Neurotoxicity of Anaesthesia

The relevance to clinical practice of recent animal work demonstrating neurotoxicty of anaesthetics to developing brain.

23rd June 2008

Providing safe and effective anaesthesia for infants during surgery is a priority of paediatric anaesthetists. Over the last decade there have been great advances in techniques, drugs and monitoring. Recently concern has arisen over potential anaesthetic neurotoxicity to the developing brain is. The issue stems from the recent publication of several studies in the animal model which demonstrated accelerated neuronal apoptosis and long term behavioural changes in rodents exposed to anaesthesia in the neonatal period. The injury is likely to involve both NMDA and GABA receptors though the exact mechanism of injury remains unknown. Recent data in primates have also found that prolonged exposure to ketamine is associated with neuronal apoptosis. The relevance of these findings to human clinical practice is very unclear. When translating animal data, significant questions arise in terms of dose, duration, timing and the human potential for recovery.

Environmental or drug effects on the developing foetus or infant is not new concept, and there is increasing community and parent awareness of these issues. The capacity for the anaesthesia community to reassure parents is limited by the fact that many anaesthetic agents are not licensed for children. The reasons for this are complex, but in part must relate to lack of safety or toxicity data for children or infants.

When considering the potential neurotoxicity of anaesthesia it is important to also recognize the well described risks associated with inadequate anaesthesia in this age group. There is increasingly good evidence that unrelieved pain causes prolonged physiological and behavioural change in human neonates.

Over the last decade advances in anaesthetic and intensive care have made surgery in the neonate considerably safer. Although it is well recognized that there are still risks associated with surgery in human neonates, there is no human clinical evidence that suggests the anaesthesia per se adds to that risk. Indeed there is evidence to suggest adequate anaesthesia and analgesia may reduce that risk. In short potential neurotoxicity associated with some anaesthetic agents in the animal model must be weighed against known adverse outcome with inadequate anaesthesia in humans.

It should also be noted that surgery in neonates and infants is rarely elective. In the majority of cases risks associated with delaying surgery are likely to far out weigh any theoretical or potential risks of anaesthesia toxicity. Nevertheless the anaesthesia community recognizes that there is an urgent need to determine which anaesthesia techniques can provide the best outcome for infants and neonates both in terms of potential toxicity and many other aspects of anaesthesia management.

Several research programs are actively addressing the issue of neurotoxicity and, as recently acknowledged by the American Society for Anesthesiologists, it is appropriate that this should be a priority for anaesthesia research. In Australia, the Australian and New Zealand College of Anaesthetists and the National Health and Medical Research Council have already taken the lead and allocated considerable funds for clinical research to address this issue.

In conclusion, we would echo the recommendations of other overseas Anaesthesia Societies and the US Food and Drug Administration in stating that the evidence from animal models does not warrant any substantial change in clinical practice at this stage. While it remains prudent to avoid elective surgery in infants the current evidence suggests a very high degree of safety for anaesthesia in this age group, and that inadequate anaesthesia and analgesia, or delay in non-elective surgery are all associated with more tangible risks.

Andrew Davidson, Royal Children's Hospital, Victoria
Jonathon De Lima, The Children's Hospital at Westmead, NSW