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Investigation of Sleep in the Intensive Care Unit (ICU-SLEEP)

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ClinicalTrials.gov Identifier: NCT03355053
Recruitment Status : Recruiting
First Posted : November 28, 2017
Last Update Posted : June 29, 2018
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Michael Brandon Westover, Massachusetts General Hospital

Brief Summary:
Sleep deprivation is common and severe in critically ill patients cared for in intensive care units (ICUs), and is hypothesized to be a key modifiable risk factor for delirium and long-term cognitive disability. Dexmedetomidine reduces the incidence of delirium in ICU patients by unknown mechanisms. This project will determine whether dexmedetomidine reduces delirium by improving sleep, whether bolus dosing vs continuous infusion is better, and the relationship of sleep quality to long-term cognitive outcomes.

Condition or disease Intervention/treatment Phase
Delirium Sleep Drug: Dexmedetomidine Phase 2

Detailed Description:
Sleep deprivation is among the most common complaints about the ICU experience. ICU sleep tends to be light and non-restorative (as opposed to deep / restorative sleep), severely fragmented, and distributed throughout the day and night rather than consolidated into nighttime hours. Sleep deprived patients suffer from sleep debt, a condition of impaired attention and memory, and cognitive slowing. Sleep disturbances in the ICU arise not only from light and noise pollution, but also from drugs that interfere with brain activity involved in restorative sleep. Sleep deprivation has also been suggested as a major modifiable risk factors for acute encephalopathy, also known as delirium. Delirium is an acute state of confusion that affects up to 80% of ICU patients, and is one of six leading causes of preventable morbidity and mortality in hospitalized elderly patients. Many patients who survive delirium experience long-term cognitive impairment and loss of independence. Current medications used in the ICU to treat sleep problems (e.g. benzodiazepines, antipsychotics) do not induce natural sleep and do not prevent delirium. In contrast, the investigators have found that the α2-adrenoceptor agonist dexmedetomidine can induce biomimetic sleep, a brain state whose pattern of electroencephalogram (EEG) activity, cerebral blood flow, and functional connectivity approximates restorative sleep. Moreover, a recent large clinical trial in post-surgical patients suggests that low-dose dexmedetomidine given overnight substantially reduces the risk of delirium. It is unknown whether this benefit is linked to improved sleep, or whether patients with better sleep while in the ICU have better long-term cognitive outcomes. The investigator's central hypothesis is that sleep deprivation substantially mediates both the short- and long-term cognitive impairments associated with delirium in critical illness. To test this hypothesis, this study is designed to systematically determine 1) the impact of prophylactic dexmedetomidine on sleep quality, 2) the optimal way to give dexmedetomidine (all night vs at the beginning of the night only), 2) the impact of sleep deprivation on short-term cognitive function and delirium, and 3) the contribution of sleep deprivation to long-term neuropsychiatric outcome following critical illness. At the conclusion of these studies, the investigators will have expanded knowledge of sleep physiology in critical illness and relationship of sleep with delirium; evaluated a new preemptive therapeutic strategy to promote sleep and prevent delirium, and developed an understanding of how sleep impacts neuropsychological outcomes after critical illness. These studies will thus will provide crucial guidance for individualized approaches to preserving long-term brain health in this vulnerable patient population.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 750 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: phase II, mechanistic, randomized, three-arm parallel group clinical trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Investigation of Sleep in the Intensive Care Unit
Actual Study Start Date : June 1, 2018
Estimated Primary Completion Date : April 1, 2022
Estimated Study Completion Date : April 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Delirium

Arm Intervention/treatment
Active Comparator: Dexmedetomidine (Dex) slow-bolus group

Study drug will be administered by the patient's nurse. Two 60 mL syringes will be supplied for each patient, containing 50 mL of Dex HCl at 4 ug/ ml Dex HCl or 50 ml normal saline (NS)), depending on randomized assignment. An initial bolus dose will be given over 45 min at 0.33 ml/kg/h (provides 1 mcg/kg/h for Dex patients) at 8PM, followed by continuous overnight infusion at 0.025 ml/kg/h (for Dex patients, provides 0.1 mcg/kg/h), for 7 consecutive nights (or until leaving the ICU), as follows:

1) Dex slow-bolus group: Dex slow bolus at 8PM over 45 min, then overnight NS until 8AM

