Pediatric Anesthesia 2010 20: 240–245 doi:10.1111/j.1460-9592.2009.03145.

Review article
The evolution of ketamine applications in children
JAMES A. ROELOFSE M B C H B , M M E D , P H D *†
*Division of Anesthesiology and Sedation, University of the Western Cape, Cape Town, South
Africa and †University College London, London, UK

Summary
Ketamine has found many applications in pediatric anesthetic
practice. Insights into the mechanism of action and the pharmaco-
kinetics and pharmacodynamics of its isomers have led to a
re-evaluation of this drug, expanding the range of applications in
children. Ketamine is a remarkably versatile drug that can be
administered through almost any route. It can also be used for
different purposes. The aim of this review is to look at the possible
applications of this drug in children.

Keywords: evolution ketamine: general anesthesia; procedural seda-

tion; analgesia; caudal analgesia

gence phenomena, especially from awakening of

Introduction
In 1957, the criteria for an ideal anesthetic agent
were spelled out; such an agent must be able to block
sensory, motor, autonomic, and cognitive functions
(1). This led to the development of drugs called the
cyclohexylamines in the 1950s. The first agent to
undergo clinical trials was called phencyclidine.
Unfortunately, studies with phencyclidine reported
severe psychomimmetic effects in many patients. In
1962, ketamine was synthesized as a drug that
appeared promising in studies. It was approved
for clinical use in 1970.
When ketamine was first introduced into clinical
practice, it was regarded as an ‘ideal and complete’
anesthetic agent, because it was believed to provide
all the requirements of surgical anesthesia – analge-
sia, immobility, amnesia, and loss of consciousness.
However, like phencyclidines, it can produce emer-
Correspondence to: James A. Roelofse, Division of Anesthesiology
and Sedation, University of the Western Cape, Private bag X1,
Tygerberg 7505, Bellville, Western Cape 7530, South Africa (email:
jaroelofse@uwc.ac.za).
general anesthesia.
Today, the role of ketamine in clinical practice is
changing as a result of evolving concepts of its
mechanism of action and the advantages of using
this drug for other purposes than just for general
anesthesia.
After all the years of clinical experience and
research with ketamine, we are well aware of the
benefits and limitations of this drug. Nevertheless,
research continues to find new applications in
children.
Pharmacology of ketamine
Ketamine is a noncompetitive N-methyl-D-aspartate
glutamate (NMDA) receptor antagonist (2). The com-
mercial preparation of ketamine is a racemic mixture
of two enantiomers, S(+) and R()) (3). It is known that
the enantiomers exhibit pharmacologic and clinical
differences. The S(+) enantiomer has four times the
potency of the R()) enantiomer and twice the analge-
sic potency of the racemate. The inhibitory effect of

