Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

PAEDIATRIC DENTISTRY REVIEW ARTICLE

USE OF ORAL MIDAZOLAM SEDATION IN PEDIATRIC DENTISTRY:

A REVIEW
1
ALI M. ALZAHRANI, BDS, MSC, SB-PD
2
AMJAD H. WYNE, BDS, MDS

ABSTRACT

Most fearful and uncooperative children can be managed with behavioral management tech-
niques. However, when behavioral management strategies fail, some form of pharmacologic sedation
or anesthesia has to be utilized. Midazolam, one of the commonly used oral sedation agent in children
has several characteristics such as safety of use, rapid onset and some degree of amnesia that makes
it a desirable sedation agent in children. Therefore, oral midazolam sedation is recommended for short
dental procedures in children. This review paper discusses various aspects of oral midazolam sedation
including, advantages of oral route of sedation, pharmacokinetics of midazolam, range of oral dose,
midazolam antagonist, and clinical procedure. The paper also includes general guidelines for sedation.
The need for appropriate training (for personnel) in sedation, provision of appropriate equipment/
monitoring devices and presence of rescue mechanisms is also emphasized.

Key Words: Oral midazolam, sedation, children, dental treatment.

INTRODUCTION well accepted by most children, and are usually per-

ceived as non-threatening.
Dental management of children with behavioral
problems remains a major challenge to dentists. The A variety of sedative drugs has been used for oral
behavioral problems are usually encountered in chil- sedation in young children including benzodiazepines.
dren younger than six years of age due to factors such Midazolam is a newer-generation benzodiazepine with
as immature reasoning, limited coping skills and anxi- wide toxic/therapeutic ratio and safety margin, and
ety/fear resulting from lack of experience.1 Provision of does not produce prolonged sedation associated with
successful dental treatment in anxious/fearful chil- other benzodiazepine such as diazepam.3 When taken
dren is largely dependent upon successfully gaining orally, midazolam is rapidly absorbed in the gas-
their cooperation. Technical skills are of a little value trointestinal tract, produces its peak effect in rela-
tively shorter time of about 30 minutes, and has a
unless the child cooperates. Use of sedation can be very
short half-life of about 1.75 hours. When given in doses
helpful in allying apprehension and minimizing an
between 0.5 to 0.75 mg/kg of body weight, oral
uncooperative child’s attempt to resist treatment.2,3
midazolam has been found to be a useful sedative
Sedation drugs are administered through various agent for pediatric dental outpatients.4-8 Midazolam
routes such as oral, inhalational, nasal, intramuscu- has also been shown to enhance anterograde amnesia
lar, subcutaneous, and intravenous routes. All these when used preoperatively in pediatric patients.4,9-11
Midazolam is a short acting anxiolytic agent,12 with
routes have certain advantages and disadvantages.
short duration of action,13-14 that makes its use limited
Oral route is complicated by variable absorption level
to short dental procedures only.
of sedation drug in gastrointestinal tract and inability
of the operator to titrate the drug dose to the desired It is of utmost importance to remember that any
effect.2 However, orally administered sedatives are type of sedation carry a risk of untoward effects. The
1
Senior Registrar in Pediatric Dentistry, Security Forces Hospital, Makah Al-Mukarrama.
2
Professor, Department of Pediatric Dentistry and Orthodontics, King Saud University College of Dentistry, Riyadh
Correspondence: Dr. Amjad H. Wyne, PO Box 60169, Riyadh 11545, Saudi Arabia. E-Mail: ahwyne@ksu.edu.sa

