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

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.

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.