In developed countries, traumatic brain injury (TBI) is the leading cause of death and disability among young adults. In the United States alone, TBI affects more than 2 million individuals annually, and the direct and indirect annual costs related to TBI are estimated at $56 billion. Each year, TBI results in 50,000 deaths and 80,000 survivors suffer from long-term disability [1
]. Severe TBI, defined as a Glasgow Coma Scale (GCS)
8, is associated with increased intracranial pressure and activates the sympathetic nervous system, resulting in an increase in plasma catecholamine levels.
There is a direct correlation between severe TBI and this catecholamine surge [3
]. Immediately after TBI, plasma epinephrine and norepinephrine levels increase several-fold, and remain elevated in those who have persistent coma or are moribund [4
]. Those with initial catecholamine levels that are only mildly elevated have been found to improve to a GCS
11 at 1
week. In those with multisystem trauma and TBI, plasma norepinephrine levels at 48
h post injury are predictive of GCS at 1
week, survival, number of ventilator days, and the length of stay (LOS); without TBI, these associations were absent [7
Systemic manifestations of this sympathetic surge include paroxysms of tachycardia, tachypnea, hypertension, and hyperpyrexia with associated motor features such as agitation and dystonia [8
]. Our group has shown that increased TBI severity also correlates with decreased heart rate variability (HRV); this is another reflection of autonomic dysfunction [9
]. Clinically, these ill-defined intermittent episodes, often a diagnosis of exclusion, are termed ‘sympathetic storms’ or ‘autonomic storms’, frequently manifest with “aggression”, or “agitation”. [12
]. This is most prevalent during the acute stage of recovery, particularly at coma emergence, with reported incidence rates up to 96% [14
]. Notably, persistent sympathetic hyperactivity is associated with increased intensive care unit (ICU) LOS, lower cognitive ability, and higher cognitive fatigue [15
]. While the full spectrum of sympathetic hyperactivity after TBI has not been systematically described nor intervened upon, our hypothesized model based on literature review and clinical experience is shown in Figure .
Conceptual model of sympathetichyperactivity after severe TBI.
One strategy to decrease sympathetic hyperactivity is pharmacologic intervention with beta (β)-blockade. Non-selective β-blockade with propranolol, in pre-clinical mouse models, reduces brain edema, improves neurologic outcomes [18
], increases cerebral perfusion [19
], and decreases cerebral hypoxia [20
]. Also, propranolol can reduce the maximum intensity of agitated episodes [14
], and even reduces aggressive behavior months after TBI [21
]. This work has led to two parallel, non-placebo-controlled, open-label, prospective, single-center studies (NCT01202110, NCT01343329), which employ early propranolol after TBI and monitor short-term endpoints, like heart rate [23
Several retrospective studies [24
], including two from our group [9
], have indicated that β-blockade exposure following TBI conveys a 4% to 23% absolute mortality advantage [3
]. This mortality benefit is even larger if stratified by early physiological measures of sympathetic excess, such as decreased HRV. Though these findings have resulted in an increase in β-blocker use in our institution from 20% to over 40% in young, severe TBI patients over a 5-year period [9
], rigorous prospective evidence regarding the feasibility, outcome benefits and safety of using of β-blockers in TBI patients is lacking.
β-blockade is just one pharmacologic strategy to reduce sympathetic hyperactivity; centrally acting alpha2
)-agonists also serve as sympatholytic agents [27
]. The prototypical centrally acting α2
-agonist, clonidine, decreases plasma catecholamines and improves outcomes in a rat model of incomplete cerebral ischemia [30
]. Clinically, clonidine decreases plasma catecholamines and cerebral vasoconstriction without altering cerebral blood flow in patients with severe TBI [31
Strong clinical data from Sweden suggest that limiting the adrenergic response after severe TBI in patients with concurrent use of metoprolol and clonidine limits the formation of cerebral edema. Although the reduction in mean arterial blood pressure may lower cerebral perfusion pressure, this group has hemodynamic and brain microdialysis data showing that the use of metoprolol and clonidine is well tolerated by TBI patients with a neurologic and mortality benefit [33
]. The Lund neurotrauma physicians in Sweden are pioneers in the nonsurgical reduction of increased intracranial pressure after severe TBI, and combined adrenergic blockade is standard of care in their TBI protocols. Even when studied outside of Sweden, the Lund concept showed better outcomes when tested against standard of care among a mixed population of aneurysmal subarachnoid hemorrhage and TBI [35
Clonidine and propranolol are lipophilic, penetrate the blood brain barrier, and are used to address the paroxysmal agitation associated with TBI [11
]. Both drugs have variable effects on memory, emotion, and cognition [36
]; however, these effects are not defined after TBI. Although the above European data have shown stable cerebral perfusion pressure when using these agents, the early empiric use of these anti-hypertensive agents is considered innovative within North American TBI environments, where feasibility and safety are not clear. Furthermore, because both clonidine and propranolol may ameliorate the spectrum of sympathetic hyperactivity after TBI, and using both drugs within common dosage frequencies would provide multiple treatment delivery opportunities per day within a complex ICU environment, we choose to study both drugs as a treatment combination.
Using our actively accruing, single-center, double-blinded, placebo-controlled, randomized clinical trial (RCT), the DASH After TBI Study, we intend to determine the effect of combined adrenergic blockade using propranolol and clonidine on: (1) short-term physiology, behavior, and cognition; and (2) long-term neuropsychological outcomes after severe TBI.