Drug: Dexmedetomidine
See description of study arms

Active Comparator: Dexmedetomidine (Dex) continuous infusion group

Study drug will be administered by the patient's nurse. Two 60 mL syringes will be supplied for each patient, containing 50 mL of Dex HCl at 4 ug/ ml Dex HCl or 50 ml normal saline (NS)), depending on randomized assignment. An initial bolus dose will be given over 45 min at 0.33 ml/kg/h (provides 1 mcg/kg/h for Dex patients) at 8PM, followed by continuous overnight infusion at 0.025 ml/kg/h (for Dex patients, provides 0.1 mcg/kg/h), for 7 consecutive nights (or until leaving the ICU), as follows:

2) Dex continuous infusion group: NS slow bolus at 8PM over 45 min, then overnight Dex until 8AM

Drug: Dexmedetomidine
See description of study arms

Placebo Comparator: Usual care + placebo group

Study drug will be administered by the patient's nurse. Two 60 mL syringes will be supplied for each patient, containing 50 mL of Dex HCl at 4 ug/ ml Dex HCl or 50 ml normal saline (NS)), depending on randomized assignment. An initial bolus dose will be given over 45 min at 0.33 ml/kg/h (provides 1 mcg/kg/h for Dex patients) at 8PM, followed by continuous overnight infusion at 0.025 ml/kg/h (for Dex patients, provides 0.1 mcg/kg/h), for 7 consecutive nights (or until leaving the ICU), as follows:

3) NS slow bolus at 8PM over 45 min, then overnight NS until 8AM

Drug: Dexmedetomidine
See description of study arms




Primary Outcome Measures :
  1. Incidence of delirium [ Time Frame: 7 days ]
    incidence of delirium, defined as any positive CAM or CAM-ICU assessment over the first 7 ICU days (Aim 1a), comparing usual care+placebo (n=250) with Dex (combined slow-bolus + low-dose overnight continuous infusion groups, n=500)


Secondary Outcome Measures :
  1. Incidence of delirium between Dex groups [ Time Frame: 7 days ]
    Incidence of delirium within the two Dex treatment subgroups within the first 7 days within the ICU, assessed by the Confusion Assessment Method (CAM) or CAM-ICU.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

  1. Admitted to MGH Blake 7 or 12, or Elllison 4 ICU at Massachusetts General Hospital.
  2. Male or female, aged >18 years
  3. Provision of signed and dated informed consent form (by patient or LAR)
  4. Stated willingness to comply with all study procedures and availability for the duration of the study
  5. No on mechanical ventilation at the time of enrollment.
  6. Have not been in the ICU for more than 48 hours before enrollment.
  7. Able to be enrolled before 7PM.
  8. For females of reproductive potential: pregnancy test is negative.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

  1. Mechanical ventilation in the previous 2 months or >5 days in an ICU in the prior month
  2. Unable to be assessed for delirium (e.g. blindness or deafness)
  3. Pregnancy or lactation
  4. Known allergic reactions to components of dexmedetomidine
  5. Follow-up would be difficult (e.g. active substance abuse, homelessness)
  6. Severe dementia, as measured by a score of ≥3.3 on the Short Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)
  7. Known pre-existing neurologic disease or injury with focal neurologic or cognitive deficits
  8. Serious cardiac disease (e.g. sick sinus syndrome, sinus bradycardia)
  9. Cardiac surgery <3 months ago
  10. Severe liver dysfunction (Child-Pugh class C)
  11. Severe renal dysfunction (receiving dialysis)
  12. Low likelihood of survival >24 hours
  13. Patient is receiving either of the anticholinergic drugs scopolamine or penehyclidine
  14. Concomitant enrollment in another study protocol that may interfere with data acquisition or reliability of measurements;
  15. Deemed unsuitable for selection by the research team or ICU providers due to any medical, legal, social, or interpersonal issues that would either compromise the study or the routine care of patients.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03355053


Contacts
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Contact: M Brandon Westover, MD/PhD 617-726-3311 mwestover@mgh.harvard.edu
Contact: Seun Akeju, MD 617-697-2824 oluwaseun.akeju@mgh.harvard.edu

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: M Brandon Westover, MD/PhD    617-726-3311    mwestover@mgh.harvard.edu   
Contact: Seun Akeju, MD    617-726-3311    oluwaseun.akeju@mgh.harvard.edu   
Sponsors and Collaborators
Massachusetts General Hospital
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: M. Brandon Westover, MD/PhD Massachusetts General Hospital

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Responsible Party: Michael Brandon Westover, MD/PhD, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT03355053     History of Changes
Other Study ID Numbers: 2017P000090
First Posted: November 28, 2017    Key Record Dates
Last Update Posted: June 29, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Delirium
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Neurocognitive Disorders
Mental Disorders
Dexmedetomidine
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action