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

Study Description

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Brief 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.

Condition or disease	Intervention/treatment	Phase
Sepsis; Delirium; Impaired Cognition	Drug: Dexmedetomidine; Drug: Propofol	Phase 3

Detailed 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 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	420 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis
Actual Study Start Date :	August 2012
Estimated Primary Completion Date :	February 2019
Estimated Study Completion Date :	September 2019

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Dexmedetomidine; Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 5 mcg/mL dexmedetomidine. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice. Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the dexmedetomidine group, dose will range from 0.15-1.5 mcg/kg/hr.	Drug: Dexmedetomidine; 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.; Other Names: Precedex; Dexdor
Active Comparator: Propofol; Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of 10 mg/mL propofol. Patients will only receive study drug while in the ICU and on mechanical ventilation, and thus will be monitored with continuous telemetry as per usual ICU practice. Dosing Range. Study drug dose will be titrated in a double-blind manner according to clinical effect to achieve a "goal" or "target" Richmond Agitation Sedation Score set by the managing clinical team. For patients in the propofol group, dose will range from 5-50 mcg/kg/min.	Drug: Propofol; 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.; Other Name: Diprivan

Outcome Measures

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Primary Outcome Measures :

1. Delirium/Coma Free Days (DCFDs) [ Time Frame: 14 days ]
   The analysis of DCFDs will be conducted using Intention-to-Treat (ITT) population, defined as all patients who were randomized and received study drug. We chose a 14 day evaluation period for delirium, because it represents the best balance of gaining valuable clinical information, while maximizing resource utilization, given the average study drug infusion to be 7 days and maximum duration to be 14 days. Thus our follow-up period will cover 7 additional days of delirium monitoring after the study drug is stopped in the majority of our patients.

Secondary Outcome Measures :

1. Ventilator-free days (VFDs) [ Time Frame: 28 Days ]
   Ventilator-free days (VFDs), i.e., days alive and free of MV at 28 days. This endpoint has been used by the NHLBI's ARDSNet in numerous critical care trials examining ICU populations.
2. 90-day Survival [ Time Frame: 1 through 90 days ]
   That sedation of mechanically ventilated severely septic patients with an alpha2 agonist (dexmedetomidine) rather than a GABAergic agent (propofol) will improve 90-day survival of ICU patients.
3. Decrease incidence and severity of long-term cognitive impairment [ Time Frame: 6 months after randomization ]
   Neuropsychological function, Activities of Daily Living (ADL) and Instrumental ADLs will be assessed 6 months after randomization using a validated and reliable telephone battery for post-ICU patients, to measure incidence, duration, and severity of dysfunction in memory, attention, reasoning, and executive function domains as well as assess independence and quality of life.
4. Markers of Inflammation [ Time Frame: Days, 1, 3, 5, 7, and 14 ]

   Plasma will be obtained on days 1, 3, 5, 7 and 14. About 30 mL of blood will be collected at each time point (150 mL max during the study). These samples will be batched analysed for the following:

   1. Genetic predictors of delirium duration, including, but not limited to, the apolipoprotein E4 polymorphism
   2. Inflammatory/coagulopathic biomarkers, (e.g., IL-1, IL-6, IL-10, CRP, sTNFR1, and HMGB1) based on their importance in sepsis and kinetic responses. Furthermore, combination of pro- and anti-inflammatory cytokine markers improves the predictive quality of these biomarkers for mortality.
   3. Other biomarkers to be determined by ongoing and future studies.
5. Organ Dysfunction [ Time Frame: 14 Days ]
   Organ dysfunctions will be tracked until conclusion of the interventional trial phase using daily SOFA scores and continuous as well as established predefined cut offs for each organ failure: Kidney, Cr > 2 mg/dL or urine < 400 cc/day; Lung, PaO2/FiO2 <300 or SaO2/FiO2 <315; Liver, total bilirubin > 2 mg/dL; Coagulation, Platelet count < 100,000/mm3; and Hemodynamic, need for vasopressor, consistent with definitions utilized in published studies of organ dysfunction in critically ill patients.
6. Acute Respiratory Distress Syndrome [ Time Frame: 14 Days ]
   Acute Respiratory Distress Syndrome - we will monitor a patient's oxygenation status by tracking daily SaO2/FiO2 ratios or PaO2/FiO2 ratios. Chest X-rays that are ordered as part of routine clinical care will be followed daily in patients who meet ARDS oxygenation threshold and patients with bilateral infiltrates confirmed by the medical team, will be considered to have ARDS. Time to onset of ARDS and duration of ARDS will be tracked until conclusion of the interventional trial phase.
7. Delirium duration, coma duration, duration of hypoactive and hyperactive delirium [ Time Frame: 14 days ]
   Delirium based on CAM-ICU status. Days of hypoactive and hyperactive delirium will be determined based on concomitant RASS score accompanying positive CAM-ICU
8. ICU and hospital lengths of stay [ Time Frame: 30 days ]
   Duration of ICU and hospital stay

