Delirium in Old Age
Conditions
Keywords
Sleep
Brief summary
This research study will evaluate the effectiveness of postoperative administration of a drug called suvorexant, to improve postoperative sleep and decrease the severity of delirium (serious confusion) in adults 65 years and older undergoing non-cardiac surgery.
Detailed description
Suvorexant is an FDA-approved drug to treat a condition called insomnia, a sleep disorder characterized by difficulty falling asleep, staying asleep or getting good quality sleep, and has been found to have a good safety profile in older adults. Since older surgical patients often have difficulties with sleep, suvorexant might improve sleep after surgery but this remains unknown. Because difficulties with sleeping after surgery have been associated with a disorder of severe confusion called delirium, administration of suvorexant after surgery may also help prevent delirium or decrease its severity. Participants will receive either a placebo or suvorexant by mouth (or feeding tube if present) on the first three nights after surgery while in the hospital. Prior to surgery, participants will be asked to wear a wristband sleep monitor and complete several questionnaires about their sleep, brief thinking and memory tests, a test of attention, and a measurement of their pupil size with a special camera. After surgery, participants will wear a comfortable headband device that records the electrical signals from the brain to measure the amount and depth of their sleep. This device will be worn for the first 3 nights from 9:00 PM to 6:00 AM after surgery or until hospital discharge, whichever occurs first. After surgery, participants will also answer several questions about their sleep quality and redo some of the brief thinking and memory tests (delirium tests), attention tests, and pupil size measurements. Additionally, the investigators will collect a blood sample prior to surgery and on the first two days after surgery. Benefits of this study include the possibility of improved sleep after surgery and fewer problems with confusion and thinking and memory problems after surgery. Risks of participation include headache, diarrhea, dry mouth, cough, abnormal dreams, dizziness, daytime tiredness and discomfort from the blood draw.
Interventions
DRUGSuvorexant 20 mg
Administer Suvorexant versus placebo every evening for Post-Operative Day (POD) 0,1, &2
DRUGPlacebo
Administer Suvorexant versus placebo every evening for Post-Operative Day (POD) 0,1, &2
Sponsors
Merck Sharp & Dohme LLC
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Dosing labels will be attached to each study drug dose and include pre-printed fields with * Protocol number * Personal ID number * Participant initials * Date * Time
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Age 65 and older 2. Undergoing non-cardiac, non-intracranial surgery, any surgical procedure not involving the skull, brain, cerebrovascular structures 3. Scheduled postoperative inpatient overnight stay 4. Able to give informed consent or has legally authorized representative able to give informed consent on their behalf 5. English-speaking
Exclusion criteria
1. Inmate of correctional facility 2. Body mass index\> 40 3. Legal blindness 4. Unable to perform study related questionnaires and assessments 5. Use of outpatient sedating sleep aids \> 2 times per any week in 1 month preceding day of surgery. Sedating sleep aids, \*See list Below. 6. History of psychotic disorder, including schizophrenia, schizoaffective disorder, schizophreniform or brief psychotic disorder. 7. History of liver failure with documented international normalized ratio (INR) of \>1.2 or with history of hepatic encephalopathy 8. History of severe sleep apnea or obesity hypoventilation syndrome requiring home bilevel positive airway pressure therapy or home ventilator or other forms of noninvasive ventilation 9. Chronic lung disease requiring home oxygen therapy 10. History of narcolepsy 11. Use of systemic (oral, intravenous, intramuscular, subcutaneous) moderate or strong CYP3A inhibitors within 1 week prior to surgery, \*See list below 12. Use of systemic (oral, intravenous, intramuscular, subcutaneous) moderate or strong CYP3A inducers within 1 week prior to surgery, \*See list below. 13. Current or planned administration of digoxin, or is currently experiencing digoxin toxicity 14. Undergoing surgery that will result in inability to take medications by mouth including laryngectomy, tracheostomy, and oral resection/reconstructive surgery 15. Undergoing surgery that will require postoperative strict bowel rest, including gastrectomy, esophagectomy, and pancreaticoduodenectomy 16. Undergoing surgery in an area that will make it unsafe to wear a headband, such as scalp or forehead procedures. 