Statins in Traumatic Brain Injury

Abstract

Summary: Traumatic brain injury (TBI) is a common cause of long-term neurological morbidity, with devastating personal and societal consequences. At present, no pharmacological intervention clearly improves outcomes, and therefore a compelling unmet clinical need remains. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or "statins," offer a potential novel therapeutic strategy for TBI. Statins are well tolerated, easy to administer, and have a long clinical track record in critically ill patients. Their side effects are well defined and easily monitored. Preclinical studies have shown significant benefit of statins in models of TBI and related disease processes, including cerebral ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage. In fact, multiple mechanisms have been defined by which statins may exert benefit after acute brain injury. Statins are currently positioned to be translated into clinical trials in acute brain injury and have the potential to improve outcomes after TBI.

Statins and Brain Dysfunction

“…17 Lastly, statins counteract the procoagulant cascade promoted by infl ammation through the following mechanisms: blunting monocytic expression of tissue factor, increasing thrombomodulin availability (important in the activation of protein C), and reducing levels of plasminogen activator inhibitor-1, which impairs the fi brinolytic system. 15 Though no studies to date have evaluated the effect of statins on delirium in patients in the ICU, this drug class has been examined in models of traumatic brain injury (TBI), 18 which involves pathophysiologic changes (eg, neuronal damage and apoptosis, neuroinfl ammation, and BBB injury) similar to those observed in other types of critical illness, including sepsis and acute respiratory distress syndrome. The benefi ts of statins observed in animal studies of TBI include increased hippocampal neuron survival and improved neurologic function.…”

“…The benefi ts of statins observed in animal studies of TBI include increased hippocampal neuron survival and improved neurologic function. [18][19][20][21][22] In humans, one clinical trial reported a reduction in amnesia and increased orientation in patients with TBI who were treated with rosuvastatin. 23 Studies investigating the effect of statins on patients with postoperative delirium, a population with different clinical profi les than patients in the ICU, have yielded inconsistent results.…”

Data gaps limit the translational potential of preclinical research

“…Total 44 100 P E R S P E C T I V E (27), and brain injury (28,29). A search of the literature reveals no systematic neuroPK studies in any mouse strain that would enable direct comparisons of CNS exposure across the various statins.…”

Antioxidant Strategies in Neurocritical Care

“…Statin therapy has also been investigated in patients with ALI; it was shown to be safe and associated with a significant decrease in bronchoalveolar lavage interleukin-8, but had no other effects compared to placebo [101]. Although preclinical studies have shown benefits from statins in models of TBI and related disease processes, including cerebral ischemia, ICH, and subarachnoid hemorrhage, clinical studies have been shortcoming [102]. The use of statins in patients with aneurysmal subarachnoid hemorrhage has been investigated in several small clinical trials.…”