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

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
Dexmedetomidine (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). Score 0 (awake/alert);
Score 1 (sleepy/responds appropriately); Score 2 (somnolent/arouses to light stimuli); Score
3 (deep sleep/arouses to deeper); Score 4 (unarousable to stimuli).

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 midazolam (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 must be administered for a
minimum of 6 hours and a maximum of 24 hours. Sedation levels, heart rate, blood pressure,
respiratory rate, ventilator settings, SpO2 and if available transcutaneous carbon dioxide
(TcCO2) and/or arterial blood gases (ABG) will be monitored and recorded in the
peri-extubation period.

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. The
means by which the subject is intubated may include nasotracheal, endotracheal or via
tracheotomy. The subject must be mechanically ventilated prior to and during the
commencement of study drug.

2. Anticipated to require a minimum of 6 hours of continuous intravenous sedation.

3. American Society of Anesthesiologists (ASA) classification of 1, 2, 3 or 4.

4. A UMSS score of 1, 2, 3 or 4 at the start of infusion of study drug.

5. A dose has been established for this subject's age based upon the diagnosis
procedures.

Status post cardiopulmonary bypass (s/p CPB):

- Low dose group: Loading dose: 0.2 mcg/kg Maintenance dose titration range
(0.025-0.5 mcg/kg/hr)

- High dose group: Loading dose: 0.5 mcg/kg Maintenance dose titration range
(0.1-0.7 mcg/kg/hr)

All other diagnoses:

- Low dose group: Loading dose: 0.3 mcg/kg Maintenance dose titration range (0.05-
0.5mcg/kg/hr)

- High dose group: Loading dose: 0.6 mcg/kg Maintenance dose titration range (0.2
- 1.4 mcg/kg/hr)

6. If female, subject is non-lactating and is either:

1. Not of childbearing potential, defined as pre-menarche, or surgically sterile
due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.

2. Of childbearing potential but is not pregnant at time of baseline.

7. 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. The infusion pump minimal capacity cannot accommodate the lowest possible maintenance
infusion rate of study drug based on subject's weight.

3. Subjects with second degree or third degree heart block unless subject has a
pacemaker or pacing wires.

4. Hypotension that persist beyond a 15 min of re-assessments prior to starting study
drug:

- Age 1 month to ≤6 months old: systolic blood pressure (SBP) <60 (millimeters of
mercury) mmHg

- Age >6 months to <2 yrs old: SBP <70 mmHg

- Age >2 to <12 yrs old: SBP <80 mmHg

- Age >12 to <17 yrs old: SBP <90 mmHg

5. Pre-existing bradycardia that persists beyond a 15 min period of re-assessment prior
to starting study drugs:

- Age 1 month to <2 months old: HR <90 beats per min (bpm)

- Age ≥2 months to <12 months old: HR <80 bpm

- Age ≥12 months to <2 yrs old: HR <70 bpm

- Age ≥ 2 to <12 yrs old: HR <60 bpm

- Age ≥ 12 to <17 yrs old: HR <50 bpm

6. Serum glutamic pyruvic transaminase (SGPT)/alanine aminotransferase (ALT): 1 month
-12 months: >165 U/L; >12 months to <17 years: ≥100 U/L.

Note: Subjects may be rescreened up to 6 hrs prior to study drug infusion (not
including subjects undergoing cardiac surgery with CPB).

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. Note: subjects who
received NMB agents intraoperatively must be, in the Investigator's opinion, free of
residual neuromuscular blockade prior to dosing with study drug.

10. Subjects who have received another investigational drug or device within the past 30
days.

11. Subjects who have received DEX in a previous investigational trial within the
previous 12 weeks.

12. 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).

13. Subjects who will require alpha-2 agonists/antagonists listed below within 48 hrs
prior to baseline.

Alpha-2 Agonists: Xylazine*, Clonidine (Catapres, Dixarit), Guanfacine (Tenex), Guanabenz
(Wytensin), Mivazerol, Guanadrel (Hylorel), Guanethidine (Ismelin) and Methyldopa
(Aldomet). * Xylazine is a veterinary product, but has abuse potentIal in humans.

Alpha-2 Antagonists: Corynanthine, Phenoxybenzamine (Dibenzyline), Phentolamine (Regitine,
Rogitine), Tolazoline (Priscoline), Yohimbine, Rauwolscine, Idazoxan, Reserpine (Serpasil)
and Mirtazapine (Remeron, Remeron Soltab).