17. Inappropriate for study inclusion based on the judgement of the principal investigator Exclusionary Medications: Moderate CYP3A inhibitors: Amprenavir, Aprepitant, Atazanavir, Ciprofloxacin, Diltiazem, Erythromycin, Fluconazole, Fosamprenavir, Imatinib, Verapamil, grapefruit juice. Strong CYP3A inhibitors: Ketoconazole, Itraconazole, Posaconazole, Clarithromycin, Nefazodone, Ritonavir, Saquinavir, Nelfinavir, Indinavir, Boceprevir, Telaprevir, Telithromycin, Conivaptan Moderate/Strong CYP3A inducers: Apalutamide, Carbamazepine, Enzalutamide, Ivosidenib, lumacaftor, Mitotane, Phenytoin, Rifampin, St. John's wort, Bosentan, Cenobamate, Dabrafenib, Efavirenz, Etravirine, Lorlatinib, Pexidartinib, Phenobarbital, Primidone, Sotorasib. Sedating sleep aids: Mirtazapine, Trazodone, Flurazepam, Temazepam, Triazolam, Estazolam, Quazepam, Clonazepam, Lorazepam, Midazolam, Alprazolam, Diazepam, Zolpidem, Zaleplon, Eszopiclone, Diphenhydramine, Doxylamine, Hydroxyzine, Suvorexant, Doxepin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Sleep Time (TST) on the First Postoperative Night | The first postoperative night that the participants received study drug (D0) | Total sleep time (TST) on first postoperative night that patient received study drug, as measured by electroencephalography (EEG). Total sleep time includes amount of time in sleep during the lights out period (defined between 21:00 and 06:00). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Postoperative Delirium Severity Score | Postoperative Day 0 through Day 5 | Three minute Confusion Assessment Method (3D-CAM ) severity scores up through postoperative day 5 or discharge, whichever occurs first, in patients receiving suvorexant vs placebo. Scores range from 0-20 and the higher score is worse. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change In Pupil Diameter Fluctuations From Preoperative Baseline Through Postoperative Day 3 | Preoperative baseline and postoperative days 1-3 | Pupillary unrest under ambient light is an index of spontaneous pupil fluctuations that occur secondary to activity of the locus coeruleus, an important brainstem nucleus involved in maintenance of wakefulness and attentional control. Decreased wakefulness has been associated with decreased pupillary unrest at ambient light, suggesting that pupillary unrest at ambient light is a marker of sleep deprivation-related alterations in wakefulness and attention. Here, infrared pupillometry will be used to measure participant's pupil diameter fluctuations under ambient light conditions both before surgery and daily up through postoperative day 3. We will compare postoperative changes in pupillary unrest at ambient light in both suvorexant and placebo-treated using a two-sided t-test. |
| Postoperative Average Electrographic Total Sleep Time Over the 3-night Recording Period | Postoperative day 0-2 | Using the electrographic headband data, differences in postoperative sleep architecture (including stage 2 and 3 NREM sleep and REM sleep) will be compared in participants who received suvorexant compared to those who received placebo using two-sample t-tests. No multiple comparison correction for multiple sleep stages is planned because these are exploratory analyses. Average total sleep time over all nights that participants receive study drug will also be compared using two-sample t-tests. |
| Postoperative Hospital Length of Stay | From Postoperative day 0 up to 4 week follow up visit | Postoperative delirium occurs in up to 40% of older surgical patients and has been associated with prolonged hospital stays, long-term cognitive impairment, and increased one-year postoperative mortality. We will record the length of hospital stay for each participant. |
| Changes in Average Response Latency on Preoperative and Postoperative Psychomotor Vigilance Testing | Preoperative baseline, and postoperative days 1-3 | Sleep deprivation results in decreased ability to sustain attention, which can be measured with the 5-minute psychomotor vigilance task. The psychomotor vigilance task measures simple reaction times to a visual stimulus over a minute to assess for slowed responses and lapses (i.e., failed response to visual stimuli). Response times, speed, and lapses will be compared between suvorexant and placebo-treated groups to see if postoperative nightly suvorexant has an effect on these sustained attention measures. Using the NASA PVT+ application on an Apple iPad, the psychomotor vigilance task will be collected before surgery, and daily on postoperative day 1-3, or until hospital discharge, whichever occurs first. Analyses will examine pre-to-postoperative change in sustained attention measures to adjust for preoperative performance variability between participants. |
| Average Postoperative Richards-Campbell Subjective Sleep Quality Scores | Postoperative days 1-5 | To assess subjective sleep quality, the Richards-Campbell subjective sleep quality questionnaire will be administered daily from postoperative day 1-5 or until hospital discharge, whichever occurs first. The total subjective sleep quality score will be compared between placebo and suvorexant groups using a two-sample t-test. |
Countries
United States
Participant flow
Recruitment details
Patients age 65 or older scheduled for non-cardiac elective surgery with planned postoperative overnight stay at Duke University Hospital and Duke Medical Pavilion were contacted to determine interest in enrollment in this study. Patients were consented in-person at preoperative visits or via electronic consent over telephone or videoconferencing.
Pre-assignment details
14 participants were never assigned to a treatment arm due to screen fail (n= 4), withdrawal by PI (n = 4), subject chose to withdraw prior to surgery (n = 3), and surgery cancellation (n =3).
