Sedatives for Ventilated Pediatric Patients

(mini-MENDS Trial)

Overseen By Rebecca Abel, MA

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Vanderbilt University Medical Center

Must not be taking: Benzodiazepines, Neuromuscular blockers

Disqualifiers: Severe developmental delay, Heart block, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

Duration: 10 days

372 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you have a benzodiazepine dependency with a medical requirement for continuous benzodiazepine, you would be excluded from participating.

What data supports the effectiveness of the drugs Dexmedetomidine and Midazolam for sedating ventilated pediatric patients?

Research shows that both Dexmedetomidine and Midazolam are effective in providing sedation for children, with Dexmedetomidine having a lower incidence of postoperative agitation compared to Midazolam. Both drugs help in reducing anxiety and ensuring smooth medical procedures in children. ^{1 2 3 4 5}

Is it safe to use sedatives like Dexmedetomidine and Midazolam in children?

Dexmedetomidine and Midazolam have been studied for use in children, with Dexmedetomidine generally being well-tolerated but sometimes causing low blood pressure and slow breathing. Midazolam is effective but can cause side effects like forgetfulness and fear reactions, which are usually not dangerous. ^{1 3 6 7 8}

How is the drug combination of Dexmedetomidine and Midazolam unique for sedating ventilated pediatric patients?

Dexmedetomidine is unique because it mimics natural sleep and helps in early recovery, while Midazolam is known for its fast onset but has side effects like cognitive impairment. This combination may offer a balance between effective sedation and minimizing undesirable effects. ^{1 2 5 6 9}

Research Team

Heidi Smith, MD, MSCI

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

This trial is for children aged from 44 weeks post-menstrual up to 11 years who need a breathing machine and sedation in the ICU at Monroe Carell Jr. Children's Hospital. It excludes those already heavily sedated for over 72 hours, with rapidly resolving respiratory issues, or expected to pass away within a day of joining.

Inclusion Criteria

Planned admission to the pediatric ICU at Monroe Carell Jr. Children's Hospital at Vanderbilt (MCJCHV)

I am on a breathing machine and under sedation.

I am between 44 weeks post-menstrual age and 11 years old.

Exclusion Criteria

Expected death or care plan for withdrawal of support measures within 24 hours of enrollment

You are unable to hear, which may make it difficult to assess your mental state.

I am dependent on benzodiazepines and need them continuously.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive continuous sedation with either dexmedetomidine or midazolam for up to 10 days while on mechanical ventilation in the ICU

10 days

Continuous monitoring in ICU

Delirium Monitoring

Delirium prevalence is monitored using ps/pCAM-ICU twice daily for up to 14 days

14 days

Follow-up

Participants are monitored for functional, psychiatric, and cognitive recovery, and incidence of post-traumatic stress symptoms

6 months

In-person evaluation at hospital discharge and 6 months post ICU discharge

Treatment Details

Interventions

• Dexmedetomidine
• Midazolam

Trial Overview The study compares two sedatives: Dexmedetomidine (an alpha-2 agonist) and Midazolam (a benzodiazepine), aiming to see which one better reduces delirium and helps with recovery in ventilated pediatric patients.

Participant Groups

Group I: Dexmedetomidine Active Control 1 Intervention

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.

Group II: Midazolam Active Control 1 Intervention

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.

Dexmedetomidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Precedex for:

• Sedation in intensive care settings
• Procedural sedation

Approved in United States as Precedex for:

• Sedation in intensive care settings
• Procedural sedation

Approved in Canada as Precedex for:

• Sedation in intensive care settings
• Procedural sedation

Approved in Japan as Precedex for:

• Sedation in intensive care settings
• Procedural sedation

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study of 54 children aged 1 to 6 years undergoing elective minor surgery, dexmedetomidine as a premedicant achieved acceptable parental separation in 90% of cases and sedation in 80% at induction, indicating its efficacy in managing preoperative anxiety.

The combination of dexmedetomidine and ketamine did not improve mask acceptance or premedication success, and the use of dexmedetomidine was associated with a low incidence of emergence agitation (2%), suggesting it may be a safer option compared to traditional premedicants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of intranasal dexmedetomidine and dexmedetomidine-ketamine for premedication in pediatrics patients: A randomized double-blind study. Bhat, R., Santhosh, MC., Annigeri, VM., et al.[2022]

In a study of 75 children aged over 5 years requiring general anesthesia, intranasal dexmedetomidine resulted in significantly better sedation during parental separation compared to oral midazolam, with 69.4% of dexmedetomidine patients achieving satisfactory sedation versus 40.5% for midazolam.

Intranasal dexmedetomidine was well-tolerated and did not cause significant changes in heart rate or blood pressure, indicating it is a safe option for pre-medication in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-medication before dental procedures: A randomized controlled study comparing intranasal dexmedetomidine with oral midazolam. Sathyamoorthy, M., Hamilton, TB., Wilson, G., et al.[2020]

Midazolam was effective in providing sedation for 36 children undergoing diagnostic examinations and short surgical procedures, with a good sedative effect achieved in 26 of the patients.

