1. Clinical Perspective: Implications of Non-Clinical Findings of Anesthetic-Induced Neurotoxicity
Sulpicio G. Soriano, M.D., F.A.A.P.
Associate Professor of Anaesthesia, Harvard Medical School
Senior Associate in Anesthesia, Children’s Hospital Boston

2. “...for there is nothing either good or bad, but thinking makes it so...”
Hamlet, Act 2, Scene 2, Shakespeare

4. Liverpool Technique
Nitrous oxide
Muscle relaxant
Hyperventilation

5. Liverpool Technique Nitrous oxide Muscle relaxant Chemical paralysis
Hyperventilation

6. Randomised Trial Of Fentanyl Anaesthesia In Preterm Babies Undergoing Surgery Anand, Sippell and Aynsley-Green Lancet 1987
Premature neonates for ligation of PDA
Randomized
Nitrous oxide and curare with fentanyl (10 μg/kg)
Nitrous oxide and curare
No fentanyl group
Metabolic acidosis
Hyperglycemia
Post operative
Ventilator requirements
Bradycardia
Intraventricular hemorrhages
hypotension

7. Pain And Its Effects In The Human Neonate And Fetus Anand KJ, Hickey PR, N Engl J Med. 1987

8. Perioperative Stress in Newborn in Cardiac Surgery Anand KJ, Hansen DD, Hickey PR, Anesthesiol. 1990

9. Blockade of NMDA Receptors Neurodegeneration in the
and Apoptotic
Neurodegeneration in the
Developing Brain
Chrysanthy Ikonomidou,* Friederike Bosch, Michael Miksa,
Petra Bittigau, Jessica VÖckler, Krikor Dikranian,
Tanya I. Tenkova, Vanya Stefovska, Lechoslaw Turski,
John W. Olney
Programmed cell death (apoptosis) occurs during normal development of the central nervous system. However, the mechanisms that determine which neurons will succumb to apoptosis are poorly understood. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors for only a few hours during late fetal or early neonatal life triggered widespread apoptotic neurodegeneration in the developing rat brain, suggesting that the excitatory neurotransmitter glutamate, acting at NMDA receptors, controls neuronal survival. These findings may have relevance to human neurodevelopmental disorders involving prenatal (drug-abusing mothers) or postnatal (pediatric anesthesia) exposure to drugs that block NMDA receptors.

10. Early Exposure to Common Anesthetic Agents Causes Widespread Neurodegeneration in the Developing Rat Brain and Persistent Learning Deficits Jevtovic-Todorovic et al, J Neurosci, 2003
Triple cocktail (P7 rat pups)
Midazolam
Isoflurane
Nitrous oxide
Histological changes
neurodegeneration
Functional changes
Morris water maze
Radial arm maze

12. Human Babies are not Large Rat Pups
Human Babies are not Large Rat Pups!! Problems with Rodent Experimental Paradigm

13. Human Babies are not Large Rat Pups
Human Babies are not Large Rat Pups!! Problems with Rodent Experimental Paradigm
Duration of exposure to drugs

14. Effect of Continuous Dosing of Ketamine on the Developing Brain Hayashi H, et al Paediat Anaesth 2003

15. Human Babies are not Large Rat Pups
Human Babies are not Large Rat Pups!! Problems with Rodent Experimental Paradigm
Duration of exposure to drugs
7 rat days  27 human months
6 hour  1 month

16. Human Babies are not Large Rat Pups
Human Babies are not Large Rat Pups!! Problems with Rodent Experimental Paradigm
Duration of exposure to drugs
Lack of precise physiological monitoring

17. Physiological Monitoring

18. Human Babies are not Large Rat Pups
Human Babies are not Large Rat Pups!! Problems with Rodent Experimental Paradigm
Duration of exposure to drugs
Lack of precise physiological monitoring
End-organ perfusion
Varying anesthetic depth
MAC values
Target-controlled infusions

19. Human Babies are not Large Rat Pups
Human Babies are not Large Rat Pups!! Problems with Rodent Experimental Paradigm
Duration of exposure to drugs
Lack of precise physiological monitoring
Interspecies variation

20. Human Babies are not Large Rat Pups
Human Babies are not Large Rat Pups!! Problems with Rodent Experimental Paradigm
Duration of exposure to drugs
Lack of precise physiological monitoring
Interspecies variation
Dose-response
Drug metabolism
Peak susceptibility

21. Periods of Rapid Synaptogenesis Dobbing and Sands Early Human Develop 1979

22. Rapid Brain Growth (after Dobbing)
rat 7 14 7
days
human 3 6 6 12 18 24
months
birth
conception

23. Rapid Brain Growth (after Dobbing)
rat 7 14 7
days
human 3 6 6 12 18 24
months
birth
conception

24. Rapid Brain Growth (after Dobbing)
rat 7 14 7
days
human 3 6 6 12 18 24
months
birth
conception

25. Human Babies are not Large Rat Pups
Human Babies are not Large Rat Pups!! Problems with Rodent Experimental Paradigm
Duration of exposure to drugs
Lack of precise physiological monitoring
Interspecies variation
Anesthesia with and without painful stimulation