Pakistan Oral & Dental Journal Vol 32, No. 3 (December 2012) 444
 Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

practitioner and support personnel should be suffi- the airway. If the patient is not making spontaneous
ciently trained, and the place must be adequately efforts to open his/her airway to relieve the obstruc-
equipped before any form of dental sedation is admin- tion, then the patient should be considered as deeply
istered, including minimal oral sedation. The Ameri- sedated.
can Academy of Pediatric Dentistry “Guidelines for
Deep Sedation (Old Terminology: Deep Seda-
Monitoring and Management of Pediatric Patients
tion/Analgesia): A drug-induced depression of con-
During and After Sedation for Diagnostic and Thera-
sciousness during which patients cannot be easily
peutic Procedures” provide basic information on den-
aroused but respond purposefully (see discussion of
tal sedation in children.15 The readers are strongly
reflex withdrawal above) after repeated verbal or
encouraged to read and consult other relevant text and
painful stimulation (e.g., purposefully pushing away
guidelines, and attend training courses before using
the noxious stimuli). The ability to maintain ventila-
any form of dental sedation.
tory function independently may be impaired. Pa-
tients may require assistance in maintaining a patent
DENTAL SEDATION
airway, and spontaneous ventilation may be inad-
The American Society of Anesthesiology updated equate. Cardiovascular function is usually maintained.
the sedation terminology and definitions in 1999,16 A state of deep sedation may be accompanied by
and The American Academy of Pediatric Dentistry has partial or complete loss of protective airway reflexes.
also listed the following three levels of sedation.15
ORAL ROUTE OF SEDATION
Minimal Sedation (Old Terminology: Anxiolysis):
The oral route is the oldest and most economical of
A drug induced state during which patients respond
all routes of drug administration. It is also the most
normally to verbal command. Although cognitive func-
universally accepted and easiest method. Most practi-
tion and coordination may somewhat be impaired,
tioners prefer the oral route of drug administration
ventilatory and cardiovascular functions are unaf-
due to high safety, minimal complications and usually
fected.
easy acceptance by children. In addition, parents also
Moderate Sedation (Old Terminology: Conscious prefer this less invasive method of drug administra-
tion.17 Other advantages of oral drug administration
Sedation or Sedation/Analgesia): A drug-induced de-
are; no specialized training required, minimum equip-
pression of consciousness during which patients re-
ment utilized and low incidence of adverse reactions.18
spond purposefully to verbal commands (e.g., “open
From the patients’ point of view, the main advantage
your eyes” either alone or accompanied by light tactile
of the oral route is avoidance of an injection with its
stimulation - a light tap on the shoulder or face, not a
inherent risks and psychological effects. Patients also
sternal rub). For older patients, this level of sedation
prefer the oral route over parenteral routs because of
implies an interactive state; for younger patients, age-
discomfort/pain associated with venipuncture or in-
appropriate behaviors (e.g., crying) occur and are ex- tramuscular administration.19 Therefore, oral seda-
pected. Reflex withdrawal, although a normal response tion is probably the most widespread form of sedation
to a painful stimulus, is not considered as the only age- used in dentistry.18 However, there are also some
appropriate purposeful response (e.g., it must be ac- disadvantages associated with the oral route, which
companied by another response, such as pushing away include dependence upon patient compliance, abort-
the painful stimulus so as to confirm a higher cognitive ing sedation if a child splashes the drug out, delayed
function). With moderate sedation, no intervention is onset of drug action, inability to titrate drug dose and
required to maintain a patent airway, and spontane- difficulty in administrating a reversal agent or emer-
ous ventilation is adequate. Cardiovascular function is gency drug in the absence of a patent intravenous line.
usually maintained. However, in the case of proce- Some other disadvantages of oral route are; unpredict-
dures that may themselves cause airway obstruction able effect of the drug, variability in drug absorption
(e.g., dental or endoscopic), the practitioner must rec- across the gastrointestinal mucosa and hepatic first-
ognize an obstruction and assist the patient in opening pass effect.19,20

Pakistan Oral & Dental Journal Vol 32, No. 3 (December 2012) 445
 Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

