Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats

Br J Anaesth. 2021 May;126(5):1009-1021. doi: 10.1016/j.bja.2021.01.033. Epub 2021 Mar 12.


Background: Structural brain abnormalities in newborn animals after prolonged exposure to all routinely used general anaesthetics have raised substantial concerns for similar effects occurring in millions of children undergoing surgeries annually. Combining a general anaesthetic with non-injurious sedatives may provide a safer anaesthetic technique. We tested dexmedetomidine as a mitigating therapy in a sevoflurane dose-sparing approach.

Methods: Neonatal rats were randomised to 6 h of sevoflurane 2.5%, sevoflurane 1% with or without three injections of dexmedetomidine every 2 h (resulting in 2.5, 5, 10, 25, 37.5, or 50 μg kg-1 h-1), or fasting in room air. Heart rate, oxygen saturation, level of hypnosis, and response to pain were measured during exposure. Neuronal cell death was quantified histologically after exposure.

Results: Sevoflurane at 2.5% was more injurious than at 1% in the hippocampal cornu ammonis (CA)1 and CA2/3 subfields; ventral posterior and lateral dorsal thalamic nuclei; prefrontal, retrosplenial, and somatosensory cortices; and subiculum. Although sevoflurane 1% did not provide complete anaesthesia, supplementation with dexmedetomidine dose dependently increased depth of anaesthesia and diminished responses to pain. The combination of sevoflurane 1% and dexmedetomidine did not reliably reduce neuronal apoptosis relative to an equianaesthetic dose of sevoflurane 2.5%.

Conclusions: A sub-anaesthetic dose of sevoflurane combined with dexmedetomidine achieved a level of anaesthesia comparable with that of sevoflurane 2.5%. Similar levels of anaesthesia caused comparable programmed cell death in several developing brain regions. Depth of anaesthesia may be an important factor when comparing the neurotoxic effects of different anaesthetic regimens.

Keywords: apoptosis; brain injury; dexmedetomidine; neuroprotection; neurotoxicity; sevoflurane; volatile anaesthetics.

MeSH terms

  • Anesthetics, Inhalation / administration & dosage
  • Anesthetics, Inhalation / toxicity*
  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Brain / drug effects
  • Brain / physiopathology
  • Cell Death / drug effects
  • Dexmedetomidine / administration & dosage
  • Dexmedetomidine / pharmacology*
  • Dose-Response Relationship, Drug
  • Hypnotics and Sedatives / administration & dosage
  • Hypnotics and Sedatives / pharmacology*
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology
  • Neurotoxicity Syndromes / etiology
  • Neurotoxicity Syndromes / prevention & control
  • Rats
  • Rats, Wistar
  • Sevoflurane / administration & dosage
  • Sevoflurane / toxicity*


  • Anesthetics, Inhalation
  • Hypnotics and Sedatives
  • Neuroprotective Agents
  • Sevoflurane
  • Dexmedetomidine