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.
Gestational age >= 35 weeks
Birth weight >= 2500g
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
Sign of Neonatal Encephalopathy
Informed consent not obtained within 20 hours of life
Congenital Brain Malformations (antenatally known)
Major Chromosomal Anomaly (antenatally diagnosed)
Congenital neuromuscular disorder
Parallel
Dexmedetomidine Infusion
DrugDexmedetomidine 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
DrugMorphine 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.
Recruitment Rate
Proportion of eligible neonates enrolled. Calculation = (Number of neonates enrolled) X 100/(Total eligible neonates)
Follow Up Rate
Percentage of neonates completing the study. Calculation = (Neonates who completed the study) x 100/ (Total neonates consented)
Adverse Event Rate
Incidence of adverse events Measurement of Adverse Event Rate = (Number of neonates experiencing) x100/ (Total neonates exposed to the intervention)
Discontinuation Rate
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)
Severity of Brain Injury on Magnetic Resonance Imaging (MRI)
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
Total duration of seizures noted during the first 72 hours of life
Stress levels measured by Salivary cortisol assay at 24 and 48 hours
Salivary cortisol levels will be used as an objective marker of neonatal stress measured in µg/dL.
Neonatal Sedation and Discomfort Levels
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.
Parental Stress Index
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.
Parental Experiences
Parental experiences captured through semi-structured interviews will be audio-recorded and transcribed.
Developmental Outcomes at 12 months
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).
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Ipsita Goswami
Lead sponsor
McMaster University
Sponsor institution
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