The article reviews emergence delirium (ED) in children, particularly its association with modern inhaled anesthetics like sevoflurane and desflurane, and highlights various factors contributing to this phenomenon, including surgical procedures, patient age, and preoperative anxiety. ED is characterized by disorientation and restlessness during recovery from anesthesia, typically affecting preschool children and often resolved spontaneously. Recommendations for management include identifying at-risk patients and implementing preventive measures such as reducing anxiety and postoperative pain.

1. Emergence Delirium (ED) in Children

2. Review Article
INTRODUCTION
The introduction of a new generation of inhaled
anesthetics like sevoflurane and desflurane into pediatric
clinicalpracticehasbeenassociatedwithagreaterincidence
of ED, a short-lived, but troublesome clinical phenomenon
of uncertain etiology [1].Avariety of anesthesia-, surgery-,
patient-, and adjunct medication-related factors have been
suggestedtoplayapotentialroleinthedevelopmentofsuch
anevent.Restlessbehavioruponemergencecausesnotonly
discomfort to the child, but also makes the caregivers and
parents feel unhappy with the quality of recovery from
anesthesia.Althoughtheseverityofagitationvaries,itoften
requires additional nursing care, as well as treatment with
analgesics or sedatives, which may delay discharge from
hospital. To reduce the incidence of this adverse event, it is
advisable to identify children at risk and take preventive
measures, such as reducing preoperative anxiety, removing
postoperative pain, and providing a quiet, stress-free
environment for post anesthesia recovery.
Emergence delirium (ED) also referred to as emergence
agitation(EA)isawelldocumentedphenomenonoccurring
inchildrenandadultsintheimmediatepostoperativeperiod.
With the recent popularity of the newer inhalation agent’s
desflurane and sevoflurane, numerous clinical studies have
been published questioning the association of these
anesthetics with an increased incidence of emergence
delirium.
Emergence delirium is defined as a dissociated state of
EMERGENCE DELIRIUM (ED) IN CHILDREN
K Raghavendran
Senior Consultant & Coordinator, Apollo Children’s Hospitals, 21, Greams Lane, Off Greams Road,
Chennai 600 006, India.
Emergence delirium in children is a state of mental dissociation that occurs while recovering from anesthetic
agents and manifests as disorientation, restlessness, irritability, screaming and involuntary activity. It usually
evolves in the first half hour after awakening from anesthesia, often lasts up to 20 minutes and usually resolves
on its own. Many factors have been suggested to play a potential role in the development of such an event.
Post anesthesia agitation has been noted more often with the newer, less soluble, inhaled anesthetics, such
as desflurane and sevoflurane, than with other volatile ones; however administration of other anesthetic
agents can also cause this disturbing recovery phenomenon. Emergence delirium occurs more often in
preschool children and seen frequently after head and neck surgeries like tonsillectomy, adenoidectomy,
tongue tie release, strabismus surgery, nasal operations etc. Treatment is with pharmacological and
environmental. Prevention may be the best treatment but no one medication is entirely effective.
Key words: Post anesthetic, Emergence delirium, Sevoflurane, Desflurane.
consciousness in which the child is inconsolable, irritable,
uncompromising or uncooperative, typically thrashing,
crying, moaning, or incoherent [2]. Additionally paranoid
ideation has been observed in combination with these
emergence behaviors. Characteristically these children do
not recognize or identify familiar and known objects or
people. Parents who witness this state claim the behavior is
unusual and uncustomary for the child.Although generally
self limiting (5-15 min) ED can be severe and may result in
physical harm to the child and particularly the site of
surgery.
Emergence delirium has been reported after the
introduction of every new anesthetic including most
inhalational agents and intravenous agents including
midazolam, remifentanil and propofol. Other drugs known
to be associated with ED include (i) atropine or scopo-
lamine, (ii) ketamine, (iii) droperidol, (iv) barbiturates and
possibly, (v) benzodiazepines [3]. The incidence of
emergence delirium in all postoperative patients is 5.3%
with a more frequent incidence in children (12-13%). The
incidence of emergence delirium after halothane,
isoflurane,sevofluraneanddesfluranerangesfrom2-55%.
It has been postulated that this phenomenon has become
more acutely noticed with the increased use of agents such
as sevoflurane and desflurane that have a rapid emergence
profile due to their low blood gas solubility profile. It was
thought that rapid emergence with lack of adequate pain
control before emergence contributed or was the cause of
this problem. This has been supported by the finding that
99 Apollo Medicine, Vol. 8, No. 2, June 2011

3. Apollo Medicine, Vol. 8, No. 2, June 2011 100
Review Article
ketorolac administration decreased the incidence of
emergence delirium three to fourfold after myringotomy
with either halothane or sevoflurane anesthesia. Several
studies have documented a reduction in ED with the
administration of fentanyl 2.5 μg/kg intraoperatively or 2.0
μg/kg fentanyl administered intranasal, 1 μg/kg in each
nostril after the induction of anesthesia. However, other
studies have noted emergence delirium in children after
sevoflurane anesthesia despite effective regional blocks to
preventpostoperativepain.Thesestudiesdemonstratedthat
delirium occurred more frequently in preschool age
children, 1 to 5 years of age, lasted 5-15 minutes in the
recovery room and often resolved spontaneously. Studies
that have also called into question whether adequate pain
management is the cause of ED include sevoflurane vs.
halothane administration in patients undergoing MRI (no
surgery)wheretheincidenceofEDwas33%insevoflurane
treated patients versus 0% in halothane treated children.
Post operative agitation can indicate any number of
sources, including pain, physiological compromise, or
anxiety.Deliriummaybeconfusedwithagitation,butitmay
also be a cause of agitation.As most of the literature on this
subject cannot differentiate between these two terms, we
refertotheproblemasEA/EDforthepurposeofthisarticle.
Possible etiological factors of pediatric
emergence delirium
• Rapid emergence
• Intrinsic characteristics of an anesthetic
• Postoperative pain
• Surgerytype
• Age
• Preoperative anxiety
• Child temperament
• Adjunct medication
ANESTHESIA-RELATED FACTORS
Rapid emergence
Postanesthesiaagitationhasbeennotedmoreoftenwith
the newer, less soluble, inhaled anesthetics, such as
desflurane and sevoflurane, than with other volatile ones. It
hasbeenpostulatedthatrapidawakeningaftertheuseofthe
insoluble anesthetics may initiate EA/ED by worsening a
child’s underlying sense of apprehension when finding him
in an unfamiliar environment. Some parents claim the
patient’sbehavioruponemergencewasthesameaswhenhe
was suddenly awakened from deep sleep. Older children
and adults usually become oriented rapidly, whereas
preschool aged children, who are less able to cope up with
environmental stresses, tend to become agitated and
delirious. However, recovery from propofol anesthesia
which is also rapid is smooth and pleasant. Several studies
have shown that sevoflurane anesthesia is associated with a
higher incidence of EA/ED compared with propofol.
Similar results were obtained when desflurane/nitrous
oxide anesthesia was compared with protocol/remifentanil
anesthesia. Delaying emergence by a slow, stepwise
decrease in the concentration of inspired sevoflurane at the
end of surgery did not reduce the incidence of EA, and thus
questions the role of abrupt awakening in the development
ofEA.StudieshaveshownasimilarincidenceofEAamong
children who entered the post anesthesia care unit (PACU)
still asleep and those who entered awake.
Intrinsic characteristics of an anesthetic
Most authors have documented that EA/ED occurs
moreoftenaftersevofluranethanafterhalothaneanesthesia
whichhasbeenconfirmedbythemanufactureritself.Some
authors have speculated that two unique, intrinsic
characteristics of sevoflurane might account for the
development of EA/ED. First, this anesthetic exerts an
irritating side effect on the central nervous system (CNS).
Second, although sevoflurane degradation products appear
to cause no organ damage themselves, data are lacking on
their possible interactions with other types of medications.
Epileptiform activity has been reported during the use of
sevoflurane anesthesia in both patients and volunteers with
no medical history of seizures [4]. However, such cases
have been sporadic and have had an uneventful recovery.
Furthermore, desflurane,which has no proconvulsant
properties,hasbeenassociatedwithasimilar,ifnotagreater
incidence of EA when compared with sevoflurane. These
facts suggest that the causality between theCNS effects of
sevoflurane and EA/ED is unlikely. As for the eventual
neurotoxic influence of sevoflurane degradation products,
there is no supporting scientific evidence. Postanesthesia
agitation has been described not only with sevoflurane and
desflurane, but also with isoflurane and, to a much lesser
extent, with halothane. In a prospective trial that included
521 children aged 3-7 year who were scheduled for elective
outpatient surgery, isoflurane was identified as an
independent risk factor for EA.Children who received
sevoflurane/isoflurane for the induction/maintenance of
anesthesia were twice as likely to develop EA when
compared with children who had any other anesthetic
regimen. Considering that sevoflurane-induced electro-
encephalogram changes are similar to those observed
during the administration of either desflurane or isoflurane,
butdifferentfromchangesrecordedwithhalothane,EA/ED
may be related to the similar CNS effects of these
anesthetics, which may affect brain activity by interfering

4. Review Article
101 Apollo Medicine, Vol. 8, No. 2, June 2011
with the balance between neuronal synaptic inhibition and
excitation in the CNS .
SURGERY-RELATED FACTORS
Pain
Postoperative pain has been the most confounding
variable when assessing a child’s behavior upon emergence
because of the overlapping clinical picture with EA/ED.
Inadequate pain relief may be the cause of agitation,
particularly after short surgical procedures for which peak
effects of analgesics may be delayed until the child is
completely awake. In several studies, the preemptive
analgesic approach successfully reduced EA/ED,
suggesting that pain may be its major source.Intraoperative
administration of IV ketorolac 1 mg/kg for minor
otorhinolaryngological procedures decreased the incidence
of EA three to four times after both halothane (42% vs. 12%)
and sevoflurane anesthesia (38% vs. 14%). Fentanyl, given
either IV 2.5μg/kg or intranasal 2μg/kg during moderately
painful surgery, also decreased EA.Alpha2 receptor
agonists may offer advantages in preventing EA because
they have both analgesic and sedative properties. On the
other hand, post anesthesia agitation has been observed
when pain was efficiently treated or even when absent.
Surgery type
Surgical procedures that involve the tonsils, thyroid,
middle ear, and eye have been reported to have higher
incidencesofpostoperativeagitationandrestlessness[5].It
has been speculated that a sense of suffocation during
emergencefromanesthesiamaycontributetoEAinpatients
undergoing head and neck surgery. However, there are no
supporting scientific data to date.
PATIENT-RELATED FACTORS
Age
Aono, et al. found that ED appeared more often with
sevoflurane than with halothane in pre schoolboys aged 3-5
year (40% vs 10%) [6]. The difference was not observed in
the school-aged population. All children received oral
diazepam for premedication and a caudal block for
preoperative pain control. The authors speculated that the
psychological immaturity of pre-school children, coupled
with the rapid awakening in a strange environment, may
have been the main cause of ED.Generally, younger
children are more likely to show altered behavior upon
recovery from anesthesia.The sub population of those aged
2-5 year seems to be the most vulnerable as they are easily
confused and frightened by unexpected and unpredictable
experiences [7]. In a recent commentary on the diagnosis of
delirium in pediatric patients, Martini addressed the role of
brain maturation in the genesis of this phenomenon [8]. He
pointed out that the pediatric brain is almost a mirror image
of a normal age-related regressive process with a
consequent decline in nor epinephrine, acetylcholine,
dopamine, and gamma amino butyric acid (GABA). Thus,
the development of cholinergic function and the
hippocampus may suggest clues about the relative
susceptibility of younger children to delirium.
Preoperative anxiety
Intense preoperative anxiety, both in children and their
parents,hasbeenassociatedwithanincreasedlikelihoodof
restless recovery from anesthesia. Kain, et al.
retrospectively searched their database to determine the
relationship between preoperative anxiety, ED, and
postoperative maladaptive behaviors [9]. They recruited
791 children who were not premedicated and underwent
surgery and genera anesthesia using sevoflurane. The odds
of having marked symptoms of ED were increased by 10%
for each increment of 10 points in the child’s state anxiety
score.However,acauseeffectrelationshipbetweenthetwo
phenomenacouldnotbedemonstrated.Otherauthorsfailed
to show a correlation between preanesthetic distress and
ED, possibly because of the small total number of patients
studied and the use of a self-developed, no standardized
observational scale for evaluating children’s distress.
Temperament
Children who are more emotional, more impulsive, less
social, and less adaptable to environmental changes were
identified to be at risk for developing post anesthesia
agitation [10]. It is likely that there is some substrate innate
to each child that will elicit, to a larger or lesser extent, a
fearful response to outside stimuli, depending on the
interaction between the child and the environment. This
reactivity, which describes the excitability, responsivity, or
arousability of the child , might be the underlying substrate
fromwhichbothpreoperativeanxietyandEDarise.Patient-
related factors are an important source of variability among
studies in the incidence of EA/ED as they are most difficult
to control when investigating this phenomenon. In general
children who are calm and quiet upon arrival to the
preoperative area and do not show any signs of distress for
procedureslikevenepunctureorinhalationalinductionwith
face mask hardly show any signs of ED/EA in the post
operativeperiod.Thisisaconsistentfindinginourhospital.
ADJUNCT MEDICATION
Numerous drugs, including anticholinergics,
droperidol, barbiturates, opioids, benzodiazepines, and
metoclopramide,maycontributetobehavioraldisturbances
after anesthesia.

5. Apollo Medicine, Vol. 8, No. 2, June 2011 102
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In summary, none of the above-discussed factors has
been proven to be the sole underlying cause of EA/ED.
However, each factor, especially when combined with the
others,mayinfluencethebehaviorofachildemergingfrom
anesthesia.The greatest barrier to a better understanding of
the EA/ED etiology arises from the difficulty in comparing
studies that used different definitions, age spans, surgical
procedures, and measuring tools, as well different sedative,
analgesic, and other adjunct medication.
ASSESSMENT TOOLS FOR MEASURING EA/ED
Applying more than 15 different rating scales to
measure EA/ED in clinical investigations suggests that
none are sufficiently specific and sensitive to assess
children’s behavior upon emergence In addition, it is
difficult to interpret behavior in small children who are not
able to verbalize pain,anxiety, hunger, or thirst. Finally,
opinions diverge on the point at which emergence extends
beyond“normal”.Agitation,whichissimpletoassess,isthe
most frequently used descriptor for emergence behavior in
childrenMostauthorsdeveloped3-5pointratingscalesthat
used either crying or thrashing requiring restraint as their
thresholdforagitation,whichhadasignificantinfluenceon
the calculated incidence of the event. Thus, Cravero, et al.
recorded EA in 80% of sevoflurane patients when crying
was used as a threshold, but in 33% of patients only when
thrashing was applied as the threshold for agitation [5].
Several studies have tried to distinguish pain-related
agitation from other sources by incorporating both pain and
agitation scales into the methodology. Postoperative
agitation alone, however, does not always indicate
significantbehavioralchangesassociatedwithdelirium.An
accurate differen-tiation of delirium from other sources of
agitation requires the identification of more complex
symptoms of an acute mental disturbance. This
differentiation may be difficult in young children who are
often oppositional and unable or unwilling to answer.
Przybylo,etal.describedanassessmenttoolthatisbasedon
the items listed in the Diagnostic and Statistical Manual of
Mental Disorders-IV for the diagnosis of delirium, but
eliminated signs and symptoms that required verbalization
or skill demonstration [11]. Their scoring system studied
perceptual disturbances, hallucinations, and psychomotor
agitation in 25 children aged 2-9 years who were
premedicated with midazolam and randomized to receive
either isoflurane or remifentanil for strabismus surgery.
