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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Vanderbilt University
Sponsor:
Information provided by (Responsible Party):
Pratik Pandharipande, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT01739933
First received: November 28, 2012
Last updated: June 18, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Sepsis
Delirium
Impaired Cognition
Drug: Dexmedetomidine
Drug: Propofol
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Altering Sedation Paradigms to Improve Brain Injury and Survival in Severe Sepsis

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Delirium/Coma Free Days (DCFDs) [ Time Frame: 14 days ] [ Designated as safety issue: No ]
    The analysis of DCFDs will be conducted using Intention-to-Treat (ITT) population, defined as all patients who were randomized to 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:
  • Ventilator-free days (VFDs) [ Time Frame: 28 Days ] [ Designated as safety issue: No ]
    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.

  • 90-day Survival [ Time Frame: 1 through 90 days ] [ Designated as safety issue: No ]
    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.

  • Decrease incidence and severity of long-term cognitive impairment [ Time Frame: 6 months after randomization ] [ Designated as safety issue: No ]
    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.

  • Markers of Inflammation [ Time Frame: Days, 1, 3, 5, 7, and 14 ] [ Designated as safety issue: No ]

    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.

  • Secondary Infections [ Time Frame: 48 Hours ] [ Designated as safety issue: No ]
    Secondary infections will be considered as any new sites of infection detected 48 hours after the original source of infection noted at enrollment. The site of infection and organism will be tracked until conclusion of the interventional trial phase.

  • Organ Dysfunction [ Time Frame: 14 Days ] [ Designated as safety issue: No ]
    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.

  • Acute Respiratory Distress Syndrome [ Time Frame: 14 Days ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 530
Study Start Date: August 2012
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 MENDS II 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 MENDS II study steering committee.
Other Name: Diprivan

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Consecutive patients will be eligible for inclusion in the MENDS II 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 severe sepsis (defined as at least 3 systemic inflammatory response (SIRS) criteria as used in the PROWESS study), suspected or known infection (origin and organism data will be collected, when available), and signs of organ dysfunction (since MV is an inclusion criteria, all patients will have at least respiratory failure, but will be assessed for additional renal and cardiovascular organ dysfunctions).

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.
  5. Benzodiazepine dependency or history of alcohol dependency based on prehospital assessment
  6. Active seizures.
  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
  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 >24 hours.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01739933

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 Recruiting
San Francisco, California, United States, 94143
Contact: Michael A. Gropper, MD, PhD    415-353-1212    gropperm@anesthesia.ucsf.edu   
Principal Investigator: Michael A. Gropper, MD, PhD         
United States, Louisiana
Baton Rouge General Medical Center Recruiting
Baton Rouge, Louisiana, United States, 70806
Contact: Hollis R O'Neal, Jr., MD    225-757-4070    honeal@lsuhsc.edu   
Principal Investigator: Hollis R O'Neal, Jr., MD         
United States, Massachusetts
Baystate Medical Center Recruiting
Springfield, Massachusetts, United States, 01107
Contact: Patrick T. Mailloux, MD    413-794-2419    patrick.mailloux@baystate.org   
Principal Investigator: Patrick T. Mailloux, MD         
United States, Michigan
Henry Ford Health System Active, not recruiting
Detroit, Michigan, United States, 48202
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      
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030-3411
Contact: Kalpalatha Guntupalli, MD    713-798-2435    kkg@bcm.edu   
Principal Investigator: Kalpalatha Guntupalli, MD         
University of Texas Health Science Center at San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Antonio R. Anzueto, MD    210-617-5256      
Principal Investigator: Antonio R. Anzueto, MD         
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Pratik P. Pandharipande, MD, MSCI Vanderbilt University
  More Information

No publications provided

Responsible Party: Pratik Pandharipande, Associate Professor of Anesthesiology, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01739933     History of Changes
Other Study ID Numbers: R01HL111111, 121380
Study First Received: November 28, 2012
Last Updated: June 18, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Vanderbilt University:
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:
Delirium
Sepsis
Toxemia
Cognition Disorders
Respiratory Insufficiency
Confusion
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Respiration Disorders
Respiratory Tract Diseases
Propofol
Dexmedetomidine
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Analgesics, Non-Narcotic

ClinicalTrials.gov processed this record on August 28, 2014