Participants by arm
| Arm | Count |
|---|---|
| Suvorexant Arm Administer Suvorexant every evening for Post-Operative Day (POD) 0, 1, and 2 | 66 |
| Placebo Arm Administer placebo every evening for Post-Operative Day (POD) 0, 1, and 2 | 57 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Never received study drug | 2 | 3 |
Baseline characteristics
| Characteristic | Total | Suvorexant Arm | Placebo Arm |
|---|---|---|---|
| Age, Continuous | 72 years STANDARD_DEVIATION 5 | 71 years STANDARD_DEVIATION 4 | 72 years STANDARD_DEVIATION 5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 116 Participants | 62 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 103 Participants | 57 Participants | 46 Participants |
| Region of Enrollment United States | 123 Participants | 66 Participants | 57 Participants |
| Sex: Female, Male Female | 51 Participants | 28 Participants | 23 Participants |
| Sex: Female, Male Male | 72 Participants | 38 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 66 | 0 / 57 |
| other Total, other adverse events | 14 / 66 | 13 / 57 |
| serious Total, serious adverse events | 9 / 66 | 9 / 57 |
Outcome results
Primary
Total Sleep Time (TST) on the First Postoperative Night
Total sleep time (TST) on first postoperative night that patient received study drug, as measured by electroencephalography (EEG). Total sleep time includes amount of time in sleep during the lights out period (defined between 21:00 and 06:00).
Time frame: The first postoperative night that the participants received study drug (D0)
Population: Participants with EEG data for total sleep time determination.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Suvorexant Arm | Total Sleep Time (TST) on the First Postoperative Night | 3.91 hours | Standard Deviation 2 |
| Placebo Arm | Total Sleep Time (TST) on the First Postoperative Night | 3.84 hours | Standard Deviation 2.07 |
p-value: 0.853t-test, 2 sided
Secondary
Peak Postoperative Delirium Severity Score
Three minute Confusion Assessment Method (3D-CAM ) severity scores up through postoperative day 5 or discharge, whichever occurs first, in patients receiving suvorexant vs placebo. Scores range from 0-20 and the higher score is worse.
Time frame: Postoperative Day 0 through Day 5
Population: Participants with 3D-CAM delirium severity scores collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Suvorexant Arm | Peak Postoperative Delirium Severity Score | 2 score on a scale |
| Placebo Arm | Peak Postoperative Delirium Severity Score | 1 score on a scale |
p-value: 0.34Wilcoxon (Mann-Whitney)
Other Pre-specified
Average Postoperative Richards-Campbell Subjective Sleep Quality Scores
To assess subjective sleep quality, the Richards-Campbell subjective sleep quality questionnaire will be administered daily from postoperative day 1-5 or until hospital discharge, whichever occurs first. The total subjective sleep quality score will be compared between placebo and suvorexant groups using a two-sample t-test.
Time frame: Postoperative days 1-5
Other Pre-specified
Change In Pupil Diameter Fluctuations From Preoperative Baseline Through Postoperative Day 3
Pupillary unrest under ambient light is an index of spontaneous pupil fluctuations that occur secondary to activity of the locus coeruleus, an important brainstem nucleus involved in maintenance of wakefulness and attentional control. Decreased wakefulness has been associated with decreased pupillary unrest at ambient light, suggesting that pupillary unrest at ambient light is a marker of sleep deprivation-related alterations in wakefulness and attention. Here, infrared pupillometry will be used to measure participant's pupil diameter fluctuations under ambient light conditions both before surgery and daily up through postoperative day 3. We will compare postoperative changes in pupillary unrest at ambient light in both suvorexant and placebo-treated using a two-sided t-test.
Time frame: Preoperative baseline and postoperative days 1-3
Other Pre-specified
Changes in Average Response Latency on Preoperative and Postoperative Psychomotor Vigilance Testing
Sleep deprivation results in decreased ability to sustain attention, which can be measured with the 5-minute psychomotor vigilance task. The psychomotor vigilance task measures simple reaction times to a visual stimulus over a minute to assess for slowed responses and lapses (i.e., failed response to visual stimuli). Response times, speed, and lapses will be compared between suvorexant and placebo-treated groups to see if postoperative nightly suvorexant has an effect on these sustained attention measures. Using the NASA PVT+ application on an Apple iPad, the psychomotor vigilance task will be collected before surgery, and daily on postoperative day 1-3, or until hospital discharge, whichever occurs first. Analyses will examine pre-to-postoperative change in sustained attention measures to adjust for preoperative performance variability between participants.
Time frame: Preoperative baseline, and postoperative days 1-3
Other Pre-specified
Postoperative Average Electrographic Total Sleep Time Over the 3-night Recording Period
Using the electrographic headband data, differences in postoperative sleep architecture (including stage 2 and 3 NREM sleep and REM sleep) will be compared in participants who received suvorexant compared to those who received placebo using two-sample t-tests. No multiple comparison correction for multiple sleep stages is planned because these are exploratory analyses. Average total sleep time over all nights that participants receive study drug will also be compared using two-sample t-tests.
Time frame: Postoperative day 0-2
Other Pre-specified
Postoperative Hospital Length of Stay
Postoperative delirium occurs in up to 40% of older surgical patients and has been associated with prolonged hospital stays, long-term cognitive impairment, and increased one-year postoperative mortality. We will record the length of hospital stay for each participant.
Time frame: From Postoperative day 0 up to 4 week follow up visit