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Running head: THE EFFECTS OF KETAMINE 1

The Effects of Ketamine Administration on the Developing Brain


Emily A. Covington
The University of Kansas















THE EFFECTS OF KETAMINE 2
The Effects of Ketamine Administration on the Developing Brain
In the 1950s, pharmaceutical companies pursued the production of an anesthetic agent
that produced sensory, motor, autonomic, and cognitive function blockade (Bhutta, 2007).
During their search, the pharmaceutical companies developed a class of drugs known as
cyclohexylamines. According to Bhutta (2007), the first agent in this class of drugs to undergo
clinical testing was phencyclidine; however, the majority of patients receiving this agent
experienced severe and prolonged psychotomimetic effects. As a result, a structural analogue of
phencyclidine known as ketamine was developed in 1962 (Roelofse, 2010). Ketamine is a
dissociative anesthetic that blocks N-methyl-D-aspartate (NMDA) type glutamate receptors and
is one-tenth as potent as phencyclidine. Ketamine has multiple effects throughout the central
nervous system, including blocking polysynaptic reflexes in the spinal cord and inhibiting
excitatory neurotransmitter effects in selected areas of the brain (Morgan, Mikhail, & Murray,
2006, p. 197). Anesthetic agents such as ketamine may pose potential deleterious effects on the
developing brain (Hall & Suresh, 2009). N-methyl-D-aspartate receptors are essential for
learning and memory processes (Paule et al., 2011). There is also evidence to suggest that the
infant brain is more responsive to agents that affect NMDA receptor function than are adult
brains (Paule et al., 2011, p. 221).
According to Motomyama & Davis (1996), Ketamine has a well established role in
pediatric anesthesia and it is routinely used for induction and maintenance of anesthesia (as
cited in Bhutta, 2007, p. 305). Ketamine has gained acceptance in anesthesia practice due to its
anesthetic and analgesia properties, short duration of action, and safe hemodynamic and
respiratory profile (Bhutta, 2007). However, the administration of this drug has numerous
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advantages and limitations. The aim of this systematic review is to evaluate the neurobehavioral
and the neurotoxic effect of ketamine administration on the immature brain.
Literature
A PubMed (2004 to April 2014) search was performed in April 2014 with the following
keywords: brain (child or infant or neonate or developing brain) and (neurodegeneration or
neurotoxicity) and (ketamine). This literature search strategy resulted in 70 related articles, and
three randomized controlled trials were selected as relevant to the previously identified topic.
The subjects for these studies included postnatal day (PND) 5 or PND 6 rhesus monkeys. In
addition, one study evaluated the brain of the fetal monkey by incorporating pregnant rhesus
females at 120 days gestation. The treated monkeys received an initial bolus of ketamine via
intramuscular or intravenous injection, followed by a continuous ketamine infusion.
Review of Studies
Zou et al. (2009) identified ketamine as a commonly used anesthetic in the pediatric
population. The administration of ketamine has been associated with enhanced neuronal
toxicity in the developing brain, but mechanisms and neuronal susceptibility to neurotoxic insult
leading to neuronal cell death remain poorly defined (Zou et al., 2009, p. 727). The goal of their
randomized controlled trial was to detect when ketamine-induced neurodegeneration occurs in
the newborn rhesus monkey. Six male and 12 female PND 5 or 6 rhesus monkeys were randomly
assigned in this study to treatment (n=9) and control (n=9) groups (Zou et al., 2009). There were
three treated and three controls included for each exposure duration time (3, 9, and 24 hours).
For the treatment group, induction of anesthesia was accomplished by an initial intramuscular
injection (20 mg/kg) of ketamine followed by a continuous intravenous infusion at a rate of 20-
50 mg/kg/h for either 3, 9, or 24 hours. According to Zou et al. (2009), Animals were
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subsequently perfused under anesthesia and brain tissue was processed for analyses using silver
and Fluoro-Jade C stains and caspase-3 immunostatin (p. 727). The results of this study
suggested that three hours of ketamine exposure produced no significant neurotoxic effects;
however, ketamine exposure in the 9-hour and 24-hour treatment groups showed substantial
neuronal cell death in the frontal cortex. Multiple aspects attribute to this articles creditability
including: random group assignments, unbiased sampling, and the use of the one-way ANOVA
for statistical analysis.
Ketamine was recognized as a frequently administered drug for a variety of pediatric
procedures (Paule et al., 2011). Possible side effects were conveyed by the conclusions that
NMDA receptor antagonists cause apoptotic cell death during the developmental period of rapid
synaptogenesis (Paule et al., 2011). In this randomized controlled trail, they tested the
hypothesis that, in rhesus monkeys, there are subsequent deficits in brain function associated
with a single 24-h bout of ketamine-induced general anesthesia during the neonatal period
(Paule et al., 2011, p. 221). Twelve PND rhesus monkeys served as subjects in this study and
were randomly assigned to the ketamine treated (n=6) and the control (n=6) groups. According
to Paule et al. (2011), For the treated monkeys, ketamine was given as an initial intramuscular
injection (20 mg/kg) to induce anesthesia followed by continuous intravenous infusion at a rate
of 20-50 mg/kg/h to maintain a light surgical plane of anesthesia for 24 h (p. 222). An
intramuscular injection of glycopyrrolate (0.01 mg/kg) was administered to both the treatment
