Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia
Condition: Encephalopathy, Hypoxic-Ischemic
MeSH terms: Brain Diseases; Brain Ischemia; Hypoxia-Ischemia, Brain; Hypoxia, Brain; Ischemia; Hypothermia; Hypoxia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This research is being done to find out the safety of the investigational study drug,
      Clonidine Hydrochloride ( CLON). , in infants who are undergoing whole body cooling for the
      treatment of hypoxic ischemic encephalopathy (HIE). The only known and effective treatment
      for HIE is therapeutic hypothermia or whole body cooling for72 hours. During the cooling
      process, babies get agitated, shiver and are uncomfortable. To treat these side effects
      morphine is frequently used. CLON is very effective in decreasing shivering in adults and
      children. Furthermore, in some preclinical studies, clonidine has been shown to be
      neuroprotective (safe for the brain in models of brain injury)..This is a Phase I-II to
      determine if low dose CLON will reduce the incidence of shivering and whether it has short
      term cardiovascular safety. In this Phase I-II study, the investigators will determine the
      (i) the maximum tolerated dose of CLON during cooling for HIE, (ii) the effects of CLON on
      heart rate, blood pressure, core body temperature and cerebral autoregulation (ability to
      maintain constant blood flow to the brain) and (iii) association between blood levels and
      changes in the above parameters. In this study the investigators hope to find ways to improve
      sedation, shivering and agitation in newborn infants with HIE on the cooling protocol. Our
      ultimate goal is determine the potential neuro-protective properties of clonidine in newborn
      babies with HIE.
    

Detailed description: 
      The most desirable sedative-analgesic agent used in infants with HIE would 1) have an
      excellent safety profile, 2) provide adequate analgesia and sedation, 3) reduce shivering, 4)
      cause minimal respiratory depression, 5) preserve cerebrovascular autoregulation, and 6)
      confer neuroprotection. Several lines of evidence suggest alpha 2 adrenergic receptor agonist
      class of sedatives-analgesics may have all these properties. The investigators have recently
      developed a sensitive assay to measure clonidine levels which will allow us to perform
      population Pharmacokinetic (PK)/Pharmacodynamic (PD) analyses of clonidine in sick newborns.
      Thus, this phase I/II trial is designed to test the hypothesis clonidine , an alpha- 2
      adrenergic receptor agonist, will reduce the incidence of shivering without adversely
      affecting heart rate (HR), blood pressure (BP), temperature regulation or cerebrovascular
      autoregulation.

      Essentially all classes of sedative-analgesic agents affect mean arterial blood pressure
      (MAP) which can alter cerebral perfusion and affect cerebrovascular autoregulation.
      Cerebrovascular autoregulation is when blood flow to the brain is held relatively constant
      over a wide range of MAPs; it ensures a steady supply of oxygenated blood to the brain, and
      is only functional within a specific range of MAP's. When MAP deviates from this range and
      drops below the lower limit of autoregulation, blood flow becomes passive to MAP and the
      brain is placed at risk for ischemic injury. Brain injury alters cerebrovascular
      autoregulation in the region of injury, and together with sub-optimal MAP after hypoxic brain
      injury could cause more brain ischemia leading to poor outcomes, seizures, and permanent
      neurologic injuries. Little information is available on the effect of HIE alone or in
      combination with hypothermia on cerebrovascular autoregulation, and no information is
      published on the direct effect of sedative-analgesics on alterations in hemodynamic
      parameters and subsequent indirect or direct effects on cerebrovascular autoregulation in
      newborns with HIE. Thus, this study will establish the safety of clonidine, a commonly used
      sedative-analgesic in infants and children, in a population of infants with HIE undergoing
      therapeutic hypothermia. A secondary exploratory outcome is to determine the efficacy of
      clonidine in reducing shivering during the cooling phase of the therapeutic hypothermia
      protocol.
    

Intervention name(s): Clonidine (Duraclon®)
Intervention type(s): Drug
Intervention description(s): Clonidine at dosing intervals of 6, 8, 12, 18 or 24 hours. If the following is observed the event will be recorded, and no additional clonidine will be given and blood will be drawn to measure plasma level of clondine.
10 mm Hg reduction in MAP or MAP ≤ 40 mm Hg sustained for ≥30 min after administration
20% drop in HR from the infant's baseline, sustained for ≥30 min after administration
HR ≤70/min, sustained for ≥30 min after administration
Intervention MeSH terms: Clonidine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment