Investigation of Sleep in the Intensive Care Unit

Massachusetts General Hospital522 enrolled

Overview

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.

Interventions

DexmedetomidineDRUG

"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."

PlaceboDRUG

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."

Eligibility

Sex: ALLMin age: 50 Years

Medical Language ↔ Plain English

Inclusion Criteria 1. Admitted or scheduled to be admitted to an MGH medical or surgical ICU (Blake 7 or 12, or Ellison 4) 2. Male or female, aged ≥ 50 years 3. Provision of signed and dated informed consent form (by patient or legally authorized representative (LAR)) 4. Stated willingness to comply with all study procedures and availability for the duration of the study 5. Not on mechanical ventilation at the time of enrollment 6. Able to be enrolled before 7PM 7. For females of reproductive potential: pregnancy test is negative Exclusion Criteria 1. Dementia, as measured by a score of ≥3.3 on the Informant Questionnaire on Cognitive Decline in the Elderly Short Form (IQCODE-SF) 2. Unable to be assessed for delirium (e.g. blindness or deafness) 3. Follow-up would be difficult (e.g. active substance abuse, homelessness) 4. Pregnancy or lactation 5. Known pre-existing neurologic disease or injury with focal neurologic or cognitive deficits 6. Serious cardiac disease (e.g. sick sinus syndrome without a pacemaker, sinus bradycardia, second- or third-degree AV block, congestive heart failure with ejection fraction \<30%) 7. Severe liver dysfunction (Child-Pugh class C) 8. Severe renal dysfunction (receiving dialysis) 9. Low likelihood of survival \>24 hours 10. Low likelihood of staying in ICU overnight 11. Known allergic reactions to components of dexmedetomidine 12. Patient is receiving or planning to go on dexmedetomidine at the time of enrollment 13. Patient is receiving either of the anticholinergic drugs scopolamine or penehyclidine; or alpha-2-agonist clonidine 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, language (non-English speaking) or interpersonal issues that would either compromise the study or the routine care of patients

Outcomes

Primary Outcomes

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.

Time frame: First 14 hospital days from start of infusion [or until hospital discharge, whichever occurs first]

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 3-, 6-, and 12 months post-enrollment