Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats

McAdams, Ryan M.; McPherson, Ronald J.; Kapur, Raj P.; Phillips, Brian; Shen, Danny D.; Juul, Sandra E.

doi:10.1038/pr.2015.45

Cited by 18 publications

(10 citation statements)

References 27 publications

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“…Dex is an α-2A adrenergic receptor agonist commonly administered to patients as a sedative and analgesic (29). Previous studies have reported Dex to be neuroprotective when combined with hypothermia (30,31). However, few studies have assessed the association between Dex and hypothermia, making the mechanism of this process unclear.…”

Section: Discussionmentioning

confidence: 99%

Hypothermic properties of dexmedetomidine provide neuroprotection in rats following cerebral ischemia‑reperfusion injury

Liu

Zhu

et al. 2019

Exp Ther Med

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Dexmedetomidine (Dex) is a sedative and analgesic agent that is widely administered to patients admitted to the intensive care unit, and has been demonstrated to result in hypothermia. Many patients have been revealed to benefit from therapeutic hypothermia, which can mitigate cerebral ischemia/reperfusion (I/R) injury following successful cardiopulmonary resuscitation. However, studies investigating the efficacy of Dex in I/R treatment is lacking. The present study aimed to investigate the efficacy of Dex in mitigating neuronal damage, and to determine the possible mechanism of its effects in a rat model of cardiac arrest (CA). CA was induced in Sprague-Dawley rats by asphyxiation for 5 min. Following successful resuscitation, the surviving rats were randomly divided into two treatment groups; one group was intraperitoneally administered with Dex (D group), whereas the control group was treated with normal saline (N group). Critical parameters, including core temperature and blood pressure were monitored following return of spontaneous circulation (ROSC). Arterial blood samples were collected at 10 min after surgery (baseline) 30 and 120 min post-ROSC; and neurological deficit scores (NDS) of the rats were taken 12 or 24 h after ROSC prior to euthanasia. The hippocampal tissue was then removed for analysis by histology, electron microscopy and western blotting. Rats in the D group exhibited a lower core temperature and higher NDS scores compared with the N group (P<0.05). In addition, Dex injection resulted in reduced expression of apoptotic and autophagy-associated factors in the hippocampus (P<0.05). Dex treatment induced hypothermia and improved neurological function in rats after ROSC following resuscitation from CA by inhibiting neuronal apoptosis and reducing autophagy, which suggested that Dex may be a potential therapy option for patients with CA.

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Section: Discussionmentioning

confidence: 99%

Hypothermic properties of dexmedetomidine provide neuroprotection in rats following cerebral ischemia‑reperfusion injury

Liu

Zhu

et al. 2019

Exp Ther Med

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“…The effect of acute (25 μg/kg) or prolonged (25 μg/ kg 3 times daily for 2 or 4 days) exposure of dexmedetomidine with TH on uninjured neonatal Lewis rats was studied [59] . Prolonged dexmedetomidine treatment in neonatal rats was not associated with abnormal brain histology (there was no increased gliosis, macrophage activation, or apoptosis in either the hypothermic or control rats).…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia

Ezzati¹,

Kawano²,

Rocha‐Ferreira³

et al. 2017

Dev Neurosci

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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.

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“…In our model, prolonged sedation of mechanically-ventilated HIE animals was feasible using either morphine or DEX, an α2-adrenergic receptor agonist that is often used in neonatal intensive care units for sedation and pain management [28,29]. While sedation with DEX may be beneficial for neonates with HIE based on animal models [30–32], PK data in the setting of HIE are lacking.…”

Section: Discussionmentioning

confidence: 99%

Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates

McAdams¹,

McPherson²,

Kapur³

et al. 2017

Dev Neurosci

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Worldwide, hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. To better understand the mechanisms contributing to brain injury and improve outcomes in neonates with HIE, better preclinical animal models that mimic the clinical situation following birth asphyxia in term newborns are needed. In an effort to achieve this goal, we modified our nonhuman primate model of HIE induced by in utero umbilical cord occlusion (UCO) to include postnatal hypoxic episodes, in order to simulate apneic events in human neonates with HIE. We describe a cohort of 4 near-term fetal Macaca nemestrina that underwent 18 min of in utero UCO, followed by cesarean section delivery, resuscitation, and subsequent postnatal mechanical ventilation, with exposure to intermittent daily hypoxia (3 min, 8% O₂ 3-8 times daily for 3 days). After delivery, all animals demonstrated severe metabolic acidosis (pH 7 ± 0.12; mean ± SD) and low APGAR scores (<5 at 10 min of age). Three of 4 animals had both electrographic and clinical seizures. Serial blood samples were collected and plasma metabolites were determined by 2-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC × GC-TOFMS). The 4 UCO animals and a single nonasphyxiated animal (delivered by cesarean section but without exposure to UCO or prolonged sedation) underwent brain magnetic resonance imaging (MRI) on day 8 of life. Thalamic injury was present on MRI in 3 UCO animals, but not in the control animal. Following necropsy on day 8, brain histopathology revealed neuronal injury/loss and gliosis in portions of the ventrolateral thalamus in all 4 UCO, with 2 animals also demonstrating putamen/globus pallidus involvement. In addition, all 4 UCO animals demonstrated brain stem gliosis, with neuronal loss present in the midbrain, pons, and lateral medulla in 3 of 4 animals. Transmission electron microscopy imaging of the brain tissues was performed, which demonstrated ultrastructural white matter abnormalities, characterized by perinuclear vacuolation and axonal dilation, in 3 of 4 animals. Immunolabeling of Nogo-A, a negative regulator of neuronal growth, was not increased in the injured brains compared to 2 control animals. Using GC × GC-TOFMS, we identified metabolites previously recognized as potential biomarkers of perinatal asphyxia. The basal ganglia-thalamus-brain stem injury produced by UCO is consistent with the deep nuclear/brainstem injury pattern seen in human neonates after severe, abrupt hypoxic-ischemic insults. The UCO model permits timely detection of biomarkers associated with specific patterns of neonatal brain injury, and it may ultimately be useful for validating therapeutic strategies to treat neonatal HIE.

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Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats

Cited by 18 publications

References 27 publications

Hypothermic properties of dexmedetomidine provide neuroprotection in rats following cerebral ischemia‑reperfusion injury

Hypothermic properties of dexmedetomidine provide neuroprotection in rats following cerebral ischemia‑reperfusion injury

Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia

Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates

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