Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia
| Status: | Completed |
|---|---|
| Conditions: | Peripheral Vascular Disease, Infectious Disease, Hospital, Neurology, Psychiatric |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Immunology / Infectious Diseases, Neurology, Psychiatry / Psychology, Other |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 1/7/2018 |
| Start Date: | October 3, 2013 |
| End Date: | April 14, 2015 |
Phase I-II Clinical Trial to Determine the Safety of Clonidine in Infants With Hypoxic Ischemic Encephalopathy During Therapeutic Hypothermia
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.
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.
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.
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.
Inclusion Criteria:
- Infants ≥35 0/7 weeks gestation with the diagnosis of HIE who are being treated with
therapeutic hypothermia, who have indwelling arterial lines
- 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 Extracorporal Membrane Oxygenation (ECMO) will be withdrawn from the
study
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