REVIEW

CURRENT
OPINION Update on pharmacological management of
procedural sedation for children
Mark G. Roback, Douglas W. Carlson, Franz E. Babl, and
Robert M. Kennedy

Purpose of review
The review provides an update on pharmacological techniques for procedural sedation for children outside
the operating room.
Recent findings
An increasing number of studies of propofol, ketamine, nitrous oxide, dexmedetomidine, and intranasal
administration of drugs for procedural sedation of children continue to be reported.
Summary
Propofol and ketamine are commonly used for procedural sedation in children and the use of
dexmedetomidine and nitrous oxide is increasing. Although the intravenous route remains the mainstay;
intranasal drug administration is increasingly used for anxiolysis and moderate sedation.
Keywords
dexmedetomidine, intranasal, ketamine, nitrous oxide, propofol

INTRODUCTION sedation providers must consider variable rates of

When choosing drugs or combinations of drugs for
the sedation of children, many factors must be con-
sidered to ensure well tolerated, successful sedation
which facilitates the completion of necessary pro-
cedures [1]. The targeted depth of sedation, the
childs health status including fasting state, and
the properties of the agents to be administered all
play important roles [2]. This chapter is dedicated to
reviewing the most common procedural sedation
drugs and combinations administered to children
outside the operating room. We will provide infor-
mation about the effects and adverse effects of these
agents, review indications and contraindications and
outline practical applications of sedation drugs,
focusing on how their use has evolved over the past
2 decades.
ORAL SEDATION
Many oral drugs have been administered to children
with the intent of achieving anxiolysis or minimal
sedation. With higher doses or coadministration of
opioids or other sedatives, deeper levels of sedation
may be achieved; however this practice has also been
associated with more adverse effects [3,4]. To deter-
mine the optimal clinical use of oral sedation,
absorption, slower onset, and longer duration of
action. Oral agents, including chloral hydrate, benzo-
diazepines, and antihistamines have been used,
sometimes with opioids, with varying degrees of
success, to sedate children for dental procedures,
radiographic imaging, urodynamic testing, and lac-
eration repair [58].
The sedative-hypnotic drug, chloral hydrate, and
the benzodiazepine, midazolam are two commonly
administered oral sedatives [3,5,8]. Oral midazolam
decreases distress in children [9], however, unreliable
absorption and first-pass hepatic metabolism cause
clinical effects to be less reliable than intranasal or
parenteral routes of administration [8].
Chloral hydrate has a wide dosing range (50
100 mg/kg, max 2 g), onset of action is 1560 min
and a duration of action of 14 h. Additionally,
chloral hydrate has no analgesic properties making
Department of Pediatrics, University of Minnesota Masonic Childrens
Hospital, Minneapolis, Minnesota, USA
Correspondence to Mark G. Roback, MD, Division of Emergency Medi-
cine, M653 East Building, 2450 Riverside Avenue, Minneapolis, MN,
55454, USA. E-mail: mgroback@umn.edu
Curr Opin Anesthesiol 2016, 29 (suppl 1):S21S35
DOI:10.1097/ACO.0000000000000316

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Therapeutics in sedation
KEY POINTS
 New options for more specific and well tolerated,
patient-centered, procedural sedation in children
are evolving.
 Ketamine and propofol are commonly administered.
 N2O and dexmedetomidine are increasingly used.
 Intranasal agents have expanded from midazolam to
include intranasal fentanyl and dexmedetomidine.
it most useful for the sedation of infants undergoing
diagnostic imaging procedures [10]. Although gener-
ally described to be well tolerated, infants and chil-
dren who receive chloral hydrate have been reported
to experience adverse effects, including respiratory
depression and apnea [5,6,10,11]. Even when admin-
istered well within the recommended maximal dose
limits, chloral hydrate can cause serious morbidity
and mortality [12].
PARENTERAL SEDATION DRUGS AND
COMBINATIONS
Midazolam
Midazolam is a rapid-onset, short-acting benzo-
diazepine that has anxiolytic, hypnotic, anticonvul-
sant, muscle relaxant, and antegrade amnestic
effects [13,14]. Midazolam has no direct analgesic
properties [10]. As recent as 2006, midazolam was
described as the most widely used intravenous (IV)
sedative in the emergency department (ED) for
adults, as well as children [15]. Over the past 10
years, the use of midazolam has evolved. Histori-
cally, midazolam has been administered IV, [16]
usually with morphine or fentanyl [1721] for mod-
erate-to-deep sedation and analgesia or orally for
anxiolysis [8]. Intranasal midazolam use for anxiol-
ysis has grown significantly in recent years [2224].
Limitations of the amnestic properties of midazolam
are emphasized in a recent comparison of midazo-
lam to propofol in children who received sedation
for upper gastrointestinal endoscopy [25].
Mechanism of action
Almost all of the effects of midazolam result from its
action on g-aminobutyric acid (GABA) type A recep-
tors in the central nervous system (CNS) [13,14].
Pharmacokinetics
Midazolam is lipophilic and has a rapid onset of
action (23 min) when administered IV. Duration of
action is generally short and clearance depends on
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hepatic cytochrome P450 enzymes which metab-
olize the drug [10,14].
Circulation
Midazolam causes a modest reduction in arterial
blood pressure and, as a result of a decrease of
systemic vascular resistance, an increase in heart
rate [14]. The negative inotropic effects of midazo-
lam, although mild in healthy children, can be
significant in children with underlying cardiac dys-
function [10].
Ventilation
Midazolam has a dose-dependent ventilatory
depressant effect [14] which is significantly poten-
tiated with the addition of opioids [1].
Adverse effects
Administration of midazolam is associated with
increased adverse respiratory events when combined
with fentanyl or with ketamine [1,1820,26].
Routine coadministration of midazolam with ket-
amine has not been found to reduce emergence
dysphoria [26,27] but may be associated with
reduced postdischarge negative behaviors [28].
Because midazolam/fentanyl provides children
with more frequent respiratory depression and less
effective sedation, ketamine and propofol-based
sedation have become more commonly administered
for moderate-to-deep sedation and analgesia
&&
[21,24,29 ].
Paradoxical reactions
Dysphoria, inconsolable crying, agitation, combat-
iveness, disorientation, and restlessness occur after
midazolam administered IV as a sole agent at a rate
of 1.43.4% in two large case series of children
[30,31]. Paradoxical reactions may also occur after
oral, rectal, or intranasal midazolam [32,33] and
may be successfully reversed with flumazenil IV
[32,34]. Paradoxical reactions are less common
when midazolam is given with an opioid [35].
Flumazenil
Flumazenil is a central-acting benzodiazepine
antagonist which can be used to counteract signifi-
cant respiratory depression because of midazolam.
Although flumazenil is primarily used as a rescue or
reversal agent for respiratory depression, it also
antagonizes the anticonvulsant properties of mid-
azolam and should not be administered in patients
who receive benzodiazepines for seizure control
and is not recommended for routine use in drug
overdoses [10,35]. Traditionally administered IV,
flumazenil has also been shown to be effective intra-
nasally [36].
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Brief procedures
Midazolam is administered alone for anxiolysis or in
conjunction with an opioid such as fentanyl to pro-
vide amnesia for residual pain during moderate-
to-deep sedation and analgesia for a variety of
procedures, including laceration repair, oncologic
procedures, endoscopy, and fracture reduction
[1523].
Administration
Anxiolysis is usually achieved with an IV dose of
0.05 mg/kg, maximum 2 mg. For sedation, midazo-
lam can be titrated IV with 0.1 mg/kg typically an
effective initial dose IV [1].
Ketamine
Ketamine has become the most widely used sedation
agent for painful procedures because of its potent
analgesic and amnestic effects with minimal respir-
atory or circulatory depression [37]. Relative sparing
of effects on protective airway reflexes makes it
especially useful for procedures in nonfasted ED
patients. Studies in the past decade have helped
clarify beneficial and adverse effects associated with
ketamine administration.
Mechanism of action
Ketamine has unique and diverse mechanisms
of action. It binds to multiple sites, including
N-methyl-d-aspartate (NMDA) and non-NMDA
glutamate, nicotinic and muscarinic cholinergic,
and opioid receptors. Ketamines primary site of
anesthetic action is in thalamocortical pathways
and the limbic system where binding inhibits glu-
tamate activation in a noncompetitive manner and
is time and concentration dependent [3840].
Pharmacokinetics
Lipophilic ketamine rapidly crosses from blood into
the brain with an approximate distribution half-life
of 24 s, redistribution half-life of 4.7 min, and elim-
&&
ination half-life of 2.2 h [41,42,43 ].
Circulation
Cardiac output is usually well maintained with
ketamine administration. Ketamine increases
blood pressure and heart rate 1030% by blocking
reuptake of norepinephrine, epinephrine, dopa-
mine, and serotonin. However, ketamine also has
a negative inotropic effect on the heart that is
usually not clinically apparent because of the sym-
pathetic stimulation [44]. In critically ill patients
whose catecholamines are depleted, ketamine
may cause marked hypotension and bradycardia
or cardiac arrest [4547].
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Procedural sedation for children Roback et al.
Intracranial pressure
Use of ketamine in ventilated patients with trau-
matic brain injury has been shown to reduce intra-
cranial pressure and improve cerebral perfusion
pressure [4850]. Recent systematic reviews have
concluded that in well ventilated patients, with
and without traumatic brain injury, ketamine does
not increase intracranial pressure [5155]. Alterna-
tive agents should be considered, however, in
patients with cerebrospinal fluid (CSF) shunt mal-
function or other conditions with acute excess CSF
accumulation, such as early postmeningitis, intra-
ventricular hemorrhage, or other causes of impaired
CSF circulation or dynamics [56,57].
Ventilation
In contrast to other sedative-analgesic agents, doses
of ketamine typically used for procedural sedation
rarely cause clinically significant effects on respirat-
ory rate, tidal volume, minute ventilation, or end-
tidal carbon dioxide, thus maintaining adequate gas
exchange during unobstructed spontaneous room
air breathing [5861]. A pooled analysis of pediatric
ketamine sedations performed in the ED found the
overall incidence of airway and respiratory adverse
events (upper airway obstruction, apnea, oxygen
desaturation less than 90%, or laryngospasm) was
3.9% with increased risk associated with initial IV
doses of more than 2.5 mg/kg or total doses more
than 5.0 mg/kg, age less than 2 years or 13 years or
older, and coadministration of anticholinergics or
benzodiazepines. The overall frequency of apnea
was 0.8% [62].
Emesis
Vomiting usually occurs during recovery from
ketamine sedation and after discharge [18]. Emesis
occurs in 825% of children with higher rates
associated with coadministration of opioids, higher
doses, intramuscular administration, and increasing
age (peak at 12 years) [27,6365]. Administration of
ondansetron reduces vomiting during recovery
from 13 to 5% and after discharge from 19 to 8%
[63]. Midazolam coadministration also reduces
vomiting but is associated with slightly increased
risk of oxygen desaturation [20,26]. The risk of
emesis does not appear to be associated with fasting
status in ED patients [18,66,67].
Laryngospasm
While upper airway reflexes are usually preserved
during ketamine sedation, there is concern for a risk
of rare, but potentially life-threatening, laryngo-
spasm during induction, maintenance, or recovery
phases. Analysis of 8282 ED ketamine sedations,
including 22 occurrences of laryngospasm, found
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Therapeutics in sedation
an incidence of 0.3% [62]. Analysis found no
association with age, dose, or other clinical factors,
[68] but associations could not be determined
with upper respiratory infection, wheezing, or other
risk factors associated with increased risk during
general anesthesia [69]. Clinicians administering
ketamine must be prepared for rapid identifica-
tion and management of laryngospasm, which is
usually brief and typically responds to continuous
positive airway pressure [70]. A low dose of succi-
nylcholine may be needed to break severe laryngo-
spasm [71,72].
Hypersalivation
Coadministration of atropine or glycopyrrolate
reduces excess salivation that occurs in some chil-
dren with ketamine administration but does not
reduce the frequency of adverse events [7377].
Use of antisialogogues may be beneficial in children
with active upper respiratory infections.
Psychotomimetic effects
Dysphoria, hallucinations, and distressed behavior
have been reported to occur in up to 7% of children
recovering from sedation with ketamine
[18,26,78,79]. This frequency is similar to obser-
vations during recovery from sedation with fentanyl
and midazolam and general anesthesia [18,28,80].
These reactions to ketamine have not been found to
be associated with childrens age [63,78]. Most
unpleasant reactions occur briefly during recovery
and postdischarge effects and changes in behavior
are similar to those after fentanyl and midazolam
sedation and resolve within the first week
[18,28,79]. Routine coadministration of midazolam
has not been found to reduce emergence dysphoria
[26,27] but may be associated with reduced postdi-
scharge negative behaviors [28]. Whether adminis-
tration of midazolam prior to ketamine sedation
may be particularly beneficial to children with high
levels of anxiety is unclear [81]. Parents should be
counseled about potential dysphoria during recov-
ery from all sedation techniques and the possibility
of subtle behavior changes and even nightmares in
the week following procedural sedation [28,82].
Psychiatric effects
Because ketamine induces schizophrenic like effects
during recovery in normal adults and has been
reported to exacerbate psychosis in patients with
schizophrenia, many clinicians avoid ketamine use
in patients with a diagnosis of psychosis [36,83,84].
More recently, ketamine has been shown to produce
a rapid, yet transient, antidepressant effect in adults
with depressive disorders [85].
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Neurotoxicity
Exposure to ketamine and other anesthetic agents
during early stages of postnatal brain development
increases central nervous system neuronal apop-
tosis in animals receiving significantly larger and
more prolonged doses than used for procedural
sedation [86]. No studies in human infants have
found evidence of neuronal injury after a single ket-
amine based sedation but use of ketamine for
repeated procedures in infants may have detrimental
effects [87].
Painful procedures
Ketamine provides significantly greater reduction in
distress with significantly less respiratory depression
in children undergoing brief painful procedures,
such as fracture reduction, burn debridement,
abscess incision and drainage, laceration repair,
lumbar puncture, and bone marrow aspiration, than
other common sedation agents [18,20,36].
Administration
Ketamine may be administered IV, intramuscularly
(IM), intranasally, or orally [36,62,63,88,89].
The following doses are for racemic ketamine. If
S-ketamine is used, doses should be about 50% of the
racemic doses.
IV administration allows for titration, facilitates
additional dosing and aids management of adverse
events. A dose of 1.52 mg/kg administered over
3060 s reliably induces dissociative-deep sedation
with full recovery between 12 h [62]. A recent study
demonstrated smaller doses (0.70.8 mg/k) of ket-
amine administered rapidly (less than 5 s) results in
35 min of sedation effective for simple fracture
reduction, with recovery by 2025 min, and had
similar low rates of adverse effects to the traditional
&&
technique [43 ].
Intramuscular administration has a similar rate
of airway and respiratory adverse events when com-
pared with IV administration, but recovery is longer
and vomiting more common [8890].
Propofol
Propofol (2,6-disopropylphenol) is a short acting, IV
administered hypnotic agent. Propofol is in oil state
at room temperature and is insoluble in aqueous
solution. The current formulation was first pro-
duced in 1986 [9193]. Propofol administered
alone, or in combination with other agents is used
in a wide variety of settings for sedation. Bolus
propofol is used for short procedural sedation,
whereas a continuous infusion may be employed
for prolonged, motionless sedation. As propofol has
Volume 29  Supplement 1  March 2016

no analgesic effect, it should be used in adjunct with
other medications such as fentanyl or ketamine for
painful procedures [93101].
Mechanism of action
Propofol is a global central nervous system depres-
sant. It potentiates GABA receptor activity, inhibits
NMDA receptors, and modulates calcium influx
through slow calcium ion channels. Propofol has
a rapid onset of action with a dose-related hypnotic
effect. Electroencephalogram (EEG) studies per-
formed during general anesthesia show that propo-
fol causes a reduction in g-wave band frequencies
[9193,102].
Pharmacokinetics
Propofol is highly protein bound and is metabolized
in the liver. Elimination half-life is long, ranging
from 13 to 44 h [92]. Despite the long half-life, blood
propofol concentrations approach steady state
within 20 min since propofol has multicompart-
ment pharmacokinetics with a very short distri-
bution half-life. Thus the effect of propofol is
rapid onset of sedation, and sedation effect typically
wears off within a few minutes, even after repeated
doses or prolonged continuous infusion [9193].
Circulation
Dose-dependent hypotension is the most common
cardiac complication [92]. Blood pressure drops of
30% or more are thought to be partially because of
inhibition of sympathetic nerve activity [93]. The
effect is related to dose and rate of administration
and is accentuated in volume-depleted patients. The
hypotension caused by propofol does not seem to
alter end-organ perfusion [96,98,103,104].
Ventilation
Propofol frequently causes apnea and airway
obstruction, even at standard induction doses [93].
Respiratory depression seems to be infusion rate
related, and generally resolves quickly during initial
drug redistribution. Propofol depresses central
inspiratory drive and may decrease respiratory rate,
minute volume, tidal volume, mean inspiratory
flow, and functional residual capacity [92,93,96,
98,103,104].
Intracranial pressure
Propofol decreases cerebral oxygen consumption,
diminishes cerebral blood flow, reduces intracranial
pressure, and has anticonvulsant properties [92,93].
Pain with injection
Propofol infusion causes significant pain in about
60% of adults and probably more often in children
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Procedural sedation for children Roback et al.
[105]. This pain can be severe and often is the only
recalled distressing part of a procedure. Pain can be
reduced by use of large antecubital veins and pre-
treatment using lidocaine in conjunction with
venous occlusion. Coadministration of a small dose
of opioid before administration also decreases the
number of patients reporting discomfort [105].
Propofol infusion syndrome
Severe metabolic acidosis, found in some children
receiving propofol sedation for more than 12 h, is
thought to be associated with mitochondrial dys-
function because of alteration of electron transport
[106].
Allergy
Propofol contains egg phosphatide; however, it is
not clear that a history of egg allergy increases the
risk of allergic reaction to propofol [107].
Radiologic procedures
Propofol infusion has been shown to be highly
effective for magnetic resonance imaging (MRI),
computed tomography (CT), nuclear medicine
scans and other prolonged studies which require
motionless sedation [96,103,108]. Sedation experts
with various clinical backgrounds have shown com-
parable efficacy, efficiency, and safety with use of
propofol [96,98,103,105,108112].
Brief/painful procedures
For brief, nonpainful procedural sedation, propofol
has been effective given in a single bolus dose with
repeated doses as needed. Propofol with a coadmi-
nistered analgesic has been shown to be effective
for fracture reduction, burn debridement, abscess
drainage, bone marrow aspiration and other painful
procedures [94,97,99,101]. The combination of
ketamine and propofol, sometimes referred to as
ketofol, has been shown to be effective for brief
painful procedures [113,114].
Administration
For prolonged, nonpainful procedural sedation, pro-
pofol is generally given as a single agent, initial
dose is 12 mg/kg IV followed by an infusion of
75200 mcg/kg/min [98,101]. For painful pro-
cedures, propofol is given in combination with an
analgesic, commonly fentanyl 1 mcg/kg IV [101].
Initial bolus dose of propofol is 1 mg/kg followed
by doses of 0.51 mg/kg to achieve the level of
sedation required [102,103]. When propofol and
ketamine are given together, the ratio of the com-
bination and the amount of drug given varies
between studies [113117].
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Therapeutics in sedation
KetaminePropofol Combination
As described previously, ketamine and propofol are
commonly administered sedatives for children.
Both drugs provide predictably consistent sedation
with manageable adverse effects [37,62,108,118]
Coadministering ketamine with propofol, ketofol,
has become a popular sedation technique in adults
because of the theoretical counteraction of the
adverse effects of each drug; the combination
allows use of smaller dose of each, thus potentially
improving the quality, safety, and duration of pro-
cedural sedation [114,119,120]. Three studies of
ketofol sedation in children have been published
[113,116,121] along with one combined child/adult
study [114]. Overall, case series of ketofol [116,121]
and comparisons of ketofol to ketamine alone [113],
propofol alone [122], or propofol along with fen-
tanyl [114] have failed to demonstrate objective
benefits of ketofol [123]. Altering the concentration
of ketamine-to-propofol also failed to show appreci-
able benefits over propofol administered alone for
procedural sedation in adults [120]. Additional stud-
ies are needed to clarify advantages and disadvan-
tages of this sedation technique in children [119].
Dexmedetomidine
Dexmedetomidine is an a-2 adrenergic agonist and
was initially approved in 1999 for sedation of adults
in the ICU [124126]. Despite lack of pediatric label-
ing, pediatric applications of dexmedetomidine
have increased. The drug possesses many properties
that are advantageous for pediatric sedation
[127,128]. The sedation provided parallels natural
sleep. There is increasing evidence supporting organ
protective effects against hypoxic-ischemic injury.
Dexmedetomidine is often used as an adjunct to
general anesthesia; its most common use outside
the operating room is for prolonged motionless
sedation. Dexmedetomidine may be used as a sole
agent or in addition to other drugs, including ket-
amine, midazolam, or opioids [129133].
Mechanism of action
Dexmedetomidine is unique because its actions are
not mediated by the GABA mimetic system and does
not, by itself, suppress the respiratory drive. It has
sedative, analgesic, and antishivering properties
[124136]. The sedative properties of dexmedeto-
midine are produced by stimulation of a-2 receptors
on presynaptic neurons [125,126,134]. The effect
is a decrease in norepinephrine release from pre-
synaptic neurons with initiation of postsynaptic
activation, attenuating central nervous system exci-
tation.
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Pharmacokinetics
There are limited numbers of studies of the pharma-
cokinetics in children. When administered IV, 93% of
dexmedetomidine is protein bound [124]. The rapid
phase redistribution half-life is approximately 7 min,
and the terminal elimination half-life is approxi-
mately 2 hours [125,126]. Dexmedetomidine is
biotransformed in the liver to inactive metabolites.
A very small amount is excreted unchanged in urine
and feces. Bioavailability of dexmedetomidine is
oral gastric 16, intranasal 65, buccal 82, and IM
104% [134,135].
Circulation
In lower doses SBP decreases of up to 30% are found.
In higher doses dexmedetomidine may cause periph-
eral vasoconstriction, which may lead to transient
systemic hypertension [129]. Heart rate decreases up
to 30% from awake measurements after initial bolus
have been reported. Children who do develop
bradycardia maintain their SBP within normal limits.
Poor end-organ perfusion because of the cardiac
output changes has not been reported [129132].
Respiratory
A key advantage of dexmedetomidine is that it
maintains ventilation and airway patency in the
presence of increasing sedation [125]. End-tidal
carbon dioxide is also maintained during spon-
taneous respiration with deep sedation in contrast
to many other sedative regiments in children. Chil-
dren with obstructive apnea have been reported to
need less artificial airway support than during seda-
tion with other agents [126,129,130].
CNS effects
Dexmedetomidine decreases cerebral blood flow in
proportion to a decrease in cerebral metabolic
rate [125]. EEG studies done under dexmedetomi-
dine sedation resembled that of natural nonrapid
eye movement sleep. Dexmedetomidine may be
particularly appropriate for EEG studies in children
[126,136,137].
Adverse effects
Dexmedetomidine has a slower onset of action and
longer half-life than some other drugs commonly
used for pediatric sedation [124126]. When pro-
longed sedation is desired, augmentation with
small amounts of other drugs may be required.
Bradycardia, hypotension, and sinus arrhythmias
have been described at standard doses, but in these
studies interventions for these adverse effects have
not been needed. Dexmedetomidine has modest
analgesic effect but requires combination with other
Volume 29  Supplement 1  March 2016

analgesics for painful procedures. These combi-
nations have been shown to increase the risk for
airway intervention [129,131,134,138].
Radiological imaging
The primary use in children for sedation is for MRI
and CT scans [130,131]. Dexmedetomidine has
compared favorably with other sedative agents in
successful outcomes for motionless sedation as a
sole agent or in combination with other agents.
When compared with propofol, the success rate of
MRI was similar, but onset of sedation and total
length of sedation are prolonged [139]. Dexmede-
tomidine may be effective in patients with devel-
opmental delay including autism, especially by the
intranasal or buccal route [133,135,138,139].
Administration
Recommended doses in studies vary. When given IV
for a prolonged procedure there is usually an induc-
tion dose of 23 mcg/kg administered over 10 min
followed by a maintenance infusion of 12 mcg/kg/
hour [128]. For short procedures, a single dose of
2 mcg/kg has shown to be effective. Suggested dos-
ing by intranasal and buccal route is 23 mcg/kg.
With less bioavailability by the oral route, doses
should be increased; suggested dosing is 5 mcg/kg
[130,131,140142].
Etomidate
Etomidate is an ultrashort acting, imidazole-derived,
sedative-hypnotic agent [143145] which is com-
monly administered to children for induction of
rapid sequence intubation [146148]. Because of its
sedative properties, rapid-onset but short duration of
action, and relative lack of significant hemodynamic
and respiratory effects, [144146] etomidate is used
for procedural sedation for brief, nonpainful pro-
cedures such as CT scans [149,150]. When adminis-
tered with an analgesic such as fentanyl, etomidate
may also be used for brief, painful procedures, such as
orthopedic reduction, abscess incision and drainage,
cardioversion, and oncology-related procedures
[15,151157].
Mechanism of action
Similar to benzodiazepines, propofol and barbi-
turates, etomidate provides sedation/anesthesia
through binding GABA receptors in the central nerv-
ous system [143,144]. Onset of action (515 s) and
time to recovery (515 min) are rapid and compar-
able to propofol and thiopental but significantly
faster than midazolam [145]. Etomidate inhibits
adrenal steroid synthesis primarily by blocking the
activity of the mitochondrial cytochrome enzyme,
CYP11B1 [143].
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Procedural sedation for children Roback et al.
Pharmacokinetics
Because of its high-fat solubility, etomidate has a large
central and very large peripheral volume of distri-
bution. Etomidate has three distinct declines in
plasma level phases which explain the shorter
duration of hypnosis (about 8 min) than duration
of adrenocortical suppression (about 8 h) following
a single dose [143].
Circulation
Etomidate has limited effects on cardiovascular
function and does not appreciably affect mean arte-
rial pressure, cardiac output, or systemic vascular
resistance [144]. At doses of 0.20.4 mg/kg IV, eto-
midate produces minimal cardiovascular changes,
even in patients with heart disease [143].
Ventilation
Similar to most sedative drugs, etomidate has dose-
dependent respiratory depressant effects and, at
higher doses or when coadministered with other
agents, may induce apnea [144]. Studies of etomi-
date for sedation report oxygen desaturations in
1739%, and infrequently, apnea [15,149,152,155].
Intracranial pressure
Similar to propofol and barbiturates, etomidate
decreases intracranial pressure which is mediated
through decrease in cerebral metabolic rate and
cerebral vasoconstriction resulting in decreased
cerebral blood flow and intracranial pressure [144].
Adverse effects
In three prospective etomidate clinical investi-
gations, injection site irritation was the most com-
mon adverse effect occurring in 1746% of children
[15,152,155]. Myoclonus, mild tremor to general-
ized rigidity or stiffness, was reported in 1222% of
patients who received etomidate. In the majority of
patients, myoclonus was mild and brief [15,152].
More severe cases generally resolve spontaneously
and did not impede completion of the procedure
[155]. The incidence and intensity of etomidate-
associated myoclonus appears to be dose-related,
may be suppressed by pretreatment with benzo-
diazepines, fentanyl, or low-dose etomidate, and
does not display seizure-like EEG activity
[144,145,158,159]. Vomiting (210%) and recovery
agitation (04%) has also been reported during
recovery from etomidate sedation [15,152,155,157].
Adrenal suppression
Following a single dose of etomidate, adrenal sup-
pression lasts for 68 h [143]. Because of even single-
dose adrenal suppression, the use of etomidate in
critically ill patients, especially those with septic
www.co-anesthesiology.com S27
Therapeutics in sedation
shock, remains controversial [160]. Although adre-
nal suppression must be considered, single-dose
etomidate for the sedation of otherwise healthy
children appears to be well tolerated [160162].
Brief procedures
As mentioned above, etomidate as a single agent
has been used successfully for brief painless
procedures [149,150] as well as painful procedures
when administered with an analgesic [15,151
157]. For procedures requiring more than only
brief sedation, longer acting agents are recom-
mended [155].
Administration
Although the recommended dose for etomidate
sedation has been listed as 0.10.2 mg/kg IV, initial
doses of 0.20.3 mg/kg have been found to be most
efficacious [15,152,155,157].
INHALED SEDATION
Potent inhaled anesthetic agents such as sevoflurane
or halothane have been reported to be effective
for deep procedural sedation for dental and endo-
scopic procedures when administered by anesthesi-
ologists [163165]. However, the use of inhaled
anesthetic agents by other providers has not been
reported. Nitrous oxide (N2O), however, has been
used extensively for procedural sedation in children
by many providers.
Nitrous Oxide
N2O gas induces anxiolysis with mild-to-moderate
dissociative sedation, analgesia and amnesia
[166,167] by NMDA, glutamate receptor antagonism,
opioid agonism, and GABAergic effects [163165].
Onset and offset of these effects occurs within
25 min [168]. Long used by dentists, the lack of
painful administration or need for venous access,
brevity of effects and development of delivery sys-
tems effective in young children have led to increas-
ing use of N2O as a sedation option for many
procedures in which pain is minor or can be con-
trolled with local anesthesia [169]. N2O can safely be
administered by specially trained nurses to healthy
children [170172].
N2O is blended with oxygen (N2O/O2) and
usually is described by the N2O component, for
example, 70% N2O is 70% N2O/30% O2. N2O indu-
ces effects in a linear dose-response pattern, yet
sedation may vary considerably because of a
patients resistance to the drugs effects. Most chil-
dren receiving 5070% N2O are mildly to moder-
ately sedated (eyes open or drowsy but easily
S28 www.co-anesthesiology.com
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
aroused to consciousness with verbal stimulus),
but moderate-to-deep sedation may occur in those
receiving more than 50% N2O, especially if coad-
ministered with an opioid [64,173176]. When
administered at higher elevations, greater concen-
trations of N2O may be needed to achieve the
desired effect [177].
Because children are partially aware during seda-
tion with N2O, preparation for the effects they will
experience is essential. Children, nave to intoxi-
cation, are frequently frightened by the floating or
tingling sensations caused by the gas. Use of guided
imagery greatly enhances the experience by helping
children to incorporate the gass effects into non-
frightening scenarios such as imagining flying to a
favorite or imaginary place [167,178]. Some older
children and teenagers prefer the partial awareness
with N2O sedation as they, like many adults, fear
loss of vigilance or control experienced during
deep sedation.
Indications
N2O sedation is most effective in reducing childrens
distress during procedures with high anxiety, but
brief minimal-to-moderate discomfort. Examples
include urethral catheterization, [179,180] venous
catheter insertion, [181,182] laceration repair, [183
184] lumbar puncture [185], and botulinum toxin
injections [186].
N2O sedation alone does not provide sufficient
analgesia for many intensely painful procedures
&
[187,188 ]. Adjunctive use of local anesthetic and/
or systemic analgesia can be very effective, resulting
in deep sedation for some patients [64]. N2O seda-
tion augmented by a hematoma block and oral
oxycodone or intranasal fentanyl can be effective
&
for forearm fracture reduction [175,188 ,189,190].
N2O along with oral oxycodone or intranasal fen-
tanyl, along with local anesthetic, can also be effec-
tive for abscess incision and drainage [64].
Delivery systems that incorporate a demand
valve which requires patient-generated negative
(inspiratory) pressure sufficient to open the valve
to allow flow of N2O are difficult for younger
children to use. A new demand system which
requires less inspiratory effort has been approved
by the FDA for use in children at least 15 kg and
4 years of age [191]. Continuous-flow systems
with nasal masks, designed for dental procedures,
provide free flow of gases and typically deliver up
to 70% N2O. These systems are easily used by all
ages but allow room air breathing through the
mouth [168]. An open gas interface can be added
to enable more effective delivery and scavenging
of gas via a full face-mask for nondental pro-
cedures [192].
Volume 29  Supplement 1  March 2016

N2O concentration is limited to a maximum of
70% to avoid hypoxia. Accidental administration of
100% N2O, because of machine or system failure,
can rapidly become lethal [193,194]. An in-line oxy-
gen analyzer should be used to assure a minimum
amount of oxygen is delivered [195]. Providers must
be familiar with the mechanisms of the N2O delivery
system used, and perform a machine or systems
check before each use to assure proper function.
A scavenging device should be an integral part of
the delivery system to minimize ambient N2O gas
exposure to healthcare workers [196]. A double mask
that decreases leakage of N2O is available in Europe
and Canada [197,198]. Treatment rooms should
have at least 1012 room air exchanges per hour
to exhaust N2O that has escaped scavenging. The
U.S. National Institute of Occupational Safety and
Health Standards has established safety guidelines
and regulations for N2O delivery [199].
Adverse effects: in healthy patients, N2O has
minimal cardiovascular or respiratory effects [168,
169,200,201]. Administration of 50% or less N2O
is considered minimal sedation and the patient
may be monitored by direct visualization and inter-
mittent assessment of their level of sedation [196].
Because N2O enhances the depressed response to
hypoxia and hypercarbia induced by opioid or
sedative agents, [202206] patients receiving these
drugs with N2O should be observed closely for mod-
erate-to-deep sedation and monitoring escalated
accordingly. As oxygen is blended with N2O, even
mild hypoxemia should prompt immediate inves-
tigation to determine the cause [201].
Mild increases in cerebral blood flow and intra-
cranial pressure and negative inotropic effects may
be significant for patients with compromised
clinical conditions, such as head injury, increased
intracranial pressure, pulmonary hypertension, or
cardiomyopathy [169].
Significant diffusion hypoxia after N2O seda-
tion without additional agents that suppress venti-
lation is unlikely [207]. However, administration of
O2 with scavenging for 23 min after discontinuing
N2O allows capture of N2O exhaled by the patient
during recovery.
Vomiting occurs in approximately 10% of chil-
dren receiving 50% N2O alone [208]. When coad-
ministered with an opiate, 2025% will have emesis
[64,171,174]. Midazolam or ondansetron may
reduce emesis to about 5% [183,190]. Risk of vomit-
ing is likely proportional to duration and concen-
tration. Providers must be especially vigilant when
administering N2O by full face mask to allow
immediate expulsion of emesis.
Protective airway reflexes are largely intact
when 50% N2O is used alone, [209211] but a
0952-7907 Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
Procedural sedation for children Roback et al.
case of laryngospasm and apparent aspiration
during 70% N2O sedation has been reported [212].
Other adverse effects include dizziness, dysphoria,
and headache, which usually resolve within 5 min of
cessation of N2O.
N2O diffuses rapidly into air-filled cavities caus-
ing volume and/or pressure increases, thus it should
be avoided in patients with areas of trapped gas,
such as pneumothorax, obstructive pulmonary dis-
ease, or bowel obstruction.
Concerns about bone marrow suppression,
neurotoxicity, cognitive dysfunction, decreased
fertility, increased spontaneous fetal loss, and
peripheral neuropathy in healthcare workers
with repeated and chronic exposure to N2O have
been raised, but the evidence is inconclusive
[213,169,214]. These adverse effects were not found
when scavenging devices and adequate room venti-
lation were used.
In patients deficient in cobalamin (vitamin B12)
or folate, N20 may inactivate methionine synthase,
essential for synthesis of DNA, RNA, catechol-
amines, and other critical cellular products [214].
INTRANASAL SEDATION
Intranasal administration of sedative-analgesic
agents provide desired effects through rapid
absorption; avoidance of first pass drug meta-
bolism in the liver; administration independent
of patient cooperation; and the painless and
quick administration of the agent with minimal
training [215,216]. Drug levels achieved with
intranasal administration may achieve levels
above the therapeutic threshold for sedation
while at the same time avoiding the high peaks
achieved with IV administration [216]. Intranasal
bioavailability varies from agent to agent. Drug
volumes should be minimized and split between
nostrils. Although intranasal agents can be
administered by drop technique, use of an atomizer
device results in less oropharyngeal run-off,
better patient acceptability, and improved effec-
tiveness [215]. Use of the most concentrated/lowest
volume drug preparation is recommended with
ideal maximum volumes of about 0.20.3 ml/
nostril to reduce runoff and allow maximal mucosal
coverage.
Intranasal fentanyl
Intranasal fentanyl, a synthetic opioid 50100 times
more potent than morphine, is an attractive intra-
nasal analgesic agent with rapid onset of analgesia
which does not sting. It bypasses gastrointestinal
and hepatic presystemic elimination with a high
www.co-anesthesiology.com S29
Therapeutics in sedation
bioavailability of 7089%, and is usually adminis-
tered at a dose of 1.5 mcg/kg [217]. Intranasal
fentanyl has been investigated in a number of
randomized controlled trials in children indicat-
ing analgesic efficacy similar to IV opioids
&&
[217,218,219 ]. The standard IV solution of fen-
tanyl (50 mcg/ml) can be used [217,220,221].
No major adverse events have been reported in
the pediatric trials of intranasal fentanyl use as an
analgesic [217]. Minor adverse events include nau-
sea/vomiting, itching, drowsiness, and a bad taste in
the mouth. As a sole agent it has a low incidence of
emesis. It can be used in combination with other
sedative agents. N2O administered in combination
with 1.5 mcg/kg intranasal fentanyl appears to have
improved analgesic efficacy and provides deeper
sedation [176]. However, the combination is also
associated with a much higher rate of emesis than
70% N2O alone (20 vs. 6%).
Intranasal dexmedetomidine
Dexmedetomidine is an attractive procedural agent
combining sedation that parallels natural sleep,
anxiolysis, analgesia, and sympatholysis [128].
Intranasal bioavailability of dexmedetomidine is
similar to the IV route and, unlike midazolam, is
not irritating to the nasal mucosa. It has been used
for preoperative anxiolysis in children in doses of
12 mcg/kg [126,217].
More recently, intranasal dexmedetomidine has
also been used for single agent sedation for CT,
echocardiography, and other painless procedures
with high rates of success and low adverse event
profiles [142,222]. Intranasal dexmedetomidine has
also been successfully used as rescue for failed chlo-
ral hydrate sedation for CT scanning, auditory
brainstem responses, and visual evoked potentials
[223]. No patient had clinically significant hemody-
namic or respiratory changes that required interven-
tion in this study.
Sedative success with intranasal dexmedetomi-
dine has also been shown in dental procedures when
combined with infiltrative local anesthesia [224]. In a
triple blind study of intranasal dexmedetomidine
(1 mcg/kg vs. 1.5 mg/kg) vs. intranasal ketamine
(5 mg/kg) vs. intranasal midazolam (0.2 mg/kg) in
children undergoing dental procedures, dexmedeto-
midine showed higher success rates (81, 86, 67 and
62% respectively) than ketamine or midazolam [224].
Intranasal dexmedetomidine has high sedation
success at 22.5 mcg/kg and seems particularly
attractive for the rescue of failed oral regimens. It
appears well tolerated without significant cardiovas-
cular effects requiring interventions. However, at
this time there is still limited experience with the
S30 www.co-anesthesiology.com
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
agent and in some settings the high cost of dexme-
detomidine may also be an impediment for more
widespread clinical use.
Intranasal ketamine
There is a large body of work demonstrating the
efficacy and safety of parenteral ketamine [37,62].
Bioavailability of intranasal ketamine is described as
50% or less. Intranasal ketamine studies for analge-
sic and sedative purposes have been published from
a range of settings prehospital, the emergency
department, postoperatively, and in dental practice
[216] Preoperative data are difficult to translate into
single agent procedural use as the target is generally
anxiolysis for mask tolerance and ease of separation
from the parents rather than sedation adequate for
procedures [225]. Few studies are high level assess-
ments of the efficacy of single agent intranasal ket-
amine use for procedural sedation.
Similar reduction of pain scores was demon-
strated in a recent comparison of intranasal ket-
amine (1 mg/kg) with intranasal fentanyl
(1.5 mcg/kg) in children for the relief of moderate-
to-severe injury-related limb pain [226]. Few ket-
amine patients were moderately sedated. Intranasal
ketamine was associated with more minor adverse
events, mainly bad taste in the mouth, drowsiness,
and dizziness than intranasal fentanyl.
To achieve sedation adequate for procedures,
rather than preoperative anxiolysis, much higher
doses of ketamine are required. In an interim
analysis of a study [89] of sedation for laceration
repair comparing 3, 6, and 9 mg/kg of intranasal
ketamine, 3 mg/kg and 6 mg/kg did not achieve
adequate sedation. However, at 9 mg/kg three of
four patients were adequately sedated with recovery
in 3570 min.
Although efficacy of intranasal ketamine for
analgesia has been demonstrated [226], because of
the limited bioavailability and increased nasal
run-off with intranasal ketamine at higher doses,
it is unclear if dissociative levels of sedation can be
achieved consistently, in particular when using
standard concentration parenteral ketamine.
Intranasal midazolam
Midazolam is rapidly absorbed across the nasal
mucosa and widely used [227,228] to induce anxiol-
ysis and amnesia during brief procedures in children,
including laceration repair, MRI and CT scans, burn-
dressing changes, dental procedures, and endoscop-
ies [215,216,229]. Midazolam provides no analgesia,
thus local anesthetic or oral/intranasal analgesics are
required for painful procedures. As a single agent
Volume 29  Supplement 1  March 2016

midazolam causes minimal respiratory effects in
healthy children but patients should be monitored
for respiratory depression especially when it is coad-
ministered with systemic analgesics or other sedative
medications [8,230233]. Adverse effects reported
include nasal irritation, unpleasant taste, nausea
and vomiting, and ataxia. The initial burning sen-
sation can be minimized by spraying intranasal lido-
caine (10 mg; 1 ml of 1% lidocaine) 1 min prior to the
intranasal midazolam [234237]. Dose: intranasal
0.30.5 mg/kg; onset: 510 min; duration: 30
60 min. Use 5 mg/ml concentration to minimize
volume.
CONCLUSION
A variety of providers administer procedural seda-
tion safely and effectively to children for a rapidly
growing assortment of procedures performed out-
side the operating room. Techniques for this prac-
tice have been investigated to better enable drug and
routes of administration to be tailored to the pro-
cedure and the needs of the individual child. Con-
tinued study is needed to better determine
effectiveness and safety of techniques, especially
in children with complex medical conditions, and
to assess long-term outcomes.
Acknowledgements
The authors wish to acknowledge Dr. Keira P. Mason for
her leadership in the multidisciplinary administration of
safe procedural sedation for children outside the OR.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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