DOSE Trial of Opioid Sparing Effect
- Conditions
- Mechanical Ventilation ComplicationCritically IllDexmedetomidine
- Interventions
- Registration Number
- NCT03938857
- Lead Sponsor
- Duke University
- Brief Summary
Multicenter, double blind randomized controlled trial of fentanyl vs. fentanyl + dexmedetomidine as the initial regimen for maintenance of sedation in mechanically-ventilated, critically ill children.
This trial will evaluate the opioid-sparing effect of dexmedetomidine when administered with fentanyl to mechanically ventilated, critically ill children. Study drug or placebo will be administered with fentanyl, which will be titrated to achieve sedation scores consistent with response to light touch. Plasma samples and bedside assessments for pain, sedation, and delirium will be collected.
- Detailed Description
Phase 1b randomized, double-blind, placebo-controlled dose escalation trial of sedation regimens in critically ill children. Testing the hypothesis of mean daily fentanyl dose through day 7 of mechanical ventilation will be reduced by ≥25% by the addition of dexmedetomidine to fentanyl therapy. This trial will involve multiple clinical sites. Randomization will occur by individual and investigators will be blinded to study/treatment arm. The statistical analysis will account for center effects, participant characteristics (including post-surgical state), and changes over time to minimize bias. In addition, PIs and study coordinators will undergo training to standardize assessment procedures. The study will randomize participants to receive placebo (fentanyl standard of care) titrated to sedation+saline placebo (bolus+infusion) or one of the following 3 Dexmedetomidine treatment arms in a sequential cohort fashion: Cohort 1: Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.2 mcg/kg/hr infusion); Cohort 2: Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.5mcg/kg/hr infusion); and, Cohort 3: Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.7mcg/kg/hr infusion).
An interim analysis is planned for this trial.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 30
- Ages 0 to <18 years at the time of enrollment.
- If < 6 months postnatal age, gestational age ≥ 35 weeks.
- Admitted to an intensive care unit.
- Planned or anticipated mechanically ventilation for ≥2 days.
- Require sedation to maintain mechanical ventilation per clinical judgment.
- No contraindication to receipt of fentanyl or dexmedetomidine per clinician judgment.
- Availability and willingness of the parent/legal guardian to provide written informed consent.
- Previous participation in this study.
- Severe traumatic brain injury as the underlying etiology for critical illness requiring mechanical ventilation or baseline pediatric cerebral performance category (PCPC) >3.
- Planned receipt of sedatives other than fentanyl or dexmedetomidine.
- Anticipated receipt of neuromuscular blockade for >48 consecutive hours during the study period.
- Receipt of fentanyl or dexmedetomidine via continuous infusion for >12 hours in the 24 hours prior to enrollment.
- Extracorporeal life support (including renal replacement therapy, extracorporeal membrane oxygenation, ventricular assist device, etc.) at the time of enrollment.
- Chronic use of or recent overdose of serotonergic agents (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase (MAO) inhibitors, cyclic antidepressants)
- Known pregnancy
- Known liver dysfunction, defined as: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2x the upper limit of normal for age
- Known or impending renal failure defined as: anuria > or equal to 12 hours prior to enrollment or requiring renal replacement therapy
- High risk children, define as: a. known heart block b. known bradyarrythmia including clinically significant bradycardia (defined as requiring chronotropic agents or cardiac pacing to treat)
- Receipt of mechanical ventilation during an admission for cardiac surgery
Note: receipt of drugs other than fentanyl or dexmedetomidine for intubation, and receipt of neuromuscular blockage for intubation, will not be considered exclusionary criteria.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Fen. SOC+saline placebo (bolus+infusion) Fentanyl Fentanyl standard of care (SOC) titrated to sedation + saline placebo (bolus + infusion) Fen. SOC+Dex.(.5mcg/kg + .25mcg/kg/hr) Dexmedetomidine Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.2mcg/kg/hr infusion) Fen. SOC+Dex.(.5mcg/kg + .5mcg/kg/hr) Dexmedetomidine Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.5mcg/kg/hr infusion) Fen. SOC+Dex.(.5mcg/kg + .25mcg/kg/hr) Fentanyl Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.2mcg/kg/hr infusion) Fen. SOC+Dex.(.5mcg/kg + .5mcg/kg/hr) Fentanyl Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.5mcg/kg/hr infusion) Fen. SOC+Dex.(.5mcg/kg + .75mcg/kg/hr) Fentanyl Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.7mcg/kg/hr infusion) Fen. SOC+Dex.(.5mcg/kg + .75mcg/kg/hr) Dexmedetomidine Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.7mcg/kg/hr infusion)
- Primary Outcome Measures
Name Time Method Mean Daily Dose of Fentanyl in mcg/kg/hr (Micrograms Per Kilogram Per Hour) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the opioid-sparing effect of dexmedetomidine when co-administered with fentanyl in children receiving mechanical ventilation. Characterization of differences between dosing exposures for the four groups will allow estimation of the opioid-sparing effect of dexmedetomidine.
- Secondary Outcome Measures
Name Time Method Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmin) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Sedation Based on RASS Scale Relative to Fentanyl Plasma Concentrations (Css) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Sedation Based on RASS Scale Relative to Fentanyl Plasma Concentrations (Cmin) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-pint scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Sedation Based on the State Behavior Scale (SBS) Relative to Fentanyl Plasma Concentrations (Cmax) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Sedation Based on SBS Scale Relative to Fentanyl Plasma Concentrations (Cmin) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Sedation Based on SBS Scale Relative to Fentanyl Plasma Concentrations (Css) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Sedation Based on SBS Scale Relative to Fentanyl Plasma Concentrations (AUC) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (Css) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Sedation Based on Richmond Agitation and Sedation Scale (RASS) Scale Relative to Fentanyl Plasma Concentrations (Cmax) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmax) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Number of Participants Experiencing a Clinically Significant Episode of Bradycardia up to 28 days or until discharge from the ICU (whichever is first) Characterize the safety profile of fentanyl and dexmedetomidine when administered alone or in combination to children receiving mechanical ventilation.
Number of Participants Experiencing a Clinically Significant Episode of Urinary Retention up to 28 days or until discharge from the ICU (whichever is first) Characterize the safety profile of fentanyl and dexmedetomidine when administered alone or in combination to children receiving mechanical ventilation.
Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmax) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Sedation Based on RASS Scale Relative to Fentanyl Plasma Concentrations (AUC) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (Cmin) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (AUC) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Mean Number of SAEs (Serious Adverse Events) Experienced by Participants up to 28 days or until discharge from the ICU (whichever is first) Sedation Based on SBS Scale Relative to Dexmedetomidine Plasma Concentrations (AUC) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The SBS is a 6-point scale that ranges from +2 to -3 with -3. Scores that are more negative reflect a more sedated state (-3). Scores that are more positive reflect a more agitated state (+2). Zero is awake and easily calmed.
Number of Participants Experiencing a Clinically Significant Episode of Hypotension up to 28 days or until discharge from the ICU (whichever is first) Characterize the safety profile of fentanyl and dexmedetomidine when administered alone or in combination to children receiving mechanical ventilation.
Sedation Based on RASS Scale Relative to Dexmedetomidine Plasma Concentrations (Css) through day 7 of mechanical ventilation or initial extubation (whichever is first) Characterize the exposure response relationships of fentanyl and dexmedetomidine when administered alone or in combination in children receiving mechanical ventilation. PK is known to be altered in children compared to adults, and in those with critical illness. Characterization of pharmacokinetic-pharmacodynamic relationships can improve dose optimization when dose may not be equivalent to plasma exposure and related effect. The RASS scale is a 10-point scale that ranges from -5 to +4 with -5=unarousable and +4=combative. Zero means the patient is alert and calm.
Number of Participants Experiencing SAEs (Serious Adverse Events) up to 28 days or until discharge from the ICU (whichever is first)
Trial Locations
- Locations (19)
Rainbow Babies and Children's Hospital, University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
MetroHealth System, Case CTSA
🇺🇸Cleveland, Ohio, United States
Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States
UMass Memorial Medical Center, Children's Center
🇺🇸Worcester, Massachusetts, United States
University of Florida, Shands Children's Hospital
🇺🇸Gainesville, Florida, United States
Our Lady of the Lake Children's Hospital
🇺🇸Baton Rouge, Louisiana, United States
Oregon Health and Science University, Doernbecher Children's Hospital
🇺🇸Portland, Oregon, United States
University of Minnesota Masonic Children's Hospital
🇺🇸Minneapolis, Minnesota, United States
Indiana University Health, Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Saint Louis University, Cardinal Glennon Children's Hospital
🇺🇸Saint Louis, Missouri, United States
University of Rochester Medical Center, Golisano Children's Hospital
🇺🇸Rochester, New York, United States
University of New Mexico Children's Hospital
🇺🇸Albuquerque, New Mexico, United States
University of Buffalo, Oishei Children's Hospital
🇺🇸Buffalo, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Wake Forest Baptist Medical Center
🇺🇸Winston-Salem, North Carolina, United States
Drexel University, St. Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
University of Texas - Health Science Center San Antonio
🇺🇸San Antonio, Texas, United States
Medical University of South Carolina Children's Hospital
🇺🇸Charleston, South Carolina, United States
Primary Children's Medical Center- University of Utah
🇺🇸Salt Lake City, Utah, United States