240  2009 Blackwell Publishing Ltd

 EVOLUTION OF KETAMINE APPLICATIONS
S(+) ketamine on the NMDA receptor was reported as
three times greater as that of the S()) ketamine (4). The
S(+) isomer appears to be cleared more rapidly,
resulting in a shorter duration of action and more
rapid recovery than the racemate. Earlier studies
suggested a lower incidence of emergence phenom-
ena with the S(+) enantiomer, there is, however, some
doubt about these claims. S(+) ketamine is shorter
acting than the racemic ketamine, with possible better
recovery characteristics. The compound has a faster
offset, allowing more easily titrated use when using
infusions.
Therapeutic applications of ketamine
Ketamine is a very popular drug, used for several
different purposes. It can be administered through
almost any route and combined with various seda-
tive and analgesic agents.
Ketamine for pediatric general anesthesia
The use of ketamine fell into disfavor in some
anesthesia communities in the early 1980s, mainly
because of the troublesome side effect profile. The
drug, however, has still a well-established role in
pediatric anesthesia for induction and maintenance
of general anesthesia. Newer and probable better
anesthetics have undoubtedly decreased the use of
ketamine for general anesthesia in children, but it is
still used as a general anesthetic agent for certain
specific procedures (5).
Children with neuromuscular disorders, poten-
tially at risk of the development of malignant
hyperthermia, may be good candidates to receive
ketamine for general anesthesia. In such cases,
volatile anesthetic agents and muscle relaxants that
may trigger malignant hyperthermia can be avoided.
A fatal case of malignant hyperthermia has been
reported following ketamine anesthesia for a diag-
nostic muscle biopsy in a 5-year-old child. Ramch-
andra et al. (6) used ketamine for general anesthesia
in children (aged 3 months to 12 years) with floppy
infant syndrome and who required diagnostic
muscle biopsy. In children who received either
intramuscular or intravenous ketamine, adequate
anesthesia was achieved, suggesting ketamine may
be an excellent and safe agent for children with
neuromuscular disorders.
 2009 Blackwell Publishing Ltd, Pediatric Anesthesia, 20, 240–245
241
Ketamine is also used for the induction of anes-
thesia in children with cyanotic heart disease, as it
increases vascular resistance and cardiac output and
does not worsen left-to-right shunting (7). Tugrul
et al. (8) reported very stable hemodynamic param-
eters, when ketamine was used for maintenance of
anesthesia in children (aged 3 months to 12 years)
undergoing cardiac surgery for correction of tetral-
ogy of Fallot.
Maldini (9) reported on the efficacy and safety of
ketamine as a single anesthetic agent in burned
children in a war area. Children (aged 2 months to
14 years) underwent several repeated anesthesias
(from 5 to 14) for necrectomy, skin drafting, debride-
ment, and redressing. Ketamine, without the use of
benzodiazepines, produced excellent anesthesia and
total amnesia. It also proved to be valuable for
analgesia in the first 12 h after the operations, with
only 1.6% of children needing further analgesia.
Hallucinations occurred in 4.2% of children.
Ketamine remains the mainstay of anesthesia
delivery in many developing countries (10). It is
used intravenously or intramuscularly for induction
and maintenance of anesthesia for various opera-
tions and is considered safe in children. Dallimore
et al. (11) explored infusion regimens using ketamine
anesthesia in children aged 1.5–12 years. They
aimed to produce a racemic ketamine manual
infusion regimen capable of maintaining a steady-
state blood concentration during anesthesia. A target
concentration of 3 lgÆml)1 was chosen. Children
required higher infusion rates than adults to main-
tain the projected steady-state concentration.
Children also have shorter context sensitive half-
lives than the adult population with prolonged
infusion. Data suggest that ketamine is probably
more suitable for operations where shorter duration
of anesthesia with better recovery characteristics is
desirable. But infusion of ketamine beyond 2 h leads
to a slow recovery period which probably disqual-
ifies ketamine for single-drug anesthesia. The drug
can be combined with other short-acting anesthetic
agents, with probably lower target blood concentra-
tions for anesthesia.
Ketamine for procedural sedation
The trend towards more ambulatory surgery outside
the operating room has created an interest in
2 42 J. A . R O E L O F S E
ketamine because of its acceptably short duration of
action, safety profile, administration through almost
any route, and sedative ⁄ analgesic effects. Pediatric
sedation techniques using ketamine are therefore
developing rapidly. Ketamine has become a popular
drug for use in dentistry, the emergency depart-
ment, dermatology, plastic procedures, and inter-
ventional radiology in children, producing a state of
dissociative sedation (12). Green and Krauss (13)
