Phase I Clinical Trial to Determine the Safety of Clonidine in Infants With HIE During Therapeutic Hypothermia.

Hypoxic ischemic encephalopathy (HIE) occurs in ~ 2-4/1000 term infants and is a major cause
of neonatal morbidity and mortality. Resulting neurologic deficits include disabling
cerebral palsy and abnormalities of speech, vision and intellect in 50-70% of surviving
infants. To date, therapeutic hypothermia started within 6 h of birth is the only
intervention known to be effective in reducing the morbidity and mortality of HIE.
Hypothermia does not totally reverse the injury in many infants and is associated with side
effects that may compromise its effectiveness. For example, hypothermia can cause intense
shivering which blocks the neuroprotective effect of therapeutic hypothermia in newborn
models. Low dose morphine is often used to reduce shivering in infants undergoing
therapeutic hypothermia, but escalating doses of sedatives/analgesics are often required.
Escalating doses of opioids and benzodiazepines causes respiratory depression and can either
cause the need for or prolong mechanical ventilation. Agonists to the central a2 -
adrenergic receptors are more effective at reducing postoperative shivering than opioid
receptor agonists and provide analgesia and sedation without respiratory depression. More
importantly, in newborn and adult animal models of brain injury, a2 - adrenergic receptor
agonists provide neuroprotection. Clonidine is an a-2 adrenergic receptor agonist that is
broadly used (off-label) for several disorders in infants and children. It is not known
which class of sedative-analgesic agents are the most beneficial infants with HIE. Little is
known about how immaturity, end organ damage and therapeutic hypothermia affect the
pharmacokinetics and pharmacodynamics (PK/PD) of sedatives-analgesics. The most desirable
sedative-analgesic agent used in infants with HIE would: (a) have an excellent safety
profile, (b) reduce shivering, (c) provide adequate analgesia and sedation, (d) cause
minimal respiratory depression, (e) preserve cerebrovascular autoregulation, and (f) confer
neuroprotection. Several lines of evidence suggest that the a2-adrenergic receptor agonist
class of sedatives-analgesics may have all these properties. We have developed a sensitive
assay to measure clonidine plasma levels that will allow us to characterize the population
PK/PD parameters of clonidine in these high risk infants. We have the tools, expertise and
patient population to conduct a phase I/II trial to test the hypotheses that clonidine is
safe and will reduce the incidence of shivering without adversely affecting heart rate,
blood pressure, temperature regulation or cerebrovascular autoregulation. Data from this
trial will inform the study design of a larger randomized-double-blind trial to determine if
clonidine as an adjunct to therapeutic hypothermia will improve neurological outcomes in
this high risk population.

Inclusion Criteria:

- Infants ≥35 0/7 weeks gestation with the diagnosis of HIE who meet the criteria and
are treated with therapeutic hypothermia

- Informed parental consent

Exclusion Criteria:

- Infants who are considered moribund and the clinical team is considering withdrawal
of support

- Infants who need > 20 µg/kg/min of dopamine or the addition of epinephrine or
dobutamine to maintain a mean arterial pressure (MAP) ≥ 45 mmHg, or milrinone for
cardiovascular support

- Baseline heart rate (HR) <80 bpm during hypothermia

- Infants suspected of major chromosomal anomalies, except trisomy 21

- Infants with major cardiovascular anomalies

- Infants with severe persistent pulmonary hypertension of the newborn who are enrolled
and who then need ECMO will be withdrawn from the study