title: Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia.
abstract: The selective α2-adrenoreceptor agonist dexmedetomidine has shown neuroprotective, analgesic, anti-inflammatory, and sympatholytic properties that may be beneficial in neonatal encephalopathy (NE). As therapeutic hypothermia is only partially effective, adjunct therapies are needed to optimize outcomes. The aim was to assess whether hypothermia + dexmedetomidine treatment augments neuroprotection compared to routine treatment (hypothermia + fentanyl sedation) in a piglet model of NE using magnetic resonance spectroscopy (MRS) biomarkers, which predict outcomes in babies with NE, and immunohistochemistry. After hypoxia-ischaemia (HI), 20 large White male piglets were randomized to: (i) hypothermia + fentanyl with cooling to 33.5°C from 2 to 26 h, or (ii) hypothermia + dexmedetomidine (a loading dose of 2 μg/kg at 10 min followed by 0.028 μg/kg/h for 48 h). Whole-brain phosphorus-31 and regional proton MRS biomarkers were assessed at baseline, 24, and 48 h after HI. At 48 h, cell death was evaluated over 7 brain regions by means of transferase-mediated d-UTP nick end labeling (TUNEL). Dexmedetomidine plasma levels were mainly within the target sedative range of 1 μg/L. In the hypothermia + dexmedetomidine group, there were 6 cardiac arrests (3 fatal) versus 2 (non-fatal) in the hypothermia + fentanyl group. The hypothermia + dexmedetomidine group required more saline (p = 0.005) to maintain blood pressure. Thalamic and white-matter lactate/N-acetylaspartate did not differ between groups (p = 0.66 and p = 0.21, respectively); the whole-brain nucleotide triphosphate/exchangeable phosphate pool was similar (p = 0.73) over 48 h. Cell death (TUNEL-positive cells/mm2) was higher in the hypothermia + dexmedetomidine group than in the hypothermia + fentanyl group (mean 5.1 vs. 2.3, difference 2.8 [95% CI 0.6-4.9], p = 0.036). Hypothermia + dexmedetomidine treatment was associated with adverse cardiovascular events, even within the recommended clinical sedative plasma level; these may have been exacerbated by an interaction with either isoflurane or low body temperature. Hypothermia + dexmedetomidine treatment was neurotoxic following HI in our piglet NE model, suggesting that caution is vital if dexmedetomidine is combined with cooling following NE.
authors.affiliation: EGA Institute for Women's Health, University College London, London, UK.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Ezzati
authors.forename: Go
authors.initials: G
authors.lastname: Kawano
authors.forename: Eridan
authors.initials: E
authors.lastname: Rocha-Ferreira
authors.forename: Daniel
authors.initials: D
authors.lastname: Alonso-Alconada
authors.forename: Jane K
authors.initials: JK
authors.lastname: Hassell
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Broad
authors.forename: Igor
authors.initials: I
authors.lastname: Fierens
authors.forename: Bobbi
authors.initials: B
authors.lastname: Fleiss
authors.forename: Alan
authors.initials: A
authors.lastname: Bainbridge
authors.forename: David L
authors.initials: DL
authors.lastname: Price
authors.forename: Pardis
authors.initials: P
authors.lastname: Kaynezhad
authors.forename: Brian
authors.initials: B
authors.lastname: Anderson
authors.forename: Mariya
authors.initials: M
authors.lastname: Hristova
authors.forename: Ilias
authors.initials: I
authors.lastname: Tachtsidis
authors.forename: Xavier
authors.initials: X
authors.lastname: Golay
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sanders
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Robertson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001238:Asphyxia Neonatorum; D002319:Cardiovascular System / Q000187:drug effects*; D003131:Combined Modality Therapy / Q000379:methods; D020927:Dexmedetomidine / Q000633:toxicity*; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain; D008297:Male; D018696:Neuroprotective Agents / Q000633:toxicity*; D011897:Random Allocation; D013552:Swine
chemical_list: D018696:Neuroprotective Agents; D020927:Dexmedetomidine
keywords: Dexmedetomidine; Hypothermia; Magnetic resonance spectroscopy; Neonatal encephalopathy