Rectal acetaminophen was given for postoperative pain
relief. The authors concluded that while 44% of children
showed altered behavior upon emergence, only 20% had
complex symptoms that were consistent with delirium.
Furthermore, none of these children either verbalized pain
or received pain medication during the assessment period,
reflecting the measurement of the phenomenon that was
independent of pain induced agitation.Sikich and Lerman
developed the pediatric anesthesia emergence delirium
(PAED)ratingscalethatconsistsoffivepsychometricitems
for the measurement of ED in children [12]. According to
theDiagnosticandStatisticalManualofMentalDisorders-
IV,threeoftheseitemsareanimportantpartofdeliriumand
may be crucial to its differentiation from pain .Adecreased
ability of the child to make eye contact with the caregiver
and a declined awareness of his surroundings reflect
disturbances in consciousness with a reduced ability to
focus, sustain, or shift attention. Less purposeful actions
suggest cognitive changes that include perception and
memory impairment as well as disorganized thinking
patterns. Two other items, restlessness and inconsolable
crying, reflect a disturbance in psychomotor behavior and
emotion, although they may also suggest pain or
apprehension. The PAED scale score correlated negatively
with the child’s age and time to awakening and was
significantly greater in children who received sevoflurane
than in those who received halothane. These results and
those of another study support the reliability and validity of
the PAED scale. Unfortunately, the authors did not define
the ED threshold, which makes the calculation of its
incidence impossible and the development of therapeutic
approaches rather difficult.
PREVENTION AND TREATMENT
Given that the EA/ED etiology is still unknown, a clear
cut strategy for its prevention has not been developed. Data
on the possible role of premedication in reducing EA/ED
have been conflicting. Preoperative administration of
midazolam decreased postoperative agitation after both
sevoflurane and desfluraneanesthesia, with no delay in
discharge from hospital. When analyzing those rare trials
that failed to reveal the difference between sevoflurane and
halothane in the incidence of EA/ED, it was striking to note
that midazolam was used consistently, although at different
dosages and via different routes of administration.
Sevoflurane at high concentrations has been shown to
enhance, and at low concentrations to block, GABA A
receptor-mediated inhibition of neurotransmission in the
CNS. Olsen, et al. Suggested that midazolam may improve
recovery after sevoflurane administration by enhancing the
inhibitory effects of GABA A receptors [13]. This
proposition is supported by findings of a calmer recovery
fromsevoflurane-maintainedanesthesiawheninducedwith
propofol but not with sevoflurane. Another possible
explanation is that stressful induction and/or a rapid return
to consciousness in non-premedicated children may result
in more behavioral disturbances upon emergence .On the
other hand, there are studies in which midazolam
premedication did not show any benefit on the quality of
recovery from anesthesia.This finding may possibly be the

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103 Apollo Medicine, Vol. 8, No. 2, June 2011
result of applying a nonspecific measuring tool or a
provision of inadequate pain control. The combination of
midazolam and a small dose of diazepam may extend the
beneficialeffectsofpremedicationuntiltherecoveryphase,
which decreases the incidence of EA/ED. Paradoxically,
Cole, et al. reported an almost nine fold higher risk of the
developmentofEAinchildrenwhowerepremeditatedwith
midazolam over those who were not premedicated before
outpatient surgery under either isoflurane or halothane
anesthesia [7]. Benzodiazepines themselves are associated
with paradoxical reactions and agitation that are reversed
with flumazenil. Furthermore, theantianalgesic effects of
midazolammightworsenpainandincreasetheincidenceof
nonspecific agitation that resembles ED. Premedication
with melatonin has proven to be a good alternative to
midazolam in reducing postoperative excitement
Oxycodone has been shown to decrease the frequency of
agitation in children undergoing halothane, but not
sevoflurane, anesthesia for myringotomy procedures. Both
oral ketamine and oral transmucosal fentanyl citrate were
also helpful, although the latter increased the incidence of
side effects. Some authors have advocated switching
anesthetics after induction, despite a lack of scientific