While some children experienced fear reactions and transient side effects, these were not life-threatening, indicating that midazolam can be safely used in pediatric settings with appropriate monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Own experience in the application of midazolam (Dormicum) before the diagnostic examinations an short surgical procedures in children]. Kurylak, D., Dylewska, K., Bała, G., et al.[2013]

In a study of 60 children aged 3-6 years undergoing dental treatment, intranasal dexmedetomidine (DEX) was found to significantly reduce postoperative agitation compared to oral midazolam (MID), with 0% incidence of agitation in the DEX group versus 20% in the MID group.

Both DEX and MID provided satisfactory sedation and similar rates of parental separation and mask acceptance, indicating that DEX is an effective alternative for preoperative sedation in pediatric dentistry with a lower risk of postoperative agitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Intranasal Dexmedetomidine and Oral Midazolam for Premedication in Pediatric Dental Patients under General Anesthesia: A Randomised Clinical Trial. Wang, L., Huang, L., Zhang, T., et al.[2021]

Sublingual dexmedetomidine is more effective than sublingual midazolam for preoperative sedation in children, as shown by a significant difference in sedation scores (6 for midazolam vs. 3.5 for dexmedetomidine) in a study of 100 children aged 1 to 12 years.

Dexmedetomidine also resulted in better mask acceptance and wake-up behavior in preschool children, indicating it may facilitate smoother anesthesia induction and recovery compared to midazolam.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of sublingual midazolam and dexmedetomidine for premedication in children. Pant, D., Sethi, N., Sood, J.[2022]

Dexmedetomidine is as effective as midazolam for premedication in children undergoing elective herniotomy, providing similar levels of sedation and anxiety relief.

Dexmedetomidine significantly reduces the incidence and severity of emergence agitation compared to midazolam, although it is associated with a higher risk of hypotension and bradycardia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of oral dexmedetomidine and oral midazolam as premedicants in children. Sajid, B., Mohamed, T., Jumaila, M.[2022]

Intranasal dexmedetomidine (1 μg/kg) provided significantly better sedation scores than oral midazolam (0.5 mg/kg) during separation and induction in children undergoing elective lower abdominal surgery, indicating its efficacy as a premedication option.

Despite differences in heart rate and blood pressure observed with dexmedetomidine, these changes did not require medical intervention, suggesting a favorable safety profile compared to midazolam.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of intranasal dexmedetomidine versus oral midazolam for paediatric premedication. Kumar, L., Kumar, A., Panikkaveetil, R., et al.[2020]

In a study involving 91 pediatric patients, dexmedetomidine was found to be a well-tolerated alternative sedative for non-intubated moderate or deep sedation, with a low incidence of serious adverse events.

While respiratory depression and hypotension were the most common treatment-emergent adverse events, they were manageable and consistent with dexmedetomidine's known safety profile, indicating its potential for safe use in children during elective procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation. Jooste, EH., Hammer, GB., Reyes, CR., et al.[2020]

In a study of 65 critically ill children with multiple trauma, dexmedetomidine was found to significantly reduce pro-inflammatory cytokines and increase anti-inflammatory cytokines compared to midazolam, indicating its superior anti-inflammatory effects.

Dexmedetomidine also led to shorter durations of mechanical ventilation and reduced length of stay in the pediatric intensive care unit (PICU) compared to midazolam, suggesting it may be more effective for managing severe trauma in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of different sedation regimens on sedation and inflammatory response in critically ill children with multiple trauma]. Tong, W., Song, C., Jin, D., et al.[2018]

References

1. India pubmed.ncbi.nlm.nih.gov

Comparison of intranasal dexmedetomidine and dexmedetomidine-ketamine for premedication in pediatrics patients: A randomized double-blind study. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Pre-medication before dental procedures: A randomized controlled study comparing intranasal dexmedetomidine with oral midazolam. [2020]

3. Poland pubmed.ncbi.nlm.nih.gov

[Own experience in the application of midazolam (Dormicum) before the diagnostic examinations an short surgical procedures in children]. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Comparison of Intranasal Dexmedetomidine and Oral Midazolam for Premedication in Pediatric Dental Patients under General Anesthesia: A Randomised Clinical Trial. [2021]

5. Italy pubmed.ncbi.nlm.nih.gov

Comparison of sublingual midazolam and dexmedetomidine for premedication in children. [2022]

6. India pubmed.ncbi.nlm.nih.gov

A comparison of oral dexmedetomidine and oral midazolam as premedicants in children. [2022]

7. India pubmed.ncbi.nlm.nih.gov

Efficacy of intranasal dexmedetomidine versus oral midazolam for paediatric premedication. [2020]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation. [2020]

9. China pubmed.ncbi.nlm.nih.gov

[Effects of different sedation regimens on sedation and inflammatory response in critically ill children with multiple trauma]. [2018]