We provide new insight into the patterns of traumatic brain injury in an animal model visualized on MRI in vivo, with demonstration of reactive gliosis by immunohistochemistry in vitro. We have pioneered a novel technology for collecting images in rodent models using a 3.0 tesla magnet and an inexpensive, single loop disposable receive coil. We were surprised by the extent of injury seen on MRI, because animals appeared generally normal and were able to recover from surgery to an extent it would not be expected in a human with a similar pattern of injury; however, when we tested sensorimotor coordination, we measured significant deficits in neurological function in TBI compared to sham surgery animals.
Our observations of hypertension and increased cardiac contractility after TBI, are consistent with reports of a hyperdynamic cardiac state during recovery from TBI in both animal models and humans.3–5
The hyperadrenergic state observed in moderate to severe TBI patients contributes to increased mortality and may guide surgical therapy 22
In our study, animals with hypotension immediately after surgery did not survive (<20%). Cardiovascular responses to TBI have been well described, and sympathetic hyperactivity following TBI in its most severe form, paroxysmal sympathetic storm, is characterized by tachycardia, hypertension, tachypnea, mydriasis, and diaphoresis. Blood pressure elevation occurs not only when intracranial pressure is elevated (Cushing response) 23
but also occurs in models of brain trauma, with or without elevation in intracranial pressure24
. The hypertension of a Cushing response is due sympathetic neuron activation, including both direct cardiac stimulation and adrenal release of circulating catecholamines 25, 26
. Severe head injury has been associated with a greater than 500 fold increase in plasma epinephrine and a 100 fold increase in plasma norepinephrine in experimental models.27
The increase in catecholamines correlates with the severity of brain injury and has a direct correlation with the increase in systolic blood pressure. Elevations in plasma catecholamines following human head injury occur immediately but may peak at 10–15 days.28
The increased ejection fraction we observed is consistent with the known effects of elevated catecholmines, and with prior research showing that head injury causes a hyperdynamic cardiac state.3–5
Prior research has also shown damage to the myocardium after severe brain injury29
. Pathologic studies showed that the myofibrillar degeneration associated with head injury was similar to the histological findings in patients with pheochromocytoma or in experimental animals following exogenous catecholamine administration, suggesting that high levels of catecholamines exerted a direct toxic effect on the myocardium30
. The pattern of injury associated with catecholamine toxicity, distinct from the inflammatory pattern characteristic of infarction, has been called contraction band necrosis30
. In traumatic brain injury, signs of cardiac dysfunction including ECG changes, arrhythmias, or necrosis, develop in 20% of patients, and cardiac complications have been identified in one third of TBI cases that result in mortality.12
The ECG abnormalities that have been described following TBI include ST-T changes, ventricular arrhythmias, and reduced heart rate variability. 31, 32
Elevated creatinine kinase and tropinin I levels are found in trauma patients with brain injury, even without mechanical chest injury.33–35
Transient, reversible left ventricular dysfunction has been described in patients with acute brain injury36
One mechanism that might explain this cardiac damage would be oxidative stress. Recent studies have shown oxidative damage in the central nervous system after traumatic brain injury37
. There is evidence that catecholamines generate free radicals leading to oxidative stress, and altered redox balance reduces nitric oxide bioavailability and impairs endothelial reactivity 6, 7
. We now show that myocardial oxidative stress after TBI can be mitigated by administration of a beta-adrenergic receptor antagonist.
Cardioprotective strategies including beta-adrenergic blockade are common in the surgical setting and there is evidence to support beta-adrenergic blockade in trauma, even in those patients with cardiac risk factors.38,11, 12,8–10
It may be that the increased contractility in TBI is not pathologic, per se, but rather a physiologic response to the increased catecholamines after TBI. This response may be necessary for homeostasis, in the short term, but it may also become deleterious particularly in patients with pre-existing cardiovascular risk factors, or possibly even in otherwise healthy individuals who experience a prolonged or extended cathecholaminergic response. Otherwise healthy individuals with adequate cardiac reserve may be able to tolerate the cardiac stimulation and oxidative stress without complications; however, in those patients with pre-existing cardiac disease or decreased cardiac reserve due to their injury, the stress of TBI may result in cardiac complications through the mechanisms we have described. Alternatively, the mechanism by which beta-adrenergic blockade may be cardioprotective in trauma may be multifactorial and could involve central effects such as inhibition of the Bezold-Jarish reflex 39
. Further research is required before our results can be extrapolated to a clinical scenario. Our results suggest that prevention of deleterious cardiovascular ROS may be a mechanism of the beneficial effect of beta-adrenergic blockade in trauma. The implications of these findings are that adrenergic blockade or antioxidant administration following TBI may protect against cardiovascular stress.