Minimizing ICU Neurological Dysfunction With Dexmedetomidine-induced Sleep (MINDDS)

Minimizing ICU Neurological Dysfunction With Dexmedetomidine-induced Sleep (MINDDS): A Randomized Placebo-controlled Trial

This study aims to determine whether, compared with placebo, the nighttime administration of a intravenous dexmedetomidine is effective at inducing sleep and preventing postoperative delirium in extubated post-cardiac surgical patients.

Study Overview

• Status: Completed
• Conditions: Sleep; Postoperative Delirium; Anesthesia
• Intervention / Treatment: Drug: Placebo; Drug: Dexmedetomidine

Detailed Description

Delirium is an acute brain dysfunction characterized by disturbances in attention, awareness, and cognition not explained by a preexisting neurocognitive disorder. Although the increased mortality rates ascribed to delirium remain debatable, delirium remains a leading cause of preventable morbidity in hospitalized elderly patients. It is also associated with prolonged hospitalization, prolonged institutionalization, and long-term cognitive deficits. Patients with pre-existing dementia, such as Alzheimer's disease, are especially vulnerable to developing delirium. The total healthcare cost attributable to delirium is estimated between $143 and $152 billion annually. In the United States, delirium occurs in approximately 80% of critically ill patients admitted to medical/surgical intensive care units (ICU), and 15% of patients admitted to cardiac surgical (CS) ICU. Most patients diagnosed with delirium also present with multiple comorbidities (sepsis, multi-organ failure) that significantly confound our understanding of this disease. Thus, to date, no pharmacological intervention to treat delirium has been identified.

There is mounting evidence to suggest that sleep deprivation may be a modifiable risk factor for the development of delirium. Presently, pharmacological treatment with no current medication (benzodiazepines, antipsychotics) induces natural sleep or reliably reduces the incidence of delirium. The investigators have found that biomimetic sleep, defined here as pharmacological induction of rapid eye movement sleep (REM) and non-REM (N1, N2, N3) sleep states using dexmedetomidine, can now be achieved in humans. The overall objective of this study is to evaluate the efficacy of biomimetic sleep in reducing the incidence and severity of delirium in extubated CSICU patients. The investigators will also assess for peri-operative electroencephalogram biomarkers of delirium, and the association between delirium and chronic neuroinflammation using positron emission tomography. The MINDDS study is poised to enable therapeutic and diagnostic discoveries to aid the care of elderly patients who are at risk for developing postoperative delirium.

• Study Type: Interventional
• Enrollment (Actual): 469
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 60
• Scheduled for a cardiac surgical procedure with planned post-operative admission to the CSICU for ≥ 24 hours
• Scheduled same day surgical admission

Exclusion Criteria:

• Blind, deafness or the inability to speak English
• Greater than 2 days of ICU admission in the month preceding the current surgical procedure
• Renal and liver failure requiring dialysis or Child-Pugh score > 5
• Follow-up difficulties (i.e. active substance abuse, psychotic disorder, homelessness)
• Previous cardiac surgery within 1 year of surgical procedure
• Allergy to dexmedetomidine
• Chronic therapy with benzodiazepines and/or antipsychotics
• Severe deficit due to structural or anoxic brain damage
• Surgical procedure requiring total circulatory arrest

Objective Drop Criteria

• Scheduled for a second surgical procedure during hospital stay
• Post-operative intubation > 12 hours

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine-induced sleep; Precedex (Dexmedetomidine) intervention: Intravenous administration of 1mcg/kg over 40 minutes.	Drug: Dexmedetomidine; Dexmedetomidine; Other Names: Precedex
Placebo Comparator: Placebo; Placebo of normal saline: Intravenous administration of normal saline over 40 minutes.	Drug: Placebo; Placebo; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Delirium	Confusion Assessment Method	Post operative day 1 (24 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Delirium Biomarkers	Blood samples will be taken including whole blood, serum, TruCulture, and PAXgene to assess proteins, DNA, and RNA.	perioperative
EEG Delirium Biomarkers	EEG burst suppression and alpha power will be analyzed for association with delirium.	intraoperative
ICU Delirium/Coma-free Days	Confusion Assessment Method	Up until postoperative day 3, or up until postoperative day 7 or discharge for patients who are delirious beyond postoperative day 5
Severity of Delirium	Confusion Assessment Method (CAM): Minimum Score=0, Maximum Score=19, Higher Scores: indicate increased severity of delirium	Up until postoperative day 3, or up until postoperative day 7 or discharge for patients who are delirious beyond postoperative day 5
30-day, 90-day, and 180-day Mortality	30-day, 90-day, and 180-day mortality	Up to postoperative day 180 (6 months)
Postoperative Cognitive Status	Telephone Montreal Cognitive Assessment (tMoCA): Minimum Score=0, Maximum Score=22, Higher Scores: indicate better cognitive function	30 days, 90 days, and 180 days postoperatively
Postoperative Health Related Quality of Life	This included the PROMIS Global Health SF V.1.1, PROMIS Physical Function SF 8b V.1.2, PROMIS Pain Interference SF 8a V.1.0, PROMIS Applied Cognition Abilities SF 8a V.1.0, and PROMIS Sleep Disturbance SF 4A V.1.0, respectively. Scores from each assessment were converted to a T-score for analysis with a mean of 50 and a standard deviation of 10, with lower scores on the PROMIS Pain Interference SF and PROMIS Sleep Disturbance SF considered better, whereas higher scores on all other assessments were considered better.	30 days, 90 days, and 180 days postoperatively

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of Hospital Stay	Medical Record Review	from postoperative day 0 until date of hospital discharge (no prespecified length possible)

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute on Aging (NIA)

Publications and helpful links

General Publications

• Shelton KT, Qu J, Bilotta F, Brown EN, Cudemus G, D'Alessandro DA, Deng H, DiBiasio A, Gitlin JA, Hahm EY, Hobbs LE, Houle TT, Ibala R, Loggia ML, Pavone KJ, Shaefi S, Tolis G, Westover MB, Akeju O. Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS): protocol for a randomised, double-blind, parallel-arm, placebo-controlled trial. BMJ Open. 2018 Apr 20;8(4):e020316. doi: 10.1136/bmjopen-2017-020316.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2017
• Primary Completion (Actual): February 11, 2022
• Study Completion (Actual): February 16, 2022

Study Registration Dates

• First Submitted: July 29, 2016
• First Submitted That Met QC Criteria: August 4, 2016
• First Posted (Estimate): August 5, 2016

Study Record Updates

• Last Update Posted (Actual): March 20, 2023
• Last Update Submitted That Met QC Criteria: February 21, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: 2016P000742; 1R01AG053582 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Immediately
• IPD Sharing Access Criteria: De-identified data and a data dictionary will be made available upon reasonable request to researchers who provide a methodologically sound proposal and whose use of the data has been approved the study authors. Data will be made available immediately following publication, with no anticipated end date, to achieve the aims specified in the approved proposal. Proposals should be directed to oluwaseun.akeju@mgh.harvard.edu.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No