Reestablishing Sleep and Circadian Alignment in Medical Intensive Care Unit (MICU) Patients Via a Mechanistic RCT of an Sleep Chronobundle

Critical Illness Clinical Trial

— ReAlign-ICU  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05551325
• Other study ID #: 2000033373
• Secondary ID: 1R01HL163659-01A
• Status: Recruiting
• Phase: N/A
• Start date: May 13, 2024
• Est. completion date: June 29, 2028

Study information

• Verified date: May 2024
• Source: Yale University
• Contact: Melissa P Knauert, MD, PhD
• Phone: 203-785-4163
• Email: melissa.knauert[@]yale.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: June 29, 2028
• Est. primary completion date: June 29, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 OR fed via enteral nutrition (e.g., "tube feeds") prior to ICU admission.
• 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.
• Have a past medical history or positive test on admission for any known disease or illness that would categorize biological samples as biosafety level 3 (BSL3) or higher. 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.

Related Conditions & MeSH terms

• Circadian Rhythm Sleep Disorder, Unspecified
• Critical Illness
• Parasomnias
• Sleep Deprivation
• Sleep Disorders, Circadian Rhythm
• Sleep Wake Disorders

Intervention

Other:
• Chronobundle - light
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.
• chronobundle - feeding
Time-restricted (daytime) intermittent feeding will include 4 meals delivered at 08:00, 12:00, 16:00 and 20:00. Each meal will include one-fourth of the recommended daily tube feed volume.
• chronobundle - mobility
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.
• chronobundle - sleep
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.

Locations

Country	Name	City	State
United States	Yale New Haven Hospital Medical Intensive Care Unit (YNHH MICU) at St Raphael's Campus	New Haven	Connecticut
United States	Yale New Haven Hospital Medical Intensive Care Unit (YNHH MICU) at York Street	New Haven	Connecticut

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Exploratory - Days without Delirium or Coma	Days alive and without delirium or coma out of the 14 days post randomization	post-treatment, 14 days post randomization
Other	Exploratory - Ventilator Free Days	Days alive and ventilator free out of 28 days post-randomization.	post-treatment, 28 days post randomization
Other	Exploratory - Time to ICU Discharge	Days to ICU discharge post-randomization.	post-treatment
Other	Exploratory - Time to Hospital Discharge	Days to hospital discharge post-randomization.	post-treatment
Other	Exploratory - Mortality	Mortality at 30 days post-randomization.	post-treatment, 30 days post-randomization
Primary	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	Circadian alignment absolute time	Clock time of individual urine 6-sulfatoxymelatonin acrophase.	post-treatment, 72 hours
Secondary	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
Secondary	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
Secondary	Overnight sleep duration	Minutes of sleep from 22:00 to 05:59 as measured by NoxA1 portable polysomnography (PSG) device.	post-treatment, 72 hours
Secondary	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
Secondary	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
Secondary	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
Secondary	Daytime sleep duration	Minutes of sleep from 06:00 to 21:59 as measured by NoxA1 portable polysomnography device.	post-treatment, 72 hours
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Atypical sleep	Presence of atypical sleep on polysomnography recording, characterized by d waves without cyclic organization, the absence of K-complexes and sleep spindles, and unusual sleep stage transitions.	post-treatment, 72 hours
Secondary	Glucose tolerance	Area under the curve per 24 hour period of continuous glucose monitoring.	post-treatment, 72 hours
Secondary	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