and control groups prior to the initiation of anesthesia and every six hours to reduce airway
secretions. Based on frequent plasma glucose measurements, a continuous infusion of
intravenous dextrose was administered to all anesthetized monkeys whereas the control group
received dextrose every two-hours via a gastrointestinal tube to maintain adequate blood glucose
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levels. At 7 months of age all animals were weaned and began training to perform a series of
cognitive function tasks as part of the National Center for Toxicological Research (NCTR)
Operant Test Battery (OTB) (Paule et al., 2011, p. 220). The OTB testing included learning
task, motivation task, color and position discrimination tasks, and short-term memory task. Paule
et al. (2011) stated, Additionally, the demonstration that several measures of OTB performance
correlate highly with measures of intelligence in children serves to highlight the relevance of
such measures (p. 221). Paule et al. (2011) found the following:
There were no significant difference in the attainment of training scores until subjects
were learning to perform the Delayed Matching-to-Sample (DMTS) task; during and
after this time, ketamine treated animals performed significantly worse than controls from
week 24 of training until week 63, a period of about 10 months. (p. 225)
Overall, this study shows that exposure to ketamine for a single 24-hour period during
development will result in neurobehavioral deficits. This article utilized random group
assignments, as well as the appropriate statistical methods; however, failed to disclose how the
sample size was determined. Paule et al. (2011) controlled physiological variables for both the
treatment and control monkeys; therefore, demonstrating that ketamine induced neurotoxicity
was not due to hypothermia, hypoxia, or randomly assigned hypoglycemia (p. 225). Testing
both male and female monkeys increased clinical relevance of the study. The study has several
features, which supports its superior quality.
Brambrink et al. (2012) offered clarification regarding the minimum exposure
required for and the extent and spatial distribution of ketamine-induced neuroapoptosis in rhesus
fetuses and neonates (p. 372). In this study, an intravenous infusion of ketamine was
administered for five hours to the pregnant (gestational day 120) or PND 6 rhesus macaques.
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Three hours after termination of the ketamine infusion, the fetal and neonatal brains were
inspected for histological evidence of apoptotic neurons (Brambrink et al., 2012). According to
Brambrink et al. (2012), Two studies were performed, one pertaining too fetal and the other to
neonatal subjects (p. 373). The pregnant females received an intravenous bolus of ketamine (10
mg/kg), followed by a five-hour ketamine infusion at a rate of 10-85 mg/kg/hr. The pregnant
females were then observed for three hours. At 8 h after time 0, ketamine anesthesia was
induced again, and a cesarean section was performed to deliver the fetus, which was euthanized
for tissue collection (Brambrink et al., 2012, p. 373). On PND 6, the neonatal rhesus macaques
were exposed to five hours of intravenous ketamine (n=4) or to no ketamine (n=5). Brambink et
al. (2012) stated:
At the end of the 3-h observation period, and after final measurements, the animals
received ketamine, followed by high-dose phenobarbital to secure a deep level of
anesthesia, and were then transcardially perfusion fixed to prepare the brain for
histopathologic analysis. (p. 374)
In addition, the control group subjects were measured at baseline and eight hours later. Both fetal
and neonatal brains were studied for evidence of apoptotic neurodegeneration as determined by
activated caspase-3 staining. Brambink et al. (2012) results concluded, Both the fetal (n=3) and
neonatal (n=4) ketamine-exposed brains had a significant increase in apoptotic profiles compared
with drug-nave controls (fetal n=4; neonatal n=5) (p. 372). They found that the ketamine
exposed fetal rhesus macaque brain had a 2.2 greater loss of neurons when compared to ketamine
exposed rhesus neonates. According to Brambink et al. (2012), It can be considered a limitation
of the current study that only a single post treatment survival interval was used and only a single
method was used to detect apoptotic profiles (p. 374). The use of a single method to detect
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apoptotic profiles may have resulted in false positives, which may introduce error or bias to this
study. The researchers selected their sample size based on evidence presented in previous studies
including those of drug-induced neuroapoptosis in neonatal nonhuman primates or rodents,
which have shown compelling evidence of apoptosis. Thus, the information from previous
studies revealed that small sample sizes, typically between three and five, would have the ability
to detect a true relationship between neonatal nonhuman primates and neonatal humans
(Brambink et al. 2012). In addition, an unpaired Student t test was used for statistical analysis.
The investigators who evaluated the activated caspase-3 stains for apoptotic cells were blinded,
and elimination of experimenter bias enriched the quality of this study. The study has numerous
features that denote its quality; however, limitations regarding apoptotic detection and
phenobarbital administration may have potentially skewed the statistical findings.
Summary of Evidence
Animal studies investigating ketamine-induced brain structural or behavioral
abnormalities are summarized in Table 1.
Table 1. The Effects of Anesthetic Exposure in Fetal or Neonatal Animals on Neuronal Structure
and Subsequent Neurological Function
Anesthetic
agent
Dose and
duration
Species Age Histopathology Neurocognitive
deficits
Reference