claim that ketamine is fundamentally different than
the other sedative ⁄ analgesic drugs in use for proce-
dural sedation, as it does not operate on the sedation
continuum. Clinical effects of ketamine should be
defined as a different sedation category (12). It is the
complete analgesia produced by the dissociative
state that allows practitioners to perform more
painful operations and make ketamine such an
attractive drug outside the operating room (14–16).
Ketamine has become increasingly popular be-
cause of a better understanding of its pharmacokinet-
ics and pharmacodynamics. It can also be safely
combined with other drugs, e.g. propofol, for various
procedures (17). Herd and Anderson (18) studied
ketamine (1–1.5 mgÆkg)1) pharmacokinetics in
children in the emergency department to predict the
duration of concentrations associated with anesthe-
sia, awakening, and analgesia. The pharmacokinetic
findings were consistent with a two-compartment
model for intravenous administration of the racemic
ketamine. Ten minutes after administration of keta-
mine 1 mgÆkg)1, the majority of children will have a
serum concentration below 0.75 mgÆl)1, a level asso-
ciated with awakening. With ketamine 1.5 mgÆkg)1,
fewer children (50%) will have a concentration below
0.75 mgÆl)1 at 10 min. After 10 min, almost all
children will have a serum concentration above
0.1 mgÆl)1, a level associated with analgesia in adults
(19). Ketamine 1 mgÆkg)1 administered intravenously
provides satisfactory serum concentrations for
children undergoing sedation for short procedures
(18). Herd et al. (20) studied ketamine pharmacody-
namics in children receiving ketamine 1–1.5 mgÆkg)1
intravenously in an emergency department. Depth of
sedation was assessed using the Children’s Hospital
of Wisconsin Sedation Scale (21). Data showed that
concentrations associated with awakening in children
are analogous to adults. The blood concentration
of 1 mgÆl)1 was associated with a sedation level of
three or less (21), 95% of children being rousable
with moderate physical stimulation or loud verbal
stimulus. The blood concentration of 1.5 mgÆl)1 was
associated with less rousable children in 95% of cases
– a sustained painful stimulus was needed to rouse
the children.
S(+) ketamine was reported to be a useful sedative
agent for diagnostic and interventional procedures
in newborns and children (22). It was also used for
long-term sedation in a child with retinoblastoma
(23). The pediatric emergency medicine literature
currently recommends that ketamine to be used in
doses of 1–1.5 mgÆkg)1 for procedural sedation
(16,24). Low-dose ketamine for sedation was studied
by Bleiberg et al. (25). They claim that one-fourth of
their children could be successfully sedated with
ketamine at doses of 0.5 mgÆkg)1. Half of their
cases zwere sedated with doses of 0.75 mgÆkg)1 or
less. They suggest a dose range of 0.5–1 mgÆkg)1
ketamine intravenously for procedural sedation.
Ketamine was also used successfully in awake,
nontrapped children with blunt trauma for proce-
dural sedation and analgesia (26). This study did not
demonstrate any major side effects. Intramuscular
ketamine in doses of 2–4 mgÆkg)1 is still used for
pediatric sedation (27,28) – it is a very useful drug in
remote areas in developing countries.
Ketamine for analgesia
Ketamine has an analgesic action at many sites both
centrally and peripherally. Besides its role as a
N-methyl-D-aspartate receptor antagonist, ketamine
induces an analgesic effect by nitric oxide synthase
inhibition (29,30). In the last decade, renewed inter-
est has focused on the use of ketamine as a co-
analgesic infusion for intra- and postoperative pain,
pain related to tumors, or neuropathic pain (31).
Studies show the efficacy of low-dose continuous
ketamine infusions (0.14–0.4 mgÆkg)1Æh)1) for neuro-
pathic pain (32). Continuous subcutaneous infusions
of ketamine 0.1 mgÆkg)1Æh)1 provided sufficient
analgesia with minimal adverse events in trauma
patients (33).
Ketamine is widely used as an adjunct to analgesics
during the perioperative period. Studies report on the
potentiation of opioid-induced analgesia and the
opioid-sparing effect of ketamine. Tucker et al.
(34) published the dose of ketamine capable of
providing clinical benefits through co-administration
 2009 Blackwell Publishing Ltd, Pediatric Anesthesia, 20, 240–245
 EVOLUTION OF KETAMINE APPLICATIONS
with opioids. A serum concentration of ketamine
30–120 ngÆml)1 can potentiate the antinociceptive
effect of fentanyl. Consensus is probably reached that
ketamine can be used for the prevention and treat-
ment of perioperative pain, and pain not related to
surgery, probably as a ketamine infusion or in
combination with other analgesic drugs. There are
numerous reports on the use of ketamine for pain
caused by advanced cancer (35,36), but limited pedi-
atric cases reported. Tsui et al. (37) reported the use of
a ketamine infusion as an effective analgesic in
combination with morphine in a 2-year-old with
