Reestablishing Sleep and Circadian Alignment in MICU Patients Via a Mechanistic RCT of an Sleep Chronobundle

Study Overview
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Brief Summary
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More than 5 million patients are admitted to the intensive care unit every year in the United States; most of these patients experience profound sleep and circadian disruption. Promotion of circadian alignment (i.e., alignment of the body's clocks) would make it possible to strategically schedule behaviors such as sleep and eating at normal body clock times, which is predicted to improve sleep quality and metabolic function. This project will test the ability of a sleep chronobundle (i.e., sleep promotion and circadian treatment bundle) to normalize circadian alignment and subsequently test if this realignment also improves sleep and metabolism.

Detailed Description
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An evidence-based treatment that simultaneously addresses intensive care unit (ICU) sleep and circadian disruption (SCD) is desperately needed. Such treatment is needed because patients admitted to the ICU are at high risk for adverse outcomes resulting directly from acute SCD. It is well established among healthy controls that acute SCD is associated with immediate negative consequences such as metabolic, cognitive, cardiovascular, respiratory, skeletal muscle, and immune dysfunction. Normalization of sleep and circadian processes improves these dysfunctions. In the ICU, sleep and circadian processes cannot be segregated, and there are likely several overlapping domains of SCD (e.g., sleep duration, timing, architecture, and continuity, and circadian alignment and amplitude). Thus, a bundled approach to sleep and circadian promotion holds the most promise for reversing SCD, normalizing broader physiologic disruptions, and improving ICU outcomes. To date, ICU sleep promotion bundles have had limited success in documenting improved sleep, and sleep bundles have commonly ignored circadian disruption and circadian-based sleep promotion strategies. This is a critical gap. Translation of circadian principles to ICU sleep promotion is essential because alignment between biologic and clock time allows for subsequent strategic scheduling of behaviors, for example, scheduling sleep promotion during the biologic night to improve sleep duration and quality. In addition, circadian alignment has broader physiologic implications and related potential to improve function across a wide variety of organ systems, for example, scheduling eating during the biologic day to improve glucose tolerance. Investigations to date have not tested the effect of a multifaceted intervention that includes promotion of both circadian alignment via photic and nonphotic zeitgebers and overnight sleep via non-pharmacologic strategies (sleep chronobundle). The overall objective of this project is to test whether a sleep chronobundle, including daytime bright light, time-restricted daytime feeding, increased daytime mobility, and overnight sleep promotion mitigates ICU SCD. A mechanistic randomized controlled trial will be used to test our central hypotheses that a sleep chronobundle will (1) align biologic and clock day-night; (2) overlap behaviors (e.g., sleeping and eating) correctly with biologic time periods; and therefore (3) improve sleep and metabolic processes in the ICU. The focus of this study is on sleep and glucose metabolism metrics because of their high relevance to critical illness.

Official Title
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Reestablishing Sleep and Circadian Alignment in Medically Critically Ill Patients Via a Mechanistic Randomized Controlled Trial of an Intensive Care Unit (ICU) Sleep Chronobundle

Conditions
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Critical Illness, Sleep Deprivation, Circadian Rhythm Sleep Disorder, Unspecified

Intervention / Treatment
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* Other: Chronobundle - light
* Other: chronobundle - feeding
* Other: chronobundle - mobility
* Other: chronobundle - sleep