Absorption of drug is affected by the presence of onstrating approximately twice the affinity as com-
food in the stomach, and the drug is subjected to ‘first- pared to diazepam.25,26
pass’ liver metabolism before reaching the general
circulation, thus varying the depth and duration of Advantages of Benzodiazepines
action. After oral administration of a sedative agent,
Benzodiazepines have been widely used for pre-
the primary absorption of most drugs takes place from
medication.27, 28 Principal advantages of this class are
small intestine. Therefore, it is important to get the
their relative safety, availability of antagonist, selec-
drug from the stomach into the small intestine as
tive anxiolytic activity and ability to produce antero-
rapidly as possible. The time required for a substance
grade amnesia. The relative safety is due to the high
to be expelled from the stomach is called “gastric
therapeutic index. The high therapeutic window im-
emptying time”. The presence of food in the stomach
plies that there is a great difference in the level of dose
will decrease the absorption of drugs into the systemic
between desired responses and that which can cause
circulation by increasing gastric emptying time, and if
side-effects.22
the drug gets bound to the food, it becomes unavailable
for absorption. Anxiety itself may delay gastric empty- In addition to the anxiolytic, sedative, and amne-
ing and therefore delay absorption and onset of action. sic effects, benzodiazepines may indirectly elevate the
It is therefore recommended that oral sedation medi- patient’s threshold for pain. This does not mean that
cations be administered in the absence of food and, the they are analgesics, but the patient appears to reach a
traditional psychological behavior management tech- state of mental indifference. In this altered state,
niques be utilized before and during oral drug admin- many patients are less perturbed by mild noxious
istration to decrease the anxiety.18, 21 stimulation that might otherwise be distressing.22
Compared with other central nervous system (CNS)
Once absorbed from the stomach or small intes-
depressant such as barbiturates and opioids, benzodi-
tine, drugs enter the hepatic portal system, allowing
azepines have minimal influence on respiration and
exposure to liver enzymes, which may metabolize a
cardiovascular function.22
percentage of the drug. The extent of this action is drug
specific and is known as the “hepatic first-pass” ef- The adverse effects profile of benzodiazepines is
fect.18,21 After leaving the liver, orally administered minimal. Excessive CNS depression and respiratory
drugs reach the systemic circulation in non-metabo- depression occur only in overdose situations. Exces-
lized form. The portion of an administered dose that sive CNS depression usually manifest as severe alter-
reaches the systemic circulation in active form is ations in consciousness, ranging from weak or inap-
available for distribution to target tissue(s) is termed propriate responses to verbal command or stimulation
as “Bioavailability”.22 to the loss of consciousness. Depression of respiration
that requires intervention is an indication that an
BENZODIAZEPINES overdose has occurred. Careful selection of the benzo-
diazepines dose decreases the likelihood of these ad-
The term “benzodiazepine” refers to the common
chemical structure shared by all of the compounds verse effects.29
within this class of drugs. The site of action for benzo-
Diazepam
diazepines are specific receptors in the central nervous
system (CNS) associated with GABA receptors. Benzo- The properties of diazepam include strong
diazepine receptors have been identified in different anti-anxiety effects but minimal somnolence and vir-
body tissues including the heart and skeletal muscles, tually no amnesia at orally prescribed doses. Diaz-
though the predominance appears to be in the central epam has long-acting metabolites (oxazepam and
nervous system.23 The low incidence of respiratory desmethyldiazepam) that have sedative properties.
depression with benzodiazepines may be related to the Consequently, the clinical duration of diazepam seda-
low density of binding sites in the brain stem.24 tion tends to be moderate to long in length. Diazepam
Midazolam has a high affinity for the benzodiazepine readily redistributes into lipid structures, and a clini-
receptor in central nervous system; in-vitro data dem- cal rebound effect can occur when this sequestered

Pakistan Oral & Dental Journal Vol 32, No. 3 (December 2012) 446
 Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

drug is re-released into the bloodstream after a meal. Metabolism

It is common for patients who have been sedated
earlier to get drowsy after eating, and so they need to Midazolam, like other benzodiazepines is
biotransformed by hepatic microsomal oxidation fol-
be warned of this possibility.29
lowed by a glucuronide conjugation.30 Initially, Mida-
Midazolam zolam is hydroxylated by Cytochrome P450-3A4 to its
primary metabolite, alphahydroxy-midazolam, and
A high water solubility of midazolam as compared minimally to inactive metabolites. These metabolites
with diazepam is the major advantage of midazolam. are then excreted in urine as glucuronide conjugates.34
Midazolam belongs to a new class of benzodiazepines Alphahydroxy-midazolam is pharmacologically active
called Imidazobenzodiazepines.30 This class also in- and has sedative properties equivalent to midazolam.
cludes the receptor antagonist flumazenil.31 The in- This major metabolite is produced in higher concen-
creased water solubility allows midazolam to be pack- trations follow-ing oral administration as a result of
aged without diluents, thus decreasing venous irrita- first-pass metabolism. Plasma clearance of midazolam
tion and dysrhythmias.30,32 The pharmacological ac- is greater in supine patients because of 40-60% in-
tions of midazolam are identical to those of other crease in hepatic blood flow during supination.32
benzodiazepines including anxiolytics, sedation and
amnesia.12 Elimination

