Improving the Sleep and Circadian Rhythms of Mechanically Ventilated Patients

• Sponsor: Brian Gehlbach (Other)
• Overall Status: Completed
• CT.gov ID: NCT01284140
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 24
• Locations: 2
• Arms: 2
• Duration (Months): 71
• Patients Per Site: 12
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The goal of this project is to determine whether the sleep and circadian rhythms of critically ill patients undergoing mechanical ventilation can be improved through practical strategies that can be employed at the bedside.

Condition or Disease	Intervention/Treatment	Phase
Critical Illness; Sleep Deprivation; Respiratory Failure; Sleep Disorders, Circadian Rhythm	Behavioral: Sleep and circadian rhythm promotion; Behavioral: Usual care	N/A

Detailed Description

Nearly 1 million patients develop respiratory failure annually in the United States; yet, the sleep of patients undergoing mechanical ventilation has received little attention. This project is designed to characterize sleep and circadian rhythmicity in critically ill patients and to explore the efficacy of a non-pharmacological intervention to improve sleep and normalize circadian phase. The study will examine the effect of a protocol employing noise reduction and enforcement of a robust light-dark cycle on sleep quality and circadian rhythmicity. A secondary analysis will examine the relationship between delirium and sleep disruption and loss of circadian rhythmicity. Circadian rhythmicity will be characterized through the measurement of urinary 6-sulfatoxymelatonin levels at frequent intervals, while sleep will be assessed using continuous polysomnography.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Improving the Sleep and Circadian Rhythms of Mechanically Ventilated Patients
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sleep promotion protocol Behavioral: 48 hours of sleep and circadian rhythm promotion including timed light exposure.	Behavioral: Sleep and circadian rhythm promotion; This multifaceted intervention attempts to enhance sleep and circadian rhythmicity through improved scheduling of nursing procedures, enforcement of a day/night routine, increased light exposure during the day, and decreased light and sound exposure during the night. The intervention began the morning after enrollment and enforced a specific period of enhanced light exposure from 9:00 a.m. to noon. The initial target of 5,000 lux administered by light box (Sunsation, SunBox Co.) was reduced to 400-700 lux after the first 10 subjects were enrolled in the study.
Active Comparator: Usual care Behavioral: 48 hours of usual care.	Behavioral: Usual care; Usual care.

Outcome Measures

Primary Outcome Measures

1. Circadian Timing [Day 1 to Day 3]

   The magnitude of the phase change in 6-sulfatoxymelatonin excretion between Day 1 and Day 3 will be compared between the intervention and usual care groups. This is done by comparing, for each group, the timing of the best-fit maximum on Day 1 with the timing of the best-fit maximum on Day 3. The result is expressed in hours. A positive value represents a phase advance from Day 1 to Day 3 (e.g. an earlier occurrence of maximum excretion on Day 3 when compared with Day 1), while a negative value represents a phase delay from Day 1 to Day 3 (e.g. a later occurrence of maximum excretion on Day 3 when compared with Day 1).

Secondary Outcome Measures

1. Normal Circadian Timing [Day 3]

   The percentage of subjects who exhibit normal circadian timing of 6-sulfatoxymelatonin excretion on Day 3 will be compared between the intervention and usual care groups.

2. Circadian Amplitude [Day 3]

   The amplitude (e.g. one half the value from peak to trough of the fitted cosine curve) of the circadian rhythm of 6-sulfatoxymelatonin on Day 3 will be compared between the usual care and intervention groups.

3. Spectral Edge Frequency 95% [Day 2]

   The difference between the polysomnographically derived daytime and nocturnal spectral edge frequency 95% parameter will be used as a measure of increased diurnal sleep/wake activity. This parameter will be compared between the usual care and intervention groups.

4. Delirium [Day 3]

   The percentage of patients who are delirious at the conclusion at the study will be compared between the intervention and usual care groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 18 years or older

• Receiving mechanical ventilation and intravenous sedation

Exclusion Criteria:

• Debilitating central nervous system disease or degenerative disorder

• Active seizures

• Persistent coma

• Renal failure requiring dialysis

• Expected to be extubated within 24 hours

• Currently receiving neuromuscular blocker

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Medical Center	Chicago	Illinois	United States	60637
2	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242

Sponsors and Collaborators

• Brian Gehlbach
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Brian K Gehlbach, MD, University of Iowa

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Brian Gehlbach, Associate Professor, University of Iowa
• ClinicalTrials.gov Identifier: NCT01284140
• Other Study ID Numbers: 201105754; 5K23HL088020
• First Posted: Jan 26, 2011
• Last Update Posted: May 7, 2018
• Last Verified: May 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Brian Gehlbach, Associate Professor, University of Iowa: Critical illness; Sleep; Polysomnography; Respiratory failure; Circadian rhythm; Sedation
• Additional relevant MeSH terms: Respiratory Insufficiency; Sleep Wake Disorders; Sleep Deprivation; Sleep Disorders, Circadian Rhythm; Critical Illness

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the medical intensive care units of the University of Chicago and the University of Iowa Hospitals and Clinics.
Pre-assignment Detail	Two subjects who acutely developed exclusion criteria were withdrawn from the study after enrollment and prior to the performance of any study-related procedures. These subjects were not analyzed.

Arm/Group Title	Sleep Promotion Protocol	Usual Care
Arm/Group Description	Behavioral: 48 hours of sleep and circadian rhythm promotion including timed light exposure. Sleep and circadian rhythm promotion: This multifaceted intervention attempts to enhance sleep and circadian rhythmicity through improved scheduling of nursing procedures, enforcement of a day/night routine, increased light exposure during the day, and decreased light and sound exposure during the night. The intervention began the morning after enrollment and enforced a specific period of enhanced light exposure from 9:00 a.m. to noon. The initial target of 5,000 lux administered by light box (Sunsation, SunBox Co.) was reduced to 400-700 lux after the first 10 subjects were enrolled in the study.	Behavioral: 48 hours of usual care. Usual care: Usual care.
Period Title: Randomization and Intervention
STARTED	11	11
COMPLETED	11	11
NOT COMPLETED	0	0
Period Title: Randomization and Intervention
STARTED	11	11
COMPLETED	6	5
NOT COMPLETED	5	6

Baseline Characteristics

Arm/Group Title	Sleep Promotion Protocol	Usual Care	Total
Arm/Group Description	Behavioral: sleep and circadian rhythm promotion including timed light exposure. Sleep and circadian rhythm promotion: This multifaceted intervention will attempt to enhance sleep and circadian rhythmicity through improved scheduling of nursing procedures, enforcement of a day/night routine, increased light exposure during the day, and decreased light and sound exposure during the night. Supplemental bright lights and eyeshades and noise cancelling headphones may also be employed.	Behavioral: usual care. Usual care: Usual care.	Total of all reporting groups
Overall Participants	6	5	11
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.2 (10.4)	59.6 (7.7)	63.7 (9.7)
Sex: Female, Male (Count of Participants)
Female	3 50%	2 40%	5 45.5%
Male	3 50%	3 60%	6 54.5%
Region of Enrollment (participants) [Number]
United States	6 100%	5 100%	11 100%
Acute Physiology and Chronic Health Evaluation II score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	25.5 (2.5)	24.4 (2.0)	25 (5.3)
Mechanically ventilated during study period (Count of Participants)
Count of Participants [Participants]	6 100%	5 100%	11 100%
Total urinary 6-sulfatoxymelatonin excretion on day 1 (micrograms) (micrograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [micrograms]	14.5 (4.7)	20.4 (8.1)	17.2 (14.5)
Body mass index (kg per meters squared) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg per meters squared]	25.0	27.4	26.4
Average peak creatinine during study period (mg per deciliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg per deciliter]	2.0 (0.6)	1.8 (0.5)	1.9 (1.3)
Propofol during study period (Count of Participants)
Count of Participants [Participants]	6 100%	5 100%	11 100%
Opioids during study period (Count of Participants)
Count of Participants [Participants]	6 100%	5 100%	11 100%
Benzodiazepines during study period (Count of Participants)
Count of Participants [Participants]	0 0%	3 60%	3 27.3%
Dexmedetomidine during study period (Count of Participants)
Count of Participants [Participants]	0 0%	1 20%	1 9.1%

Outcome Measures

1. Primary Outcome

Title	Circadian Timing
Description	The magnitude of the phase change in 6-sulfatoxymelatonin excretion between Day 1 and Day 3 will be compared between the intervention and usual care groups. This is done by comparing, for each group, the timing of the best-fit maximum on Day 1 with the timing of the best-fit maximum on Day 3. The result is expressed in hours. A positive value represents a phase advance from Day 1 to Day 3 (e.g. an earlier occurrence of maximum excretion on Day 3 when compared with Day 1), while a negative value represents a phase delay from Day 1 to Day 3 (e.g. a later occurrence of maximum excretion on Day 3 when compared with Day 1).
Time Frame	Day 1 to Day 3

Outcome Measure Data

Analysis Population Description

Subjects with 24-hour 6-sulfatoxymelatonin excretion profiles from both Day 1 and Day 3.

