Study Evaluating Safety and Efficacy of Dexmedetomidine (DEX) in Intubated and Mechanically Ventilated Pediatric Intensive Care Unit (PICU) Subjects

• Absolute time and percentage of time on study drug that the subject is in a UMSS range of 1 3 while intubated [ Time Frame: 6 to 24 hours ] [ Designated as safety issue: Yes ]
• • Absolute time and percentage of time on study drug the subject is out of the target sedation range while intubated (UMSS score 0 or 4) [ Time Frame: 6 to 24 hours ] [ Designated as safety issue: Yes ]
• Total amount of rescue medication required for sedation and analgesia [ Time Frame: 6 to 24 hours ] [ Designated as safety issue: Yes ]
• Time to first dose of rescue medication for sedation and analgesia [ Time Frame: 6 to 24 hours ] [ Designated as safety issue: Yes ]
• Time to extubation [ Time Frame: 6 to 24 hours ] [ Designated as safety issue: Yes ]

An estimated 175 subjects will be enrolled at approximately 40 investigative sites. Subjects will be divided into two treatment groups to receive either high dose or low dose DEX. The loading and maintenance doses in both groups will be stratified according to the presence or absence of cardiopulmonary bypass. The level of sedation will be assessed using the University of Michigan Sedation Scale (UMSS). Based on these scores and clinical judgment, additional sedation with intravenous midazolam will be administered according to the label. The UMSS scores must be documented before the administration of every MDZ dose and within five minutes after each dose of MDZ. Fentanyl or morphine may be administered to treat pain. Subjects may be extubated after beginning of study drug but are not required to be as part of the study.

The efficacy and safety parameters that will be monitored include sedation levels, heart rate, blood pressure and ventilation indicators. Once subjects have met site-specified respiratory criteria, they will undergo tracheal extubation. The dexmedetomidine infusion may be continued during and after extubation if further sedation is required post-extubation. The continuous infusion of dexmedetomidine may be administered for a minimum of 6 hours and a maximum of one week. Sedation levels, heart rate, blood pressure, respiratory rate, transcutaneous CO2 or arterial blood gases (if available) and oxygen saturation will be monitored and recorded in the peri-extubation period.

• Drug: Dexmedetomidine
  Study drug titrated up or down to maintain target UMSS range.
• Drug: Midazolam
  Rescue medication for sedation according to UMSS scores
• Drug: Fentanyl
  Rescue medication for pain based on UMSS scores
• Drug: Morphine
  Rescue medication for pain based on UMSS scores.

• Active Comparator: Dexmedetomidine Low Dose
  Interventions:

  • Drug: Dexmedetomidine
  • Drug: Midazolam
  • Drug: Fentanyl
  • Drug: Morphine
• Active Comparator: Dexmedetomidine High dose
  Interventions:

  • Drug: Dexmedetomidine
  • Drug: Midazolam
  • Drug: Fentanyl
  • Drug: Morphine

Inclusion Criteria:

1. Initially intubated and mechanically ventilated pediatric subjects (>1 month (birth age corrected for prematurity) to <17 years of age) in an intensive care setting.
2. Anticipated to require a minimum of 6 hours of continuous intravenous sedation.
3. ASA classification of 1, 2, 3, or 4.
4. Age range > 1 month to < 17 years old.
5. If female, subject is non-lactating and is either not of childbearing potential,or childbearing potential but is not pregnant at time of baseline.
6. Subject's parent(s) or legal guardian(s) has/have voluntarily signed and dated the informed consent document approved by the Institutional Review Board. Assent will be obtained where age-appropriate and according to state regulations.

Exclusion Criteria:

1. Pediatric subjects with neurological conditions that prohibit an evaluation of sedation in the opinion of the investigator (e.g. increased intracranial pressure or extensive brain surgery).
2. Age > 17 years.
3. Subjects with second degree or third degree heart block unless subject has a pacemaker or pacing wires.
4. Hypotension based on repeat assessments prior to starting study drug
5. Pre-existing bradycardia prior to starting study drugs
6. SGPT (ALT): 1 month - 12 months: > 165 U/L; > 12 months to 17 years: > 100 U/L.
7. Subjects who have a known allergy to dexmedetomidine, MDZ, morphine or fentanyl.
8. Requirement for medications other than DEX, midazolam, morphine or fentanyl for sedation and pain control.
9. Subjects with immobility form neuromuscular disease, paralysis from administration of neuromuscular blocking agents, spinal cord injury above T5, or subjects with muscle weakness form congenital or systemic medical illness etiologies.
10. Subjects who have received another investigational drug within the past 30 days.
11. Subjects who, in the opinion of the investigator, have any other condition where the risks of DEX would be expected to outweigh its benefits (e.g. cardiogenic shock on > 2 vasopressors).