Emma G Duerden1, Ting Guo1, Lorin Dodbiba1, M Mallar Chakravarty2,3, Vann Chau1,4, Kenneth J Poskitt5, Anne Synnes5, Ruth E Grunau5, Steven P Miller1,4. 1. Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Ontario. 2. Cerebral Imaging Centre, Douglas Mental Health University Institute, Montreal, Quebec. 3. Departments of Psychiatry and Biomedical Engineering, McGill University, Montreal, Quebec. 4. University of Toronto, Toronto, Ontario. 5. Department of Pediatrics, University of British Columbia and Children's & Women's Health Centre of British Columbia, and Child & Family Research Institute, Vancouver, British Columbia, Canada.
Abstract
OBJECTIVE: Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome. METHODS: 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] = 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. RESULTS: Total midazolam dose predicted decreased hippocampal volumes (β = -1.8, p < 0.001) and increased MD (β = 0.002, p = 0.02), whereas invasive procedures did not (β = 0, p > 0.5 each). Lower cognitive scores were associated with hippocampal growth (β = -0.31, p = 0.003), midazolam dose (β = -0.27, p = 0.03), and surgery (β = -8.32, p = 0.04). INTERPRETATION: Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned.
OBJECTIVE: Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome. METHODS: 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] = 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. RESULTS: Total midazolam dose predicted decreased hippocampal volumes (β = -1.8, p < 0.001) and increased MD (β = 0.002, p = 0.02), whereas invasive procedures did not (β = 0, p > 0.5 each). Lower cognitive scores were associated with hippocampal growth (β = -0.31, p = 0.003), midazolam dose (β = -0.27, p = 0.03), and surgery (β = -8.32, p = 0.04). INTERPRETATION:Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned.
Authors: Emma G Duerden; Ruth E Grunau; Ting Guo; Justin Foong; Alexander Pearson; Stephanie Au-Young; Raphael Lavoie; M Mallar Chakravarty; Vann Chau; Anne Synnes; Steven P Miller Journal: J Neurosci Date: 2017-12-18 Impact factor: 6.167
Authors: Alan Leviton; Stephen R Hooper; Scott J Hunter; Megan N Scott; Elizabeth N Allred; Robert M Joseph; T Michael O'Shea; Karl Kuban Journal: Pediatr Neurol Date: 2017-12-21 Impact factor: 3.372
Authors: Ting Guo; Emma G Duerden; Elysia Adams; Vann Chau; Helen M Branson; M Mallar Chakravarty; Kenneth J Poskitt; Anne Synnes; Ruth E Grunau; Steven P Miller Journal: Neurology Date: 2017-01-18 Impact factor: 9.910
Authors: Sandra L Staveski; Karen Boulanger; Lee Erman; Li Lin; Christina Almgren; Chloe Journel; Stephen J Roth; Brenda Golianu Journal: Pediatr Crit Care Med Date: 2018-08 Impact factor: 3.624