Clinical trial NCT01739933: The MENDS2 Study, Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients With Acute Respiratory Failure
Official title: Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sepsis
Delirium
Impaired Cognition
Keywords: 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
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2012-12-04
Enrollment: 438
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility 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.

Primary outcomes:
measure: Delirium/Coma Free Days (DCFDs)
timeFrame: 14 days
Secondary outcomes:
measure: Ventilator-free Days (VFDs)
timeFrame: 28 Days
measure: Death at 90 Days
timeFrame: 1 through 90 days
measure: Cognitive Function Utilizing the Telephone Interview for Cognitive Status Total (TICS-T)
timeFrame: 6 months after randomization
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Baton Rouge
country: United States
facility: Baton Rouge General Medical Center and Our Lady of The Lakes Regional Medical Center
state: Louisiana
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Asheville
country: United States
facility: Mission Hospital
state: North Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Fort Worth
country: United States
facility: Texas Health Harris Fort Worth
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Vanderbilt University Medical Center
name: Pratik P. Pandharipande, MD, MSCI
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hughes CG, Mailloux PT, Devlin JW, Swan JT, Sanders RD, Anzueto A, Jackson JC, Hoskins AS, Pun BT, Orun OM, Raman R, Stollings JL, Kiehl AL, Duprey MS, Bui LN, O'Neal HR Jr, Snyder A, Gropper MA, Guntupalli KK, Stashenko GJ, Patel MB, Brummel NE, Girard TD, Dittus RS, Bernard GR, Ely EW, Pandharipande PP; MENDS2 Study Investigators. Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis. N Engl J Med. 2021 Apr 15;384(15):1424-1436. doi: 10.1056/NEJMoa2024922. Epub 2021 Feb 2.
citation: Chandrasekhar R, Hughes CG, Pun BT, Orun OM, Ely EW, Pandharipande PP. Statistical analysis plan for the Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure trial. Crit Care Resusc. 2020 Mar;22(1):63-71. doi: 10.51893/2020.1.oa7.