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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).

SUBMITTER: Azimaraghi O

PROVIDER: S-EPMC7371384 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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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.

Azimaraghi Omid O Hammer Maximilian M Santer Peter P Platzbecker Katharina K Althoff Friederike C FC Patrocinio Maria M Grabitz Stephanie D SD Wongtangman Karuna K Rumyantsev Sandra S Xu Xinling X Schaefer Maximilian S MS Fuller Patrick M PM Subramaniam Balachundhar B Eikermann Matthias M

BMJ open 20200719 7

<h4>Introduction</h4>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 t ...[more]

PMID: 32690536

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Project description:Study objectivesThe safety profile of the dual orexin receptor antagonists (DORAs) are currently unknown with regard to nocturnal responsivity among people with insomnia. We compared the auditory awakening thresholds (AATs) of the DORA suvorexant (10 and 20 mg) versus placebo in 12 individuals with DSM-5 insomnia.MethodsThe study used a double-blind, placebo-controlled, three-way crossover design. Participants were randomly assigned to a treatment sequence that included placebo, suvorexant 10 mg, and suvorexant 20 mg. At the time of maximum drug concentration, auditory tones were played during stable stage N2 sleep. Tones increased by 5-decibel (db) increments until the participant awakened. The db at awakening was recorded as the AAT and compared between conditions. The proportion of awakenings higher than 85 db was also compared between conditions. Finally, sensitivity analyses were also conducted using surrounding thresholds (80 db and 90 db).ResultsThe mean AAT did not differ significantly between either dose of suvorexant compared to placebo. Moreover, the proportions of individuals who remained asleep at the AAT 85 db cutoff did not differ across conditions. In addition, wake after sleep onset decreased and total sleep time increased in the suvorexant 20 mg condition compared to placebo.ConclusionsSuvorexant (10 and 20 mg) preserved the ability to respond to nocturnal stimuli, whereas the 20-mg dose improved the sleep of people with insomnia. This suggests that DORAs such as suvorexant can effectively treat insomnia while allowing patients to awaken to nocturnal stimuli in the environment.Clinical trial registrationRegistry: ClinicalTrials.gov; Title: A Phase IV 3-Way Double-blind, Randomized, Crossover Study to Compare the Awakening Threshold Effects (Responsivity) of Belsomra 10 mg and 20 mg to Placebo in Non-elderly Insomniacs; Identifier NCT03312517; URL: https://clinicaltrials.gov/ct2/show/NCT03312517.CitationDrake CL, Kalmbach DA, Cheng P, Roth T, Tran KM, Cuamatzi-Castelan A, Atkinson R, SinghM, Tonnu CV, Fellman-Couture C. Can the orexin antagonist suvorexant preserve the ability to awaken to auditory stimuli while improving sleep? J Clin Sleep Med. 2019;15(9):1285-1291.

Project description:Study objectivesSuvorexant (MK-4305) is an orexin receptor antagonist being developed for the treatment of insomnia. This report describes the effects of nighttime administration of suvorexant on polysomnography (PSG) sleep parameters in healthy young men.DesignRandomized, double-blind, placebo-controlled, 4-period crossover PSG study, followed by an additional 5(th) period to assess pharmacokinetics.SettingSleep laboratory.ParticipantsHealthy young men between 18 and 45 years of age (22 enrolled, 19 completed).InterventionsPeriods 1-4: suvorexant (10 mg, 50 mg, or 100 mg) or placebo 1 h before nighttime PSG recording. Period 5: suvorexant 10 mg, 50 mg, or 100 mg.Measurements and resultsIn Periods 1-4, overnight sleep parameters were recorded by PSG and next-morning residual effects were assessed by psychomotor performance tests and subjective assessments. Statistically significant sleep-promoting effects were observed with all doses of suvorexant compared to placebo. Suvorexant 50 mg and 100 mg significantly decreased latency to persistent sleep and wake after sleep onset time, and increased sleep efficiency. Suvorexant 10 mg significantly decreased wake after sleep onset time. There were no statistically significant effects of suvorexant on EEG frequency bands including delta (slow wave) activity based on power spectral analysis. Suvorexant was well tolerated. There was no evidence of next-day residual effects for suvorexant 10 mg. Suvorexant 50 mg statistically significantly reduced subjective alertness, and suvorexant 100 mg significantly increased reaction time and reduced subjective alertness. There were no statistically significant effects of any suvorexant dose on digit symbol substitution test performance. In Period 5, plasma samples of suvorexant were collected for pharmacokinetic evaluation. The median T(max) was 3 hours and apparent terminal t(½) was 9-13 hours.ConclusionsIn healthy young men without sleep disorders, suvorexant promoted sleep with some evidence of residual effects at the highest doses.

Project description:Importance:Obstructive sleep apnea has been associated with postoperative delirium, which predisposes patients to major adverse outcomes. Positive airway pressure may be an effective intervention to reduce delirium in this population. Objectives:To determine if preoperative obstructive sleep apnea is associated with postoperative incident delirium in the intensive care unit and if preoperative positive airway pressure adherence modifies the association. Design, Setting, and Participants:A retrospective single-center cohort study was conducted at a US tertiary hospital from November 1, 2012, to August 31, 2016, among 7792 patients admitted to an intensive care unit who underwent routine Confusion Assessment Method for the intensive care unit after major surgery. Patients were adults who had undergone a complete preoperative anesthesia assessment, received general anesthesia, underwent at least 1 delirium assessment, were not delirious preoperatively, and had a preoperative intensive care unit stay of less than 6 days. Statistical analysis was conducted from August 20, 2019, to January 11, 2020. Exposures:Self-reported obstructive sleep apnea, billing diagnosis of obstructive sleep apnea, or STOP-BANG (Snoring, Tiredness, Observed Apnea, Blood Pressure, Body Mass Index, Age, Neck Circumference and Gender) questionnaire score greater than 4, as well as self-reported use of preoperative positive airway pressure. Main Outcomes and Measures:Delirium within 7 days of surgery. Results:A total of 7792 patients (4562 men; mean [SD] age, 59.2 [15.3] years) met inclusion criteria. Diagnosed or likely obstructive sleep apnea occurred in 2044 patients (26%), and delirium occurred in 3637 patients (47%). The proportion of patients with incident delirium was lower among those with obstructive sleep apnea than those without (897 of 2044 [44%] vs 2740 of 5748 [48%]; unadjusted risk difference, -0.04; 99% credible interval [CrI], -0.07 to -0.00). Positive airway pressure adherence had minimal association with delirium (risk difference, -0.00; 99% CrI, -0.09 to 0.09). Doubly robust confounder adjustment eliminated the association between obstructive sleep apnea and delirium (risk difference, -0.01; 99% CrI, -0.04 to 0.03) and did not change that of preoperative positive airway pressure adherence (risk difference, -0.00, 99% CrI, -0.07 to 0.07). The results were consistent across multiple sensitivity analyses. Conclusions and Relevance:After risk adjustment, this study found no association between obstructive sleep apnea and postoperative delirium in the context of usual care in the intensive care unit, with 99% CrIs excluding clinically meaningful associations. With limited precision, no association was found between positive airway pressure adherence and delirium. Selection bias and measurement error limit the validity and generalizability of these observational associations; however, they suggest that interventions targeting sleep apnea and positive airway pressure are unlikely to have a meaningful association with postoperative intensive care unit delirium.

Project description:BACKGROUND:Accurate prediction of delirium in the intensive care unit (ICU) may facilitate efficient use of early preventive strategies and stratification of ICU patients by delirium risk in clinical research, but the optimal delirium prediction model to use is unclear. We compared the predictive performance and user convenience of the prediction model for delirium (PRE-DELIRIC) and early prediction model for delirium (E-PRE-DELIRIC) in ICU patients and determined the value of a two-stage calculation. METHODS:This 7-country, 11-hospital, prospective cohort study evaluated consecutive adults admitted to the ICU who could be reliably assessed for delirium using the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist. The predictive performance of the models was measured using the area under the receiver operating characteristic curve. Calibration was assessed graphically. A physician questionnaire evaluated user convenience. For the two-stage calculation we used E-PRE-DELIRIC immediately after ICU admission and updated the prediction using PRE-DELIRIC after 24 h. RESULTS:In total 2178 patients were included. The area under the receiver operating characteristic curve was significantly greater for PRE-DELIRIC (0.74 (95% confidence interval 0.71-0.76)) compared to E-PRE-DELIRIC (0.68 (95% confidence interval 0.66-0.71)) (z score of -?2.73 (p?<?0.01)). Both models were well-calibrated. The sensitivity improved when using the two-stage calculation in low-risk patients. Compared to PRE-DELIRIC, ICU physicians (n?=?68) rated the E-PRE-DELIRIC model more feasible. CONCLUSIONS:While both ICU delirium prediction models have moderate-to-good performance, the PRE-DELIRIC model predicts delirium better. However, ICU physicians rated the user convenience of E-PRE-DELIRIC superior to PRE-DELIRIC. In low-risk patients the delirium prediction further improves after an update with the PRE-DELIRIC model after 24 h. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02518646 . Registered on 21 July 2015.

Dataset Information

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.

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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.

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