Goal-Directed Sedation in Mechanically Ventilated Infants and Children (mini-MENDS)

Maximizing Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study

Ventilated pediatric patients are frequently over-sedated and the majority suffer from delirium, a form of acute brain dysfunction that is an independent predictor of increased risk of dying, length of stay, and costs. Universally prescribed sedative medications-the GABA-ergic benzodiazepines-worsen this brain organ dysfunction and independently prolong duration of ventilation and ICU stay, and the available alternative sedation regimen using dexmedetomidine, an alpha-2 agonist, has been shown to be superior to benzodiazepines in adults, and may mechanistically impact outcomes through positive effects on innate immunity, bacterial clearance, apoptosis, cognition and delirium. The mini-MENDS trial will compare dexmedetomidine and midazolam, and determine the best sedative medication to reduce delirium and improve duration of ventilation, and functional, psychiatric, and cognitive recovery in our most vulnerable patients-survivors of pediatric critical illness.

Study Overview

• Status: Recruiting
• Conditions: Delirium; Critical Illness; Post Traumatic Stress Disorder; Executive Dysfunction; Sedation Complication
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Midazolam

Detailed Description

The need for mechanical ventilation (MV) following acute respiratory and myocardial failure is the leading cause of admission to the pediatric intensive care unit (PICU). Over 90% of MV pediatric patients receive continuous sedation, most commonly with gamma-aminobutyric acid (GABA) agonist benzodiazepines. Recently, the investigators demonstrated that exposure to the benzodiazepine midazolam contributed to iatrogenic harm in pediatric patients-prolonging PICU length of stay and increasing the prevalence and duration of delirium. Delirium is prevalent in the PICU with rates of up to 30% in older children, over 50% in infants and toddlers, and up to 60-70% in those on MV. Delirium in children is a significant contributor to longer duration of MV, substantial consequential costs, prolonged ICU stay, and mortality. Adult studies have shown that an alternative sedation paradigm using dexmedetomidine, an alpha-2 agonist, decreases the prevalence and duration of delirium, duration of MV, ICU length of stay, cost, and infection rates compared to benzodiazepine-based sedation. Furthermore, the FDA recently published warnings regarding the possible role of anesthetics, including benzodiazepines, on cognitive dysfunction in children. Dexmedetomidine has unique anti-inflammatory and anti-oxidant characteristics that are appealing given the association between inflammation, and endothelial and blood-brain barrier (BBB) injury with prolonged delirium and worse cognitive impairment in adults. To this end, there has been no large pediatric cohort study to examine the relationship between sedative choice and exposure in the ICU (a much longer exposure) with cognitive impairment among pediatric survivors. The investigators, therefore, propose mini-MENDS (Maximizing Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children STUDY), in which the investigators will determine whether sedation of MV pediatric patients with an alpha-2 agonist (dexmedetomidine) versus a GABA-ergic benzodiazepine (midazolam) will decrease daily prevalence of delirium (Aim 1A) and duration of MV (Aim 1B), will be associated with better functional, psychiatric, and cognitive recovery (Aim 2), and reduced levels of pro-inflammatory cytokines and biomarkers of endothelial and blood brain barrier injury (Aim 3). To accomplish these aims, the investigators will randomize 372 pediatric patients on MV, aged 44 weeks post-menstrual age to 11 years, to receive goal-directed continuous sedation with either dexmedetomidine or midazolam for up to 10 days. Our primary outcome, daily prevalence of delirium, will be objectively measured by trained research nurses who are blinded to intervention arm. Screening for delirium will be completed using the Preschool or Pediatric Confusion Assessment Methods for the ICU (ps/pCAM-ICU), based on developmental age, twice daily for up to 14 days while in the PICU. Cognition, functional status, and parental/patient psychological health will be assessed at enrollment (baseline), hospital discharge (DC), and 6 months following ICU-DC during an in-person evaluation by the pediatric neuropsychiatry team. Blood will be collected on days 1, 3, and 5 post-randomization to measure cytokines, markers of endothelial and BBB injury, and for safety.