Ketamine

20 mg/kg IM,
20-50 mg/kg/h
continuous IV
infusion for
either 3, 9 or
24 h


Rhesus
monkeys
(Macaca
mulatta)

P 5 or 6

Increased neuronal
cell death in layers
II and III of the
frontal cortex in
the 9 h and 24 h
exposure groups

Not assessed

Zou et al.
(2009)

Ketamine

20 mg/kg IM,
20-50 mg/kg/h
continuous IV
infusion for
24 h

Rhesus
monkeys

P 5 or 6

(Training
began at 7
months)

Not assessed

At 10 months,
control animals
significantly
outperformed the
ketamine-exposed
animals for the
next 10 months. At
3.5 years cognitive

Paule et al.
(2011)





(Continued)
THE EFFECTS OF KETAMINE 8
Anesthetic
agent
Dose and
duration
Species Age Histopathology Neurocognitive
deficits
Reference
impairment, poorer
performance in
learning and color
and position
discrimination, as
well as decreased
motivation



Ketamine

Fetuses:
10 mg/kg IV,
10-85 mg/kg/h
continuous IV
infusion for 5h.
At 8 h (prior to
cesarean
section), 10
mg/kg IV, 50-
85 mg/kg/h
continuous IV
infusion
Neonates:
20 mg/kg IV,
20-50 mg/kg/h
continuous IV
infusion for 5 h


Rhesus
macaque

E 120 or
P 6

Ketamine exposed
groups (fetal and
neonatal), and the
5 h exposure
duration is
sufficient to induce
neuroapoptosis

Not assessed

Brambrink et
al. (2012)
IM=intramuscular; IV=intravenous; P=postnatal day; E=embryotic day
Discussion
After reviewing the literature, prolonged administration of ketamine was found to
negatively impact the pediatric population. Cognitive impairments and neurotoxic effects on the
immature brain were present after extended use of this agent. Three-hour administration of
ketamine showed no significant neuronal cell death; however, five-hour administration
demonstrated induction of neuroapoptosis. According to Zou et al. (2009):
In summary, it is clear that the topography, characteristics and neuronal susceptibility to
the neurotoxic insult that leads to ketamine-induced neuronal cell death depends on the
dose, the duration of exposure, the receptor subtype activated and the cell type, as well as
the stage of development at the time of exposure. (p. 730)
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Paule et al. (2011) evaluated the neurobehavioral impairments associated with ketamine
exposure. Their observations demonstrated that prolonged ketamine exposure during sensitive
periods of brain development resulted in long-lasting brain function deficits as well as
subsequent functional deficits (Paule et al., 2011). Ketamine is not commonly administered as a
sole anesthetic agent; therefore, anesthesia providers should be cautious when administering it in
combination with other drugs for a prolonged duration. The use of NMDA antagonist and
aminobutyric acid (GABA) mimetic drugs are of extreme importance when evaluating induction
of neuroapoptosis in the developing brain. In addition to clinical anesthesia, these medications
have a potential for public health relevance. Brambrink et al. (2012) states:
Alcohol, the most widely and frequently abused drug in human experience, which has
damaged more fetal brains than any drug in human history, is also an NMDA antagonist,
as is phencyclidine, a dissociative anesthetic and notorious psychotomimetic drug of
abuse. In recent years, ketamine has become a popular drug of abuse in the United States
and other regions of the world. (p. 381)
Pregnant mothers may choose to abuse agents with GABA-mimetic properties or NMDA
blockades which may also lead to fetal neurotoxicity.
The literature revealed strong evidence that sustained exposure to ketamine would result
in neurodegeneration in the developing brain. The similarity of a nonhuman primate to that of
a human, especially during pregnancy makes the monkey an exceptionally good animal model
for assessing potential neurotoxic effects of anesthetics (Zou et al., 2009, p. 729). Therefore,
evaluating the rhesus monkeys brain response to ketamine allows enhanced generalization to the
pediatric population. Delineating a threshold for dose and duration of ketamine exposure may
further the clinical application of ketamine.
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Conclusion
Overall, ketamine is an important aspect of the anesthetists armamentarium. Like other
anesthetics, ketamine has numerous clinical advantages and adverse effects. In pediatric clinical
situations, ketamine should not be utilized for cases requiring extended anesthetic exposure as
these studies suggested that prolonged ketamine administration in the pediatric population may
lead to neurotoxic and neurobehavioral deficits. Limited evidence exists regarding the long-term
effects of ketamine administration during the neurological development stage. Anesthesia
providers should be cognizant of the potential damaging effects that prolonged ketamine
exposure can have on the developing brain, especially in the pediatric population.














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Brambrink, A. M., Evers, A. S., Avidan, M. S., Farber, N. B., Smith, D. J., Martin, L. D.,
Olney, J. W. (2012). Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus
macaque brain. Anesthesiology, 116(2), 372-384. doi: 10.1097/ALN.0b013e318242b2cd
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