Midazolam Dose Correlates with

Abnormal Hippocampal Growth and

Neurodevelopmental Outcome in Preterm
Infants
Midazolam
• Midazolam is a favored sedative-hypnotic agent for procedural sedation
because its water solubility allows it to be administered via several different
routes (eg, oral, IV, IM, intranasal, and rectal).
• Midazolam has a rapid onset of action when administered IV (2-5 min)
• is easily titrated
• associated with less pain at the injection site
• has a shorter duration of action than other commonly used benzodiazepines.
• The dose-response curve is highly variable in children; weight-based dosing
produces variable levels of sedation in agitated children of the same weight;
this is common with IM and PO dosing.
Hippocampus
• part of the limbic system
• hippocampus is an arching band of nerve fibers (fornix) combining the
hippocampal formations in the left and right brain hemispheres look
like a horseshoe-shaped structure.
• located in the brain’s, inner medial region of temporal lobes
• plays important roles in the consolidation of information from short-
term memory to long-term memory, and in spatial memory that
enables navigation.
• located in the allocortex, with neural projections into the neocortex.
Introduction
• Neonates born very preterm (N = 138, 51% male, 24–32 weeks of
gestation) admitted to the NICU at Children’s & Women’s Health
Centre of British Columbia, Vancouver, Canada were enrolled in the
study over a 7-year period (2006– 2012).
• Neonates between the age of 24-32 weeks gestation were eligible.
• Exclusion criteria: congenital malformation or syndrome, antenatal
infections, or ultrasound evidence of a large parenchymal
hemorrhagic infarction.
Objective
• To assess the effect of the number of invasive procedures and the influence of
the benzodiazepine midazolam on the macro- and micro structural growth of
the hippocampus in very preterm born neonates
• to determine the relationship between early hippocampal growth and
neurodevelopmental outcomes, accounting for the number of invasive
procedures, total dose of midazolam, and other parameters of systemic illness.
• linear regression models were performed to examine the association of Bayley-
III scores with the weekly volumetric and microstructural growth of the
hippocampus, accounting for invasive procedures, midazolam, and other
analgesic/sedative exposures, as well as other clinical variables using final
models.
Method
• A total of 138 neonates (51% male, median gestational age = 27.7 weeks)
underwent magnetic resonance imaging and diffusion tensor imaging (DTI)
scans, early in life (postmenstrual age [PMA] 5 32.3 weeks) and at term
equivalent age (PMA = 40.2 weeks).
• Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean
diffusivity (MD) were obtained from the hippocampus.
• Cognitive, language, and motor abilities were assessed using the Bayley
Scales of Infant Development–III at 18.7 months median corrected age.
• Models testing the association of invasive procedures with hippocampal
volumes and DTI measures accounted for birth gestational age, sex, PMA,
dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical
ventilation, hypotension, and surgeries
MRI
• Neonates were scanned without pharmacological sedation
• scans were performed as soon as the neonate was clinically stable for
transport (median age = 32.3 weeks, interquartile range [IQR] = 30.7–
34) and again at term-equivalent age (median age = 40.2 weeks, IQR =
38.9–42).
• T1-weighted images were acquired using coronal or sagittal
sequences.
• T2-weighted images were acquired for neuroradiological assessment
of brain injury using an axial fast spin echo
• A neuroradiologist (K.J.P.) scored the T1-weighted anatomical images
for brain injury severity.
• White matter injury was defined as foci exhibiting T1 hyperintensity
without marked T2 hypointensity, or as low-intensity T1 foci, and was
scored on a 3-point scale
• none = 0, minimal = 1, moderate–severe = 2–3 combined) previously
shown to predict neurodevelopmental outcome.
• Intraventricular hemorrhage was graded
• none = 0, mild = 1–2, and moderate–severe = 3– 4)
• Cerebellar hemorrhage was recorded (present/absent).
Image Analysis
• Segmentations of hippocampal volume and total cerebral volume
(TCV) on T1-weighted MRIs were performed.
• an expert manually segmented the left and right hippocampi and the
total cerebrums (excluding the midbrain and ventricles) on both the
early and term equivalent age MRI to create the input atlases.
• The hippocampus was segmented in the MRI scans of 22 randomly
selected neonates (44 images in total)
• Segmentations were based on the intensity differences between the
white matter of the temporal lobe (low intensity) and the gray matter
of the hippocampus (high intensity).
DTI Analysis
• Allows for the 3-dimensional mapping and characterization of the
diffusion of bounded water within tissues and is an indirect measure
of microstructural integrity.
• Describes the degree of anisotropy of water molecules in tissues and
the orientation of diffusion anisotropy in relation to tissues.
• To assess the microstructural integrity of the hippocampus, a manual
region of interest was drawn in the axial plane of each DT image in
the hippocampal head, primarily in the gray matter, at the level of the
midbrain, posterior to the uncus/amygdala in the medial temporal
lobe
• Diffusion measures of AD and RD were extracted. MD was calculated
based on the average of the principle diffusion directions. After the
AD, RD, and MD values were recorded, the values were plotted by
gestational age (GA) at scan to identify outlying data points.
Demographic and Clinical Data Collection
• Was collected from the infants’ NICU charts by a neonatal nurse and a
neurologist.
• To assess exposure to stress/pain in the neonates, each invasive
procedure was documented daily by nursing staff, including but not
limited to heel lances, intubations, intravenous or central line
insertion, and intramuscular injection
• We quantified neonatal procedural pain/stress as the number of
invasive procedures (eg, heel lance, peripheral intravenous or central
line insertion, chest-tube insertion, tape removal, and nasogastric
tube insertion) during the stay in the NICU
Neurodevelopmental Outcomes at 18
Months Corrected Age
• Infants (n = 117, 85%) and their parent(s) returned to the
neurodevelopmental follow-up clinic at Children’s & Women’s Health
Centre of British Columbia at 18 months of age corrected for
prematurity (median age = 18.7 months, IQR = 18.3–19.2).
• All children returning for follow-up were scanned twice as neonates,
both early in life and at term equivalent age.
• Developmental abilities were assessed using the Bayley Scales of
Infant and Toddler Development, 3rd edition (Bayley-III), which yields
cognitive, language, and motor composite scores that are
standardized with a mean of 100 and a SD of 15.
Statistical Analysis
• To assess invasive procedures and midazolam exposure in relation to
hippocampal growth, the hippocampal volumes and DTI measures
from the early and late scans were modeled using generalized
estimating equations for repeated measures data.
• Bonferroni method- due to 2 prior hypotheses, the alpha level for the
statistical models addressing these hypotheses was set to 0.025.
Results