Pediatric Anesthetic Neurotoxicity An Update

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 --- 1981 the safest time from womb to tomb!

7. Nitrous oxide, versed, isoflurane (oxygen) 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. Fold Increase Apoptosis Post Natal Day 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 Scored @ 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)