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.

Quantification of the severity of hypoxic-ischemic brain injury in a neonatal preclinical model using measurements of cytochrome-c-oxidase from a miniature broadband-near-infrared spectroscopy system

“…4 Preclinical studies of perinatal HI, using newborn pigs (similar gross anatomical features of human neonatal brain 5 ) have been used to investigate cerebral energetics and metabolism during and after HI and to develop neuroprotective therapeutic strategies. 1,[6][7][8][9][10] Phosphorous ( 31 P) and proton ( 1 H) magnetic resonance spectroscopy (MRS) are gold standard magnetic resonance (MR) techniques for assessing injury severity, as the decline in cerebral energy measured in this manner correlates strongly with neurodevelopmental outcome. 11,12 Studies have demonstrated that 31 P-MRS-measured inorganic phosphate/exchangeable phosphate pool (Pi/epp), phosphocreatine (PCr)/Pi, and total nucleotide triphosphate (NTP)/epp ∼1 to 2 h after HI correlate linearly with the decline in cerebral energetics leading to secondary energy failure.…”

The alterations effects in phosphorus of erythropoietin and U-74389G

“…Thus, signi icantly higher Pi and pH (both p < 0.01) were noticed in patients with CLI than healthy control ones. Ezzati et al assessed [20] the wholebrain (phosphorus-31 and regional proton MRS biomarkers) nucleotide triphosphate/exchangeable phosphate pool was similar (p = 0.73) over 48h in large White male piglets. Kamath, et al recommend [21] to all patients with a history of previous thyroid operation, who come with vague symptoms like fatigue, muscle aches to undergo estimation of serum calcium, phosphorus and parathyroid hormone (PTH) screened for delayed hypoparathyroidism.…”

Effect of Intranasally Delivered rh-VEGF165 on Angiogenesis Following Cerebral Hypoxia-Ischemia in the Cerebral Cortex of Newborn Piglets

“…Newborn piglets offer a large brain size, the presence of gyri and sulci, similar white/grey matter ratio, and developmental age at term similar to the human brain. Our laboratory [ 26 ] and other investigators [ 25 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] have used the newborn piglet model as it provides the advantage of real-time measurements of physiologic parameters such as arterial blood gases and continuous blood pressure monitoring, which allows titration of FiO 2 to achieve a precise and reproducible degree of hypoxia-ischemia [ 25 , 27 , 32 , 38 ].…”