Arm/Group Title	Sleep Promotion Protocol	Usual Care
Arm/Group Description	Behavioral: 48 hours of sleep and circadian rhythm promotion including timed light exposure. Sleep and circadian rhythm promotion: This multifaceted intervention attempts to enhance sleep and circadian rhythmicity through improved scheduling of nursing procedures, enforcement of a day/night routine, increased light exposure during the day, and decreased light and sound exposure during the night. The intervention began the morning after enrollment and enforced a specific period of enhanced light exposure from 9:00 a.m. to noon. The initial target of 5,000 lux administered by light box (Sunsation, SunBox Co.) was reduced to 400-700 lux after the first 10 subjects were enrolled in the study.	Behavioral: 48 hours of usual care. Usual care: Usual care.
Measure Participants	6	5
Number [hours]	3.6	-2.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Usual Care
	Comments	Nonlinear regression using the least-squares approach was used to fit a single 24-hour cosine curve to all normalized data in each group on each day of 24-hour urine collection. Model parameters of acrophase and amplitude and their standard errors were derived from these curves. Using the extra sum-of-squares F test, the null hypothesis that model parameters of amplitude and phase were the same on Day 1 and Day 3 was tested for the Usual Care group.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	Extra sum-of-squares F test
	Comments	The null hypothesis that model parameters of amplitude and phase were the same on Day 1 and Day 3 was not rejected for the Usual Care group.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sleep Promotion Protocol
	Comments	Nonlinear regression using the least-squares approach was used to fit a single 24-hour cosine curve to all normalized data in each group on each day of 24-hour urine collection. Model parameters of acrophase and amplitude and their standard errors were derived from these curves. Using the extra sum-of-squares F test, the null hypothesis that model parameters of amplitude and phase were the same on Day 1 and Day 3 was tested for the Sleep promotion group.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0074
	Comments
	Method	Extra sum-of-squares F test
	Comments	This result suggests that the best-fit values for amplitude and phase are different between Day 1 and Day 3 in the Sleep Promotion group.

2. Secondary Outcome

Title	Normal Circadian Timing
Description	The percentage of subjects who exhibit normal circadian timing of 6-sulfatoxymelatonin excretion on Day 3 will be compared between the intervention and usual care groups.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Subjects with 24-hour 6-sulfatoxymelatonin excretion profiles from both Day 1 and Day 3.

Arm/Group Title	Sleep Promotion Protocol	Usual Care
Arm/Group Description	Behavioral: 48 hours of sleep and circadian rhythm promotion including timed light exposure. Sleep and circadian rhythm promotion: This multifaceted intervention attempts to enhance sleep and circadian rhythmicity through improved scheduling of nursing procedures, enforcement of a day/night routine, increased light exposure during the day, and decreased light and sound exposure during the night. The intervention began the morning after enrollment and enforced a specific period of enhanced light exposure from 9:00 a.m. to noon. The initial target of 5,000 lux administered by light box (Sunsation, SunBox Co.) was reduced to 400-700 lux after the first 10 subjects were enrolled in the study.	Behavioral: 48 hours of usual care. Usual care: Usual care.
Measure Participants	6	5
Count of Participants [Participants]	3 50%	1 20%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sleep Promotion Protocol, Usual Care
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Circadian Amplitude
Description	The amplitude (e.g. one half the value from peak to trough of the fitted cosine curve) of the circadian rhythm of 6-sulfatoxymelatonin on Day 3 will be compared between the usual care and intervention groups.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Subjects with 24-hour 6-sulfatoxymelatonin excretion profiles from both Day 1 and Day 3.

