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| ID | Type | Description | Link |
|---|---|---|---|
| R01NS102190 | U.S. NIH Grant/Contract | View source |
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| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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Sleep deprivation is common and often severe in critically ill patients cared for in intensive care units (ICUs) and is hypothesized to be a modifiable risk factor for delirium, which in turn is hypothesized to be a modifiable risk factor for long-term cognitive disability following recovery from critical illness. Dexmedetomidine (Dex) reduces the incidence of delirium in ICU patients by unknown mechanisms. The Investigation of Sleep in the Intensive Care Unit (ICU-SLEEP) Trial aims to determine whether Dex reduces delirium by improving sleep, whether a low- and/or very-low dose continuous infusion of Dex increases delirium-free days more, and the relationship between sleep deprivation in the ICU to long-term cognitive outcomes.
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 factor for acute encephalopathy, also known as delirium. Delirium is an acute state of confusion that affects up to 50% of non-ventilated 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, the ICU-SLEEP trial aims to: 1A) Compare the burden of delirium, as measured by the number of delirium-free days (DFDs), in ICU patients non-ventilated at study enrollment, who are receiving biomimetic sleep induced by Dex, given as a continuous overnight 1) very-low-dose or 2) low-dose infusion vs. 3) usual care and placebo; 1B) Assess whether the 1) very-low-dose continuous overnight infusion of Dex increases DFDs compared to the 2) low-dose continuous overnight infusion; 2A) Determine whether Dex reduces ICU delirium via reducing sleep deprivation, using causal mediation analysis; 2B) Determine the associations between specific components of acute cognitive impairment, seen in sleep deprivation and delirium, with specific measures of sleep deprivation; 3A) Determine whether ICU patients treated with Dex while in the hospital have a lower incidence of long-term cognitive impairment; 3B) Determine whether any differences in long-term cognitive impairment between ICU survivors treated with Dex vs. usual care and placebo are mediated by differences in sleep deprivation. The knowledge gained will provide insights into the mechanisms by which Dex prevents delirium and guidance on the optimal dosing strategy for prophylactic Dex, which can be used to design pivotal phase 3 clinical trials.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dexmedetomidine, continuous very-low-dose overnight infusion | Active Comparator | Patients randomized to this study arm will receive dexmedetomidine, given as a very-low-dose (0.1 mcg/kg/hour group; rate of 0.075 mL/kg/hour at a concentration of 1.33 mcg/mL) continuous overnight infusion. Study drug will be provided by the MGH research pharmacy as a clear liquid and delivered by the research staff directly to the patient's ICU nurse, in a 60 mL syringe/bag (s). Nursing will then administer the study drug intravenously each night (11 hours; 8PM through 7AM) until either discharge from the ICU or up to 7 consecutive nights, whichever occurs first. |
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| Dexmedetomidine, continuous low-dose overnight infusion | Active Comparator | Patients randomized to this study arm will receive dexmedetomidine, given as a low-dose (0.3 mcg/kg/hour group; rate of 0.075 mL/kg/hour at a concentration of 4 mcg/mL) continuous overnight infusion. Study drug will be provided by the MGH research pharmacy as a clear liquid and delivered by the research staff directly to the patient's ICU nurse, in a 60 mL syringe/bag (s). Nursing will then administer the study drug intravenously each night (11 hours; 8PM through 7AM) until either discharge from the ICU or up to 7 consecutive nights, whichever occurs first. |
