MENDS Study: Trial in Ventilated ICU Patients Comparing an Alpha2 Agonist Versus a Gamma Aminobutyric Acid (GABA)-Agonist to Determine Delirium Rates, Efficacy of Sedation, Analgesia and Discharge Cognitive Status

Sponsor

Vanderbilt University (Other)

Overall Status

Completed

CT.gov ID

NCT00095251

Collaborator

(none)

100

Enrollment

Location

Arms

148

Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Delirium has recently been shown as a predictor of death, increased cost, and longer length of stay in ventilated patients. Sedative and analgesic medications relieve anxiety and pain, but may contribute to patients' transitioning into delirium. It is possible that modifying the paradigm for sedation using novel therapies targeted at different receptors, such as dexmedetomidine targeting alpha2 receptors and sparing the GABA receptors, could provide efficacious sedation yet reduce the development, duration, and severity of acute brain dysfunction (delirium).

Condition or Disease	Intervention/Treatment	Phase
Delirium	Drug: Dexmedetomidine Drug: Lorazepam	Phase 2

Detailed Description

Delirium occurs in 60-80% of ventilated Intensive Care Unit (ICU) patients and is independently associated with prolonged hospital stay, higher cost, a 3-fold increased risk of dying by six months and ongoing neuropsychological dysfunction. Hypothesis: Based on our preliminary work, we hypothesize that standard use of GABA agonist sedatives such as lorazepam and propofol may contribute to ICU delirium and its attendant untoward clinical outcomes. An alternative sedation strategy targeting alpha2 receptors and sparing GABA receptors (dexmedetomidine) might reduce delirium, provide adequate sedation, reduce analgesic requirement, and concurrently improve cognitive performance.

Long-term objective: To standardize and compare different strategies of sedation and analgesia for ventilated ICU patients in order to optimize their clinical outcomes focusing on delirium and the long-term neuropsychological dysfunction of ICU survivors.

Specific Aims:

to study prevalence and duration of delirium in critically ill patients using differential exposure to alpha2 vs. GABA receptor agonists while evaluating efficacy of sedation and analgesia;
to compare clinical outcomes including duration of mechanical ventilation, ICU length of stay and severity of neuropsychological dysfunction at hospital discharge; and
to develop pharmacokinetic and pharmacodynamic models for dexmedetomidine and lorazepam when used for up to 5 days in ICU patients.

Relationship to anesthesiology: We will study whether the adverse clinical outcomes associated with ICU delirium including long-term neuropsychological dysfunction can be modified by the choice of psychoactive agents frequently used by anesthesiologists and intensivists.

Design: A blinded, randomized controlled trial of adult mechanically ventilated patients using a sedation strategy of dexmedetomidine ± fentanyl versus lorazepam ± fentanyl, with relevant outcomes and safety monitoring.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Prevention

Official Title:

A Randomized, Double-blind Trial in Ventilated ICU Patients Comparing Treatment With an Alpha2 Agonist Versus a Gamma Aminobutyric Acid (GABA)-Agonist to Determine Delirium Rates, Efficacy of Sedation, Analgesia and Discharge Cognitive Status

Study Start Date :

Aug 1, 2004

Actual Primary Completion Date :

Aug 1, 2007

Actual Study Completion Date :

Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Dexmedetomidine group Patients in the dexmedetomidine arm will receive a bolus dose of 1 μg/kg infused over 10 minutes followed by an infusion started at 0.15- 0.45 μg/kg/hr. The patient's managing physician will have the option of beginning the dexmedetomidine infusion without a bolus in circumstances where the patient's sedation level is adequate at enrollment or in the presence of baseline bradycardia /hypotension. Dexmedetomidine will be titrated every 10 minutes to achieve set target RASS score. The maximum dexmedetomidine infusion will be 1.5 μg/kg/hr.	Drug: Dexmedetomidine a bolus dose of 1 μg/kg infused over 10 minutes followed by an infusion started at 0.15- 0.45 μg/kg/hr. Dexmedetomidine will be titrated every 10 minutes to achieve set target RASS score. The maximum dexmedetomidine infusion will be 1.5 μg/kg/hr.
Active Comparator: Lorazepam group Patients in the lorazepam arm will receive a bolus dose of 1-3 mg followed by an infusion started at 1-3 mg/hr. Lorazepam infusion will be titrated every 10 minutes to achieve set target RASS score. The maximum lorazepam infusion will be 10 mg /hr.	Drug: Lorazepam Patients in the lorazepam arm will receive a bolus dose of 1-3 mg followed by an infusion started at 1-3 mg/hr. Lorazepam infusion will be titrated every 10 minutes to achieve set target RASS score. The maximum lorazepam infusion will be 10 mg /hr.

Arm

Intervention/Treatment

Active Comparator: Dexmedetomidine group

Patients in the dexmedetomidine arm will receive a bolus dose of 1 μg/kg infused over 10 minutes followed by an infusion started at 0.15- 0.45 μg/kg/hr. The patient's managing physician will have the option of beginning the dexmedetomidine infusion without a bolus in circumstances where the patient's sedation level is adequate at enrollment or in the presence of baseline bradycardia /hypotension. Dexmedetomidine will be titrated every 10 minutes to achieve set target RASS score. The maximum dexmedetomidine infusion will be 1.5 μg/kg/hr.

Drug: Dexmedetomidine

a bolus dose of 1 μg/kg infused over 10 minutes followed by an infusion started at 0.15- 0.45 μg/kg/hr. Dexmedetomidine will be titrated every 10 minutes to achieve set target RASS score. The maximum dexmedetomidine infusion will be 1.5 μg/kg/hr.

Active Comparator: Lorazepam group

Patients in the lorazepam arm will receive a bolus dose of 1-3 mg followed by an infusion started at 1-3 mg/hr. Lorazepam infusion will be titrated every 10 minutes to achieve set target RASS score. The maximum lorazepam infusion will be 10 mg /hr.

Drug: Lorazepam

Outcome Measures

Primary Outcome Measures

achieving target sedation level [Patients will receive study drug for a maximum of 120 hours (5 days)]
The patients' managing team will set the "goal" or "target" as medically indicated using the RASS 37. A trained research nurse or physician blinded to patients' group assignment and medical management will perform measurement of the "actual" RASS level every 12 hours. Comparisons will be made between the actual and target RASS levels to determine the primary outcome measure, which is the accuracy of achieving the target sedation level.

Secondary Outcome Measures

duration and severity of delirium [Patients will receive study drug for a maximum of 120 hours (5 days)]
Delirium will be measured using the CAM-ICU, every 12 hours, by the same research personnel performing the assessment of the patients' sedation level. Together, these instruments take on average only 1 to 2 minutes to perform. Delirium is said to be present if the patients are responsive to verbal stimulation with eye opening (i.e., RASS -3 or better) and are found to have an acute change or fluctuation in the course of their mental status, inattention, and either disorganized thinking or an altered level of consciousness.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female adult patients admitted to the medical and surgical ICU for critical illnesses requiring mechanical ventilation with expectation of being mechanically ventilated for greater than 24 hours

Exclusion Criteria:

Subjects who are less than 18 years of age
Subjects who are pregnant (a pregnancy test will be performed on all women of child bearing age)
Inability to obtain informed consent from the patient or his/her surrogate
Subjects in the ICU due to a lack of beds elsewhere in the hospital, triage issues, or withdrawal of care decisions rather than severity of illness
Subjects admitted with alcohol or drug overdoses, suicide attempts, or alcohol/delirium tremens
Subjects who are physiologically benzodiazepine dependent, and at risk for withdrawal syndromes
Subjects with chronic pain syndromes on maintenance narcotics
Subjects treated within the last 30 days with a drug or device that has not received regulatory approval as of study entry
Subjects with a psychiatric history for which they are on neuroleptic treatment
Subjects with documented moderate to severe dementia
Subjects with anoxic brain injuries, strokes, neurotrauma, or neuromuscular disorders such as myasthenia gravis or Guillain Barre syndrome
Medical team following patient unwilling to use the sedation regimens
Subjects whose family and/or physician have not committed to aggressive support for 72 hours or who are likely to withdraw within 72 hours
Subjects who are moribund and not expected to survive 24 hours
Subjects not expected to survive hospital discharge due to preexisting uncorrectable medical condition
Documented allergy to study medications
Subjects who have either Child-Pugh Class B or C cirrhosis
Subjects with active coronary artery disease at time of screening as defined by any recent evidence of ischemia, documented myocardial infarction, or coronary intervention within the past 6 months.
Subjects with advanced heart block at time of screening