Back to results

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

Primary Purpose

Delirium

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Dexmedetomidine

Lorazepam

About this trial

This is an interventional prevention trial for Delirium focused on measuring Delirium, Hypnotics and Sedatives, Adrenergic alpha-Agonists, efficacy of sedation, cognitive impairment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Dexmedetomidine group

Lorazepam group

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

achieving target sedation level

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

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.

Full Information

NCT ID

NCT00095251

First Posted

November 1, 2004

Last Updated

September 10, 2018

Sponsor

Vanderbilt University

1. Study Identification

Unique Protocol Identification Number

NCT00095251

Brief Title

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

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 Type

Interventional

2. Study Status

Record Verification Date

September 2018

Overall Recruitment Status

Completed

Study Start Date

August 2004 (undefined)

Primary Completion Date

August 2007 (Actual)

Study Completion Date

December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Vanderbilt University

4. Oversight

Data Monitoring Committee

Yes

5. 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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Delirium

Keywords

Delirium, Hypnotics and Sedatives, Adrenergic alpha-Agonists, efficacy of sedation, cognitive impairment

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Dexmedetomidine group

Arm Type

Active Comparator

Arm Description

Arm Title

Lorazepam group

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Dexmedetomidine

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Lorazepam

Intervention Description

Primary Outcome Measure Information:

Title

achieving target sedation level

Description

Time Frame

Patients will receive study drug for a maximum of 120 hours (5 days)

Secondary Outcome Measure Information:

Title

duration and severity of delirium

Description

Time Frame

Patients will receive study drug for a maximum of 120 hours (5 days)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

E Wesley Ely, MD, MPH

Organizational Affiliation

Vanderbilt University Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Vanderbilt University Medical Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

15082703

Citation

Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-62. doi: 10.1001/jama.291.14.1753.

Results Reference

background

PubMed Identifier

15071384

Citation

Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, Stiles RA, Truman B, Bernard GR, Dittus RS, Ely EW. Costs associated with delirium in mechanically ventilated patients. Crit Care Med. 2004 Apr;32(4):955-62. doi: 10.1097/01.ccm.0000119429.16055.92.

Results Reference

background

PubMed Identifier

11797025

Citation

Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, Truman B, Dittus R, Bernard R, Inouye SK. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001 Dec;27(12):1892-900. doi: 10.1007/s00134-001-1132-2. Epub 2001 Nov 8.

Results Reference

background

PubMed Identifier

11730446

Citation

Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, Truman B, Speroff T, Gautam S, Margolin R, Hart RP, Dittus R. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001 Dec 5;286(21):2703-10. doi: 10.1001/jama.286.21.2703.

Results Reference

background

PubMed Identifier

10335730

Citation

Inouye SK, Schlesinger MJ, Lydon TJ. Delirium: a symptom of how hospital care is failing older persons and a window to improve quality of hospital care. Am J Med. 1999 May;106(5):565-73. doi: 10.1016/s0002-9343(99)00070-4.

Results Reference

background

PubMed Identifier

9565386

Citation

Inouye SK, Rushing JT, Foreman MD, Palmer RM, Pompei P. Does delirium contribute to poor hospital outcomes? A three-site epidemiologic study. J Gen Intern Med. 1998 Apr;13(4):234-42. doi: 10.1046/j.1525-1497.1998.00073.x.

Results Reference

background

PubMed Identifier

10732935

Citation

Ostermann ME, Keenan SP, Seiferling RA, Sibbald WJ. Sedation in the intensive care unit: a systematic review. JAMA. 2000 Mar 15;283(11):1451-9. doi: 10.1001/jama.283.11.1451.

Results Reference

background

PubMed Identifier

7966844

Citation

Marcantonio ER, Juarez G, Goldman L, Mangione CM, Ludwig LE, Lind L, Katz N, Cook EF, Orav EJ, Lee TH. The relationship of postoperative delirium with psychoactive medications. JAMA. 1994 Nov 16;272(19):1518-22.

Results Reference

background

PubMed Identifier

11511942

Citation

Dubois MJ, Bergeron N, Dumont M, Dial S, Skrobik Y. Delirium in an intensive care unit: a study of risk factors. Intensive Care Med. 2001 Aug;27(8):1297-304. doi: 10.1007/s001340101017.

Results Reference

background

PubMed Identifier

11762266

Citation

Maze M, Scarfini C, Cavaliere F. New agents for sedation in the intensive care unit. Crit Care Clin. 2001 Oct;17(4):881-97. doi: 10.1016/s0749-0704(05)70185-8.

Results Reference

background

PubMed Identifier

20669496

Citation

National Research Council (US) Committee on Future Directions for Cognitive Research on Aging; Stern PC, Carstensen LL, editors. The Aging Mind: Opportunities in Cognitive Research. Washington (DC): National Academies Press (US); 2000. Available from http://www.ncbi.nlm.nih.gov/books/NBK44833/

Results Reference

background

Citation

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.

Results Reference

background

PubMed Identifier

29363356

Citation

Stollings JL, Thompson JL, Ferrell BA, Scheinin M, Wilkinson GR, Hughes CG, Shintani AK, Ely EW, Girard TD, Pandharipande PP, Patel MB. Sedative Plasma Concentrations and Delirium Risk in Critical Illness. Ann Pharmacother. 2018 Jun;52(6):513-521. doi: 10.1177/1060028017753480. Epub 2018 Jan 24.

Results Reference

derived

PubMed Identifier

20233428

Citation

Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK, Herr DL, Maze M, Ely EW; MENDS investigators. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14(2):R38. doi: 10.1186/cc8916. Epub 2010 Mar 16. Erratum In: Crit Care. 2011;15(1):402.

Results Reference

derived

PubMed Identifier

18073360

Citation

Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, Shintani AK, Thompson JL, Jackson JC, Deppen SA, Stiles RA, Dittus RS, Bernard GR, Ely EW. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007 Dec 12;298(22):2644-53. doi: 10.1001/jama.298.22.2644.

Results Reference

derived

Links:

URL

http://www.ICUdelirium.org

Description

This is an educational website on delirium in the ICU.

Learn more about this trial

We'll reach out to this number within 24 hrs