Encephalopathy, Hypoxic-Ischemic
Conditions
Brief 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.
Interventions
DRUGClonidine (Duraclon®)
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
Sponsors
University of Maryland
Johns Hopkins University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
35 Weeks to 42 Weeks
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Steady State Clonidine Blood Levels During Hypothermia | 3 days | Trough clonidine blood levels were measured after 4-7 doses of clonidine were given intravenously with a dosing interval of every 8 hrs. Mean and standard deviation (SD) of the number of doses given prior to levels being drawn was 5.3 (mean) and 0.37 (SD). Time after last dose before measurement was 9hrs (mean) and 2.7hrs (SD). |
| Amount of Morphine Given | Up to 2 days | Intravenous morphine (mg/kg) was given. The standard dose is 0.05 mg/kg per dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Presence of Shivering After Clonidine | 48hrs | Babies were assessed after administration of clonidine for the presence or absence of shivering. |
| Time to Passive Rewarming | Beginning at 72 hours up to 12 hours | Following 2 hours of therapeutic hypothermia, the temperature of the thermo-blanket is adjusted up half degree per hour allowing passive rewarming until 36.5 degrees is reached |
Countries
United States
Participant flow
Pre-assignment details
Study medication was not administered for one participant
Participants by arm
| Arm | Count |
|---|---|
| Clonidine Infants With HIE Infants in this group will receive Intravenous clonidine at 1µg/kg/dose either every 6 or 8 hrs from the start of cooling to the end of re-warming
Clonidine (Duraclon®): Clonidine at dosing intervals of 4, 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 | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
Baseline characteristics
| Characteristic | Clonidine Infants With HIE |
|---|---|
| Age, Continuous | 38.2 weeks |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Amount of Morphine Given
Intravenous morphine (mg/kg) was given. The standard dose is 0.05 mg/kg per dose
Time frame: Up to 2 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clonidine Infants With HIE | Amount of Morphine Given | 0.02 mg/kg |
Primary
Steady State Clonidine Blood Levels During Hypothermia
Trough clonidine blood levels were measured after 4-7 doses of clonidine were given intravenously with a dosing interval of every 8 hrs. Mean and standard deviation (SD) of the number of doses given prior to levels being drawn was 5.3 (mean) and 0.37 (SD). Time after last dose before measurement was 9hrs (mean) and 2.7hrs (SD).
Time frame: 3 days
Population: Only 8 babies were assessed for this outcome because the rest did not have a steady state trough level performed during cooling
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clonidine Infants With HIE | Steady State Clonidine Blood Levels During Hypothermia | 0.6 ng/ml |
Secondary
Presence of Shivering After Clonidine
Babies were assessed after administration of clonidine for the presence or absence of shivering.
Time frame: 48hrs
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clonidine Infants With HIE | Presence of Shivering After Clonidine | 0 Participants |
Secondary
Time to Passive Rewarming
Following 2 hours of therapeutic hypothermia, the temperature of the thermo-blanket is adjusted up half degree per hour allowing passive rewarming until 36.5 degrees is reached
Time frame: Beginning at 72 hours up to 12 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clonidine Infants With HIE | Time to Passive Rewarming | 8.7 Hours |