The MENDS2 Study, Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients With Acute Respiratory Failure
Condition: Sepsis; Delirium; Impaired Cognition
MeSH terms: Sepsis; Delirium; Cognitive Dysfunction
Intervention: Dexmedetomidine; Propofol
Intervention description: 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.; 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.
Intervention MeSH terms: Dexmedetomidine; Propofol
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 438.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
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

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.
    

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.