severe cancer pain. Pain was relieved, and quality of
life of the child was improved. A continuous low-dose
ketamine infusion and patient-controlled analgesia
with morphine for postoperative analgesia in a 13-
year-old girl undergoing correction of scoliosis is
reported (38). Good analgesia as well as a potentially
opioid-sparing effect was demonstrated. White (39)
reported the use of a long-term ketamine infusion, as
an opioid adjunct, for 37 days in a 9-year-old child
with 42% body surface area burns. Ketamine
provided excellent analgesia and was well tolerated.
Becke et al. (40) used intraoperative low-dose
S-ketamine to reduce postoperative pain and
morphine consumption, in infants and children
undergoing urological surgery. The study was not
conclusive of a true preventative effect of ketamine on
postoperative pain and morphine consumption.
Ketamine has been used intravenously and by peri-
tonsillar infiltration to reduce postoperative pain after
adenotonsillectomy (41). Aspinall and Mayor (42)
showed that intravenous ketamine 0.5 mgÆkg)1
provides effective postoperative analgesia after
adenotonsillectomy. Other studies (43,44) failed to
demonstrate a decrease in postoperative pain in
children undergoing tonsillectomy when pretreated
with ketamine.
The combination of intranasal sufentanil and
midazolam was compared with intranasal ketamine
and midazolam for sedation and postoperative
analgesia in children undergoing dental extractions
(45). Children in the sufentanil group received
1 lgÆkg)1 of sufentanil and 0.3 mgÆkg)1 of midazo-
lam, 20 min before induction of anesthesia. The
ketamine group children received ketamine
5 mgÆkg)1 and midazolam 0.3 mgÆkg)1 intranasally.
Effective postoperative analgesia for multiple dental
extractions was provided in both groups – in the
 2009 Blackwell Publishing Ltd, Pediatric Anesthesia, 20, 240–245
243
sufentanil group, 72% of children did not need
rescue analgesia, compared to 52% in the ketamine
group.
A low-dose ketamine infusion may be an excellent
option for the prevention and treatment of pain in
undeveloped countries, where equipment and
the availability of other potent analgesics may be
lacking.
Future research in this area should consider the
perioperative infusion of ketamine followed by long-
term administration of other NMDA receptor antag-
onists to prevent persistent pain.
Ketamine for regional anesthesia
The popularity of regional anesthesia in children is
increasing as it provides satisfactory operating
conditions and excellent perioperative analgesia.
There are several studies in literature showing that
ketamine provides satisfactory perioperative analge-
sia as the sole agent in a pediatric caudal block.
Naguib et al. (46) used ketamine 0.5 mgÆkg)1 for
caudal administration with excellent results. Lee and
Sanders (47) compared caudal ropivacaine 0.2%
1 mlÆkg)1 with caudal ropivacaine 0.2% 1 mlÆkg)1
plus ketamine 0.25 mgÆkg)1 in children undergoing
circumcision under general anesthesia. The median
duration of analgesia was longer in the ropiva-
caine ⁄ ketamine group; less escape analgesia was
used in this group. Semple et al. (48) showed that
the duration of caudal blockade with ketamine
was significantly higher with doses of ketamine
0.5–1 mgÆkg)1. Marhofer et al. (49) compared the
analgesic efficacy of preservative-free S(+)-ketamine
with that of bupivacaine for caudal block in children.
The authors reported that caudal block with
S(+)-ketamine at 1.0 mgÆkg)1 provides similar
intra- and postoperative analgesia than bupivacaine.
Gunes et al. (50) compared the effect of single-dose
caudal ropivacaine, ropivacaine plus ketamine,
and ropivacaine plus tramadol in children for
postoperative analgesia – all three groups had
sufficient analgesia, but the duration of analgesia
was longer in the ropivacaine ⁄ ketamine group.
Gunduz et al. (51) investigated whether the addition
of tramadol or lidocaine to ketamine would enhance
the quality of intra- and postoperative analgesia
in children. Both combinations provided very effec-
tive and long duration of analgesia. Duration of
2 44 J. A . R O E L O F S E
analgesia was longer than in other studies, and the
authors believe this is because of the effect of
ketamine.
The safety of ketamine for regional anesthsia is
debated because of the potential for neurotoxicity
(52). It is clear from many studies that the addition of
caudal opioids and ketamine may offer analgesic
advantages over local anesthetic alone. The potential
of low-dose ketamine for analgesia seems real and
should be investigated further.
In children, ketamine has always had a place in
the clinical practice of anesthesia. Further studies
may lead to widespread use and even new indica-
tions for its use. This systematic review highlights
some areas where research with ketamine is war-
ranted. Ketamine is an exciting agent of value for
emergency medicine as well as pain practitioners,
and there is still more to discover.
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Accepted 5 August 2009