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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

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ClinicalTrials.gov Identifier: NCT00095251
Recruitment Status : Completed
First Posted : November 2, 2004
Last Update Posted : September 11, 2018
Sponsor:
Information provided by (Responsible Party):
Wes Ely, Vanderbilt University

Tracking Information
First Submitted Date  ICMJE November 1, 2004
First Posted Date  ICMJE November 2, 2004
Last Update Posted Date September 11, 2018
Study Start Date  ICMJE August 2004
Actual Primary Completion Date August 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 20, 2011)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
Delirium
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 20, 2011)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
Efficacy of sedation
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
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).
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Condition  ICMJE Delirium
Intervention  ICMJE
  • 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.
  • 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.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Dexmedetomidine
  • 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.
    Intervention: Drug: Lorazepam
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Estimated Enrollment  ICMJE
 (submitted: June 23, 2005)
100
Original Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 2016
Actual Primary Completion Date August 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00095251
Other Study ID Numbers  ICMJE IRB#031089
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Wes Ely, Vanderbilt University
Study Sponsor  ICMJE Vanderbilt University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: E Wesley Ely, MD, MPH Vanderbilt University Medical Center
PRS Account Vanderbilt University Medical Center
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP