervention delivered [