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)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111111-03
Application #
8693008
Study Section
Clinical Trials Review Committee (CLTR)
Program Officer
Harabin, Andrea L
Project Start
2012-08-15
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
Siew, Edward D; Fissell, William H; Tripp, Christina M et al. (2017) Acute Kidney Injury as a Risk Factor for Delirium and Coma during Critical Illness. Am J Respir Crit Care Med 195:1597-1607
Zakrison, Tanya L; Polk, Travis M; Dixon, Rachel et al. (2017) Paying it forward: Four-year analysis of the Eastern Association for the Surgery of Trauma Mentoring Program. J Trauma Acute Care Surg 83:165-169
Marra, Annachiara; Pandharipande, Pratik P; Patel, Mayur B (2017) Intensive Care Unit Delirium and Intensive Care Unit-Related Posttraumatic Stress Disorder. Surg Clin North Am 97:1215-1235
Alali, Aziz S; Mukherjee, Kaushik; McCredie, Victoria A et al. (2017) Beta-blockers and Traumatic Brain Injury: A Systematic Review, Meta-analysis, and Eastern Association for the Surgery of Trauma Guideline. Ann Surg 266:952-961
Boehm, Leanne M; Dietrich, Mary S; Vasilevskis, Eduard E et al. (2017) Perceptions of Workload Burden and Adherence to ABCDE Bundle Among Intensive Care Providers. Am J Crit Care 26:e38-e47
Kenes, Michael T; Stollings, Joanna L; Wang, Li et al. (2017) Persistence of Delirium after Cessation of Sedatives and Analgesics and Impact on Clinical Outcomes in Critically Ill Patients. Pharmacotherapy 37:1357-1365
Vella, Michael A; Crandall, Marie L; Patel, Mayur B (2017) Acute Management of Traumatic Brain Injury. Surg Clin North Am 97:1015-1030
Wilson, Jo E; Carlson, Richard; Duggan, Maria C et al. (2017) Delirium and Catatonia in Critically Ill Patients: The Delirium and Catatonia Prospective Cohort Investigation. Crit Care Med 45:1837-1844
Boehm, Leanne M; Vasilevskis, Eduard E; Dietrich, Mary S et al. (2017) Organizational Domains and Variation in Attitudes of Intensive Care Providers Toward the ABCDE Bundle. Am J Crit Care 26:e18-e28
Pandharipande, Pratik P; Ely, E Wesley; Arora, Rakesh C et al. (2017) The intensive care delirium research agenda: a multinational, interprofessional perspective. Intensive Care Med 43:1329-1339

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