Title: Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in mechanically ventilated patients at high risk of delirium.
Funder: Department of Health (England)

Abstract: Aims: The primary aim is to investigate the efficacy of statins initiated early for the prevention or treatment of ICU delirium. Hypothesis: The hypothesis is that statins, which are known to have potent anti-inflammatory effects may have a beneficial role in preventing delirium in critically ill patients. By using statins to prevent delirium, potentially the extent of subsequent dementia-related pathology in patients would be reduced. Background: Delirium is extremely common in mechanically ventilated ICU patients, 63% in the study population (9). It is associated with worse outcomes and in effect delirium is an independent predictor of dementia (10). While the pathophysiology of delirium is not firmly established there is robust evidence to support an inflammatory process, neuroinflammation, independent of the cause. Statins have been shown to modulate the inflammatory cascade, regulate inflammatory cell recruitment, activation and apoptosis and reduce cytokine and protease activity (11-12). The clinical picture in ICU survivors is one of a dementia-like illness. Delirium in ICU patients is an independent predictor of a 10-fold higher likelihood of cognitive impairment at 1 year. In animal models inflammation drives changes that are consistent with subsequent cognitive impairment; animals treated with statins perform significantly better in a postoperative cognitive assessment. With pre-existing CNS damage and associated inflammation, peripheral inflammation can activate microglia already primed by pre-existing pathology (13). Some authors have suggested that the subsequent acute neuroinflammation causes long term cognitive impairment (14). Design : Randomised, placebo controlled, double-blind effectiveness clinical trial to evaluate the effect of simvastatin on number of delirium/coma free days in 142 adult patients at high risk of delirium in the ICU. Target population : Mechanically ventilated patients in ICU receiving sedatives or analgesics. Intervention : Patients to receive once daily simvastatin 80mg or identical placebo tablets enterally for up to 28 days or duration of ICU stay. Clinical Management : Patients will be screened routinely for delirium. They will be sedated with infusions of propofol and fentanyl using a standardised analgesia/sedation protocol. Consent : Written informed consent will be sought from the patients if possible, but in the majority, because of the effects of sedation and critical illness, informed consent will be sought from a Personal Legal representative. Randomisation : Randomisation will be conducted by a computer generated list with block randomisation. Patient variables : Information on baseline characteristics and risk factors for delirium will be collected. Baseline cognitive function will be estimated using a validated informant questionnaire. 6 months following discharge patient’s cognitive function will be assessed using a validated telephone mini-battery of tests. Outcomes : The primary outcome is delirium/coma free days at 28 days. Secondary outcomes include cognitive function, number of ventilator days, duration of critical care and hospital stay, survival at 6 months, safety and a simple cost effective analysis. Recruitment : ICU at Watford General Hospital. Summary of benefits: As delirium is increasingly detected in patients it is being treated - usually with haloperidol. Simvastatin is well tolerated and familiar, costs less than £5 for 28 days’ treatment. By comparison an ICU bed-day costs over £1800. Clinicians will know to continue statins as a priority in patients already on statins and make informed decisions regarding giving statins as a preventative/treatment for delirium. If statins improve cognitive outcomes patients will reach rehabililtation goals more quickly, enjoy an improved quality of life with a reduction in the personal, psychological and financial burdens of patients with cognitive impairment. If results are negative patients will not be exposed to an ineffective drug with the potential, as with all drugs, for harm.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL