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

September 10, 2018 updated by: Wes Ely, Vanderbilt University

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

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

100

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
achieving target sedation level
Time Frame: 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.
Patients will receive study drug for a maximum of 120 hours (5 days)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
duration and severity of delirium
Time Frame: 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.
Patients will receive study drug for a maximum of 120 hours (5 days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University

Investigators

  • Principal Investigator: E Wesley Ely, MD, MPH, Vanderbilt University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2004

Primary Completion (Actual)

August 1, 2007

Study Completion (Actual)

December 1, 2016

Study Registration Dates

First Submitted

November 1, 2004

First Submitted That Met QC Criteria

November 1, 2004

First Posted (Estimate)

November 2, 2004

Study Record Updates

Last Update Posted (Actual)

September 11, 2018

Last Update Submitted That Met QC Criteria

September 10, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB#031089

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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