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

May 18, 2026 updated by: Yale University

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Estimated)

160

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Recruiting
        • Yale New Haven Hospital Medical Intensive Care Unit (YNHH MICU) at St Raphael's Campus
      • New Haven, Connecticut, United States, 06520
        • Recruiting
        • Yale New Haven Hospital Medical Intensive Care Unit (YNHH MICU) at York Street

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion:

  • Critically ill patients admitted to the MICU who require mechanical ventilation, noninvasive ventilation, high flow nasal cannula, or vasopressor support and who remain on qualifying support as of 09:00 on study randomization day. Randomization will occur on the second or third calendar day following MICU admission. MICU admission must have occurred within 24 hours of hospital admission.
  • Age greater than or equal to 18 years old.

Exclusion:

  • Not expected to remain in the MICU for at least 48 hours post-randomization.
  • 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 that is reasonably expected to impact the central circadian clock (e.g., cardiac arrest); (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.
  • Positive for SARS-CoV.

Urine 6-sulfatoxymelatonin measures will be considered for all patients who make sufficient urine and have an appropriate bladder catheter in place during the indicated time points. However, we will exclude patients from urine measures if they have a history or positive test for any known disease or illness that would categorize biological samples as BSL3 or higher. This includes HIV, West Nile virus, Monkeypox, and Mycobacterium tuberculosis (TB).

Note: Patients who leave the MICU within 24 hours of randomization are excluded from further study activities. Patients who leave the MICU between 24 and 48 hours post-randomization continue all study activities but will not be included in the primary analysis. Patients who remain in the MICU for at least 48 hours post-randomization will continue all study activities and be included in the primary analysis.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Control
Usual ICU care.
Experimental: Chronobundle
The chronobundle will include bright daytime light, time-restricted intermittent feeding, enhanced exercise/mobility, and overnight sleep promotion.
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.
Other: 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.
Other: chronobundle - feeding
For patients receiving enteral feeds, 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.
Other: chronobundle - mobility
While in the MICU, exercise/mobility sessions led by physical therapy or occupational therapy providers will occur twice daily between 09:00 and 16:00 (i.e., one additional session beyond usual care); intensity will be determined by clinical status and documented in the chart by our physical therapy service. Patients in other hospital locations (e.g., general medical ward post-MICU discharge) will receive one additional session beyond usual care via a study staff-led exercise/mobility session; intensity will be determined by clinical status.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Circadian alignment based on diurnal heart rate variation
Time Frame: post-treatment, 72 hours
Individual heart rate nadir compared to population normal nadir of 04:00. Maximum difference +/- 12 hours.
post-treatment, 72 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overnight sleep duration
Time Frame: post-treatment, 72 hours
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
Time Frame: post-treatment, 72 hours
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
Time Frame: post-treatment, 72 hours
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)
Time Frame: post-treatment, 72 hours
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
Time Frame: post-treatment, 72 hours
Minutes of sleep from 06:00 to 21:59 as measured by NoxA1 portable polysomnography device.
post-treatment, 72 hours
Daytime REM proportion
Time Frame: post-treatment, 72 hours
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
Time Frame: post-treatment, 72 hours
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)
Time Frame: post-treatment, 72 hours
Number of arousals per hour of sleep from 06:00 to 21:59 as measured by NoxA1 portable polysomnography device.
post-treatment, 72 hours
Atypical sleep
Time Frame: post-treatment, 72 hours
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
Time Frame: post-treatment, 72 hours
Area under the curve per 24 hour period of continuous glucose monitoring.
post-treatment, 72 hours
Urine 6-sulfatoxymelatonin acrophase change from normal
Time Frame: post-treatment, 72 hours
Individual urine 6-sulfatoxymelatonin acrophase compared to population normal acrophase of 03:30. Maximum difference +/- 12 hours. Urine 6-sulfatoxymelatonin measures will be completed for all patients who make sufficient urine and have an appropriate bladder catheter in place during the indicated time points.
post-treatment, 72 hours
Urine 6-sulfatoxymelatonin acrophase absolute time
Time Frame: post-treatment, 72 hours
Clock time of individual urine 6-sulfatoxymelatonin acrophase. Urine 6-sulfatoxymelatonin measures will be completed for all patients who make sufficient urine and have an appropriate bladder catheter in place during the indicated time points.
post-treatment, 72 hours
Urine 6-sulfatoxymelatonin acrophase change from day 1 to day 4
Time Frame: Day 1 and post-treatment, 72 hours
Change in individual urine 6-sulfatoxymelatonin acrophase between day 1 observation and day 4 observation period (after 72 hours intervention). Urine 6-sulfatoxymelatonin measures will be completed for all patients who make sufficient urine and have an appropriate bladder catheter in place during the indicated time points.
Day 1 and post-treatment, 72 hours
Biologic night sleep duration
Time Frame: post-treatment, 72 hours
Minutes of sleep during biologic night (melatonin onset to offset) as measured by NoxA1 portable polysomnography device. Biologic night determination will be completed for all patients who make sufficient urine and have an appropriate bladder catheter in place during the indicated time points.
post-treatment, 72 hours
Biologic night REM proportion
Time Frame: post-treatment, 72 hours
Proportion of Stage REM sleep during biologic night (melatonin onset to offset) as measured by NoxA1 portable polysomnography device. Biologic night determination will be completed for all patients who make sufficient urine and have an appropriate bladder catheter in place during the indicated time points.
post-treatment, 72 hours
Biologic night NREM3 proportion
Time Frame: post-treatment, 72 hours
Proportion of Stage NREM3 sleep during biologic night (melatonin onset to offset) as measured by NoxA1 portable polysomnography device. Biologic night determination will be completed for all patients who make sufficient urine and have an appropriate bladder catheter in place during the indicated time points.
post-treatment, 72 hours
Biologic night arousal index (continuity)
Time Frame: post-treatment, 72 hours
Number of arousals per hour of sleep during biologic night (melatonin onset to offset) as measured by NoxA1 portable polysomnography device. Biologic night determination will be completed for all patients who make sufficient urine and have an appropriate bladder catheter in place during the indicated time points.
post-treatment, 72 hours

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Exploratory - Days without Delirium or Coma
Time Frame: post-treatment, 14 days post randomization
Days alive and without delirium or coma out of the 14 days post randomization
post-treatment, 14 days post randomization
Exploratory - Ventilator Free Days
Time Frame: post-treatment, 28 days post randomization
Days alive and ventilator free out of 28 days post-randomization.
post-treatment, 28 days post randomization
Exploratory - Time to ICU Discharge
Time Frame: post-treatment
Days to ICU discharge post-randomization.
post-treatment
Exploratory - Time to Hospital Discharge
Time Frame: post-treatment
Days to hospital discharge post-randomization.
post-treatment
Exploratory - Mortality
Time Frame: post-treatment, 30 days post-randomization
Mortality at 30 days post-randomization.
post-treatment, 30 days post-randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Melissa P Knauert, MD, PhD, Yale University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 13, 2024

Primary Completion (Estimated)

June 29, 2029

Study Completion (Estimated)

June 29, 2029

Study Registration Dates

First Submitted

September 19, 2022

First Submitted That Met QC Criteria

September 19, 2022

First Posted (Actual)

September 22, 2022

Study Record Updates

Last Update Posted (Actual)

May 20, 2026

Last Update Submitted That Met QC Criteria

May 18, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2000033373
  • 1R01HL163659-01A1 (U.S. NIH Grant/Contract: National Heart, Lung, and Blood Institute/NIH/DHHS)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Critical Illness

Clinical Trials on Chronobundle - light

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Senegal

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe