Hypoxic Ischemic Brain Injury, Neonatal Encephalopathy, Perinatal Anoxic-ischemic Brain Injury
Conditions
Keywords
sedation, analgesia, dexmedetomidine, morphine
Brief summary
About \ 3/ 1000 live-born newborns may suffer from brain injury due to a transient drop in oxygen supply to the brain during the birth process. The degree of brain injury that ensues in the first 72 hours after the injury is directly proportional to the severity of long-term childhood disabilities (e.g., cerebral palsy and developmental delays). Whole-body cooling during the first 3 days of life is proven effective in reducing the severity of brain injury. However, cooling therapy leads to pain, shivering, stress, and discomfort. The best way to alleviate the pain and agitation of cooled newborns is unknown. Standard practice is to provide morphine infusion to reduce pain. Recently, a new drug called dexmedetomidine has been tested in small studies and has been found to be safe during cooling in newborns. Dexmedetomidine has added beneficial effects such as anti-inflammation, faster recovery, and shorter hospital stays. This study is going to test the feasibility of conducting a future clinical trial to compare the effects of using Dexmedetomidine versus morphine in the management of cooling-related pain/agitation on the severity of brain injury in the first week of life. The study will also examine the effect of dexmedetomidine compared to morphine on short-term clinical outcomes, parental experiences and developmental outcomes at 1 year.
Interventions
DRUGDexmedetomidine Infusion
Dexmedetomidine infusion given for sedation during therapeutic hypothermia. Dexmedetomidine infusion at a starting dose of 0.2 μg/kg/h, with titration in 0.1 μg/kg/h increments with a maximum of 0.5 μg/kg/h based on objective assessment of sedation.
Morphine infusion given for sedation during therapeutic hypothermia. Morphine infusion at a starting dose of 4 μg/kg/h, with titration in 2 μg/kg/h increments with a maximum of 10 μg/kg/h based on objective assessment of sedation.
Sponsors
Ipsita Goswami
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 20 Hours
Healthy volunteers
No
Inclusion criteria
1. Gestational age \>= 35 weeks 2. Birth weight \>= 2500g 3. Sign of perinatal hypoxic event (any of the following): (a) Arterial Cord blood gas or postnatal gas within 1 hour of life pH \<= 7.00 OR Base Deficit \>= 16 (b) Arterial Cord blood gas postnatal gas within 1 hour of life pH 7.00 -7.15 AND Acute sentinel intrapartum event 4. Sign of Neonatal Encephalopathy 5. Initiation of Therapeutic Hypothermia within 8 hours of life
Exclusion criteria
1. Informed consent not obtained within 20 hours of life 2. Congenital Brain Malformations (antenatally known) 3. Major Chromosomal Anomaly (antenatally diagnosed) 4. Congenital neuromuscular disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Event Rate | From enrollment to 7 days of life | Incidence of adverse events Measurement of Adverse Event Rate = (Number of neonates experiencing) x100/ (Total neonates exposed to the intervention) |
| Discontinuation Rate | From enrollment to 7 days of life | Need for intervention discontinuation due to adverse effects. Measurement of Discontinuation Rate = (Number of neonates for whom the intervention discontinued) x 100/ (Total neonates consented) |
| Protocol Adherence Rate | through study completion, average 1 year | Percentage of correct drug adjustment based on changes in COMFORTneo scale as per protocol. Calculation of Drug Administration Compliance = (Number of correctly administered medication per month) x 100/ (Total number of participant enrolled per month) |
| Recruitment Rate | Day 1 | Proportion of eligible neonates enrolled. Calculation = (Number of neonates enrolled) X 100/(Total eligible neonates) |
| Follow Up Rate | From enrollment to 1 year of age | Percentage of neonates completing the study. Calculation = (Neonates who completed the study) x 100/ (Total neonates consented) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Full Oral Feeds | up to 4 weeks of life | Days of life when participant is receiving all oral feeds either breast or bottle |
| Length of Hospital Stay | up to 4 weeks of life | Day of life when discharged home |
| Days on invasive and non-invasive respiratory support | Up to 4 weeks of life | Day of life when comes off all respiratory support to room air |
| Cumulative dose of PRN opioid boluses given during therapeutic hypothermia | up to 4 days of life | Total dose of morphine and fentanyl given during therapeutic hypothermia measured in mg/kg of morphine equivalent |
| Severity of Brain Injury on Magnetic Resonance Imaging (MRI) | From enrollment to 10 days of life | The T1 and T2 weighted images, diffusion-weighted images, and magnetic resonance spectroscopy (MRS) are additionally evaluated to determine the level of brain damage. MRI scoring system reported by Weeke et al. will be used to classify brain injury based on 4 subscores, including grey matter (basal ganglia, thalamus, PLIC, brainstem, perirolandic cortex, and hippocampus), white matter/cortex (including optic radiation and corpus callosum), and cerebellum. |
| Seizure Burden during Therapeutic Hypothermia | From enrollment to 72 hours of life | Total duration of seizures noted during the first 72 hours of life |
| Stress levels measured by Salivary cortisol assay at 24 and 48 hours | From enrollment to 48 hours of life | Salivary cortisol levels will be used as an objective marker of neonatal stress measured in µg/dL. |
| Neonatal Sedation and Discomfort Levels | From enrollment to 4 days of life | COMFORT neo scores during the period of therapeutic hypothermia. It consists of 7 behavioural items (alertness, calmness/agitation, respiratory response, crying, body movement, facial tension and muscle tone), of which six items should be scored (respiratory response or crying depends on the presence of invasive ventilation). The neonate will be observed for 2 minutes to score. Total scores range from 7 to 35. A score \>14 is considered a sign of distress and undersedation. A score \< 9 suggests oversedation. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Parental Stress Index | Up to 4 weeks of life | Parental Stress Index - Short Form (PSI-SF) will be administered to parents of study subjects at discharge from NICU to compare stress levels between neonates of the two groups. The short form is derived from the original Parental Stress Index (PSI). It consists of 36 items across three subscales namely (i) Parental Distress (PD): stress related to personal factors (e.g., depression, lack of support), (ii) Parent-Child Dysfunctional Interaction (P-CDI): stress about the child not meeting expectations and (iii) Difficult Child (DC): stress due to child's behavioral difficulties. Each item is rated 1 (Strongly Disagree) to 5 (Strongly Agree). Percentiles based on normative data are used to interpret scores. \>85th percentile indicates clinically significant stress, 90th-99th percentile indicates highly elevated stress. |
| Developmental Outcomes at 12 months | Between 10-14 months of enrollment | Ages and Stages Questionnaire-3rd edition (ASQ-3) to assess five areas of childhood development: Communication, Gross motor, Fine motor, Problem-solving, and Personal-social through parent/caregiver reports. Each item is answered as Yes (10 points), Sometimes (5 points) and Not Yet (0 points). Each domain has 6 questions, hence a maximum 60 points per domain. After summing scores for each domain, total score is interpretated as: (i) Above Cutoff (Development is on schedule), (ii) Close to Cutoff (within 1 SD) (Monitor, Child may need re-screening soon) and (iii) Below Cutoff (Referral to specialist for further evaluation recommended). |
| Parental Experiences | From discharge to 4 weeks post-discharge | Parental experiences captured through semi-structured interviews will be audio-recorded and transcribed. |
Countries
Canada
Contacts
Primary ContactIPSITA GOSWAMI, MD
Outcome results
None listed