PHARMACOKINETICS OF MIDAZOLAM Midazolam has a short elimination half-life of

1.5-3.0 hours compared with more than 20 hours of
Absorption diazepam.35 However, the pharmacological duration of
action is generally only 60-120 minutes.36 Plasma
Midazolam is rapidly absorbed from the gas-
clearance of midazolam is 5.8-9.0 ml/min/kg in healthy
trointestinal tract following oral administration.25
individuals but is decreased in elderly individuals.33
Drowsiness has been noticed 15 minutes after an oral Almost 90% of an orally administered dose of radiola-
dose, with peak effects within 30-90 minutes.32 Due to beled midazolam is excreted within 24 hours.25 The
liver first-pass metabolism, only 40-50% of orally ad- major route of elimination is kidney, with less than
ministered dose reaches the systemic circulation. 10% excreted in the faeces within 5 day.25 Midazolam
Parenteral routes of administration result in higher has been associated with accumulation and prolonged
bioavailability and rapid onset times. sedation in patients with renal dysfunction.34,37

Distribution Pharmacodynamics

Midazolam has a volume of distribution (Vd) of Midazolam has anxiolytic, muscle relaxant, anti-
1-2.5 L/kg in normal healthy individuals.25,30 Obese convulsant, sedative, hypnotic and amnesic proper-
patients have an increased Vd because of enhanced ties.12, 25 At higher dose, midazolam may produce res-
distribution to peripheral adipose tissues. 25,30 piratory depression. There are no effects of midazolam
Midazolam is extensively bound to plasma proteins reported on cardiovascular system when used alone.38
primarily albumin with a free fraction representing
ORAL MIDAZOLAM SEDATION
only 4% of a given dose.25 The pharmacological effect of
midazolam ranges from one to four hours. The dura- The clinical use of midazolam is primarily re-
tion of effect is determined primarily by the rate of served as premedication/sedation drug, though it
movement from the central to the peripheral compart- also has anticonvulsant and muscle relaxant proper-
ment.32 Midazolam has a short distribution half-life of ties. One of the limiting factors in the use of midazolam
several minutes because of fast tissue uptake.30 Re- for sedation is the short length of action.39 So,
turn to baseline values for objective neurological tests midazolam can be used effectively in pediatric pa-
is reported 1.5 hour after intravenous injection and 2 tients for short, mildly painful and minimally inva-
hours after oral adminis-tration.33 sive procedures.40

Pakistan Oral & Dental Journal Vol 32, No. 3 (December 2012) 447
 Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

Pediatric Dose of Oral Midazolam Some studies have reported that administration of
higher oral midazolam doses (0.75 or 1.0 mg/kg) may
Midazolam has been used orally at doses between result in a greater incidence of side effects such as loss
0.2-1.0 mg/kg with onset of action between 20-30
of balance and head control, blurred vision and dys-
minutes.12,41,42 Several studies have been conducted to
phasia as compared with placebo or 0.5 mg/kg of
determine an optimal dose of oral midazolam for seda-
midazolam.49 Similarly, Dionne50 reported that oral
tion by comparing various doses of oral midazolam.
midazolam at doses of 0.75 to 1.0 mg/kg produced a
Singh et al41 found that oral midazolam in a dose of 0.5
higher incidence of side effects and decreased respira-
mg/kg is suitable premedication for child patients
tion manifesting as oxygen saturation values below
(ASA Category I) during short dental procedures.
80% in some children. On the other hand, many stud-
Another study compared two dosages of oral midazolam
ies reported that oral midazolam is safe and effective
(0.3 mg/kg or 0.5 mg/kg) in 31 physically and neuro-
sedative agent at doses of 0.5mg - 1.0mg/kg.4,6,7,46 Litman
logically compromised pediatric (3-18 years) dental
patients; both dosages proved successful, without in- et al51 reported that the use of 0.7mg/kg oral midazolam
traoperative or postoperative complications.43 Fraone did not result in clinical respiratory depression nor
et al44 evaluated the effect of orally administered upper airway obstruction, though in some children
midazolam with a dose of 0.5mg/kg in three age groups: caused an increased level of sedation beyond minimal
group I (24-35 months) group II (36-47 months) and sedation.
group III (47-59 months), with conclusion that there
It is advisable to monitor children receiving
were no significant clinical differences among the
midazolam for early signs of hypoventilation or apnea.
three groups. On the other hand, Saarnivaara et al45
Respiratory depression appears to be dose related and
recommended oral midazolam dose of 0.5 mg/kg for
dosage regimens should be strictly followed.25,39 Some
children less than five years and 0.4 mg/kg for older
authors advise against routine use of concomitant
children. Ma et al7 concluded that oral midazolam in
administration of an opiate-like analgesic, which could
the doses between 0.5 – 1.0 mg/kg can be a safe and
acceptable sedation drug especially in children over 3 both intensify respiratory depression and increase the
years of age. Somri et al46 compared three doses of oral likelihood of an adverse cardiopulmonary event.48
midazolam, between 0.5 to 1.0 mg/kg in 3-10 year old However, others have used the combination without
children, with conclusion that 0.75 mg/kg appears to complication.39,52 Decreased oxygen saturation and
be the optimal dose in terms of effectiveness and depressed respiration can be mostly resolved with
safety. The preceding studies especially the more re- verbal stimulation, release of airway obstruction, and/
cent ones establish the efficacy of oral midazolam or supply of posi-tive pressure ventilation with oxygen.
doses between 0.5 mg/kg to 0.75 mg/kg as sedative When given in sedative doses without any additional
agent to manage apprehensive pediatric dental medications, no clinically significant respiratory de-
patients. pression has been reported.

Side Effects of Midazolam Drug Interactions

Midazolam is virtually free of any serious side Midazolam is metabolized in the liver by the
effects when given in recommended oral doses. The cyto-chrome P450 oxidase system. Cimetidine, a
major risk associated with high doses of midazolam is cyto-chrome P450 oxidase system inhibitor, increases
hypoventilation and associated hypoxemia.39 Respira- the mean steadystate concentration of midazolam by
tory depression has been reported in adults,47 how-ever, as much as 80%.53 In individuals pretreated with
there have been few reports of respiratory depression either cimetidine or ranitidine the bioavailability of
in chil-dren. One reason for the numerous early re- mida-zolam increased by approximately 30%.54 Mida-
ports of apnea in adults was the old dose guideline that zolam often has an earlier onset of action and in-
underestimated the relative potency of midazolam, creased sedation in individuals pretreated with an H2
which is now believed to be three to four times more receptor antagonist. Omeprazole may also inhibit the
potent than diaz-epam (not twice as was originally oxidative metabolism of midazolam.55 Macrolide anti-
thought).48 biotics are also known cytochrome P450 enzyme in-

Pakistan Oral & Dental Journal Vol 32, No. 3 (December 2012) 448
 Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

hibitors. Conversely, rifampin acts as a cytochrome Oral Midazolam with Nitrous Oxide
P450 enzyme inducer and may enhance the clearance
of midazolam.56 Erythromycin reduces the clearance of Oral midazolam is often used in combination with
nitrous oxide for dental sedation in children. A study
oral and intravenous midazolam and increase its half-
by Pisalchaiyong et al64 compared the effectiveness of
life.57 Oral contraceptives (for adult patients) prolong
the elimination half-life of diazepam and may inhibit oral diazepam and midazolam alone and in combina-
tion with nitrous oxide for sedating autistic patients
the metabolism of midazolam by a similar mecha-
during dental treatment; the midazolam/nitrous oxide
nism.58
combination was found significantly more effective
Anterograde Amnesia than diazepam/nitrous oxide combination. A study by
Al-Zahrani et al4 reported that combination of oral
Anterograde amnesia is a lack of recall of events midazolam (0.6mg/kg) and nitrous oxide (30-50%) is
occurring from the time of administration of a drug effective and safe in young dental patients who need
onwards. This is to be distinguished from retrograde minimal restorative treatment. Ozen et al8 have also
amnesia, which is a lack of recall of events occurring recently reported similar results with combination of
before the drugs administration. Midazolam affects 0.5 mg/kg oral midazolam and nitrous oxide (50%) in
memory process by impairing the ability to acquire 4-6 year old children. The use of nitrous oxide may
new information.9,59 The amnesic effect of midazolam prolong the working time to some extent and simulta-
appears to be independent of the sedation quality. neously incorporates its own desirable effects (such as
Midazolam produces anterograde amnesia and may analgesia) in the clinical situation.
indirectly enhance the retention of material learned
before treatment as consequence of the reduced learn- Midazolam has also been used in combination with
ing of information presented after the drug takes various other sedatives. Review of literature on use of
effect. The amnesia achieved with midazolam has various drug combinations is beyond the scope of this
been shown to be greater than that seen with diaz- review. However, it is strongly emphasized that com-
epam.60 The amnesic effect of midazolam generally bining two or more of these drugs enhances the seda-
persists for 20 to 30 minutes.61 tive effects of each of these substances, increasing the
risk of respiratory depression and overdose. The
Flumazenil: A Midazolam Antagonist sedationist must have knowledge and training in us-
ing these drug combinations and management of any
Flumazenil is an imidazobenzodiazepine deriva-
possible untoward effects.
tive that antagonizes the action of benzodiazepine on
the central nervous system. The safety of midazolam CLINICAL PROCEDURE
sedation has been significantly improved by availabil-
ity of flumazenil. Previous studies investigating the Patients Selection
efficacy of flumazenil have demonstrated significantly
Healthy patients (ASA 1 Category – Table 1)65
shorter recovery times, increased patient alertness
and consequently earlier discharge home.62 For the between the age of 4-12 years, and in Behavior Cat-
egory of Frankle Scale 2 (Table 2)66 needing short
reversal of the sedative effects of benzodiazepines
dental procedures are normally selected for oral
administered for conscious sedation in pediatric pa-
tients older than one year of age, the recommended midazolam sedation. Experienced operators, in se-
lected patients can perform more invasive dental treat-
initial dose is 0.01 mg/kg (up to 0.2 mg) administered
ment including extractions with midazolam oral seda-
intravenously over 15 seconds. In case the desired
level of consciousness is not gained within 45 seconds, tion. Utmost care has to be taken in patient selection
to avoid any medical complication during and after
further injections of 0.01 mg/kg (up to 0.2 mg) can be
sedation. Patients who have recently used medica-
administered and repeated at 60 seconds intervals
where necessary up to a maximum of 4 additional tions such as erythromycin or anticonvulsants that
may have interference with pharmacokinetics of
times to achieve full consciousness and normal cardio-
midazolam are not selected for midazolam sedation.
respiratory function.63

Pakistan Oral & Dental Journal Vol 32, No. 3 (December 2012) 449
 Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

Pre-sedation Appointment TABLE 3: APPROPRIATE INTAKE OF FOOD AND

LIQUIDS BEFORE ELECTIVE SEDATION15
The patients who are suitable for oral midazolam
Ingested Material Minimum
are appointed for confirmation of medical/dental sta- Fasting
tus and clinical/radiographic examinations. Full ver- Period
bal and written explanation is provided to parents (hours)
regarding the sedation procedure, type of medication
Clear liquids: water, fruit juices 2
that will be used with its safety and side effects. The without pulp, carbonated beverages,
reason to select midazolam and other option of treat- clear tea, black coffee
ment including advantages and disadvantages of each Breast milk 4
technique are also explained. A written consent is Infant formula 6
obtained from parents for sedation of their child. The Nonhuman milk: because nonhuman 6
milk is similar to solids in gastric
emptying time, the amount ingested
TABLE 1: THE AMERICAN SOCIETY OF
must be considered when determining
ANESTHESIOLOGISTS (ASA) PHYSICAL STATUS
an appropriate fasting period
CLASSIFICATION65
Light meal: a light meal typically 6
Classification Description consists of toast and clear liquids.
Class 1 A normal healthy patient Meals that include fried or fatty foods
or meat may prolong gastric empty-
Class 2 A patient with mild systemic ing time. Both the amount and type
disease of foods ingested must be considered
Class 3 A patient with severe systemic when determining an appropriate
disease fasting period.
Class 4 A patient with severe systemic
disease that is a constant threat TABLE 4: PATIENT’S DISCHARGE CRITERIA72
to life
— The patient is able to response to his or her
Class 5 A moribund patient who is not name
expected to survive without op-
eration — Respond to touching or shaking his/her hand
Class 6 A declared brain-dead patient — Ability to maintain a standing posture
whose organs are being removed — Absence of dizziness or disorientation
for donor purposes. — Acceptable vital signs (close to base-line)

TABLE 2: FRANKL BEHAVIORAL RATING consent forms are designed per ethical and legal re-
SCALE66
quirements in area of the practitioner. Preoperative
Category Frankl Behavioral Rating Scale instructions (both verbal and written) are provided to
Rating 1 Definitely negative: Child refuse treat- the parents, including nothing per mouth at least 6
ment, cries forcefully, fearfully, or hours before the appointment (Table 3)15. They are
display any overt evidence of extreme advised to call for cancellation if the child gets ill (flu,
negativism. cough, fever etc).
Rating 2 Negative: Reluctant to accept treat-
ment and some evidence of negative Medications
attitude (not profound).
Rating 3 Positive: The child accepts treatment Midazolam has a disagreeable taste that is diffi-
but may be cautious. The child is cult to mask.67 Children may refuse to swallow it, and
welling to comply with the dentist, expectorate whole or part of the drug. The clinician
but may have some reservations. then becomes uncertain about how much medication
Rating 4 Definitely negative: This child has a has actually been ingested by the child. Various home-
good rapport with the dentist and is made preparations to mask the bad taste have been
interested in the dental treatment. suggested.67-69 An oral midazolam syrup was used by

Pakistan Oral & Dental Journal Vol 32, No. 3 (December 2012) 450
 Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

AlZahrani et al4 in their study of oral midazolam A mouth prop (scissor type) is placed in the side of
pediatric dental sedation; with no case of drug expec- the mouth not being treated. Then, topical anesthesia
toration during their study. The syrup is prepared in is applied for 2 minutes followed by appropriate local
a concentration of 2mg/ml with stability of 30 days if anesthesia (2% lidocaine with epinephrine 1:100,000).
kept refrigerated. The mixture consists of intravenous Rubber dam is applied when needed and the required
restorative treatment accomplished.
midazolam (ampoules of Dormicum@ 15 mg/3ml, F.
Hoffinan - La Roche Ltd, Basel, Switzerland). The All hemodynamic parameters are monitored dur-
dilution of Dormicum ampoules is carried out by using ing the course of the treatment. At the end of dental
dye-free flavoured syrup. The diluents consist of sorbi- procedures, hemodynamic parameters are again re-
tol 45g, sucrose 15g, saccharine 0.2g, sodium benzoate corded and the child then transferred to quite room
0.15g, citric acid 2g in 100ml of distilled water. Then and monitored for recovery. The child is discharged
45ml of diluents syrup and 30ml of intravenous when he/she fulfills the discharge criteria (Table 4).
midazolam (10 ampoules x 3ml which contain 10x15mg Before the discharge, hemodynamic parameters are
= 150mg midazolam) are mixed. The final preparation again recorded. Post-sedation instructions (both ver-
bal and written) are given to the parents. Parents are
has midazolam 2mg/ml.
instructed to give juice only after two hours from
Sedation Protocol discharge and give slowly to avoid vomiting. Parents
are advised to observe the child for rest of the day.
The child is first examined on the day of sedation They must not allow the child to play with sharp
for medical clearance. Then the patient’s weight is objects or walk on stairs alone. The parents are pro-
taken by electronic weight scale. Baseline blood pres- vided with a telephone number in case of any problem.
sure, heart rate, and oxygen saturation are recorded.
The following physiological parameters are re-
The dose of midazolam is calculated for the child and
corded at base line, during, after and at discharge:
then the syrup given to the child in a cup with the
assistance of his/her parents. The appointment is – Heart rate (HR)
postponed if the child expectorates whole or part of the
– Systolic blood pressure (SBP)
drug. The child then waits in a quiet room with his/her
parents, and signs of onset of sedation are observed – Diastolic blood pressure (DBP)
every 5 minutes after drug administration. The follow- – Oxygen saturation (SaO2%)
ing signs are observed in determination of onset of
Tachycardia and hypertension are considered if
sedation:10
there was an increase in heart rate and blood pressure
– Glazed look respectively more than 20% from baseline value. If the
heart rate and blood pressure decreased more than
– Delayed eye movement 20% from baseline, it is considered as bradycardia and
– Lack of muscle coordination hypotension respectively.70 Hypoxemia is evaluated
based on pulse oximeter recordings. Oxygen satura-
– Slurred speech tion from 95% or above is considered normal. Any
reading less than 95% is recorded.71
– Sleep

