DOSE Trial of Opioid Sparing Effect
Condition: Dexmedetomidine; Mechanical Ventilation Complication; Critically Ill
MeSH terms: Critical Illness
Intervention: Fentanyl; Dexmedetomidine; Dexmedetomidine; Dexmedetomidine
Intervention description: Fentanyl standard of care; Dexmedetomidine (0.5 mcg/kg + 0.2 mcg/kg/hr); Dexmedetomidine (0.5 mcg/kg + 0.5 mcg/kg/hr); Dexmedetomidine (0.5 mcg/kg + 0.7 mcg/kg/hr)
Intervention MeSH terms: Fentanyl; Dexmedetomidine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: Phase 1b randomized, double-blind, placebo-controlled dose escalation trial. 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); Cohort 3: Fentanyl SOC titrated to sedation + Dexmedetomidine (0.5mcg/kg bolus load + 0.7mcg/kg/hr infusion).
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 30.0
Sex: All
Maximum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Ages 0 to <18 years at the time of enrollment.

          2. If < 6 months postnatal age, gestational age ≥ 35 weeks.

          3. Admitted to an intensive care unit.

          4. Planned or anticipated mechanically ventilation for ≥2 days.

          5. Require sedation to maintain mechanical ventilation per clinical judgment.

          6. No contraindication to receipt of fentanyl or dexmedetomidine per clinician judgment.

          7. Availability and willingness of the parent/legal guardian to provide written informed
             consent.

        Exclusion Criteria:

          1. Previous participation in this study.

          2. Severe traumatic brain injury as the underlying etiology for critical illness
             requiring mechanical ventilation or baseline pediatric cerebral performance category
             (PCPC) >3.

          3. Planned receipt of sedatives other than fentanyl or dexmedetomidine.

          4. Anticipated receipt of neuromuscular blockade for >48 consecutive hours during the
             study period.

          5. Receipt of fentanyl or dexmedetomidine via continuous infusion for >12 hours in the 24
             hours prior to enrollment.

          6. Extracorporeal life support (including renal replacement therapy, extracorporeal
             membrane oxygenation, ventricular assist device, etc.) at the time of enrollment.

          7. 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)

          8. Known pregnancy

          9. Known liver dysfunction, defined as: aspartate aminotransferase (AST) or alanine
             aminotransferase (ALT) >2x the upper limit of normal for age

         10. Known or impending renal failure defined as: anuria > or equal to 12 hours prior to
             enrollment or requiring renal replacement therapy

         11. 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)

         12. 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.