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| Usual care and placebo (normal saline) | Placebo Comparator | Patients randomized to this study arm will receive standard ICU care plus a normal saline placebo, given as a continuous overnight infusion, at a rate of 0.075 mL/kg/hour. Study drug will be provided by the MGH research pharmacy as a clear liquid and delivered by the research staff directly to the patient's ICU nurse, in a 60 mL syringe/bag (s). Nursing will then administer the study drug intravenously each night (11 hours; 8PM through 7AM) until either discharge from the ICU or up to 7 consecutive nights, whichever occurs first. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dexmedetomidine | Drug | "Dex (Precedex, Dexmedetomidine HCl Injection) is produced by Pfizer Inc, NY, Ny (formerly Hospira). Dex is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89. Dex is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0. Each mL contains 118 mcg of dexmedetomidine hydrochloride equivalent to 100 mcg (0.1mg) of dexmedetomidine and 9 mg of sodium chloride in water. The solution is preservative-free and contains no additives or chemical stabilizers. The MGH Pharmacy currently obtains Dex from the supplier as a solution in 50 mL clear-glass bottles, as a clear liquid, at a concentration of 4mcg/mL." |
| Measure | Description | Time Frame |
|---|---|---|
| In-hospital Delirium-free days (IH-DFDs) | In-hospital Delirium-free days (IH-DFDs) are calculated as the sum of days without delirium during the first 14 hospital days from start of infusion in the two Dex treatment arms combined (arms 1 and 2) vs. usual care (arm 3). Delirium is defined as any positive Confusion Assessment Method (CAM) or CAM for the ICU (CAM-ICU) assessment, with each yielding a binary result (1 = delirious/CAM+, 0 = non-delirious/CAM-). For each patient, delirium is assessed twice daily. If a patient has any positive delirium assessments on any given day of the assessment days, they are considered to have had delirium during these days. Days with coma are counted together with delirium. | First 14 hospital days from start of infusion [or until hospital discharge, whichever occurs first] |
| Measure | Description | Time Frame |
|---|---|---|
| ICU-Delirium-free days (ICU-DFDs) | ICU-Delirium-free days (ICU-DFDs) are calculated as the sum of days without delirium during the first 7 ICU days from start of infusion in the two Dex treatment arms combined (arms 1 and 2) vs. usual care (arm 3). Delirium is defined as any positive Confusion Assessment Method (CAM) or CAM for the ICU (CAM-ICU) assessment, with each yielding a binary result (1 = delirious/CAM+, 0 = non-delirious/CAM-). For each patient, delirium is assessed twice daily. If a patient has any positive delirium assessments on any given day of the assessment days, they are considered to have had delirium during these days. Days with coma are counted together with delirium. |
| Measure | Description | Time Frame |
|---|---|---|
| Spearman correlation coefficient (rho) between sleep quality and acute cognitive function | Spearman's correlation coefficient (rho) describes the correlation between sleep quality on the previous night, as measured by the Sleep Quantity-quality (SQ) score, and acute cognitive function, as measured by the Acute Cognitive Function (ACF) score. | First 14 ICU days from start of infusion [or until ICU discharge, whichever occurs first] |
Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| M. Brandon Westover, MD, PhD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16778263 | Background | Hardin KA, Seyal M, Stewart T, Bonekat HW. Sleep in critically ill chemically paralyzed patients requiring mechanical ventilation. Chest. 2006 Jun;129(6):1468-77. doi: 10.1378/chest.129.6.1468. | |
| 21358853 | Background | Fanfulla F, Ceriana P, D'Artavilla Lupo N, Trentin R, Frigerio F, Nava S. Sleep disturbances in patients admitted to a step-down unit after ICU discharge: the role of mechanical ventilation. Sleep. 2011 Mar 1;34(3):355-62. doi: 10.1093/sleep/34.3.355. |
| Label | URL |
|---|---|
| Airgoâ„¢ \[Internet\]. Airgoâ„¢. \[cited 2022 Jul 8\]. Available from: https://www.myairgo.com | View source |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 12, 2024 | Jun 19, 2024 | SAP_000.pdf |
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| ID | Term |
|---|---|
| D003693 | Delirium |
| ID | Term |
|---|---|
| D003221 | Confusion |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D020927 | Dexmedetomidine |
