2. Pediatric Anesthetic Neurotoxicity
An Update
Phil G Morgan, MD
University of Washington

3. Disclosures
Sadly, none

4. What do we tell parents?

5. Developmental Neurotoxicity
Animal Studies (How we got worried)
Rodents
Primates
Others
Clinical Studies (Does it actually matter?)
Retrospective
Prospective
Obstetric Studies
Mechanisms/Therapies
2015, what we tell parents
FDA gets involved

6. Anesthesia
the safest time from womb to tomb!

7. Nitrous oxide, versed, isoflurane (oxygen) Posterior cingulate cortex
Jevtovic-Todorovic, J Neurosci (2003)
Posterior cingulate cortex
Subiculum

8. Nitrous oxide, versed, isoflurane (oxygen)
Thalamus
Jevtovic-Todorovic, J Neurosci (2003)

9. Jevtovic-Todorovic,
J Neurosci (2003)

10. Exposed Exposed Unexposed Unexposed
Jevtovic-Todorovic, J Neurosci (2003)

12. Fold Increase Apoptosis
Post Natal Day
Yon et al., Neurosci, 2005

13. Post Natal Day
Fold Increase Apoptosis
Yon et al., Neurosci, 2005

14. Apoptosis, Thalamus Anesthetic No Anesthetic Yon et al,
Neurosci (2005)

15. Yon et al, Neurosci (2005)

16. Guinea Pigs
in utero
Rizzi et al, Brain Pathol (2008)

17. Caspase-3 Staining
Rizzi et al, Brain Pathol (2008)

18. Neuronal Density
Rizzi et al, Brain Pathol (2008)

21. What about primates?

22. Rhesus macaques were studied at a fetal age of G120 (corresponds in brain age to a late third-trimester human fetus), or at a neonatal age of P6 (corresponds to brain age of a 4–6-month-old human infant).
Ansgar Brambrink

23. Fetal, EGA 120; PN6: 5 hours, propofol
Creeley et al., BJA 2013, 110, 29.

25. Creeley et al., BJA 2013, 110, 29.
Brambrink et al., Anesth 2010, 112, 834

26. Primates (multiple exposures)
Rhesus monkeys
3 4-h exposures
5 months
N=8/9
Raper J, et al.
Anesth 2015

28. Nice, but what about humans

29. 2009

30. 2009

31. 2009
1153 monozygotic twins, single exposure before age 3 years
Time of exposure not available
Standardized achievement tests

32. 2008

33. 2011
Twins
DiMaggio et al., A&A, 2011

35. All Studies
Lin EP et al, 2017

36. All Studies
Lin EP et al, 2017

37. Enter the GAS study
And the T-Rex study
And the Mask study
And the UCSF study
And the PANDA study

38. GAS Study

39. Davidson,
Lancet, 2016

40. GAS Study
Davidson,
Lancet, 2016

41. Davidson,
Lancet, 2016

42. GAS Study
Strong evidence that exposure of just under an hour to a sevoflurane GA in infancy does not increase the risk of adverse neurodevelopmental outcome at two years of age.
This is the strongest clinical evidence to date that just under an hour of sevoflurane GA in infancy does not result in significant neurotoxicity.
Davidson, 2016

43. MASK Study
Mayo Clinic combination of retrospective and prospective studies.
Preliminary findings indicate that similar to their prior published study, multiple anesthetic exposures, but not a single exposure, are associated with an increased frequency of learning disability and attention deficit hyperactivity disorder.

44. UCSF Study
28 infants (<1 year of age) exposed to volatile anesthetic for longer than 2 hours exhibited a deficit in recognition memory compared with matched controls assessed between the ages of 6 and 11 years

45. PANDA Study
The PANDA study was an ambidirectional, sibling-matched cohort study examining neurodevelopmental
outcomes at ages 8 to 15 years in ASA 1 or 2 patients who had inguinal hernia surgery before the age of 3 against an unexposed sibling.
A bias toward higher socioeconomic status among test
participant families.
Mostly males; average length of anesthetic exposure was 84 minutes.

46. PANDA Study
Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood.

47. Anesthetic Neurotoxicity
Fetal

48. Guinea Pigs
in utero
Rizzi et al, Brain Pathol (2008)

52. CUMC Study Maternal exposure
Pregnant women between the ages of 18 and 45 with normal pregnancies between 2005 and 2010.
Infants exposed to maternal regional anesthesia had greater brain volumes in bilateral frontal and right occipital lobes than infants who had no maternal exposure.

53. Mechanisms?

55. Wu J et al., Anesth , 624

56. Na et al.,
Neurotox Teratol
2017

57. Conclusions I Multiple mechanisms proposed
May be possible to mitigate the effects

58. What do we tell parents?
2015
Discuss with parents and other caretakers the risks and benefits of procedures requiring anesthetics or sedatives, as well as the known health risks of not treating certain conditions.
Recognize that current anesthetics and sedatives are necessary for infants and children who require surgery or other painful and stressful procedures

59. So, What do we tell parents?
A survey by the
Pediatric Anesthesiology
Leadership Consortium and Directors
2015

66. FDA
12/14/2016
The FDA is warning that repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.

67. So, What do we tell parents?
Health care professionals should balance the benefits of appropriate anesthesia in young children and pregnant women against the potential risks, especially for procedures that may last longer than 3 hours or if multiple procedures are required in children under 3 years. Discuss with parents, caregivers, and pregnant women the benefits, risks, and appropriate timing of surgery or procedures requiring anesthetic and sedation drugs.

68. Conclusions II
Some anesthetics are neurotoxic in animals but exposure must be significant
Effect is developmentally restricted and time dependent
There is strongly suggestive data supporting some neurotoxicity in humans with multiple (or prolonged) exposures
Should not avoid necessary procedures

69. Thank you