Alternative technique or mitigating strategy for sevoflurane-induced neurodegeneration: a randomized controlled dose-escalation study of dexmedetomidine in neonatal rats

Lee, J.-R.; Lin, Erica P.; Hofacer, Rylon D.; Upton, Brian A.; Lee, S.Y.; Ewing, L.; Joseph, Bernadin; Loepke, Andreas W.

doi:10.1093/bja/aex219

Cited by 40 publications

(52 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, DEX has neuroprotective effects in the hypoxic‐ischemic neonatal brain (Ren et al, 2016; Zhou et al, 2018) and in an acute hyperoxic neonatal rat model (Endesfelder et al, 2017; Sifringer et al, 2015). In contrast, DEX does not ameliorate the injury induced by sevoflurane, and induces neural apoptosis in neonatal rats (Lee et al, 2017). Although many reports have shown that DEX is protective against anesthesia‐induced neurodegeneration, few reports have shown high mortality rates under high‐dose DEX with sevoflurane anesthesia in neonatal rats (Lee et al, 2017; Perez‐Zoghbi et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, DEX does not ameliorate the injury induced by sevoflurane, and induces neural apoptosis in neonatal rats (Lee et al, 2017). Although many reports have shown that DEX is protective against anesthesia‐induced neurodegeneration, few reports have shown high mortality rates under high‐dose DEX with sevoflurane anesthesia in neonatal rats (Lee et al, 2017; Perez‐Zoghbi et al, 2017). Thus, the efficiency of DEX against sevoflurane‐induced neurodegeneration is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dexmedetomidine reduced sevoflurane‐induced neurodegeneration and long‐term memory deficits in neonatal rats

Goyagi¹

2019

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

Exposure to sevoflurane and other inhalational anesthetics can induce neurodegeneration in the developing brain. Although dexmedetomidine (DEX) has provided neuroprotection against hypoxic ischemic injury, relatively little is known about whether it has the neuroprotective effects against anesthetic‐induced neurodegeneration. This study examined whether DEX improves the long‐term cognitive dysfunction observed after exposure of neonatal rats to 3% sevoflurane. Seven‐day‐old rats received intraperitoneal saline (DEX 0) or DEX (6.6, 12.5, 25 μg/kg) 30 min before exposure to 3% sevoflurane with 21% oxygen for 4 h (n = 10 per group). The pups in the control group received only DEX 25 μg/kg without anesthesia. The escape latency in the Morris water maze was significantly increased in the DEX 0 group compared with the sham and control group, and the escape latency, but not the swimming path length, was significantly shorter at post‐natal day 47 in the DEX 25 than in the DEX 0 group. The percent time spent in the quadrant was significantly decreased in the DEX 0 group compared with the sham and control group, and the percent time spent in the quadrant was significantly increased in the DEX 25 group compared with the DEX 0 groups. The freezing times of the DEX 0 and 6.6 groups were significantly decreased compared with those in the sham, control and DEX 25 groups. The number of NeuN‐positive cells in the CA1 region was significantly decreased in the DEX 0 and 6.6 groups compared with the sham, control and DEX 25 groups. These findings indicate pre‐treatment with DEX may improve long‐term cognitive function and ameliorate the neuronal degeneration induced by sevoflurane exposure in neonatal rats.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine reduced sevoflurane‐induced neurodegeneration and long‐term memory deficits in neonatal rats

Goyagi¹

2019

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…The total dose of dexmedetomidine per animal ranged from 2 to 525 µg/kg. In 17 studies, dexmedetomidine was administered in combination with another anesthetic agent, including ketamine (75 mg/kg intraperitoneal or intravenous infusion at 20 to 50 mg/kg/h for a period of 12 hours), propofol (intraperitoneal 30 mg/kg/d for a period of 7 days to 100 mg/kg and 1.2 mg/kg/min as continuous infusion for 6 hours), and inhalation anesthetic (isoflurane 0.75%‐2.0%, sevoflurane 2.5%‐4% up to 6 hours) …”

Section: Resultsmentioning

confidence: 99%

“…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%

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

Hoorn

Hoeks

Essink

et al. 2019

Pediatric Anesthesia

View full text Add to dashboard Cite

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.

show abstract

Alternative technique or mitigating strategy for sevoflurane-induced neurodegeneration: a randomized controlled dose-escalation study of dexmedetomidine in neonatal rats

Cited by 40 publications

References 46 publications

Dexmedetomidine reduced sevoflurane‐induced neurodegeneration and long‐term memory deficits in neonatal rats

Dexmedetomidine reduced sevoflurane‐induced neurodegeneration and long‐term memory deficits in neonatal rats

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

Contact Info

Product

Resources

About