clinical perspective: implications of non-clinical findings of anesthetic-induced 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 SchoolSenior Associate in Anesthesia, Children’s Hospital Boston
sulpicio.soriano@childrens.harvard.edu
“...for there is nothing either good or bad, but thinking makes it so...”
Hamlet, Act 2, Scene 2, Shakespeare
Liverpool Technique
• Nitrous oxide• Muscle relaxant• Hyperventilation
Liverpool Technique
• Nitrous oxide• Muscle relaxant Chemical paralysis• Hyperventilation
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
Pain And Its Effects In The Human Neonate And FetusAnand KJ, Hickey PR, N Engl J Med. 1987
Perioperative Stress in Newborn in Cardiac SurgeryAnand KJ, Hansen DD, Hickey PR, Anesthesiol. 1990
Blockade of NMDA Receptorsand Apoptotic
Neurodegeneration in theDeveloping 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.
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
Human Babies are not Large Rat Pups!!Problems with Rodent Experimental Paradigm
Human Babies are not Large Rat Pups!!Problems with Rodent Experimental Paradigm
• Duration of exposure to drugs
Effect of Continuous Dosing of Ketamine on the Developing Brain Hayashi H, et al Paediat Anaesth 2003
Rspl II Temp II Par II Hcp CA1 DG Thal ld Thal md Thal vm Hypothal Amyg bm0
5000
10000
De
nsi
ty o
f d
eg
en
era
ting
ce
lls (
/mm
3)
Saline
Ketamine 1 dose
Ketamine 4 doses
Ketamine 7 doses
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
Human Babies are not Large Rat Pups!!Problems with Rodent Experimental Paradigm
• Duration of exposure to drugs• Lack of precise physiological monitoring
Physiological Monitoring
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
Human Babies are not Large Rat Pups!!Problems with Rodent Experimental Paradigm
• Duration of exposure to drugs• Lack of precise physiological monitoring• Interspecies variation
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
Periods of Rapid SynaptogenesisDobbing and Sands Early Human Develop 1979
Rapid Brain Growth (after Dobbing)
months
rat
human
3 6 6 12
18
7 14
7 days
conception birth24
Rapid Brain Growth (after Dobbing)
months
rat
human
3 6 6 12
18
7 14
7 days
conception birth24
Rapid Brain Growth (after Dobbing)
months
rat
human
3 6 6 12
18
7 14
7 days
conception birth24
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
Altered Nociceptive Neuronal Circuits After Neonatal Peripheral InflammationRuda 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
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
Is Anesthesia Harmful to the Neonate’s Brain?
Established Neurotoxins
Ethanol Fetal Alcohol Syndrome
Established Neurotoxins
EthanolAntiepileptic drugs
phenytoin
phenobarbitalbenzodiazepinevalproic acid
Fetal Alcohol Syndrome
Fetal MalformationsDevelopmental delayMicrocephaly
Established Neurotoxins
EthanolAntiepileptic drugs
phenytoin
phenobarbitalbenzodiazepinevalproic acid
Anesthetic Drugsketamine
isofluranepropofol
Fetal Alcohol Syndrome
Fetal MalformationsDevelopmental delayMicrocephaly
?
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
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)
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
Is Anesthesia Harmful to the Neonate’s Brain?
Boston Circulatory Arrest StudyNewburger 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
Boston Circulatory Arrest Trial
Wechsler Preschool and Primary Scale of Intelligence
full-scale verbal performance
WIS
C-I
II
0
20
40
60
80
100
120
4 year8 year
Boston Circulatory Arrest Trial
Wechsler Preschool and Primary Scale of Intelligence
full-scale verbal performance
WIS
C-I
II
0
20
40
60
80
100
120
4 year8 year
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
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
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
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 x x
Yr 2 assessment
x x x
Yr 5 assessment
x x x
• Alleviation of pain and suffering
• Blunting stress response
“...for there is nothing either good or bad, but thinking makes it so...”
• Alleviation of pain and suffering
• Blunting stress response
“...for there is nothing either good or bad, but thinking makes it so...”
• Irrefutable laboratory data• Long-term effects in
humans ?
• Alleviation of pain and suffering
• Blunting stress response
“...for there is nothing either good or bad, but thinking makes it so...”
• Irrefutable laboratory data• Long-term effects in
humans ?• No other alternative
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