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

Delirium Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00095251
• Other study ID #: IRB#031089
• Status: Completed
• Phase: Phase 2
• Start date: August 2004
• Est. completion date: December 2016

Study information

• Verified date: September 2018
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: December 2016
• Est. primary completion date: August 2007
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Delirium

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View 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. Epub 2001 Nov 8. — View 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. — View 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. — View 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. — View 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. Review. — View 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.

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. — View 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. Review. — View 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. — View 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. Review. — View Citation

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.

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Patients will receive study drug for a maximum of 120 hours (5 days)
Secondary	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.	Patients will receive study drug for a maximum of 120 hours (5 days)

External Links

•   This is an educational website on delirium in the ICU.