• Study Type: Interventional
• Enrollment (Estimated): 372
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Heidi Smith, MD, MSCI; Phone Number: (615) 936-6808; Email: heidi.smith@vumc.org
• Study Contact Backup: Name: Rebecca Abel, MA; Phone Number: (615) 875-3763; Email: rebecca.abel@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: Alex Barry, RN, MBA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 11 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients will be eligible for enrollment if they are 1) aged 44 weeks post-menstrual age and up to 11 years, 2) planned admission to the pediatric ICU at Monroe Carell Jr. Children's Hospital at Vanderbilt (MCJCHV), and 3) requiring mechanical ventilation (MV) and sedation. Pre-pubescent children (<11 years) are typically different from older children who often behave physiologically more similar to adults. Pre-pubescent children are more likely to be admitted to the PICU and are undergoing a steeper curve of neurocognitive maturation. Therefore, these patients may be at greatest risk for worse brain dysfunction.

Exclusion Criteria: Patients will be excluded (i.e., not approached for consent) if any one is present:

1. Receiving continuous sedation for > 72 hours prior to screening.
2. Rapidly resolving respiratory failure at screening, with planned immediate liberation from MV.
3. Severe developmental delay at baseline defined as a score of ≥ 4 (severe disability) on the Pediatric Cerebral Performance Category (PCPC) Scale, referencing cognitive status prior to critical illness.
4. Clinically significant 2nd or 3rd degree heart block or bradycardia < 60 beats per minute.
5. Benzodiazepine dependency with ongoing medical requirement of continuous benzodiazepine (infusion).
6. Inability to co-enroll with another study.
7. Expected death or care plan for withdrawal of support measures within 24 hours of enrollment.
8. Bilateral vision loss.
9. Deafness that will preclude delirium evaluation.
10. Inability to understand English that will preclude delirium evaluation. The inability to understand English in verbal participants will not result in exclusion when the research staff is proficient and/or translation services are actively available in that particular language.
11. Documented allergy to either dexmedetomidine or midazolam.
12. Medical requirement of continuous (infusion) neuromuscular blockade administration that is planned ongoing for at least 48 hours at time of screening.

13. Inability to start the informed consent process within the 72 hours from the time that all inclusion criteria were met (possible reasons):

