R33HL151951

Maximizing Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study (MINI-MENDS) - 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, we 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, itself a manifestation of acute brain dysfunction, is prevalent in the PICU with rates of up to 30% in older children, over 50% in infants and toddlers, and over 60% in pediatric patients requiring MV. Delirium in children is a significant contributor to longer duration on MV, prolonged PICU length of stay, and death, with significant consequential costs.

Adult studies have shown that an alternative sedation paradigm using dexmedetomidine, an alpha-2 agonist, decreases the duration of delirium and coma, length of MV, ICU length of stay, cost, and infection rates compared to benzodiazepine-based sedation. Dexmedetomidine has unique anti-inflammatory and anti-oxidant characteristics, making it an appealing sedative agent as inflammation, endothelial, and blood-brain barrier (BBB) injury are mechanistically associated with prolonged delirium and worse cognitive impairment in adults.

Though sedation may be unavoidable in PICUs, a dexmedetomidine-based regimen may complement goal-directed sedation, as over-sedation (30%) rather than under-sedation (10%) is common in the PICU setting, and thus far, sedation protocolization alone has not demonstrated a significant impact on improving outcomes in pediatric patients.

The FDA recently published warnings regarding the possible role of anesthetics, including benzodiazepines, on cognitive development in children. We therefore propose MINI-MENDS (Maximizing the Efficacy of Goal-Directed Sedation to Reduce Neurological Dysfunction in Mechanically Ventilated Infants and Children Study), in which we will test the hypotheses that sedation of MV pediatric patients with an alpha-2 agonist (dexmedetomidine) versus a GABA-ergic agent (midazolam) will:

(Aim 1A) Decrease daily delirium prevalence,
(Aim 1B) Decrease length of MV,
(Aim 2A) Improve functional and behavioral recovery,
(Aim 2B) Be associated with fewer symptoms of post-traumatic stress,
(Aim 2C) Decrease the incidence of cognitive impairment, and
(Aim 3) Reduce levels of pro-inflammatory cytokines and biomarkers of endothelial and blood-brain barrier injury.

We will randomize 372 pediatric patients on MV, aged 6 months to 11 years, to receive goal-directed continuous sedation with either dexmedetomidine or midazolam for up to 10 days. The study will have 80% power to detect at least a 10% absolute reduction in daily delirium prevalence between groups, which is a clinically meaningful outcome. Extrapolation of current pediatric data would estimate a 10% decrease in delirium prevalence to be associated with a 1.2-day (20%) decrease in PICU LOS and 15% lower odds of dying.

Vanderbilt University Medical Center

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Nashville, Tennessee 37203 United States

Single Zip Code

Single-Site Investigator-Initiated Clinical Trials (R61/R33 Clinical Trial Required) (PAR-18-406)

Amendment Since initial award the End Date has been extended from 07/31/25 to 07/31/26 and the total obligations have increased 348% from $847,552 to $3,794,136.