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Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy*

Jaiswal, Stuti J. MD, PhD1,2; Vyas, Anuja D. MD3; Heisel, Andrew J. MD2; Ackula, Haritha MD3; Aggarwal, Ashna1; Kim, Nick H. MD3; Kerr, Kim M. MD3; Madani, Michael MD4; Pretorius, Victor MD4; Auger, William R. MD3; Fernandes, Timothy M. MD3; Malhotra, Atul MD3; Owens, Robert L. MD3

doi: 10.1097/CCM.0000000000004004
Neurologic Critical Care

Objectives: To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting.

Design: Parallel-arm, randomized, double-blinded, placebo-controlled trial.

Setting: Academic medical center in La Jolla, California.

Patients: Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy.

Interventions: Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU.

Measurements and Main Results: Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5–1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2–3 d] vs ramelteon 3 d [2–5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1–3 d] vs ramelteon 3 d [2–4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3–5 d] vs 4 d [3–6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2–3.2; p = 0.717), all placebo versus ramelteon, respectively.

Conclusions: Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.

1Scripps Research Translational Institute, La Jolla, CA.

2Division of Hospital Medicine, Scripps Clinic/Scripps Green Hospital, La Jolla, CA.

3Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Diego School of Medicine, La Jolla, CA.

4Division of Cardiovascular and Thoracic Surgery, University of California San Diego School of Medicine, La Jolla, CA.

*See also p. 1813.

All of the above authors contributed to this article by participation in the research and preparation of the article. Additionally, all authors had access to the data and a role in writing the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, by grant from National Institutes of Health/National Center for Advancing Translational Sciences flagship Clinical and Translational Science Award Grant (KL2 TR001112 and UL1 TR001114).

Drs. Jaiswal and Maholtra received support for article research from the National Institutes of Health. Drs. Jaiswal, Fernandes, and Owens disclosed off-label product use of ramelteon for delirium prevention. Dr. Owens received funding from ResMed (consulting), Novartis, and expert testimony. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Trial Registration: Registered at NCT02691013. Registered on February 24, 2016, by principal investigator, Dr. Owens.

Data Statement: The protocol and de-identified data for this study are available upon reasonable request to the authors via email to

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