Participation Criteria
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Eligibility Criteria
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Inclusion: MICU patients admitted within 24 hours as of 09:00 on day of enrollment (study day 1). Intubated and not having passed a spontaneous breathing trial or expected to be extubated in the next 24 hours as of enrollment. Age greater than or equal to 18 years old. Exclusion: Not expected to make >250 mL urine per 24 hours. Imminently dying or with a hospice status. At significant risk for pre-existing circadian abnormalities including: (1) severe chronic brain injury (injury greater than 30 days ago resulting in the inability to live independently); (2) acute brain injury of any severity (injury less than 30 days ago including acute intracranial bleed, traumatic brain injury, central nervous system infection, tumor); (3) documented circadian disorder (<1% population) or blind/disease of the optic nerve; (4) current or recent (last 1 year) shiftwork; and (5) homelessness, incarceration, or institutionalization. At elevated risk of aspiration due to structural or functional abnormality of the gastrointestinal tract. Admitted to the ICU for treatment of diabetic ketoacidosis or hyperosmolar state; this diagnosis will be established via review of the medical record for a description of diabetes in the past medical history or the presence of diabetes medication on the confirmed home medication list AND hyperglycemia attributed to diabetic ketoacidosis or diabetic hyperosmolar state by the admitting care team in their written assessment of the patient. Having a history of hypoglycemia without documented full neurological recovery; this diagnosis will be established via review of the patient's past medical history in the medical record; Having a history suggesting an abnormally high risk of suffering hypoglycemia (e.g., known insulin secreting tumor, history of unexplained or recurrent hypoglycemia or fulminant hepatic failure); this diagnosis will be established via review of the patient's past medical history in the medical record. Admitted due to complications of a suicide attempt. Admitted due to an acute drug overdose or active alcohol withdrawal. For the Oral glucose tolerance testing sub-study, we will EXCLUDE PATIENTS meeting the following criteria: Hemoglobin less than 10.0 grams per deciliter. Active cardiac ischemia. Active significant bleed (decrease in hemoglobin of more than 2.0 grams per deciliter in 24 hours). Receipt of a blood transfusion during the current hospital admission.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1 randomization of patients to control or intervention
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>Usual ICU care. | |
| Experimental: Chronobundle<br>The chronobundle will include bright daytime light, time-restricted intermittent feeding, enhanced exercise/mobility, and overnight sleep promotion. | Other: Chronobundle - light<br>* Bright daytime light from 09:00 to 13:00 starting on day 1. The light will be 10,000 lux at 12 and provide a minimal intensity of 1,250 lux at the angle of the eye (30 to 36 distance). The light has a temperature of 5,000 Kelvin indicating a high blue wavelength content which should maximize circadian effects (validated device Sunbox Lighting, Maryland). Following the 09:00 to 13:00 bright light, the room lights will remain on and the curtains will remain open to maximize daytime light exposure while not decreasing bright light tolerance.<br>Other: chronobundle - feeding<br>* Time restricted (daytime) intermittent feeding will include 4 meals delivered at 09:00, 12:00, 15:00 and 18:00. Each meal will include one-fourth of the recommended daily tube feed volume.<br>Other: chronobundle - mobility<br>* Exercise/mobility sessions will occur twice per day between 09:00 and 16:00; intensity will be determined by clinical status and documented in the chart by our physical therapy service.<br>Other: chronobundle - sleep<br>* Overnight sleep promotion will occur between 22:00 and 06:00 with a more restricted sleep period between 00:00 and 04:00. This will be achieved by rescheduling non-urgent care. There will be no changes to urgent care. Additionally, room lights will be dimmed, curtains drawn, and room doors closed. Television screens will be fitted with blue light-blocking filters.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circadian alignment change from normal | Individual urine 6-sulfatoxymelatonin acrophase compared to population normal acrophase of 03:30. Maximum difference +/- 12 hours. | post-treatment, 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circadian alignment absolute time | Clock time of individual urine 6-sulfatoxymelatonin acrophase. | post-treatment, 72 hours | 
| Change in Circadian alignment from day 1 to day 3 | Change in individual urine 6-sulfatoxymelatonin acrophase between period 1 and period 3 (first 24 hours and last 24 hours of monitoring) | Day 1 and post-treatment, 72 hours | 
| Circadian alignment based on diurnal heart rate variation | Individual heart rate nadir compared to population normal nadir of 04:00. Maximum difference +/- 12 hours. | post-treatment, 72 hours | 
| Overnight sleep duration | Minutes of sleep from 22:00 to 05:59 as measured by NoxA1 portable polysomnography (PSG) device. | post-treatment, 72 hours | 
| Overnight Rapid Eye Movement (REM) proportion | Proportion of Stage REM sleep from 22:00 to 05:59 as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Overnight non-rapid eye movement stage 3 (NREM3) proportion | Proportion of Stage NREM3 sleep from 22:00 to 05:59 as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Overnight arousal index (continuity) | Number of arousals per hour of sleep from 22:00 to 05:59 as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Daytime sleep duration | Minutes of sleep from 06:00 to 21:59 as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Daytime REM proportion | Proportion of Stage REM sleep from 06:00 to 21:59 as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Daytime NREM3 proportion | Proportion of Stage NREM3 sleep from 06:00 to 21:59 as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Daytime arousal index (continuity) | Number of arousals per hour of sleep from 06:00 to 21:59 as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Biologic night sleep duration | Minutes of sleep during biologic night (melatonin onset to offset) as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Biologic night REM proportion | Proportion of Stage REM sleep during biologic night (melatonin onset to offset) as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Biologic night NREM3 proportion | Proportion of Stage NREM3 sleep during biologic night (melatonin onset to offset) as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Biologic night arousal index (continuity) | Number of arousals per hour of sleep during biologic night (melatonin onset to offset)as measured by NoxA1 portable polysomnography device. | post-treatment, 72 hours | 
| Atypical sleep | Presence of atypical sleep on polysomnography recording, characterized by δ waves without cyclic organization, the absence of K-complexes and sleep spindles, and unusual sleep stage transitions. | post-treatment, 72 hours | 
| Glucose tolerance | Area under the curve per 24 hour period of continuous glucose monitoring. | post-treatment, 72 hours | 
| Matsuda's Index | Matsuda Index to be calculated according to published algorithms from data produced during the oral glucose tolerance test. | post-treatment, 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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critical illness, sleep deficiency, circadian misalignment