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Mechanisms of neurotoxicity of anaesthetic agents
- 1. Mechanisms of neurotoxicity of anaesthetic agents Andrew Davidson Royal Children’s Hospital, Melbourne
- 2. Outline • Why we need to understand mechanisms • Key principles in neuronal development and neurotoxicity • What neurotoxic effects have been described • Possible mechanisms
- 3. Anaesthetic exposure Clinical effect
- 4. Bradford Hill’s guidelines for causation • Strength of association • Consistency • Specificity • Temporality • Biologic gradient • Plausibility • Coherence • Experiment • Analogy
- 5. Bradford Hill’s guidelines for causation • Strength of association • Consistency • Specificity • Temporality • Biologic gradient • Plausibility • Coherence • Experiment • Analogy
- 6. Anaesthetic exposure Clinical effect Clinical studies Biological variability in population studies Effects are usually small with considerable degrees of uncertainty ?
- 7. Half the Anaesthetic exposure Clinical effect ? Clinical studies Clinical studies constrained by defining the exposure
- 8. Anaesthetic exposure Different Clinical effect ? Clinical studies Clinical studies constrained by defining the effect
- 9. Anaesthetic exposure Clinical effect ? Clinical studies Different population Clinical studies constrained by defining the population
- 10. Bradford Hill’s guidelines for causation • Strength of association • Consistency • Specificity • Temporality • Biologic gradient • Plausibility • Coherence • Experiment • Analogy
- 11. Anaesthetic exposure Clinical effect A B C D E Mechanisms Tighter control of experimental conditions – greater certainty in each prediction Deductive logic to predict the phenomenon
- 12. Clinical effect A B C D E Half the Anaesthetic exposure Mechanisms
- 13. Anaesthetic exposure Different Clinical effect A B C D E Mechanisms
- 14. Anaesthetic exposure Clinical effect A B C D E Mechanisms Different population
- 15. Anaesthetic exposure Clinical effect A B C D E Therapy Mechanisms
- 16. Anaesthetic exposure Clinical effect A B C D E Population focus Patient focus Politics and culture will influence the preferred approach
- 17. Anaesthetic exposure Clinical effect A B C D E Problem with mechanisms More flexibility, but only as strong as the weakest link
- 18. Anaesthetic exposure Clinical effect A B C D E Problem with mechanisms G H F J I Never that simple….
- 19. Bradford Hill’s guidelines for causation • Strength of association • Consistency • Specificity • Temporality • Biologic gradient • Plausibility • Coherence • Experiment • Analogy
- 20. Key principles in neurotoxicty and brain development
- 21. Normal development • Stages of normal development • Neurogenesis & proliferation • Migration • Differentiation • Synapse formation • Myelination • Receptor function changes during development • Both number of neurons and number of synapse halves during development • Neural density greatest in foetus; trimmed in neonatal period and infancy • Number of synapses greatest in infancy; trimmed during later childhood
- 22. Normal development • GABA & NMDA receptors directly involved in • Cell proliferation • Migration • Cell survival • Dendritic maturation • GABA & NMDA receptors indirectly involved in balance of activity and hence generation of trophic factors, differentiation and growth
- 23. Effects seen in vitro
- 24. • Apoptosis • Altered neurogenesis • Changes in dendritic architecture • Mitochondrial degeneration • Aberrant cell cycle re-entry • Destabilisation of cyto skeleton
- 25. Apoptosis • Ketamine, isoflurane, midazolam, propofol, sevoflurane • Dose effect • Combination worse • Window of vulnerability day 7 in a rat • Also seen in monkey, guinea pig, mouse, lamb and pig • Some evidence for long term neurobehavioural effect
- 26. • 7-day old rat Ikonomidou et al. Blockade of NMDA Receptors and Apoptotic Neurodegeneration in the Developing Brain. Science 1999; 283, 5398 Same effect with Ketamine (20 mg/kg x7) Saline Treatment MK-801 (0.5 mg/kg)
- 27. • Day 6 monkeys • 5hrs isoflurane
- 28. • Day 6 monkeys • 5hrs isoflurane
- 30. Neurogenesis • Isoflurane and sevoflurane • Hippocampal neural precursor cells • No death of neural progenitors • Decrease neuronal proliferation
- 31. Dendritic architecture • First two weeks: decrease in synaptic and dendritic spine density • Older: increase in number of dendrites
- 32. • Day 15 rat pups • 5hrs anaesthesia: propofol, ketamine, midazolam • Increased dendritic spine density Control KetaminePropofol
- 33. • Day 16 rat pups • Isoflurane, desflurane, sevoflurane • 30, 60, 120 minutes • No cell death • Increased spine density Control 120 min60 min30 min
- 34. Spine density and age at exposure
- 35. • Isoflurane, nitrous oxide and midazolam • Mitochondrial degenration • Persistent effect Degeneration of mitochondria
- 36. • Ketamine induces aberrant cell cycle reentry, leading to apoptotic cell death Abnormal re entry into cell cycle
- 37. • In vitro culture 4 hrs isoflurane • Isoflurane results in RhoA activation, cytoskeletal depolymerization, and apoptosis • Inhibition of RhoA activation or prevention of downstream actin depolymerization significantly attenuated isoflurane-mediated neurotoxicity Destabilization of cytoskeleton
- 38. • Apoptosis • Neurogenesis • Dendritic architecture • Mitochondrial degeneration • Aberrant cell cycle re-entry • Destabilisation of cyto skeleton • Linked? • “Downstream” effects? • Underlying single mechanism? • Mechanism must be related to development
- 40. • GABA activation leads to neuronal quiescence and because neuronal development is activity dependent, this leads to cell death • Upregulation of NMDA receptors during blockade leads to subsequent excitotoxic cell death
- 41. Up regulation of NMDA • Up regulation during blockade, exicitotoxic upon withdrawal • BUT • Apoptosis occurs during delivery • Occurs with agents that have no NMDA activity – e.g. propofol • Some NMDA antagonists are protective – e.g. xenon
- 42. • S ketamine and racemic ketamine have same toxicity for same dose on mg/kg • BUT, High concentration with direct application to tumour cells, not neurons
- 43. Use it or lose it • During development we have an oversupply of neurons and synapses • More than half degenerate via apoptosis • Inactivity triggers cell death via a loss of trophic factors • Synapse and dendritic development are also activity dependent
- 47. Abnormal neuroinhibition • All volatile agents probably have similar effects at equivalent MAC; implying a pharmacodynamic effect • BUT, • GABA is excitatory in developing neurons • Xenon and dexmedetomidine cause inhibition but no apoptosis • GABA antagonists do not reverse the toxic effect • Tetrodotoxin does not change dendritic morphology
- 50. • Tetrodotoxin blocks GABA and NMDA and has no effect on the developing neuron
- 51. Abnormal neuroinhibition • Cannot be directly related to GABA or NMDA • May be related to the final “balance of activity” • But cannot explain all observations • Perhaps the uncertainty in neurotoxic mechanism is not unexpected as we don’t really understand the mechanism for anaesthetic action! • And general anaesthetics are “dirty” drugs that act on multiple receptors
- 52. Summary • There are multiple effects • Likely to be multiple mechanisms • Mechanisms are still poorly understood • Essential that more mechanistic research is done • A long way from translation of mechanistic research to human clinical practice
- 53. Anaesthetic exposure Clinical effect A B C D E G H F J I ? ? ? ? ? ?