The MENDSII Study, Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients With Acute Respiratory Failure (MENDSII)
|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|
- 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.
- 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:
- Genetic predictors of delirium duration, including, but not limited to, the apolipoprotein E4 polymorphism
- 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.
- 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.
|Study Start Date:||August 2012|
|Estimated Study Completion Date:||December 2018|
|Estimated Primary Completion Date:||June 2018 (Final data collection date for primary outcome measure)|
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.
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.
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.
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01739933
|Contact: Pratik P. Pandharipande, MD, MSCIfirstname.lastname@example.org|
|Contact: Christopher G. Hughes, MDemail@example.com|
|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||Recruiting|
|Baton Rouge, Louisiana, United States, 70806|
|Contact: Hollis R O'Neal, Jr., MD 225-757-4070 firstname.lastname@example.org|
|Principal Investigator: Hollis R O'Neal, Jr., MD|
|United States, Massachusetts|
|Tufts Medical Center||Recruiting|
|Boston, Massachusetts, United States, 02111|
|Contact: John Devlin, Pharm.D 617-373-8171 email@example.com|
|Principal Investigator: John Devlin, Pharm.D|
|Principal Investigator: Eric Garpestad, MD|
|Baystate Medical Center||Recruiting|
|Springfield, Massachusetts, United States, 01107|
|Contact: Patrick T. Mailloux, MD 413-794-2419 firstname.lastname@example.org|
|Principal Investigator: Patrick T. Mailloux, MD|
|United States, North Carolina|
|Asheville, North Carolina, United States, 28801|
|Contact: Gregg Stashenko, MD, MHS email@example.com|
|Principal Investigator: Gregg Stashenko, MD, MHS|
|United States, Tennessee|
|Vanderbilt University Medical Center||Recruiting|
|Nashville, Tennessee, United States, 37232-8300|
|Contact: Pratik P. Pandharipande, MD, MSCI 615-343-6268 firstname.lastname@example.org|
|Contact: Christopher G. Hughes, MD 615-343-6268|
|Principal Investigator: Christopher Hughes, MD|
|United States, Texas|
|Texas Health Harris Fort Worth||Recruiting|
|Fort Worth, Texas, United States, 76104|
|Contact: Allison Snyder, MSN, APRN, ACNS-BC, CCRN 817-250-6350 AllisonSnyder@texashealth.org|
|Principal Investigator: Allison Snyder, MSN, APRN, ACNS-BC, CCRN|
|Baylor College of Medicine||Recruiting|
|Houston, Texas, United States, 77030-3411|
|Contact: Kalpalatha Guntupalli, MD 713-798-2435 email@example.com|
|Principal Investigator: Kalpalatha Guntupalli, MD|
|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|
|Principal Investigator:||Pratik P. Pandharipande, MD, MSCI||Vanderbilt University|