Objectives
• Review the pathologic processes which cause Anesthetic induced
developmental neurotoxicity(AIDN)
• List current studies investigating the effects of Neurotoxicity
• Recognize factors important to AIDN
• Describe mechanisms of neurotoxicity in the Elderly
• Comprehend practical guidelines associated with AIDN
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1. The following are true statements regarding
anesthetic neurotoxicity except
A. Inhalational agents can cause neuro-apoptosis in pediatric population
B. Intravenous agents are relatively safe in neonates
C. It is recommended to reduce the duration of exposure to < 2hours
D. Neuro-apoptosis is the mechanism of neurotoxicity
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A. Inhalationals can cause neuro-apoptosis in pediatric
population.
• This is true. Developmental neurotoxicity is a common
feature of all three drugs, isoflurane, sevoflurane and
desflurane.
Anesthesiology.2011 Mar;114(3):578-87. Istaphanous GK, Howard J et al;Comparison of the
neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane
in neonatal mice.
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B. Intravenous agents are relatively
safe in neonates
• This is not true. Many intravenous anesthetics, among them
barbiturates, benzodiazepines, propofol,and etomidate promote
inhibitory neurotransmission by enhancing GABA-A-induced currents
in neuronal tissue. A small number of intravenous anesthetics (for
example ketamine) inhibit excitatory neurotransmission by blocking N-
methyl-D-aspartate (NMDA) receptors, a subtype of glutamate
receptors.
• The modulation of these receptors causes significant imbalance in
their functioning, only recently has it been recognized that this could
be potentially damaging to neuronal cells in immature brains.
Anesthesiol Clin.2016 Sep;34(3):439-51.
General Anesthetics and Neurotoxicity: How Much Do We Know?
Jevtovic-Todorovic V.
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C. It is recommended to reduce the duration of
exposure to < 2hours.
This is True.
In several clinical studies, no behavioral, academic, or cognitive abnormalities have
been observed following anesthetic exposures of less then 2h(Davidson et al.,
2016; Fan et al., 2013).Furthermore deficits have been observed following
exposure times of 2 h or longer (Andropoulos etal., 2014; Wilder et al., 2009).
Taken together, three factors appear to induce AIDN in animal models
1. Susceptibility during developmental phase
2. Higher dosage of anesthetic
3. Longer duration of exposure.
Davidson, A.J., etal; Lancet 387 (10015), 239–250, 2016
Fan, Q., et al J. Anesth. 27 (4), 493–499,2013
Andropoulos, D.B., et al,Paediatr. Anaesth. 24 (3), 266–274, 2014
Wilder, R.T., et al;Anesthesiology 110 (4), 796–804, 2009
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D. Neuro-apoptosis is the mechanism of
neurotoxicity
• This is true.
• Anesthetic agents initiate apoptosis through several mechanisms like
mitochondrial disruption and endoplasmic reticulum release of
calcium. Caspase activation is the final stage after intrinsic and
extrinsic apoptotic cascade initiation.
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2. You are the anesthesiologist caring for a 6 month old child presenting for inguinal
hernia repair. The parents would like to know the risk of general anesthesia. What
conclusions can be reached about neurodevelopmental outcomes in children less
than 2 years old? ( Which is true)
A. There is no evidence that less than 1 h of sevoflurane anesthesia in
infancy increases the risk of adverse neurodevelopmental outcome
compared with awake-regional anesthesia
B. Local anesthetics are toxic to children less than 2 years old
C. Regional anesthesia with sedation is not an acceptable alternative
to general anesthesia in children
D. General anesthesia does not affect learning and memory in children
who receive multiple anesthetics before 2 years old.
Go to Q3
A. There is no evidence that less than 1 h of sevoflurane anesthesia in infancy increases
the risk of adverse neurodevelopmental outcome compared with
awake-regional anesthesia
• This is a true statement. A brief anesthetic duration less than 1 hour would not increase risk of neurodevelopmental outcome
according to the GAS study; see below.
• In an international assessor-masked randomised controlled equivalence trial, the investigators recruited infants born at greater than 26
weeks’ gestation and younger than 2 months, and who had inguinal herniorrhaphy, Infants were randomly assigned to receive either
awake-regional anaesthesia or sevoflurane-based general anesthesia. The primary outcome was Intelligence Quotient measured at 5
years and secondary outcome was neurodevelopment score at 2 years. The results of the primary outcome are not yet available. For
the secondary outcome, they found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of
adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia.
Davidson, A.J., etal; Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional
anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.Lancet 387 (10015), 239–250,
2016
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D. General anesthesia does not affect learning and memory in
children who receive multiple anesthetics before 2 years old.
• This is not correct. Multiple exposures to General anesthesia may affect learning and memory.
• There is still ongoing debate as to whether children who receive multiple anesthetics before 2 years of age are more likely to
have learning disabilities and alterations in memory later in life.
• A retrospective cohort study looked at over 5000 children born from 1976 through 1982. They found more reading, written,
language, and math learning disabilities in the 593 patients who had more than one exposure to anesthesia (example- two,
three or multiple times) before the age of 4 years compared to those not receiving anesthesia or one exposure to anesthesia.
Risk factors for learning disabilities included more than one anesthetic exposure and general anesthesia lasting longer than 2
hours.
Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth
cohort. Anesthesiology. 2009;110:796–804.
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Mitochondrial disruption
• This is True.
• General anesthetics could jeopardize the integrity of the
mitochondrial membrane and activate the intrinsic apoptotic
cascade. Early exposure to general anesthesia causes
mitochondrial enlargement and disruption of the cristae and
inner mitochondrial membrane. General anesthetics may
disturb mitochondrial fission and fusion leading to anesthetic-
induced developmental neurodegeneration.