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Contacts

Contact: Pratik P. Pandharipande, MD, MSCI	615-343-6268	pratik.pandharipande@vanderbilt.edu
Contact: Christopher G. Hughes, MD	615-343-6268	christopher.hughes@vanderbilt.edu

Locations

United States, California
University of California, San Francisco	Active, not recruiting
San Francisco, California, United States, 94143
United States, Louisiana
Baton Rouge General Medical Center and Our Lady of The Lakes Regional Medical Center	Active, not recruiting
Baton Rouge, Louisiana, United States, 70806
United States, Massachusetts
Tufts Medical Center	Recruiting
Boston, Massachusetts, United States, 02111
Contact: John Devlin, Pharm.D 617-373-8171 j.devlin@northeastern.edu
Principal Investigator: John Devlin, Pharm.D
Principal Investigator: Eric Garpestad, MD
Baystate Medical Center	Active, not recruiting
Springfield, Massachusetts, United States, 01107
United States, North Carolina
Mission Hospital	Active, not recruiting
Asheville, North Carolina, United States, 28801
United States, Tennessee
Vanderbilt University Medical Center	Recruiting
Nashville, Tennessee, United States, 37232-8300
Contact: Pratik P. Pandharipande, MD, MSCI 615-343-6268 pratik.pandharipande@vanderbilt.edu
Contact: Christopher G. Hughes, MD 615-343-6268
Principal Investigator: Christopher Hughes, MD
United States, Texas
Texas Health Harris Fort Worth	Active, not recruiting
Fort Worth, Texas, United States, 76104
Baylor College of Medicine	Active, not recruiting
Houston, Texas, United States, 77030-3411
Houston Methodist Hospital	Recruiting
Houston, Texas, United States, 77030
Contact: Joshua Swan, Pharm.D, BCPS 713-441-0165 SJTSwan@houstonmethodist.org
Principal Investigator: Joshua Swan, Pharm.D, BCPS
University of Texas Health Science Center at San Antonio	Active, not recruiting
San Antonio, Texas, United States, 78229
United States, Wisconsin
University of Wisconsin	Active, not recruiting
Madison, Wisconsin, United States, 53706

Sponsors and Collaborators

Vanderbilt University Medical Center

Investigators

Principal Investigator:	Pratik P. Pandharipande, MD, MSCI	Vanderbilt University Medical Center

  Study Documents (Full-Text)

Documents provided by Pratik Pandharipande, Vanderbilt University Medical Center:

Study Protocol  [PDF] October 1, 2018

Statistical Analysis Plan  [PDF] January 4, 2019

More Information

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Responsible Party:	Pratik Pandharipande, Professor of Anesthesiology, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier:	NCT01739933 History of Changes
Other Study ID Numbers:	R01HL111111 ( U.S. NIH Grant/Contract ); 121380 ( Other Identifier: Vanderbilt University Institutional Review Board )
First Posted:	December 4, 2012
Last Update Posted:	January 9, 2019
Last Verified:	January 2019

Keywords provided by Pratik Pandharipande, Vanderbilt University Medical Center:

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

Additional relevant MeSH terms:

Sepsis; Delirium; Cognitive Dysfunction; Infection; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Cognition Disorders	Propofol; Dexmedetomidine; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists