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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Wes Ely, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00095251
First received: November 1, 2004
Last updated: February 5, 2013
Last verified: February 2013
  Purpose

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 Intervention Phase
Delirium
Drug: Dexmedetomidine
Drug: Lorazepam
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • achieving target sedation level [ Time Frame: Patients will receive study drug for a maximum of 120 hours (5 days) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Patients will receive study drug for a maximum of 120 hours (5 days) ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 100
Study Start Date: August 2004
Estimated Study Completion Date: December 2013
Primary Completion Date: August 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00095251

Locations
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: E Wesley Ely, MD, MPH Vanderbilt University
  More Information

Additional Information:
Publications:
Stern P, Carstensen L. The Aging Mind: Opportunities in Cognitive Research. National Research Council. Washington, D.C. National Academy of Press. 2000;1st ed:1-249.
Maldonado J, Wysong A, Starre Pvd, Block T. Postoperative Sedation and the Incidence of ICU Delirium in Cardiac Surgery Patients. ASA. 2004;Abstract and Poster Presentation.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Wes Ely, Professor of Medicine, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00095251     History of Changes
Other Study ID Numbers: IRB#031089
Study First Received: November 1, 2004
Last Updated: February 5, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Vanderbilt University:
Delirium
Hypnotics and Sedatives
Adrenergic alpha-Agonists
efficacy of sedation
cognitive impairment

Additional relevant MeSH terms:
Delirium
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Adrenergic alpha-Agonists
Dexmedetomidine
Gamma-Aminobutyric Acid
Lorazepam
Hypnotics and Sedatives
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
GABA Agents
Central Nervous System Depressants
Central Nervous System Agents
Therapeutic Uses
Anticonvulsants
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
GABA Modulators
Antiemetics
Autonomic Agents

ClinicalTrials.gov processed this record on April 17, 2014