Impact of anaesthetics and surgery on neurodevelopment: an update

Abstract

Accumulating preclinical and clinical evidence suggests the possibility of neurotoxicity from neonatal exposure to general anaesthetics. Here, we review the weight of the evidence from both human and animal studies and discuss the putative mechanisms of injury and options for protective strategies. Our review identified 55 rodent studies, seven primate studies, and nine clinical studies of interest. While the preclinical data consistently demonstrate robust apoptosis in the nervous system after anaesthetic exposure, only a few studies have performed cognitive follow-up. Nonetheless, the emerging evidence that the primate brain is vulnerable to anaesthetic-induced apoptosis is of concern. The impact of surgery on anaesthetic-induced brain injury has not been adequately addressed yet. The clinical data, comprising largely retrospective cohort database analyses, are inconclusive, in part due to confounding variables inherent in these observational epidemiological approaches. This places even greater emphasis on prospective approaches to this problem, such as the ongoing GAS trial and PANDA study.

Keywords: brain, anaesthesia, molecular effects; nerve, damage (postoperative); nerve, neurotransmitters; nerve, regeneration.

Fig 1

Proposed mechanisms of anaesthetic-induced neurodegeneration in the newborn involving the intrinsic and extrinsic apoptotic cell death pathways. Suppression of synaptic signalling is proposed to attenuate neurotrophic survival signals leading to activation of the intrinsic apoptotic cascade. This involves mobilization of the pro-apopotic protein Bax, which in turn induces cytochrome c (Cyto. C) release from mitochondria, activation of caspase-9, and subsequent induction of caspase 3 cleavage to provoke apoptosis. Anti-apoptotic effectors such as Bcl oppose this pathway. The extrinsic pathway is stimulated by ligands binding to death receptors located on the cell membrane that cause caspase 8 activation, which then cleaves and activates caspase 3. These ligands include cytokines such as TNF-α.