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.