The MENDS2 Study, Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients With Acute Respiratory Failure (MENDS2)
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|ClinicalTrials.gov Identifier: NCT01739933|
Recruitment Status : Completed
First Posted : December 4, 2012
Results First Posted : June 7, 2021
Last Update Posted : June 7, 2021
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|Condition or disease||Intervention/treatment||Phase|
|Sepsis Delirium Impaired Cognition||Drug: Dexmedetomidine Drug: Propofol||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||438 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Investigator, Outcomes Assessor)|
|Official Title:||Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis|
|Actual Study Start Date :||May 15, 2013|
|Actual Primary Completion Date :||July 2019|
|Actual Study Completion Date :||July 2019|
Active Comparator: Dexmedetomidine
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.
For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 0.75 mcg/kg/hr of dexmedetomidine. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
Active Comparator: Propofol
Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice.
Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.
For patients in the propofol group, dose will range from 5-50 mcg/kg/min. For example, a 70 kg patient would receive 10.5 mL of study drug per hour, which would provide 25 mcg/kg/min of propofol. This dose range has been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the MENDS2 study steering committee.
Other Name: Diprivan
- Delirium/Coma Free Days (DCFDs) [ Time Frame: 14 days ]The analysis of DCFDs will be conducted using Intention-to-Treat (ITT) population, defined as all patients who were randomized and received study drug. We chose a 14 day evaluation period for delirium, because it represents the best balance of gaining valuable clinical information, while maximizing resource utilization, given the average study drug infusion to be 7 days and maximum duration to be 14 days. Thus our follow-up period will cover 7 additional days of delirium monitoring after the study drug is stopped in the majority of our patients.
- Ventilator-free Days (VFDs) [ Time Frame: 28 Days ]Ventilator-free days (VFDs), i.e., days alive and free of mechanical ventilation (MV) at 28 days. This endpoint has been used by the National Heart, Lung, and Blood Institute (NHLBI) ARDSNet in numerous critical care trials examining ICU populations.
- Death at 90 Days [ Time Frame: 1 through 90 days ]That sedation of mechanically ventilated severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will improve 90-day survival of ICU patients.
- Cognitive Function Utilizing the Telephone Interview for Cognitive Status Total (TICS-T) [ Time Frame: 6 months after randomization ]The Telephone Interview for Cognitive Status is a standardized test of cognitive functioning that monitors changes in cognitive functioning over time. The TICS-T consists 11 items including wordlist memory, orientation, attention, repetition, conceptual knowledge and nonverbal praxis. Age-adjusted total scores on the TICS-T range from 0 to 100 with a mean of 50+/-10; lower scores indicate worse cognition, and a score of 35 or less indicates cognitive impairment.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Consecutive patients will be eligible for inclusion in the MENDS2 study if they are:  adult patients (≥18 years old)  in a medical and/or surgical ICU and  on MV and requiring sedation and  have suspected or known infection
Patients will be excluded (i.e., not consented) for any of the following reasons:
- Rapidly resolving organ failure, indicated by planned immediate discontinuation of MV, at time of screening for study enrollment
- Pregnant or breastfeeding
- Severe dementia or neurodegenerative disease, defined as either impairment that prevents the patient from living independently at baseline or IQCODE >4.5, measured using a patient's qualified surrogate. This exclusion also pertains to mental illnesses requiring long-term institutionalization, acquired or congenital mental retardation, severe neuromuscular disorders, Parkinson's disease, and Huntington's disease. It also excludes patients in coma or with severe deficits due to structural brain diseases such as stroke, intracranial hemorrhage, cranial trauma, malignancy, anoxic brain injury, or cerebral edema.
- History of 2nd or 3rd degree heart block, bradycardia < 50 beats/minute, pacemaker for bradyarrythmias or uncompensated shock.If patient has a pacemaker for bradyarrythmias, then patient does not meet this exclusion criterion and may be enrolled.
- Benzodiazepine dependency or history of alcohol dependency based on the medical team's decision to institute a specific treatment plan involving benzodiazepines (either as continuous infusions or intermittent intravenous boluses) for this dependency.
- Active seizures during this ICU admission being treated with intravenous benzodiazepines.
- Expected death within 24 hours of enrollment or lack of commitment to aggressive treatment by family/medical team (e.g., likely to withdraw life support measures within 24 hrs of screening)
- Inability to understand English or deafness or vision loss that will preclude delirium evaluation. The inability to understand English (for example in Spanish-only or Mandarin-only speaking patients) will not result in exclusion at centers where the research staff is proficient and/or translation services are actively available in that particular language; these patients will not be followed in the long-term follow-up phase of the trial since the testing materials are primarily available only in English. Patients with laryngectomies and those with hearing deficits are eligible for enrollment if their medical condition permits them to communicate with research staff.
Inability to obtain informed consent from an authorized representative within 48 hours of meeting all inclusion criteria, i.e., developing sepsis and qualifying organ dysfunction criteria for the following reasons:
- Attending physician refusal.
- Patient and/or surrogate refusal.
- Patient unable to consent and no surrogate available.
- 48-hour period of eligibility was exceeded before the patient was screened.
- Medical team following patient unwilling to use the sedation regimens.
- Documented allergy to propofol or dexmedetomidine.
- Current enrollment in a study that does not allow co-enrollment or that uses delirium as a primary outcome.
- Patients who are on muscle relaxant infusions at time of screening with plans to maintain paralysis >48 hours.
- Greater than 96 hours on mechanical ventilation prior to meeting all inclusion criteria.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01739933
|United States, California|
|University of California, San Francisco|
|San Francisco, California, United States, 94143|
|United States, Louisiana|
|Baton Rouge General Medical Center and Our Lady of The Lakes Regional Medical Center|
|Baton Rouge, Louisiana, United States, 70806|
|United States, Massachusetts|
|Tufts Medical Center|
|Boston, Massachusetts, United States, 02111|
|Baystate Medical Center|
|Springfield, Massachusetts, United States, 01107|
|United States, North Carolina|
|Asheville, North Carolina, United States, 28801|
|United States, Tennessee|
|Vanderbilt University Medical Center|
|Nashville, Tennessee, United States, 37232-8300|
|United States, Texas|
|Texas Health Harris Fort Worth|
|Fort Worth, Texas, United States, 76104|
|Baylor College of Medicine|
|Houston, Texas, United States, 77030-3411|
|Houston Methodist Hospital|
|Houston, Texas, United States, 77030|
|University of Texas Health Science Center at San Antonio|
|San Antonio, Texas, United States, 78229|
|United States, Wisconsin|
|University of Wisconsin|
|Madison, Wisconsin, United States, 53706|
|Principal Investigator:||Pratik P. Pandharipande, MD, MSCI||Vanderbilt University Medical Center|
Documents provided by Pratik Pandharipande, Vanderbilt University Medical Center:
|Responsible Party:||Pratik Pandharipande, Professor of Anesthesiology, Vanderbilt University Medical Center|
|Other Study ID Numbers:||
R01HL111111 ( U.S. NIH Grant/Contract )
121380 ( Other Identifier: Vanderbilt University Institutional Review Board )
|First Posted:||December 4, 2012 Key Record Dates|
|Results First Posted:||June 7, 2021|
|Last Update Posted:||June 7, 2021|
|Last Verified:||May 2021|
Long term cognitive impairment
Acute Respiratory Distress
Markers of inflammation
Systemic Inflammatory Response Syndrome
Nervous System Diseases
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists