Study protocol for a randomised controlled trial evaluating the effects of the orexin receptor antagonist suvorexant on sleep architecture and delirium in the intensive care unit

Abstract

Introduction: Insomnia frequently occurs in patients admitted to an intensive care unit (ICU). Sleep-promoting agents may reduce rapid eye movement sleep and have deliriogenic effects. Suvorexant (Belsomra) is an orexin receptor antagonist with Food and Drug Administration (FDA) approval for the treatment of adult insomnia, which improves sleep onset and maintenance as well as subjective measures of quality of sleep. This trial will evaluate the efficacy of postoperative oral suvorexant treatment on night-time wakefulness after persistent sleep onset as well as the incidence and duration of delirium among adult cardiac surgical patients.

Methods and analysis: In this single-centre, randomised, double-blind, placebo-controlled trial, we will enrol 120 patients, aged 60 years or older, undergoing elective cardiac surgery with planned postoperative admission to the ICU. Participants will be randomised to receive oral suvorexant (20 mg) or placebo one time a day starting the night after extubation. The primary outcome will be wakefulness after persistent sleep onset. The secondary outcome will be total sleep time. Exploratory outcomes will include time to sleep onset, incidence of postoperative in-hospital delirium, number of delirium-free days and subjective sleep quality.

Ethics and dissemination: Ethics approval was obtained through the 'Committee on Clinical Investigations' at Beth Israel Deaconess Medical Center (protocol number 2019P000759). The findings will be published in peer-reviewed journals.

Trial registration number: This trial has been registered at clinicaltrials.gov on 17 September 2019 (NCT04092894).

Keywords: anaesthetics; cardiac surgery; clinical trials; delirium & cognitive disorders; sleep medicine.

Conflict of interest statement

Competing interests: ME also received compensation for serving on the advisory board for Suvorexant in 2018.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Pathophysiology of insomnia and delirium after cardiac surgery. ICU, intensive care unit; REM, rapid eye movement; TST, total sleep time; GABA, gamma-aminobutyric acid

Figure 2

Study flow and eligibility criteria. BMI, body mass index; CABG, coronary artery bypass graft ICU, intensive care unit; RASS, Richmond Agitation Sedation Scale.

Figure 3

Data derived from a portable EEG monitor with six 6 electrodes, including four 4 active channels (R1, R2, L1, L2), one reference channel (CT), and one ground channel (CB). The acquisition montage mimics electrodes placed according to the International 10–20 System – Fp1, Fp2, F7, and F8, each referenced to FpZ. The raw 250 Hz EEG is converted to European Data Format and filtered at low and high frequency (LFF 0.3Hz- HFF 35 Hz). Similarly, EMG is approximated from changes in forehead muscle tone in channels Fp1-F8 and Fp2-F7. These channels will be filtered as EMGs(LFF 10 Hz, HFF 70 Hz). Absence of muscle tone from these leads will assist in scoring REM sleep. (A) EEG waveform, (B) corresponding multitaper spectrogram and its characteristics at different vigilance states (C) during a full night sleep (7.5 hours). While the raw whole night EEG (A) does not allow immediate interpretation, sleep architecture is distinguishable in the corresponding multitaper spectrogram (B). Spectrograms will be used to assist and accelerate sleep staging by trained sleep physicians. C-1-Awake: active wakefulness presents with strong alpha activity (8–13 Hz) in both, the raw EEG and the power spectrum. C-2-NREM Sleep: absence of spindles and predominance of slow delta waves (0.5–2 Hz) in sleep stage 3 are observed. The multitaper spectrogram is dominated by strong delta power. C-3-REM: alpha and theta waves present during rapid eye movement (REM) sleep in the absence of K-complexes or spindles is observed in the EEG which corresponds with REM sleep, accordingly the spectrogram is dominated by theta and alpha power.