Anesthesia, Postoperative Delirium, Sleep
Conditions
Brief summary
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.
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.
Interventions
DRUGDexmedetomidine
Dexmedetomidine
DRUGPlacebo
Placebo
Sponsors
Massachusetts General Hospital
National Institute on Aging (NIA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Delirium | Post operative day 1 (24 hours) | The number of patients with delirium is reported using the Confusion Assessment Method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ICU Delirium/Coma-free Days | Up until postoperative day 3, or up until postoperative day 7 or discharge for patients who are delirious beyond postoperative day 5 | Confusion Assessment Method |
| 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 | Confusion Assessment Method (CAM): Minimum Score=0, Maximum Score=19, Higher Scores: indicate increased severity of delirium |
| Cumulative 30-day, 90-day, and 180-day Mortality | Up to postoperative day 180 (6 months) | The number of cumulative deaths occurring at 30-days, 90-days, and 180-days |
| Postoperative Cognitive Status | 30 days, 90 days, and 180 days postoperatively | Telephone Montreal Cognitive Assessment (tMoCA): Minimum Score=0, Maximum Score=22, Higher Scores: indicate better cognitive function |
| Postoperative Health Related Quality of Life | 30 days, 90 days, and 180 days postoperatively | 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. |
| Blood Delirium Biomarkers | perioperative | Blood samples will be taken including whole blood, serum, TruCulture, and PAXgene to assess proteins, DNA, and RNA. |
| EEG Delirium Biomarkers | intraoperative | EEG alpha power will be analyzed for association with delirium. |
Countries
United States
Participant flow
Pre-assignment details
There were no significant events in the study following enrollment but prior to assignment of participants to an arm or group. All enrolled subjects were assigned to either of the two study groups.
Participants by arm
| Arm | Count |
|---|---|
| Dexmedetomidine-induced Sleep Precedex (Dexmedetomidine) intervention: Intravenous administration of 1mcg/kg over 40 minutes.
Dexmedetomidine: Dexmedetomidine | 188 |
| Placebo Placebo of normal saline: Intravenous administration of normal saline over 40 minutes.
Placebo: Placebo | 206 |
| Total | 394 |
Baseline characteristics
| Characteristic | Dexmedetomidine-induced Sleep | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 129 Participants | 157 Participants | 286 Participants |
| Age, Categorical Between 18 and 65 years | 59 Participants | 49 Participants | 108 Participants |
| Age, Continuous | 67.5 years | 70.0 years | 69.0 years |
| Delirium Incidence at Baseline | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 179 Participants | 194 Participants | 373 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 10 Participants | 18 Participants |
| Preoperative Cognitive Status | 19.0 score on a scale | 19.0 score on a scale | 19.0 score on a scale |
| Preoperative Health Related Quality of Life Applied Cognition | 52.4 Values are reported using a T-Score. | 51.2 Values are reported using a T-Score. | 51.7 Values are reported using a T-Score. |
| Preoperative Health Related Quality of Life Global Health - Mental | 56.0 Values are reported using a T-Score. | 56.0 Values are reported using a T-Score. | 56.0 Values are reported using a T-Score. |
| Preoperative Health Related Quality of Life Global Health - Physical | 50.8 Values are reported using a T-Score. | 50.8 Values are reported using a T-Score. | 50.8 Values are reported using a T-Score. |
| Preoperative Health Related Quality of Life Pain Interference | 40.7 Values are reported using a T-Score. | 40.7 Values are reported using a T-Score. | 40.7 Values are reported using a T-Score. |
| Preoperative Health Related Quality of Life Physical Function | 44.6 Values are reported using a T-Score. | 46.4 Values are reported using a T-Score. | 45.5 Values are reported using a T-Score. |
| Preoperative Health Related Quality of Life Sleep Disturbance | 50.5 Values are reported using a T-Score. | 50.5 Values are reported using a T-Score. | 50.5 Values are reported using a T-Score. |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 182 Participants | 202 Participants | 384 Participants |
| Sex: Female, Male Female | 44 Participants | 62 Participants | 106 Participants |
| Sex: Female, Male Male | 144 Participants | 144 Participants | 288 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 188 | 4 / 206 |
| other Total, other adverse events | 0 / 188 | 0 / 206 |
| serious Total, serious adverse events | 0 / 188 | 0 / 206 |
Outcome results
Primary
Incidence of Delirium
Confusion Assessment Method
Time frame: Post operative day 1 (24 hours)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dexmedetomidine-induced Sleep | Incidence of Delirium | 5 Participants |
| Placebo | Incidence of Delirium | 16 Participants |
p-value: 0.02995% CI: [0.1, 0.83]Regression, Logistic
Secondary
30-day, 90-day, and 180-day Mortality
30-day, 90-day, and 180-day mortality
Time frame: Up to postoperative day 180 (6 months)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dexmedetomidine-induced Sleep | 30-day, 90-day, and 180-day Mortality | In Hospital Mortality | 3 Participants |
| Dexmedetomidine-induced Sleep | 30-day, 90-day, and 180-day Mortality | 30 Days | 3 Participants |
| Dexmedetomidine-induced Sleep | 30-day, 90-day, and 180-day Mortality | 90 Days | 4 Participants |
| Dexmedetomidine-induced Sleep | 30-day, 90-day, and 180-day Mortality | 180 Days | 4 Participants |
| Placebo | 30-day, 90-day, and 180-day Mortality | 180 Days | 4 Participants |
| Placebo | 30-day, 90-day, and 180-day Mortality | In Hospital Mortality | 1 Participants |
| Placebo | 30-day, 90-day, and 180-day Mortality | 90 Days | 1 Participants |
| Placebo | 30-day, 90-day, and 180-day Mortality | 30 Days | 1 Participants |
Secondary
Blood Delirium Biomarkers
Blood samples will be taken including whole blood, serum, TruCulture, and PAXgene to assess proteins, DNA, and RNA.
