Safety of general anaesthetics on the developing brain: are we there yet?

Abstract

Thirty years ago, neurotoxicity induced by general anaesthetics in the developing brain of rodents was observed. In both laboratory-based and clinical studies, many conflicting results have been published over the years, with initial data confirming both histopathological and neurodevelopmental deleterious effects after exposure to general anaesthetics. In more recent years, animal studies using non-human primates and new human cohorts have identified some specific deleterious effects on neurocognition. A clearer pattern of neurotoxicity seems connected to exposure to repeated general anaesthesia. The biochemistry involved in this neurotoxicity has been explored, showing differential effects of anaesthetic drugs between the developing and developed brains. In this narrative review, we start with a comprehensive description of the initial concerning results that led to recommend that any non-essential surgery should be postponed after the age of 3 yr and that research into this subject should be stepped up. We then focus on the neurophysiology of the developing brain under general anaesthesia, explore the biochemistry of the observed neurotoxicity, before summarising the main scientific and clinical reports investigating this issue. We finally discuss the GAS trial, the importance of its results, and some potential limitations that should not undermine their clinical relevance. We finally suggest some key points that could be shared with parents, and a potential research path to investigate the biochemical effects of general anaesthesia, opening up perspectives to understand the neurocognitive effects of repetitive exposures, especially in at-risk children.

Keywords: anaesthetic drugs; apoptosis; biochemical mechanisms; duration of exposure; neuro-developmental risks; paediatric anaesthesia; single and multiple exposures.

Fig 1

Effect of an action potential on a glutamatergic synapse with principal targets of main anaesthetic drugs (NMDA and GABA_A receptors). A presynaptic depolarisation leads to an influx of calcium into the presynaptic neuron and the release of neurotransmitters into the synaptic cleft. Glutamate targets its postsynaptic receptors, leading to an influx of cations in the postsynaptic neuron and facilitates further depolarisation. NR2A subunit-containing receptors are synaptic receptors whereas NR2B subunit-containing receptors are extrasynaptic. The blockade of NR2B receptors has neuroprotective effects; however, in the developing brain, the associated blockade of NR2A receptors is deleterious. GABA targets its postsynaptic receptors leading to a chloride exchange. In the immature brain, the NKCC1 transporters are predominant, leading to a high intracellular concentration of chloride. The activation of the GABA receptor leads to the release of chloride ions into the synaptic cleft, favouring a further depolarisation. When the brain matures, the KCC2 transporters become more predominant than the NKCC1 transporters, leading to a lower intracellular concentration of chloride in the neuron. When the GABA_A receptor is activated, chloride is driven inwardly into the postsynaptic neuron. This favours a hyperpolarisation of the postsynaptic membrane; the activation of the GABA receptor inhibits the transmission of the influx. This phenomenon, when the GABA_A receptor changes from an excitatory to an inhibitory role, is called the GABA shift. NMDA antagonist anaesthetic drugs will block the NMDA receptor and reduce the depolarisation and thus excitation of the postsynaptic neuron after the arrival of the presynaptic depolarisation. GABA agonist drugs will favour depolarisation and excitation in the immature brain, but hyperpolarisation and inhibition in the more developed brain after the GABA shift. If the summation of the postsynaptic depolarisations and hyperpolarisations are sufficient, a new action potential will progress along the postsynaptic neuron. Specific biochemical cycles allow the recycling of glutamate and GABA by specific reuptake mechanisms. Glutamate can be transformed into the non-active glutamine in the astrocytes via the glutamine synthetase. Once sent back to the neurons, the glutamine can be transformed back to glutamate via the glutaminase. Glutamate can then be used directly or transformed further into GABA via the glutamate decarboxylase. GABA recaptured by the astrocytes can be changed into glutamate via the mitochondria. GABA, γ-amino-butyric acid; Gln, glutamine; Glu, glutamate; KCC2, K–Cl cotransporter isoform 2; NKCC1, Na–K–2Cl cotransporter isoform 1; NMDA, N-methyl-d-aspartate

Fig 2

Timeline of a selection of relevant publications and the Food and Drug Administration (FDA) recommendations (concerning the toxicity of general anaesthetic drugs on the developing brain). Studies involving rodents are in italic fonts in purple boxes, non-human primates in bold fonts in green boxes, and human studies in blue boxes. Numbers refer to the reference list of this review. Exclamation marks in red boxes correspond to the FDA's Anesthetic and Life Support Drugs Advisory Committee meetings with deliberations and recommendations on the issue of neurotoxicity of general anaesthesia on the developing brain.

Fig 3

(a) Number of samples necessary to reach the statistical objectives of the GAS trial, from left to right: 1. Blue: targeted sample size to take into account attrition (722 children), purple: sample size obtained via sample size calculation (598 children), and green: observed sample size in the GAS trial (447 children). 2. Red: missing data treated with imputations in the GAS trial. 3. Sample size required to take into account the interim analysis at 2 yr of age (multiple hypothesis testing with the Bonferroni correction). 4. Sample size required to take into account the observed attrition. 5. Sample sizes required to control the single event rate below given thresholds in cohorts detecting no events (for one analysis only). The absence of detection of events in the GAS trial shows that the estimated proportion of the population that would experience the event has an upper 95% confidence interval limit around 1%. (b) Sample size as a function of the expected difference and equivalence margin in an equivalence trial with a power of 90% and a type 1 error risk of 5%. The sample size estimated for the GAS trial is represented in blue.