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The MENDS2 Study, Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients With Acute Respiratory Failure (MENDS2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01739933
Recruitment Status : Completed
First Posted : December 4, 2012
Results First Posted : June 7, 2021
Last Update Posted : June 7, 2021
Sponsor:
Information provided by (Responsible Party):
Pratik Pandharipande, Vanderbilt University Medical Center

Brief Summary:
Ventilated ICU patients frequently have sepsis and the majority have delirium, a form of brain dysfunction that is an independent predictor of increased risk of dying, length of stay, costs, and prolonged cognitive impairment in survivors. Universally prescribed sedative medications-the GABA-ergic benzodiazepines-worsen this brain organ dysfunction. The available alternative sedation regimens, the shorter acting GABA-ergic propofol, and the alpha2 agonist, dexmedetomidine, have both been shown to be superior to benzodiazepines, and yet are different with regard to their effects on innate immunity, bacterial clearance, apoptosis, cognition and delirium. The MENDS2 study will compare propofol and dexmedetomidine, and determine the best sedative medication to reduce delirium and improve survival and long-term brain function in our most vulnerable patients- the ventilated septic patient.

Condition or disease Intervention/treatment Phase
Sepsis Delirium Impaired Cognition Drug: Dexmedetomidine Drug: Propofol Phase 3

Detailed Description:
The need for mechanical ventilation (MV) secondary to sepsis is the leading cause of admission to the intensive care unit, often necessitating sedation for patient safety and comfort. Recently, we have learned that these sedative medications contribute to iatrogenic injury, such as prolonging ventilator time and ICU length of stay and exacerbating acute brain dysfunction. This acute brain dysfunction, manifested as delirium and coma, occurs in 50%-70% of MV septic patients and is a significant contributor not only to death but also to functional and cognitive decline, which can persist for years after recovery of lung and other organ function, levying significant costs to patients and society. Despite advances in the management of acute respiratory failure and sepsis, few clinical trials have examined the effects that supportive therapies, like sedation, may have on both short- and long-term outcomes in this vulnerable population. The gamma-aminobutyric acid (GABA)-ergic benzodiazepines, in particular, have been shown to increase brain dysfunction, promote infection, and prolong MV. Therefore, the short-acting GABA-ergic sedative propofol and the alpha2 agonist dexmedetomidine are becoming widely used to sedate septic MV patients. There are only a few randomized trials, however, to guide clinicians when selecting between these and other sedatives, and none have explored the mechanisms underlying the differences in outcomes, though some data indicate that GABA-ergic and alpha2 agonist agents have very different effects on innate immunity, apoptosis, arousability, and respiratory drive. In early animal and human studies, dexmedetomidine had more anti-inflammatory effects than the GABA-ergic agents; dexmedetomidine improved bacterial clearance, whereas propofol impaired it. In addition, sedation with dexmedetomidine instead of benzodiazepines reduces delirium by 20%-30% and improves arousability, cognition, and attentiveness in ventilated patients. Alpha2 agonists induce unconsciousness at the brainstem-more akin to natural sleep-which may improve autonomic function and immunity. All these factors converge to suggest that sedation with an alpha2 agonist rather than a GABAergic agent may improve outcomes, including brain function, MV, and survival, for septic MV patients. We therefore propose the MENDS2 (Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure) study, in which we will test the hypotheses that sedation of MV severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will (Aim 1A) increase days alive without delirium or coma, (Aim 1B) increase ventilator-free days, (Aim 2A) improve 90-day survival, (Aim 2B) decrease long-term cognitive impairment, and (Aim 3) reduce the pro-inflammatory cytokine cascade following sepsis. We will randomize 420 ventilated, severely septic patients requiring goal-directed sedation with dexmedetomidine or propofol, giving the study 85% power to detect a difference of 1.5 delirium/coma-free days and an absolute difference in mortality of 12% between the two groups.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 438 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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


Arm Intervention/treatment
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.

Drug: Dexmedetomidine
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.
Other Names:
  • Precedex
  • Dexdor

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.

Drug: Propofol
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Consecutive patients will be eligible for inclusion in the MENDS2 study if they are: [1] adult patients (≥18 years old) [2] in a medical and/or surgical ICU and [3] on MV and requiring sedation and [4] have suspected or known infection

Exclusion Criteria:

Patients will be excluded (i.e., not consented) for any of the following reasons:

  1. Rapidly resolving organ failure, indicated by planned immediate discontinuation of MV, at time of screening for study enrollment
  2. Pregnant or breastfeeding
  3. 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.
  4. 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.
  5. 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.
  6. Active seizures during this ICU admission being treated with intravenous benzodiazepines.
  7. 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)
  8. 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.
  9. 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:

    1. Attending physician refusal.
    2. Patient and/or surrogate refusal.
    3. Patient unable to consent and no surrogate available.
    4. 48-hour period of eligibility was exceeded before the patient was screened.
  10. Prisoners.
  11. Medical team following patient unwilling to use the sedation regimens.
  12. Documented allergy to propofol or dexmedetomidine.
  13. Current enrollment in a study that does not allow co-enrollment or that uses delirium as a primary outcome.
  14. Patients who are on muscle relaxant infusions at time of screening with plans to maintain paralysis >48 hours.
  15. Greater than 96 hours on mechanical ventilation prior to meeting all inclusion criteria.

Information from the National Library of Medicine

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


Locations
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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
Mission Hospital
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
Sponsors and Collaborators
Vanderbilt University Medical Center
Investigators
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Principal Investigator: Pratik P. Pandharipande, MD, MSCI Vanderbilt University Medical Center
  Study Documents (Full-Text)

Documents provided by Pratik Pandharipande, Vanderbilt University Medical Center:
Study Protocol  [PDF] October 1, 2018
Statistical Analysis Plan  [PDF] October 10, 2019

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pratik Pandharipande, Professor of Anesthesiology, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT01739933    
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
Keywords provided by Pratik Pandharipande, Vanderbilt University Medical Center:
Delirium
Delirium/coma-free days
Long term cognitive impairment
Sedation
Intensive care
Mechanical Ventilation
Dexmedetomidine
Propofol
Coma-free days
Sepsis
Organ dysfunction
Acute Respiratory Distress
Markers of inflammation
Additional relevant MeSH terms:
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Sepsis
Delirium
Cognitive Dysfunction
Infections
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Dexmedetomidine
Propofol
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents