Early Simvastatin Tx Does Not Decrease Delirium Duration in Criticall Ill Patients

Simvastatin did not reduce the duration of delirium or coma in a randomized controlled trial of critically ill patients on mechanical ventilation (MV), reports The Lancet Respiratory Medicine.¹

Valerie J. Page, MBBCh, from the Imperial College, London, United Kingdom, and colleagues sought to determine whether the anti-inflammatory properties of simvastatin could prevent or shorten delirium and coma in critically ill patients on mechanical ventilation (MV) in the Modifying Delirium Using Simvastatin (MoDUS) trial (International Standard Randomised Controlled Trial Registry number: ISRCTN89079989).

Delirium can lead to poor outcomes, longer hospital stays, increased costs, and long-term cognitive impairment.^2,3 Given the putative anti-inflammatory effects of statins, researchers hypothesized that high-dose simvastatin might ameliorate neuroinflammation-associated delirium.⁴

The researchers randomly assigned 142 patients in a single-center intensive care unit (ICU) who needed MV within 72 hours of hospital admission to receive either 80 mg simvastatin, delivered enterally or orally (n=71; mean age, 61.9 years), or placebo (n=71; mean age, 62.1 years) for up to 28 days.

The primary outcome was the number of days patients were alive and delirium- and coma-free in the first 14 days after receiving simvastatin or placebo. Secondary outcomes included ventilator-, delirium-, and coma-free days to day 28, and 6-month mortality, length of critical care and hospital stay, and safety with regard to elevated creatine kinase and alanine transaminase concentrations, and serious adverse events related to the study drug.

The difference in delirium- and coma-free days at day 14 was not significant with either simvastatin (5.7 days; standard deviation [SD], 5.1]) or placebo (6.1 days; SD, 5.2; mean difference 0.4 days, 95% CI, –1.3 to 2.1; P =.66). Likewise, there were no significant differences in the secondary outcomes, including hospital length of stay and all-cause mortality at 6 months (42% vs 31% in the simvastatin and placebo groups, respectively).

The most common adverse event was an elevated creatine kinase concentration up to more than 10 times the upper limit of normal (simvastatin, 11% vs placebo, 4%; P =.208). None of the patients had a serious adverse event related to simvastatin, and most of the discontinuations of the study drug occurred when patients were discharged from the intensive care unit (ICU).

“If statin medication was going to work in ICU delirium, simvastatin would be the statin drug of choice as it penetrates the brain,” explained Dr Page in an email interview with Pulmonology Advisor. “It may be that statin drugs would work in a different, less sick population to reduce delirium. I am now working on reducing patients’ exposure to drugs that we know contribute to ICU delirium, in particular, sedative medication.”

Summary and Clinical Applicability

The putative anti-inflammatory effects of statins were thought to quell the neuroinflammation responsible for delirium in patients on MV. However, in this randomized double-blind placebo-controlled study, there was no difference between simvastatin and placebo in critically ill patients on MV.

Study Limitations

• The researchers did not monitor the amount of simvastatin that was absorbed by patients
• Bedside nurses, not the researchers, screened for delirium
• The researchers assumed that patients who were discharged from the ICU were free of delirium
• The study was not designed to screen for delirium severity

Disclosures: Valerie J. Page, MBBCh, received fees from Orion Pharma (UK) and the British Medical Journal. E. Wesley Ely, MD, received fees from Orion Pharma (UK), Abbott, and Pfizer.

References

1. Page VJ, Casarin A, Ely EW, et al. Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial [published online July 19, 2017]. Lancet Respir Med. pii: S2213-2600(17)30234-5. doi:10.1016/S2213-2600(17)30234-5
2. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med. 2013;369:1306-1016.
3. Vasilevskis E, Holtz C, Girard T, et al. The cost of delirium in the intensive care unit: attributable costs of care intensity and mortality [abstract]. J Hosp Med. 2015;10(suppl 2). http://www.shmabstracts.com/abstract/the-cost-of-delirium-in-the-intensive-care-unit-attributable-costs-of-care-intensity-and-mortality/ Accessed August 9, 2017.
4. Ritter C, Tomasi CD, Dal-Pizzol F, et al. Inflammation biomarkers and delirium in critically ill patients. Crit Care. 2014;18:R106.