    1. Attending physician refusal
    2. 72-hour period of eligibility was exceeded before the patient was enrolled
    3. Legal Authorized Decision Maker (e.g. legal guardian/power of attorney) refusal
    4. Legal Authorized Decision Maker (e.g. legal guardian/power of attorney) unavailable
    5. Legal Authorized Decision Maker (e.g. legal guardian/power of attorney) is non-English speaking and available research staff is not proficient and/or translation services are not available in that particular language.
14. Adjusted dosing weight is > 50 kg at time of screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dexmedetomidine; Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of either 4 mcg/mL or 8 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 0.2-2.0 mcg/kg/hr.	Drug: Dexmedetomidine; For patients in the dexmedetomidine group, dose will range from 0.2-2.0 mcg/kg/hr. For example, a 10 kg patient on an infusion of 1 mcg/kg/hr of dexmedetomidine would receive 10 mcg of study drug per hour. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the mini-MENDS study steering committee.; Other Names: Precedex; Dexdor
Active Comparator: Midazolam; Route and Concentration. The study drug will be administered intravenously (IV) by continuous infusion at concentrations of either 0.5 mg/mL or 1 mg/mL midazolam. 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 midazolam group, dose will range from 0.025-0.25 mg/kg/hr.	Drug: Midazolam; For patients in the midazolam group, dose will range from 0.025-0.25 mg/kg/hr. For example, a 10 kg patient on an infusion of 0.15 mg/kg/hr of midazolam would receive 1.5 mg of midazolam per hour. This dose range have been selected after literature review and discussions with critical care practitioners, investigational pharmacists, and the mini-MENDS study steering committee.; Other Names: Versed; Dormicum; Hypnovel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily prevalence of delirium	The analysis of delirium prevalence will be conducted using a modified Intention-to-Treat (ITT) population, defined as all patients who were randomized and received study drug. The investigators 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 5 days and maximum duration to be 10 days. Thus our follow-up period will cover 9 additional days of delirium monitoring after the study drug is stopped in the majority of our patients.	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of mechanical ventilation (MV)	Days of mechanical ventilation (Time vs. days) and impact of sedation will be determined.	14 days
Incidence of long-term cognitive impairment.	Maladaptive behavior and cognitive dysfunction (memory, attention, executive dysfunction) will be assessed 6 months post ICU discharge.	6 months post ICU discharge
Incidence of post-traumatic stress symptoms in patients and parents/caregivers	Assessment of post-traumatic stress symptoms in patients and parents at 6 months post ICU discharge	Baseline - 6 months post ICU discharge
Functional status	Functional status will be assessed using a parental questionnaire tool (The Functional Status Scale and Ages and Stages Questionnaire) based on a conceptual framework of adaptive behavior, activities of daily living, and global functional morbidity.	Baseline - 6 months post ICU discharge
Markers of Inflammation, endothelial and blood brain barrier injury	Plasma will be obtained on days 1, 3, and 5. About 5 mL of blood will be collected at each time point (maximum of 15 mL during the study). These samples will be batched and analyzed for the following: Pro- and anti-inflammatory cytokines: C-reactive protein (CRP), Tumor necrosis factor (TNF)-alpha, Interleukin (IL)-1β, IL-6, IL-10, and sTNFR1; Endothelial and Blood-Brain-Barrier injury: E-selectin, plasminogen activator inhibitor-1 (PAI-1), and S100B; Other biomarkers/genetic predictors to be determined by ongoing and future studies	Days 1, 3, and 5
ICU and hospital lengths of stay	Duration of pediatric ICU and hospital stay	30 days
Mortality	In-hospital and 90-day mortality	90 days
Incidence of Iatrogenic Withdrawal Syndrome	Patients who receive study drug infusion for > 3 days will undergo withdrawal assessment upon study drug weaning at least once daily.	30 days
Sedation Level	Level of sedation will be measured using the Richmond Agitation-Sedation Scale (RASS) at least once daily by the research and medical teams and compared to the goal RASS score determined by the medical team.	up to 30 days or while receiving continuous sedation
Organ Dysfunction	Trends of organ dysfunctions during critical illness can be monitored using the Pediatric Sequential Organ Failure Assessment (pSOFA) tool. The pSOFA score is based on continuous as well as established predefined age-appropriate cut offs for each organ failure. The investigators will track pSOFA for up to 14 days. The following organ systems are tracked with the pSOFA: Creatinine (kidney); PaO2/FiO2 or SaO2/FiO2 (lung); Total bilirubin (hepatic); Platelet count (coagulation); Glasgow coma score (neurologic); Hemodynamic indices with +/- need for vasopressor (cardiovascular) These organ dysfunction consistent with definitions utilized in published studies of organ dysfunction in critically ill pediatric patients.	14 days

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Pfizer
• Investigators: Principal Investigator: Heidi Smith, MD, MSCI, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2021
• Primary Completion (Estimated): April 17, 2026
• Study Completion (Estimated): September 16, 2026

Study Registration Dates

• First Submitted: November 2, 2020
• First Submitted That Met QC Criteria: March 11, 2021
• First Posted (Actual): March 17, 2021

Study Record Updates

• Last Update Posted (Estimated): September 29, 2025
• Last Update Submitted That Met QC Criteria: September 23, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: pediatrics; critical care; delirium; agitation; sedation
• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Aberrant Motor Behavior in Dementia; Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Pathologic Processes; Disease Attributes; Behavioral Symptoms; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Dyskinesias; Psychomotor Disorders; Stress Disorders, Traumatic; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Delirium; Critical Illness; Psychomotor Agitation; Stress Disorders, Post-Traumatic; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Azoles; Imidazoles; Benzazepines; Benzodiazepines; Midazolam; Dexmedetomidine
• Other Study ID Numbers: HL151951; R61HL151951 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD that underlie the results reported at the conclusion of the trial (text, tables, figures, and appendices) after deidentification.
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following publication.
• IPD Sharing Access Criteria: To achieve approved aims via email proposal to PIs.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No