26. Altered Nociceptive Neuronal Circuits After Neonatal Peripheral Inflammation Ruda MA, et al. Science 2000
Freund’s adjuvant injected into left hind paw
P 0, 1, 3, 7, 14 rat pups
Increased spinal nociceptive spinal circuits
Behavioral changes
Decreased latency in treated paw
Increased pain scores

27. Human Babies are not Large Rat Pups
Human Babies are not Large Rat Pups!! Problems with Rodent Experimental Paradigm
Duration of exposure to drugs
Lack of precise physiological monitoring
Interspecies variation
Anesthesia with and without painful stimulation
Neuroprotective effects of anesthetics

28. Is Anesthesia Harmful to the Neonate’s Brain?

29. Established Neurotoxins
Ethanol
Fetal Alcohol Syndrome

30. Established Neurotoxins
Ethanol
Antiepileptic drugs
phenytoin
phenobarbital
benzodiazepine
valproic acid
Fetal Alcohol Syndrome
Fetal Malformations
Developmental delay
Microcephaly

31. Established Neurotoxins
Ethanol
Antiepileptic drugs
phenytoin
phenobarbital
benzodiazepine
valproic acid
Anesthetic Drugs
ketamine
isoflurane
propofol
Fetal Alcohol Syndrome
Fetal Malformations
Developmental delay
Microcephaly ?

32. Neonatal Anesthesia/Surgery
Highest morbidity and mortality rates Cohen M A&A (1989)
Emergent
Congenital anomalies
Pre-existing brain injury
Changing physiology
Transitional circulation
Cardiorespiratory instability

33. Outcome of Neonatal Surgery
Cohort studies- poor neurodevelopmental outcome
Laprotomy, Chacko J, Pediat Surg Int (1999)
Esophageal Atresia, Bouman NH, J PEdiatr Surg (1999)
Patent Ductus Arteriosus,. J Paediatr Child Health (1996), J Pediatr (2007)

34. Outcome of Neonatal Surgery
Cohort studies- poor neurodevelopmental outcome
Laprotomy, Chacko J, Pediat Surg Int (1999)
Esophageal Atresia, Bouman NH, J PEdiatr Surg (1999)
Patent Ductus Arteriosus,. J Paediatr Child Health (1996), J Pediatr (2007)
Confounding variables
Prematurity
Coexisting malformations
Genetic syndromes
Sepsis
Surgical and intensive care management
Anesthetic drugs

35. Is Anesthesia Harmful to the Neonate’s Brain?
Boston Circulatory Arrest Study
Newburger et al
single-center, prospective, randomized trial of 171 infants who underwent an arterial switch operation for D-transposition of the great arteries
Standardized anesthetic and analgesia
Fentanyl-based anesthetic
Fentanyl infusions for sedation
Postoperative Seizures
Neurodevelopmental Assessment

36. Boston Circulatory Arrest Trial

37. Boston Circulatory Arrest Trial

38. Initiatives by the Pediatric Anesthesia Community
Neonatal Drug Development Initiative Workshops
Society for Pediatric Anesthesia
Awareness-educational programs
Registry and complications database
American Society of Anesthesiology
Increased awareness
Funding investigators
Multi-center Randomized Control Trial

39. Summary Proceedings From the Neonatal Pain-Control Group, Neonatal Drug Development Initiative Anand et al, Pediatrics 2006
Determination of the effects of analgesic drug exposure on long-term global developmental outcomes
neurotransmitter systems
state regulation (arousal, attention, behavioral control, orientation),
executive function (active working memory, inhibitory control, planning and capacity to shift strategies)
organization (temporal-sequential ordering)
memory, learning, consolidation, language, and neuromotor skills

40. GAS Study Multi-national, multi-center collaborative group
Andrew Davidson, Melbourne, Australia
Mary Ellen McCann, Boston, USA
Neil Morton, Glasgow, Scotland
Randomized controlled equivalence trial
Inguinal hernia in infants
Spinal (bupivacaine) versus general (sevoflurane) anesthesia
Neurodevelopmental assessments at 2 and 5 years

41. GAS Study Multi-national, multi-center collaborative group
Andrew Davidson, Melbourne, Australia
Mary Ellen McCann, Boston, USA
Neil Morton, Glasgow, Scotland
Randomized controlled equivalence trial
Inguinal hernia in infants
Spinal (bupivacaine) versus general (sevoflurane) anesthesia
Neurodevelopmental assessments at 2 and 5 years
Timeline
2007
2008
2009
2010
2011
2012
2013
2014
Recruit x
Yr 2 assessment
Yr 5 assessment

43. “...for there is nothing either good or bad, but thinking makes it so...”
Alleviation of pain and suffering
Blunting stress response

44. “...for there is nothing either good or bad, but thinking makes it so...”
Alleviation of pain and suffering
Blunting stress response
Irrefutable laboratory data
Long-term effects in humans ?

45. “...for there is nothing either good or bad, but thinking makes it so...”
Alleviation of pain and suffering
Blunting stress response
Irrefutable laboratory data
Long-term effects in humans ?
No other alternative