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

NCT01739933 | Completed Phase 3 Results DMC

• 2 other identifiers: R01HL111111121380
• Study Type: interventional
• Target: 438
• Locations: 1 country
• Sites: 11

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.

Conditions

Sepsis; Delirium; Impaired Cognition

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Delirium/Coma Free Days (DCFDs)

  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.

  14 days

Secondary Outcomes (3)

• Ventilator-free Days (VFDs)

  28 Days

• Death at 90 Days

  1 through 90 days

• Cognitive Function Utilizing the Telephone Interview for Cognitive Status Total (TICS-T)

  6 months after randomization

Study Arms (2)

Dexmedetomidine

ACTIVE COMPARATOR

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

Propofol

ACTIVE COMPARATOR

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

Interventions

Dexmedetomidine DRUG

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.

Also known as: Precedex, Dexdor

Dexmedetomidine

Propofol DRUG

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.

Also known as: Diprivan

Propofol

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Patients will be excluded (i.e., not consented) for any of the following reasons:
• Rapidly resolving organ failure, indicated by planned immediate discontinuation of MV, at time of screening for study enrollment
• Pregnant or breastfeeding
• 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.
• Active seizures during this ICU admission being treated with intravenous benzodiazepines.
• 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)
• Attending physician refusal.
• Patient and/or surrogate refusal.
• Patient unable to consent and no surrogate available.
• hour period of eligibility was exceeded before the patient was screened.
• Prisoners.
• Medical team following patient unwilling to use the sedation regimens.
• Documented allergy to propofol or dexmedetomidine.
• Current enrollment in a study that does not allow co-enrollment or that uses delirium as a primary outcome.
• Patients who are on muscle relaxant infusions at time of screening with plans to maintain paralysis \>48 hours.

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (11)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Baton Rouge General Medical Center and Our Lady of The Lakes Regional Medical Center

Baton Rouge, Louisiana, 70806, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Baystate Medical Center

Springfield, Massachusetts, 01107, United States

Location

Mission Hospital

Asheville, North Carolina, 28801, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232-8300, United States

Location

Texas Health Harris Fort Worth

Fort Worth, Texas, 76104, United States

Location

Baylor College of Medicine

Houston, Texas, 77030-3411, United States

Location

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

University of Wisconsin

Madison, Wisconsin, 53706, United States

Location

Related Publications (2)

• Hughes CG, Mailloux PT, Devlin JW, Swan JT, Sanders RD, Anzueto A, Jackson JC, Hoskins AS, Pun BT, Orun OM, Raman R, Stollings JL, Kiehl AL, Duprey MS, Bui LN, O'Neal HR Jr, Snyder A, Gropper MA, Guntupalli KK, Stashenko GJ, Patel MB, Brummel NE, Girard TD, Dittus RS, Bernard GR, Ely EW, Pandharipande PP; MENDS2 Study Investigators. Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis. N Engl J Med. 2021 Apr 15;384(15):1424-1436. doi: 10.1056/NEJMoa2024922. Epub 2021 Feb 2.

  PMID: 33528922 DERIVED

• Chandrasekhar R, Hughes CG, Pun BT, Orun OM, Ely EW, Pandharipande PP. Statistical analysis plan for the Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure trial. Crit Care Resusc. 2020 Mar;22(1):63-71. doi: 10.51893/2020.1.oa7.

  PMID: 32102644 DERIVED

MeSH Terms

Conditions

Sepsis; Delirium; Cognition Disorders; Acute Lung Injury

Interventions

Dexmedetomidine; Propofol

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Lung Injury; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Limitations and Caveats

Sample size readjusted to 420 with approval from NIH and DSMB

Results Point of Contact

• Title: Dr. Pratik Pandharipande, Vice Chair Faculty Affairs, PI
• Organization: Vanderbilt University Medical Center

pratik.pandharipande@vumc.org

6153436268

Study Officials

• Pratik P. Pandharipande, MD, MSCI

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Anesthesiology

Study Record Dates

• First Submitted: November 28, 2012
• First Posted: December 4, 2012
• Study Start: May 15, 2013
• Primary Completion: July 1, 2019
• Study Completion: July 1, 2019
• Last Updated: June 7, 2021
• Results First Posted: June 7, 2021

Record last verified: 2021-05

Locations

US (11)