Clinical Perspective: Implications of NonClinical Findings of AnestheticInduced Neurotoxicity

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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, Childrens
  Hospital Boston
• sulpicio.soriano_at_childrens.harvard.edu

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

• Nitrous oxide
• Muscle relaxant
• Hyperventilation

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Liverpool Technique

• Nitrous oxide
• Muscle relaxant Chemical paralysis
• Hyperventilation

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Randomised Trial Of Fentanyl Anaesthesia In
Preterm Babies Undergoing SurgeryAnand, 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

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Pain And Its Effects In The Human Neonate And
FetusAnand KJ, Hickey PR, N Engl J Med. 1987
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Perioperative Stress in Newborn in Cardiac
SurgeryAnand KJ, Hansen DD, Hickey PR,
Anesthesiol. 1990
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Blockade of NMDA Receptors and Apoptotic Neurodege
neration 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.
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Early Exposure to Common Anesthetic Agents
CausesWidespread Neurodegeneration in the
Developing Rat Brainand Persistent Learning
DeficitsJevtovic-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

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

• Duration of exposure to drugs

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Effect of Continuous Dosing of Ketamine on the
Developing Brain Hayashi H, et al Paediat
Anaesth 2003
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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
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Human Babies are not Large Rat Pups!!Problems
with Rodent Experimental Paradigm

• Duration of exposure to drugs
• Lack of precise physiological monitoring

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Physiological Monitoring
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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

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

• Duration of exposure to drugs
• Lack of precise physiological monitoring
• Interspecies variation

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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

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Periods of Rapid SynaptogenesisDobbing and Sands
Early Human Develop 1979
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Rapid Brain Growth (after Dobbing)
rat
7
14
7
days
human
months
3
6
24
birth
conception
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Rapid Brain Growth (after Dobbing)
rat
7
14
7
days
human
months
3
6
24
birth
conception
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Rapid Brain Growth (after Dobbing)
rat
7
14
7
days
human
months
3
6
24
birth
conception
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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

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Altered Nociceptive Neuronal Circuits After
Neonatal Peripheral InflammationRuda MA, et al.
Science 2000

• Freunds 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

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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

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Is Anesthesia Harmful to the Neonates Brain?
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Established Neurotoxins

• Ethanol

• Fetal Alcohol Syndrome

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Established Neurotoxins

• Ethanol
• Antiepileptic drugs
• phenytoin
• phenobarbital
• benzodiazepine
• valproic acid

• Fetal Alcohol Syndrome
• Fetal Malformations
• Developmental delay
• Microcephaly

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Established Neurotoxins

• Ethanol
• Antiepileptic drugs
• phenytoin
• phenobarbital
• benzodiazepine
• valproic acid
• Anesthetic Drugs
• ketamine
• isoflurane
• propofol

• Fetal Alcohol Syndrome
• Fetal Malformations
• Developmental delay
• Microcephaly
• ?

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Neonatal Anesthesia/Surgery

• Highest morbidity and mortality rates Cohen M AA
  (1989)
• Emergent
• Congenital anomalies
• Pre-existing brain injury
• Changing physiology
• Transitional circulation
• Cardiorespiratory instability

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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)

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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

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Is Anesthesia Harmful to the Neonates 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

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Boston Circulatory Arrest Trial
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Boston Circulatory Arrest Trial
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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

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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

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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

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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

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...for there is nothing either good or bad, but
thinking makes it so...

• Alleviation of pain and suffering
• Blunting stress response

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...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 ?

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...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

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