Last updated on January 2019

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


Brief description of study

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 medicationsthe GABA-ergic benzodiazepinesworsen 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 MENDS II 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 Study 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 brainstemmore akin to natural sleepwhich 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 MENDS II (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.

Clinical Study Identifier: NCT01739933

Contact Investigators or Research Sites near you

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Pratik P. Pandharipande, MD, MSCI

University of California, San Francisco
San Francisco, CA United States
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Pratik P. Pandharipande, MD, MSCI

Baton Rouge General Medical Center and Our Lady of The Lakes Regional Medical Center
Baton Rouge, LA United States
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Eric Garpestad, MD

Tufts Medical Center
Boston, MA United States
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Patrick T. Mailloux, MD

Baystate Medical Center
Springfield, MA United States
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Pratik P. Pandharipande, MD, MSCI

Mission Hospital
Asheville, NC United States
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Christopher Hughes, MD

Vanderbilt University Medical Center
Nashville, TN United States
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Allison Snyder, MSN, APRN, ACNS-BC, ...

Texas Health Harris Fort Worth
Fort Worth, TX United States
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Pratik P. Pandharipande, MD, MSCI

Baylor College of Medicine
Houston, TX United States
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Joshua Swan, Pharm.D, BCPS

Houston Methodist Hospital
Houston, TX United States
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Pratik P. Pandharipande, MD, MSCI

University of Texas Health Science Center at San Antonio
San Antonio, TX United States
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Robert Sanders, MBBS, PhD

University of Wisconsin
Madison, WI United States
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Recruitment Status: Open


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