Dexmedetomidine-Induced Neuroapoptosis Is Dependent on Its Cumulative Dose

Liu, Jia-Ren; Yuki, Koichi; Baek, Chong Wha; Han, Xiaohui; Soriano, Sulpicio G.

doi:10.1213/ane.0000000000001527

Cited by 44 publications

(43 citation statements)

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“…In a study by Pancaro et al [40] , dexmedetomidine at very high doses did result in neuroapoptosis in the sensory cortex and the thalamus. Liu et al [39] exposed neonatal rat pups to increasing cumulative doses of dexmedetomidine delivered as 5 intraperitoneal injections over 6 h, including 50, 125, and 250 μg/kg. The lower dose corre- There is no change in the level of neuroapoptosis from baseline.…”

Section: Effect Of Anesthesia On the Developing Brainmentioning

confidence: 99%

Effect of Anesthesia on the Developing Brain: Infant and Fetus

2017

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Section: Effect Of Anesthesia On the Developing Brainmentioning

confidence: 99%

Effect of Anesthesia on the Developing Brain: Infant and Fetus

2017

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“…The changes seen in preclinical studies are greatest with exposure to gamma‐aminobutyric acid (GABA) agonists and N‐methyl‐D‐aspartate (NMDA) antagonists such as volatile anesthetics (eg, sevoflurane), propofol, midazolam, ketamine, and nitrous oxide. There is less evidence for such changes with opioids (eg, remifentanil) and conflicting evidence with alpha‐2 agonists (eg, dexmedetomidine), with neurodegeneration occurring with doses larger than those used clinically . Furthermore, these preclinical studies showed a dose‐response relation: higher doses of anesthesia (ie, longer anesthesia) are associated with more morphologic and functional changes.…”

Section: Introductionmentioning

confidence: 99%

An open label pilot study of a dexmedetomidine‐remifentanil‐caudal anesthetic for infant lower abdominal/lower extremity surgery: The T REX pilot study

Szmuk

Andropoulos

McGowan

et al. 2018

Pediatric Anesthesia

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Summary Background Concern over potential neurotoxicity of anesthetics has led to growing interest in prospective clinical trials using potentially less toxic anesthetic regimens, especially for prolonged anesthesia in infants. Preclinical studies suggest that dexmedetomidine may have a reduced neurotoxic profile compared to other conventional anesthetic regimens; however, coadministration with either anesthetic drugs (eg, remifentanil) and/or regional blockade is required to achieve adequate anesthesia for surgery. The feasibility of this pharmacological approach is unknown. The aim of this study was to determine the feasibility of a remifentanil/dexmedetomidine/neuraxial block technique in infants scheduled for surgery lasting longer than 2 hours. Methods Sixty infants (age 1‐12 months) were enrolled at seven centers over 18 months. A caudal local anesthetic block was placed after induction of anesthesia with sevoflurane. Next, an infusion of dexmedetomidine and remifentanil commenced, and the sevoflurane was discontinued. Three different protocols with escalating doses of dexmedetomidine and remifentanil were used. Results One infant was excluded due to a protocol violation and consent was withdrawn prior to anesthesia in another. The caudal block was unsuccessful in two infants. Of the 56 infants who completed the protocol, 45 (80%) had at least one episode of hypertension (mean arterial pressure >80 mm Hg) and/or movement that required adjusting the anesthesia regimen. In the majority of these cases, the remifentanil and/or dexmedetomidine doses were increased although six infants required rescue 0.3% sevoflurane and one required a propofol bolus. Ten infants had at least one episode of mild hypotension (mean arterial pressure 40‐50 mm Hg) and four had at least one episode of moderate hypotension (mean arterial pressure <40 mm Hg). Conclusion A dexmedetomidine/remifentanil neuraxial anesthetic regimen was effective in 87.5% of infants. These findings can be used as a foundation for designing larger trials that assess alternative anesthetic regimens for anesthetic neurotoxicity in infants.

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“…Detection of caspase‐3 enables to identify neurons that are undergoing apoptotic degeneration. Less (or similar to control) caspase‐3 activity suggests less apoptosis and more caspase‐3 activity suggests more apoptosis after exposure to dexmedetomidine compared to control (Table ) . Two studies showed no caspase‐3 activity 6 hours after a single or repeated dose of dexmedetomidine varying between 1 and 75 μg/kg .…”

Section: Resultsmentioning

confidence: 96%

“…The effects of dexmedetomidine alone on caspase‐3 activity were investigated in eight studies (Tables and ) . Detection of caspase‐3 enables to identify neurons that are undergoing apoptotic degeneration.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, six other studies did show caspase‐3 activity after a total dose of dexmedetomidine ranging from 25 and 250 μg/kg. Of these six studies, four studies found the same amount of activity as in the control group and two studies found more activity than in the control group . Additionally, one study investigated synaptic cleft width using electromicroscopy; an increase in width was not shown …”

Section: Resultsmentioning

confidence: 99%

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A systematic review and narrative synthesis on the histological and neurobehavioral long‐term effects of dexmedetomidine

Hoorn

Hoeks

Essink

et al. 2019

Pediatric Anesthesia

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SummaryBackgroundRecent experimental studies suggest that currently used anesthetics have neurotoxic effects on young animals. Clinical studies are increasingly publishing about the effects of anesthesia on the long‐term outcome, providing contradictory results. The selective alpha‐2 adrenergic receptor agonist dexmedetomidine has been suggested as an alternative nontoxic sedative agent.AimsThe aim of this systematic review was to assess the potential neuroprotective and neurobehavioral effects of dexmedetomidine in young animals and children.MethodsSystematic searches separately for preclinical and clinical studies were performed in Medline Ovid and Embase on February 14, 2018.ResultsThe initial search found preclinical (n = 661) and clinical (n = 240) studies. A total of 20 preclinical studies were included. None of the clinical studies met the predefined eligibility criteria. Histologic injury by dexmedetomidine was evaluated in 11 studies, and was confirmed in three of these studies (caspase‐3 activation or apoptosis). Decrease of injury caused by another anesthetic was evaluated in 16 studies and confirmed in 13 of these. Neurobehavioral tests were performed in seven out of the 20 studies. Of these seven rodent studies, three studies tested the effects of dexmedetomidine alone on neurobehavioral outcome in animals (younger than P21). All three studies found no negative effect of dexmedetomidine on the outcome. In six studies, outcome was evaluated when dexmedetomidine was administered following another anesthetic. Dexmedetomidine was found to lessen the negative effects of the anesthetic.ConclusionIn animals, dexmedetomidine was found not to induce histologic injury and to show a beneficial effect when administered with another anesthetic. No clinical results on the long‐term effects in children have been identified yet.

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Dexmedetomidine-Induced Neuroapoptosis Is Dependent on Its Cumulative Dose

Cited by 44 publications

References 41 publications

Effect of Anesthesia on the Developing Brain: Infant and Fetus

Effect of Anesthesia on the Developing Brain: Infant and Fetus

An open label pilot study of a dexmedetomidine‐remifentanil‐caudal anesthetic for infant lower abdominal/lower extremity surgery: The T REX pilot study

A systematic review and narrative synthesis on the histological and neurobehavioral long‐term effects of dexmedetomidine

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