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

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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

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Boston Circulatory Arrest Trial

Wechsler Preschool and Primary Scale of Intelligence

full-scale verbal performance

WIS

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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