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

Primary Purpose

Delirium, Critical Illness, Sedation Complication

Status
Recruiting
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Dexmedetomidine
Midazolam
Sponsored by
Vanderbilt University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Delirium focused on measuring pediatrics, critical care, agitation, sedation, delirium

Eligibility Criteria

44 Weeks - 11 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients will be eligible for enrollment if they are 1) aged ≥ 6 months and < 11 years, 2) admitted to the pediatric ICU at Monroe Carell Jr. Children's Hospital at Vanderbilt (MCJCHV), and 3) on mechanical ventilation (MV) requiring 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 > 48 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. Inability to understand English or deafness 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.
  10. Documented allergy to either dexmedetomidine or midazolam.
  11. Medical requirement of continuous (infusion) neuromuscular blockade administration that is planned ongoing for at least 48 hours at time of screening.
  12. Inability to start the informed consent process within the 48 hours from the time that all inclusion criteria were met (possible reasons):

    1. Attending physician refusal
    2. 48-hour period of eligibility was exceeded before the patient was screened
    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.

Sites / Locations

  • Vanderbilt University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Dexmedetomidine

Midazolam

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Duration of mechanical ventilation (MV)
Days of mechanical ventilation (Time vs. days) and impact of sedation will be determined.
Incidence of long-term cognitive impairment.
Maladaptive behavior and cognitive dysfunction (memory, attention, executive dysfunction) will be assessed 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
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.
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
ICU and hospital lengths of stay
Duration of pediatric ICU and hospital stay
Mortality
In-hospital and 90-day mortality
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.
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.
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.

Full Information

First Posted
November 2, 2020
Last Updated
August 11, 2023
Sponsor
Vanderbilt University Medical Center
Collaborators
Pfizer, National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT04801589
Brief Title
Goal-Directed Sedation in Mechanically Ventilated Infants and Children
Acronym
mini-MENDS
Official Title
Maximizing Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 10, 2021 (Actual)
Primary Completion Date
June 2025 (Anticipated)
Study Completion Date
June 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University Medical Center
Collaborators
Pfizer, National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Delirium, Critical Illness, Sedation Complication, Executive Dysfunction, Post Traumatic Stress Disorder
Keywords
pediatrics, critical care, agitation, sedation, delirium

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Double-blind
Allocation
Randomized
Enrollment
372 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dexmedetomidine
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Midazolam
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Dexmedetomidine
Other Intervention Name(s)
Precedex, Dexdor
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Midazolam
Other Intervention Name(s)
Versed, Hypnovel, Dormicum
Intervention Description
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.
Primary Outcome Measure Information:
Title
Daily prevalence of delirium
Description
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.
Time Frame
14 days
Secondary Outcome Measure Information:
Title
Duration of mechanical ventilation (MV)
Description
Days of mechanical ventilation (Time vs. days) and impact of sedation will be determined.
Time Frame
14 days
Title
Incidence of long-term cognitive impairment.
Description
Maladaptive behavior and cognitive dysfunction (memory, attention, executive dysfunction) will be assessed 6 months post ICU discharge.
Time Frame
6 months post ICU discharge
Title
Incidence of post-traumatic stress symptoms in patients and parents/caregivers
Description
Assessment of post-traumatic stress symptoms in patients and parents at 6 months post ICU discharge
Time Frame
Baseline - 6 months post ICU discharge
Title
Functional status
Description
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.
Time Frame
Baseline - 6 months post ICU discharge
Title
Markers of Inflammation, endothelial and blood brain barrier injury
Description
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
Time Frame
Days 1, 3, and 5
Title
ICU and hospital lengths of stay
Description
Duration of pediatric ICU and hospital stay
Time Frame
30 days
Title
Mortality
Description
In-hospital and 90-day mortality
Time Frame
90 days
Title
Organ Dysfunction
Description
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.
Time Frame
14 days
Title
Incidence of Iatrogenic Withdrawal Syndrome
Description
Patients who receive study drug infusion for > 3 days will undergo withdrawal assessment upon study drug weaning at least once daily.
Time Frame
30 days
Title
Sedation Level
Description
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.
Time Frame
up to 30 days or while receiving continuous sedation

10. Eligibility

Sex
All
Minimum Age & Unit of Time
44 Weeks
Maximum Age & Unit of Time
11 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: Receiving continuous sedation for > 72 hours prior to screening. Rapidly resolving respiratory failure at screening, with planned immediate liberation from MV. 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. Clinically significant 2nd or 3rd degree heart block or bradycardia < 60 beats per minute. Benzodiazepine dependency with ongoing medical requirement of continuous benzodiazepine (infusion). Inability to co-enroll with another study. Expected death or care plan for withdrawal of support measures within 24 hours of enrollment. Bilateral vision loss. Deafness that will preclude delirium evaluation. 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. Documented allergy to either dexmedetomidine or midazolam. Medical requirement of continuous (infusion) neuromuscular blockade administration that is planned ongoing for at least 48 hours at time of screening. Inability to start the informed consent process within the 72 hours from the time that all inclusion criteria were met (possible reasons): Attending physician refusal 72-hour period of eligibility was exceeded before the patient was enrolled Legal Authorized Decision Maker (e.g. legal guardian/power of attorney) refusal Legal Authorized Decision Maker (e.g. legal guardian/power of attorney) unavailable 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. Adjusted dosing weight is > 50 kg at time of screening.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Heidi Smith, MD, MSCI
Phone
(615) 936-6808
Email
heidi.smith@vumc.org
First Name & Middle Initial & Last Name or Official Title & Degree
Rebecca Abel, MA
Phone
(615) 875-3763
Email
rebecca.abel@vumc.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Heidi Smith, MD, MSCI
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alex Barry, RN, MBA

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.

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Goal-Directed Sedation in Mechanically Ventilated Infants and Children

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