Time frame: perioperative
Secondary
EEG Delirium Biomarkers
EEG burst suppression and alpha power will be analyzed for association with delirium.
Time frame: intraoperative
Secondary
ICU Delirium/Coma-free Days
Confusion Assessment Method
Time frame: Up until postoperative day 3, or up until postoperative day 7 or discharge for patients who are delirious beyond postoperative day 5
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dexmedetomidine-induced Sleep | ICU Delirium/Coma-free Days | 0 Days | 0 Participants |
| Dexmedetomidine-induced Sleep | ICU Delirium/Coma-free Days | 1 Day | 6 Participants |
| Dexmedetomidine-induced Sleep | ICU Delirium/Coma-free Days | 2 Days | 8 Participants |
| Dexmedetomidine-induced Sleep | ICU Delirium/Coma-free Days | 3 Days | 146 Participants |
| Placebo | ICU Delirium/Coma-free Days | 3 Days | 152 Participants |
| Placebo | ICU Delirium/Coma-free Days | 0 Days | 2 Participants |
| Placebo | ICU Delirium/Coma-free Days | 2 Days | 16 Participants |
| Placebo | ICU Delirium/Coma-free Days | 1 Day | 7 Participants |
Secondary
Postoperative Cognitive Status
Telephone Montreal Cognitive Assessment (tMoCA): Minimum Score=0, Maximum Score=22, Higher Scores: indicate better cognitive function
Time frame: 30 days, 90 days, and 180 days postoperatively
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dexmedetomidine-induced Sleep | Postoperative Cognitive Status | 30 Days | 20.0 score on a scale |
| Dexmedetomidine-induced Sleep | Postoperative Cognitive Status | 90 Days | 20.0 score on a scale |
| Dexmedetomidine-induced Sleep | Postoperative Cognitive Status | 180 Days | 20.0 score on a scale |
| Placebo | Postoperative Cognitive Status | 30 Days | 20.0 score on a scale |
| Placebo | Postoperative Cognitive Status | 90 Days | 20.0 score on a scale |
| Placebo | Postoperative Cognitive Status | 180 Days | 21.0 score on a scale |
Secondary
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.
Time frame: 30 days, 90 days, and 180 days postoperatively
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Global Health - Physical (30 Days) | 50.8 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Global Health - Physical (90 Days) | 54.1 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Global Health - Physical (180Days) | 57.7 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Global Health - Mental (30 Days) | 59.0 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Global Health - Mental (90 Days) | 59.0 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Global Health - Mental (180 Days) | 62.5 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Physical Function (30 Days) | 49.9 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Physical Function (90 Days) | 40.7 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Physical Function (180 Days) | 40.7 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Pain Interference (30 Days) | 49.9 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Pain Interference (90 Days) | 40.7 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Pain Interference (180 Days) | 40.7 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Applied Cognition (30 Days) | 54.6 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Applied Cognition (90 Days) | 53.0 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Applied Cognition (180 Days) | 54.6 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Sleep Disturbance (30 Days) | 50.5 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Sleep Disturbance (90 Days) | 48.4 T-Score |
| Dexmedetomidine-induced Sleep | Postoperative Health Related Quality of Life | PROMIS Sleep Disturbance (180 Days) | 46.2 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Applied Cognition (90 Days) | 54.6 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Global Health - Physical (30 Days) | 47.7 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Pain Interference (30 Days) | 52.3 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Global Health - Physical (90 Days) | 54.1 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Sleep Disturbance (180 Days) | 46.2 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Global Health - Physical (180Days) | 54.1 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Pain Interference (90 Days) | 40.7 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Global Health - Mental (30 Days) | 56.0 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Applied Cognition (180 Days) | 54.6 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Global Health - Mental (90 Days) | 62.5 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Pain Interference (180 Days) | 40.7 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Global Health - Mental (180 Days) | 62.5 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Sleep Disturbance (90 Days) | 48.4 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Physical Function (30 Days) | 52.3 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Applied Cognition (30 Days) | 53.0 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Physical Function (90 Days) | 40.7 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Sleep Disturbance (30 Days) | 50.5 T-Score |
| Placebo | Postoperative Health Related Quality of Life | PROMIS Physical Function (180 Days) | 40.7 T-Score |
Secondary
Severity of Delirium
Confusion Assessment Method (CAM): Minimum Score=0, Maximum Score=19, Higher Scores: indicate increased severity of delirium
Time frame: Up until postoperative day 3, or up until postoperative day 7 or discharge for patients who are delirious beyond postoperative day 5
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexmedetomidine-induced Sleep | Severity of Delirium | 3.0 score on a scale |
| Placebo | Severity of Delirium | 3.0 score on a scale |
p-value: 0.2495% CI: [0.89, 1.03]Regression, Linear
Other Pre-specified
Length of Hospital Stay
Medical Record Review
Time frame: from postoperative day 0 until date of hospital discharge (no prespecified length possible)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexmedetomidine-induced Sleep | Length of Hospital Stay | 6.0 days |
| Placebo | Length of Hospital Stay | 6.0 days |