| D000077330 | Saline Solution |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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Single-center, prospective, phase II, double-blind, placebo-controlled, three-arm, parallel-group, mechanistic, randomized clinical trial
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| Placebo | Drug | From the package insert: "0.9% Sodium Chloride Injection, USP is sterile and nonpyrogenic. It is produced by Pfizer Inc, NY, Ny (formerly Hospira). It is a parenteral solution containing sodium chloride in water for injection intended for intravenous administration. Each 100 mL of 0.9% Sodium Chloride Injection, USP contains 900 mg sodium chloride in water for injection. Electrolytes per 1000 mL: sodium (Na+ ) 154 mEq; chloride (Cl- ) 154 mEq. The osmolarity is 308 mOsmol/L (calc.). The pH is 5.6 (4.5 to 7.0). This solution contains no bacteriostat, antimicrobial agent or added buffer and is intended only as a single-dose injection. When smaller doses are required, the unused portion should be discarded. 0.9% Sodium Chloride Injection, USP is a parenteral fluid and electrolyte replenisher. Sodium Chloride, USP is chemically designated NaCl, a white crystalline powder freely soluble in water. Water for Injection, USP is chemically designated H2O." |
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| First 7 ICU days from start of infusion [or until ICU discharge, whichever occurs first] |
| Sleep Quantity-quality (SQ) score | The Sleep Quantity-quality (SQ) score is a sleep composite measure formed by averaging the z-scores for raw measures of sleep quality (total sleep time (TST), sleep fragmentation index (SFI), time in N2, time in N3), where a higher SQ score indicates better outcomes. | First 14 ICU days from start of infusion [or until ICU discharge, whichever occurs first] |
| Acute Cognitive Function (ACF) score | The Acute Cognitive Function (ACF) score is a reliable change index controlling for practice effects (RCI+PE) for a composite of acute cognitive measures. These include twice daily Confusion Assessment Method-Severity (CAM-S; Short Form (0-7) & Long Form (0-19), where higher scores indicate increased severity of delirium symptoms); and Psychomotor Vigilance Test (PVT) scores collected in the first 7 ICU days from start of infusion [or until ICU discharge, whichever occurs first]. Composites will be formed by averaging z-scores for CAM-S and PVT scores, where a higher ACF score indicates better outcomes. | First 14 ICU days from start of infusion [or until ICU discharge, whichever occurs first] |
| Long-term Cognitive Function (LCF) score | The Long-term Cognitive Function (LCF) score is a composite average of z-scores from long-term cognitive outcome measures of the different components, where a higher LCF score indicates better outcomes. | 3-, 6-, and 12 months post-enrollment |
| Average Causal Mediation Effect (ACME) of sleep deprivation on delirium-free days | Causal effect of sleep deprivation (SD) on In-hospital Delirium-free days (IH-DFDs) and ICU-Delirium-free days (ICU-DFDs), where SD is quantified by the Sleep Quantity-quality (SQ) score. | First 14 ICU days from start of infusion [or until ICU discharge, whichever occurs first] |
| Average Causal Mediation Effect (ACME) of sleep deprivation on acute cognitive outcomes | Causal effect of sleep deprivation (SD) on acute cognitive outcomes, where SD is quantified by the Sleep Quantity-quality (SQ) score, and acute cognitive function is quantified by the Acute Cognitive Function (ACF) score. | First 14 ICU days from start of infusion [or until ICU discharge, whichever occurs first] |
| Average Causal Mediation Effect (ACME) of sleep deprivation on long-term cognitive outcomes | Causal effect of sleep deprivation (SD) on long-term cognitive outcomes, where SD is quantified by the Sleep Quantity-quality (SQ) score, and long-term cognitive function is quantified by the Long-term Cognitive Function (LCF) score. | First 14 ICU days from start of infusion [or until ICU discharge, whichever occurs first]; 3-, 6-, and 12 months post-enrollment |
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| Computing Comorbidity Scores (Charlson Comorbidity Index) | View source |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D000077324 |
| Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |