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 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 530 ventilated, severely septic patients requiring goal-directed sedation with dexmedetomidine or propofol, giving the study 90% power to detect a difference of 1.5 delirium/coma-free days and an absolute difference in mortality of 10% between the two groups.

Public Health Relevance

Lay Statement on MENDS II: 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 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. (End of Abstract)

National Institute of Health (NIH)
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Clinical Trials Review Committee (CLTR)
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Harabin, Andrea L
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Vanderbilt University Medical Center
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Gaspardo, Pietro; Peressoni, Luca; Comisso, Irene et al. (2014) Delirium among critically ill adults: evaluation of the psychometric properties of the Italian 'Confusion Assessment Method for the Intensive Care Unit'. Intensive Crit Care Nurs 30:283-91
Morandi, Alessandro; Hughes, Christopher G; Thompson, Jennifer L et al. (2014) Statins and delirium during critical illness: a multicenter, prospective cohort study. Crit Care Med 42:1899-909
Andresen, Jennifer M; Girard, Timothy D; Pandharipande, Pratik P et al. (2014) Burst suppression on processed electroencephalography as a predictor of postcoma delirium in mechanically ventilated ICU patients. Crit Care Med 42:2244-51
Jackson, James C; Pandharipande, Pratik P; Girard, Timothy D et al. (2014) Depression, post-traumatic stress disorder, and functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort study. Lancet Respir Med 2:369-79
Brummel, N E; Girard, T D; Ely, E W et al. (2014) Feasibility and safety of early combined cognitive and physical therapy for critically ill medical and surgical patients: the Activity and Cognitive Therapy in ICU (ACT-ICU) trial. Intensive Care Med 40:370-9
Hughes, Christopher G; Girard, Timothy D; Pandharipande, Pratik P (2013) Daily sedation interruption versus targeted light sedation strategies in ICU patients. Crit Care Med 41:S39-45
Pandharipande, P P; Girard, T D; Jackson, J C et al. (2013) Long-term cognitive impairment after critical illness. N Engl J Med 369:1306-16
Smith, Heidi A B; Brink, Emily; Fuchs, Dickey Catherine et al. (2013) Pediatric delirium: monitoring and management in the pediatric intensive care unit. Pediatr Clin North Am 60:741-60