Sanchez V., Feinstein S.D., Lunardi N., et al: General anesthesia causes long-term impairment of
mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology 2011; 115:
pp. 992-1002
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B. Release of calcium from endoplasmic
reticulum
• This is True.
• The endoplasmic reticulum could be an important target of
anesthesia-induced developmental neurotoxicity. Isoflurane,
Sevoflurane and desflurane activates inositol 1,4,5-trisphosphate
receptors (InsP
3
R), producing an exaggerated and prolonged
calcium release, and increases cytosolic calcium.
Zhao Y., Liang G., Chen Q., et al: Anesthetic-induced neurodegeneration mediated via inositol 1,4,5-trisphosphate
receptors. J Pharmacol Exp Ther 2010; 333: pp. 14-22
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D. Tauopathy and destabilization of micro
tubules
• This is the correct answer. Taupathy and destabilization of microtubules do
not contribute to pediatric neurotoxicity.
• The accumulation of the Tau(t) protein otherwise called neurofibrillary
tangles can occur in Alzheimer’s dementia. The potential for accumulation
of this protein in multiple exposures to isoflurane and sevoflurane are
thought to contribute to neurotoxicity in the elderly.
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A. Volatile Anesthetics
• This has been implicated in neurotoxicity .
• We now have considerable in vitro and animal data
implicating volatile anesthetics in inducing
neurotoxicity. These changes are dependent on dose
and long duration of anesthetic exposure. Also, infant
rats received a combination of drugs commonly used
in pediatric anesthesia (midazolam, nitrous oxide, and
isoflurane) in doses sufficient to maintain a surgical
plane of anesthesia for 6 hrs and it was observed that
this caused widespread apoptotic neurodegeneration
in the developing brain.
Chiao S, Zuo Z. A Double-Edged Sword: Volatile Anesthetic Effects on the Neonatal Brain. Brain Sciences. 2014;4(2):273-294.
Jevtovic-Todorovic V et al; Early exposure to common anesthetic agents causes widespread neurodegeneration
in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–882
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B. Propofol
• Growing evidence shows that propofol could
induce developmental neurotoxicity in multiple
models (e.g., animal model and cell culture
system), raising serious concerns regarding the
safety of using it in propofol anesthesia. Propofol
causes developmental neurotoxicity by cell death
in neurons and oligodendrocytes, dysregulation of
neurogenesis, abnormal dendritic development,
and decreases in neurotrophic factor expression.
Bosnjak ZJ, Logan S, Liu Y, Bai X. Recent Insights into Molecular Mechanisms of Propofol-Induced Developmental
Neurotoxicity: Implications for the Protective Strategies. Anesthesia and analgesia. 2016;123(5):1286-1296.
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C. Dexmedetomidine
• Recent evidence has demonstrated the anti-apoptotic effect of
dexmedetomidine in different brain injury models. It was found to
prevent cortical apoptosis in vitro and in vivo and attenuate
isoflurane-induced injury in the developing brain, providing
neurocognitive protection.
Robert D. Sanders, et al; Dexmedetomidine Attenuates Isoflurane-induced Neurocognitive Impairment
in Neonatal Rats. Anesthesiology 2009;110(5):1077-1085
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D. Ketamine
• Ketamine is an NMDA antagonist. 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.
Ikonomidou C., Bosch F., Miksa M., Bittigau P., Vockler J., Dikranian K., et al. . (1999). Blockade of NMDA receptors and
apoptotic neurodegeneration in the developing brain. Science 283, 70–74.
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5. You have 79 year old patient coming in for a pituitary surgery. The family is
worried about cognitive dysfunction in the postoperative period. All the following
are potential mechanisms by which anesthetics can cause neurotoxic effects in
elderly patients except?
A. Excessive accumulation of amyloid- Beta and neurofibrillary tangles.
B. Altered calcium homeostasis
C. Neuroinflammation triggered by surgically-induced systemic
inflammation
D. Developmental Apoptosis
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A. Excessive accumulation of amyloid- Beta
and neurofibrillary tangles
• This is True.
• Amyloid-β is the protein that is strongly implicated in the pathogenesis
of Alzheimers dementia. Excessive amyloid-β accumulates
extracellularly and forms plaques. These plaques cause direct neuronal
toxicity and an inflammatory response by interacting with the brain’s
primary immune surveillance cell, the microglia. It is thought that the
inhaled anesthetics promote amyloid-β production and aggregation and
lead to cognitive decline.
Eckenhoff R.G., Johansson J.S., Wei H., et al: Inhaled anesthetic enhancement of amyloid-beta oligomerization and
cytotoxicity. Anesthesiology 2004; 101: pp. 703-709
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B. Altered calcium homeostasis
• This is True.
• Another major mechanism thought to underlie Alzheimer’s dementia
is calcium dysregulation. This is one mechanism that might be shared
with neurotoxicity of the young . It is now thought that mutations in
calcium channels, or exposure to drugs that interact with them, may
lead to an exaggerated release of calcium triggering apoptosis.
Propofol appears to be much less provocative in this regard.
Wei H., and Xie Z.: Anesthesia, calcium homeostasis and Alzheimer’s disease. Curr Alzheimer Res 2009; 6: pp. 30-35
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D. Developmental Apoptosis
• This is False.
• This is a phenomenon in the developing brain and not in older population.
• During the phase of synaptogenesis in the developing brain, there is a fine
balance between γ-aminobutyric acid (GABA)-mediated versus glutamate-
mediated neurotransmission. A disturbance in the glutamatergic and
GABAergic balance during this crucial stage of brain development may
excessively signal developing neurons to undergo apoptosis. General
anesthetics could potentially disrupt the glutamate and GABA signaling balance
promoting excessive activation of neuroapoptosis.
End of Set
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