Arm/Group Title	Sleep Promotion Protocol	Usual Care
Arm/Group Description	Behavioral: 48 hours of sleep and circadian rhythm promotion including timed light exposure. Sleep and circadian rhythm promotion: This multifaceted intervention attempts to enhance sleep and circadian rhythmicity through improved scheduling of nursing procedures, enforcement of a day/night routine, increased light exposure during the day, and decreased light and sound exposure during the night. The intervention began the morning after enrollment and enforced a specific period of enhanced light exposure from 9:00 a.m. to noon. The initial target of 5,000 lux administered by light box (Sunsation, SunBox Co.) was reduced to 400-700 lux after the first 10 subjects were enrolled in the study.	Behavioral: 48 hours of usual care. Usual care: Usual care.
Measure Participants	6	5
Mean (Standard Deviation) [percent of 24-hour mean 6-sulfatoxymelat]	36.6 (14.5)	11.0 (17.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sleep Promotion Protocol, Usual Care
	Comments	Nonlinear regression using the least-squares approach was used to fit a single 24-hour cosine curve to all normalized data in each group on each day of 24-hour urine collection. This resulted in 4 separate best-fit curves. The model parameter of amplitude was derived from the best-fit curves.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Spectral Edge Frequency 95%
Description	The difference between the polysomnographically derived daytime and nocturnal spectral edge frequency 95% parameter will be used as a measure of increased diurnal sleep/wake activity. This parameter will be compared between the usual care and intervention groups.
Time Frame	Day 2

Outcome Measure Data

Analysis Population Description

Polysomnography was not conducted on any participants due to logistical constraints.

Arm/Group Title	Sleep Promotion Protocol	Usual Care
Arm/Group Description	Behavioral: 48 hours of sleep and circadian rhythm promotion including timed light exposure. Sleep and circadian rhythm promotion: This multifaceted intervention attempts to enhance sleep and circadian rhythmicity through improved scheduling of nursing procedures, enforcement of a day/night routine, increased light exposure during the day, and decreased light and sound exposure during the night. The intervention began the morning after enrollment and enforced a specific period of enhanced light exposure from 9:00 a.m. to noon. The initial target of 5,000 lux administered by light box (Sunsation, SunBox Co.) was reduced to 400-700 lux after the first 10 subjects were enrolled in the study.	Behavioral: 48 hours of usual care. Usual care: Usual care.
Measure Participants	0	0

5. Secondary Outcome

Title	Delirium
Description	The percentage of patients who are delirious at the conclusion at the study will be compared between the intervention and usual care groups.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Subjects still on study in the ICU on Day 3.

Arm/Group Title	Sleep Promotion Protocol	Usual Care
Arm/Group Description	Behavioral: 48 hours of sleep and circadian rhythm promotion including timed light exposure. Sleep and circadian rhythm promotion: This multifaceted intervention attempts to enhance sleep and circadian rhythmicity through improved scheduling of nursing procedures, enforcement of a day/night routine, increased light exposure during the day, and decreased light and sound exposure during the night. The intervention began the morning after enrollment and enforced a specific period of enhanced light exposure from 9:00 a.m. to noon. The initial target of 5,000 lux administered by light box (Sunsation, SunBox Co.) was reduced to 400-700 lux after the first 10 subjects were enrolled in the study.	Behavioral: 48 hours of usual care. Usual care: Usual care.
Measure Participants	6	5
Count of Participants [Participants]	2 33.3%	2 40%

Adverse Events

Time Frame	From the day of enrollment until the completion of all bedside assessments 3 days later.
Arm/Group Title	Sleep Promotion Protocol		Usual Care
Arm/Group Description	Behavioral: 48 hours of sleep and circadian rhythm promotion including timed light exposure. Sleep and circadian rhythm promotion: This multifaceted intervention attempts to enhance sleep and circadian rhythmicity through improved scheduling of nursing procedures, enforcement of a day/night routine, increased light exposure during the day, and decreased light and sound exposure during the night. The intervention began the morning after enrollment and enforced a specific period of enhanced light exposure from 9:00 a.m. to noon. The initial target of 5,000 lux administered by light box (Sunsation, SunBox Co.) was reduced to 400-700 lux after the first 10 subjects were enrolled in the study.		Behavioral: 48 hours of usual care. Usual care: Usual care.
All Cause Mortality
	Sleep Promotion Protocol		Usual Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/11 (36.4%)		2/11 (18.2%)
Serious Adverse Events
	Sleep Promotion Protocol		Usual Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Sleep Promotion Protocol		Usual Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/11 (0%)

Limitations/Caveats

Lower dose light intervention received by one subject; the study design resulted in significant attrition, limiting the number of evaluable patients; baseline differences in the timing of maximal melatonin excretion may have influenced the results.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.