Statins and Brain Dysfunction

Abstract

Delirium is a manifestation of acute brain dysfunction that occurs in up to 80% of patients who are critically ill and is associated with higher mortality and long-term cognitive impairment (LTCI), which is akin to a dementia-like cognitive disability. [1][2][3][4][5][6][7] This acquired cognitive impairment-critical illness brain injury-has important public health implications for both younger and older patients (the latter an increasingly larger proportion of the population), threatening the functional independence and quality of life of millions of ICU survivors in the coming decades. Given that delirium in the ICU represents early brain dysfunction during critical illness and can be easily assessed using validated bedside instruments, 1,8 novel therapies that prevent or treat delirium may prevent its associated immediate and long-term sequelae.Findings from animal and human studies suggest a neuroinfl ammatory pathogenesis of delirium and longterm brain dysfunction associated with critical illness. We propose a testable hypothesis, based on existing data, that the pleiotropic effects of statin medications can mitigate the mechanisms of delirium and LTCI associated with critical illness. Specifi cally, that statins may modify two processes leading to brain injury: neuroinfl ammation and activation of proinfl ammatory microglia. Effects on Neuroinflammation During Critical IllnessAn intense systemic infl ammatory response to illness or injury is a key mediator of organ dysfunction during critical illness. Several conditions that often lead to an ICU admission are examples of the deleterious effects of systemic infl ammation (eg, severe sepsis, trauma, acute respiratory distress syndrome). Proinfl ammatory cytokines (eg, tumor necrosis factor [TNF]-a and IL-1 b ) and chemokines (eg, monocytic chemoattractant protein [MCP]-1) activate leukocytes and endothelial cells (which express leukocyteDelirium is a frequent form of acute brain dysfunction in patients who are critically ill and is associated with poor clinical outcomes, including a critical illness brain injury that may last for months to years. Despite widespread recognition of signifi cant adverse outcomes, pharmacologic approaches to prevent or treat delirium during critical illness remain unproven. We hypothesize that commonly prescribed statin medications may prevent and treat delirium by targeting molecular pathways of infl ammation (peripheral and central) and microglial activation that are central to the pathogenesis of delirium. Systemic infl ammation, a principal mechanism of injury, for example, in sepsis, acute respiratory distress syndrome, and other critical illnesses, can cause neuronal apoptosis, blood-brain barrier injury, brain ischemia, and microglial activation. We hypothesize that the known pleiotropic effects of statins, which attenuate such neuroinfl ammation, may redirect microglial activation and promote an antiinfl ammatory phenotype, thereby offering the potential to reduce the public health burden of delirium and its associated l...

Rosuvastatin versus placebo for delirium in intensive care and subsequent cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial

“…Some experts have suggested that randomised trials of delirium should assess statins with both high and low lipophilic properties given the uncertainty about the effects on neuroinflammation. 8 However, both a lipophilic (ie, simvastatin) and non-lipophilic (ie, rosuvastatin) statin have been assessed in large randomised trials of patients with acute respiratory distress syndrome with similar findings of no beneficial effects on mortality and ventilator-free days. 23,61 Rosuvastatin was used in the SAILS trial on the basis of its superior bioavailability, risk of hepatic dysfunction, and drug–drug interactions.…”

“…Data from both animal and human studies 5–8 offer indirect evidence that neuroinflammation, with associated oxidative damage and apoptosis, is an important part of the pathophysiology of delirium in the intensive care unit and subsequent long-term cognitive impairment. Severe sepsis is an archetype of systemic inflammation, including neuroinflammation.…”

“…20 Consequently, there is great interest in further evaluating the effect of statins on delirium in intensive care and subsequent cognitive function in randomised trials. 8,19–22 …”

Statins and Delirium During Critical Illness

“…Statins have anti-inflammatory (9, 10), endothelial function-enhancing (11, 12), and anticoagulant effects (13, 14) that may interrupt the pathologic events thought to lead to delirium during critical illness. These pleiotropic effects make statins promising candidates for the treatment of delirium during critical illness (15) since they might interrupt the neuroinflammatory cascade hypothesized to contribute to delirium (16, 17). In addition, evidence suggests that treatment of acutely ill patients with statins can reduce inflammation (18–20) whereas abrupt cessation of statins may cause rebound inflammation (21), leading to adverse cardiovascular outcomes (22–25).…”

Treating an Established Episode of Delirium in Palliative Care: Expert Opinion and Review of the Current Evidence Base With Recommendations for Future Development

“…65 A role for statins in both the treatment and the prevention of delirium in critically ill patients has been postulated. 125,126 With proinflammatory cytokines involved in the pathophysiology of delirium, future studies may examine the role of anti-inflammatory medications as adjuvant agents in combination with other medications.…”