evidence supporting this practice.Various preemptive
analgesic approaches, including caudal block, fentanyl,
ketorolac, clonidine, and dexmedetomidine, have been
recommended to eliminate pain as a potential source of
discomfortandagitation.OnetrialsuggeststhatIVfentanyl
1μg/kg before the conclusion of sevoflurane anesthesia
decreases EA even after no painful procedures, while
leaving the time of discharge unchanged [14]. On the other
hand, parental presence in the operating theater appeared to
have no influence on the incidence and/or severity of
distress behavior upon emergence. As for managing EA/
ED, certain steps should be taken to protect the child from
self-injury. Holding, as a means of providing physical
restraint, and engaging more than one caregiver are often
necessary. As the child may be upset by environmental
stimuli,itisimportanttoprovideaquiet,darkenedrecovery
room. The decision of whether to treat EA/ED with
additional medication depends upon the severity and
duration of symptoms. Many studies have shown that EA/
ED is self-limited, resolving without pharmacological
intervention over time. Rescue medication includes
analgesics,benzodiazepines,andhypnotics.FentanylIV1-
2μg/kg, propofol IV 0.5-1.0 mg/kg, and midazolam IV
0.02–0.10 mg/kg have all been used for the treatment of ED
[15].Asinglebolusdoseofdexmedetomidine0.5μg/kgwas
also shown to be efficient in the PACU forED. Voepel-
Lewis, et al. found that PACU nurses caring for agitated
children most often administered analgesics/sedatives as
the first intervention, irrespective of the primary cause of
agitation[16].However,themosteffectiveinterventionwas
reuniting with a parent. The authors also developed the
postoperative agitation algorithm, which may serve as a
guide for the assessment and treatment of ED in the PACU.
LONG-TERM CONSEQUENCES
There is no evidence that EA/ED has any impact on
long-term outcome [17].Akin, et al. suggested that ED and
new-onsetpostoperativemaladaptivebehaviorchangesare
closely associated. The authors found that the odds ratio of
having one or more new onset postoperative maladaptive
behavior changes is 1.43 for children with marked
emergence status when compared with children with no
symptoms of ED, but did not suggest a cause effect
relationship between these two phenomena.
SUMMARY
It appears that almost half a century after the first cases
of emergence agitation/emergence delirium(EA/ED) were
reported[18],wedonotknowmuchmoreaboutitsetiology,
nor do we have a reliable assessment tool or clear-cut
preventive strategy for this short lived but troublesome
clinical event. Both sevoflurane and desflurane (and
possibly isoflurane) are indisputably associated with a
higher incidence of altered behavior upon emergence than
areeitherhalothaneorpropofol.Itisdoubtlessthatyounger
age, preoperative anxiety, and pain are all important
contributory factors. However, there are still many
questions that deserve answers. What links the above-
mentioned inhaled anesthetics to EA/ED? Are we able to
identify a child who is at risk for the development of ED
without engaging psychologists to interpret extensive
questionnaires about their temperaments? Will the use of
complicated psychometric tests for the evaluation of a
child’s mental status upon emergence change our
therapeutic approach when either agitation or delirium
occurs? Finally, shall we wait for this behavior to resolve
spontaneously and risk a child’s self injury and parental
distress, or treat it routinely and face potential adverse
effectsofthegivenmedication?Obviously,furthertrialsare
necessary to discover the underlying causes of EA/ED and
to determine which factors might help predict and
potentially prevent it. For consistency, it seems reasonable
for studies to target the most vulnerable population of
preschool aged children scheduled for similarly painful
surgical procedures and to stratify patients with regard to
their temperament. In addition, pain must be tightly
controlled and standardized measuring tools used to
evaluate post anesthesia behavior.
It is important to remember that several life threatening
considerations (e.g., hypoxia, severe hypercarbia, hypo-
tension, hypoglycemia, increased intracranial pressure)
may also result in disorientation and altered mental status.

7. Apollo Medicine, Vol. 8, No. 2, June 2011 104
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These entities must be diagnosed and treated promptly.
Bladder distention may also yield a similar clinical picture.
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