Effects of Anaesthetic Agents on the Developing Brain

OVERVIEW

• There is concern that sedatives and anaesthetic agents may have harmful effects on the developing brain

MECHANISMS OF NEUROTOXICTY

NMDA antagonists and GABA agonists both trigger neuronal apoptosis in experimental infant animals via both:

• receptor upregulation following blockade resulting in overexcitation
• decreased trophic stimulation

Effects are:

• dose and time dependent
• shown for all sedative/anaesthetic agents in animal studies
• worse with agents or combinations that work via both NMDA and GABA receptor
• maximal at the time of peak synaptogenesis (in humans this is 20-26 weeks gestation)

It is unclear whether these agents speed up normal apoptosis or trigger new events

EVIDENCE

• Direct evidence in humans lacking but some evidence that early exposure to anaesthesia may result in learning problems later in life
• There is also evidence that pain may promote neuronal apoptosis at least as severe as anaesthetic agents
• paradoxically, ketamine has also been found to have neuroprotective effects in some studies
• No current guidelines on what to do in light of the above findings

CLINICAL IMPLICATIONS

• uncertain
• direct evidence based on animal studies (mainly rat pups at high doses) and may not be applicable in the clinical setting
• Limiting exposure seems sensible
• consider limiting the use of  combinations of NMDA antagonists and GABA agonists
• overall the benefits of using these agents currently outweighs the risks

References and Links

• Sun, L. Early childhood general anaesthesia exposure and neurocognitive development. Br. J. Anaesth. (2010) 105 (suppl 1): i61-i68.doi: 10.1093/bja/aeq302 [Free Full Text]
• Rappaport B, Mellon RD, Simone A, Woodcock J. Defining safe use of anesthesia in children. N Engl J Med. 2011 Apr 14;364(15):1387-90. doi: 10.1056/NEJMp1102155. Epub 2011 Mar 9. PubMed PMID: 21388302.  [Free Full Text]
• Green SM, Coté CJ. Ketamine and neurotoxicity: clinical perspectives and implications for emergency medicine. Ann Emerg Med. 2009 Aug;54(2):181-90. doi: 10.1016/j.annemergmed.2008.10.003. Epub 2008 Nov 6. Review. PubMed PMID: 18990467.