Neurotoxicity of anesthetics in the developing brain of fetal rabbits and neuroprotective agents

There is increasing concern that exposure of the developing brain to anesthetics might be associated with impaired neurodevelopmental outcome in children undergoing surgery during their early life or even before birth. 

Preclinical experiments in rodents and non-human primates have consistently shown that virtually all commonly used anesthetics cause apoptotic neurodegeneration that result in persisting neurocognitive impairment.  In humans, several retrospective clinical studies did show that exposure to anesthesia before the age of 3-4 years is associated with developmental and behavioural disorders later in life, and even structural brain deficits, for example: lower school grades, lower IQ test scores, a higher risk for language disability at the age of 10 years and a higher incidence of developmental and behavioural disorders. Other clinical studies failed to demonstrate this association.

The developing brain might also be exposed to anesthesia even before birth, when pregnant women undergo surgery under anesthesia, either for maternal reasons or for fetal surgery. The former is not that rare; e.g. in UZ Leuven 189 non-obstetric procedures in 171 patients were done during the last 16 years, for a total of 35612 general anesthesia for other reasons. Operations on the fetus are often performed without general anesthesia, such as fetoscopic treatment of congenital diaphragmatic hernia, in which the fetus gets directly anesthesia and immobilization. However, other major procedures such as myelomeningocele repair require general anesthesia.  In 2017 and the first nine months of 2018, our center performed a total of 246 fetal procedures, of which 21 were prenatal myelomeningocele repairs under general anesthesia. Though not many, it is estimated that the indications for fetal surgery will continue to increase, especially if they can be done by minimal access.

In the literature, concerns are growing about potential disadvantageous effects of anesthetics on the brain of the human fetus. The fetus might even be more susceptible to adverse neurocognitive effects of anesthetics than young children.

In this PhD project, the fetal rabbit model will be used to investigate these neurotoxic effects on the fetal brain, both on short and on long term.  The brain damage will be evaluated using histology of the brain and neurocognitive testing.  The neurotoxic effects of 1 MAC sevoflurane without surgery will be compared with these of  the combination of 1 MAC sevoflurane with surgery.  Clinically, the most basic choice for maintenance consists of volatile anesthetics versus total intravenous anesthesia, therefore the effects on the fetal brain of sevoflurane will be compared with propofol maintenance anesthesia.  The noble gases Xenon, Argon and the intravenous agent dexmedetomidine exert potential neuroprotective properties by attenuating the apoptosis of neurons in the brain.  The effects of adding these agents to sevoflurane will be evaluated.