As the above signs are observed after the drug Evaluation of the Drug Side Effect
administration, the patient is then moved to the oper- The patient is observed in the recovery room for
ating room/surgery carried by his/her parent. In the any side effect such as nausea, vomiting. The side
operating room; pulse oximeter clip (Vitalmax 800 effects may also be evaluated by asking the parents or
Monitoring Equipment: Pace Tech. Inc., Clearwater, the child’s guardian through telephone.
FL 34615) is attached to the child’s big toe of right foot.
The blood pressure cuff is attached to left arm by a GENERAL GUIDELINES FOR SEDATION
trained assistant and the patient is immobilized for The American Academy of Pediatric Dentistry has
his/her safety using a papoose board (Olympic, Medi- provided following guidelines for pediatric dental se-
cal Group, Seattle, WA). dation.15

Pakistan Oral & Dental Journal Vol 32, No. 3 (December 2012) 451
 Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

Candidates oximeters, and defibrillators must have a safety and

function check on a regular basis as required by local
Patients who are in ASA I category are considered
regulations.
appropriate candidates for minimal sedation. Practi-
tioners are encouraged to consult with appropriate
Personnel
specialists and/or an anesthesiologist for patients sus-
pected of increased risk of experiencing adverse seda- The Practitioner
tion events.
The practitioner responsible for the treatment of
Facilities the patient and/or the administration of drugs for
The practitioner who uses sedation must have sedation must be competent to use such techniques, to
immediately available facilities, personnel, and equip- provide the level of monitoring required, and to man-
ment to manage emergency and rescue situations. The age complications of these techniques (i.e., to be able to
most common serious complications of sedation in- rescue the patient). Because the level of intended
volve compromise of the airway or depressed respira- sedation may be exceed, the practitioner must be
tions resulting in airway obstruction, hypoventilation, sufficiently skilled to provide rescue should the child
hypoxemia, and apnea. Hypotension and cardiopul- progress to a level of deep sedation. The practitioner
monary arrest may occur, usually from inadequate must be trained in, and capable of providing, at the
recognition and treatment of respiratory compromise. minimum, bag-valve-mask ventilation to be able to
Other rare complications may also include seizures oxygenate a child who develops airway obstruction or
and allergic reactions. Facilities providing pediatric apnea. Training in maintenance of advanced pediatric
sedation should monitor for, and be prepared to treat, airway skills is required; regular skills reinforcement
such complications. is strongly encouraged.

Back-up Emergency Services Support Personnel

A protocol for access to back-up emergency ser- The use of moderate sedation shall include provi-
vices shall be clearly identified, with an outline of the sion of a person, in addition to the practitioner, whose
procedures necessary for immediate use. For non- responsibility is to monitor appropriate physiologic
hospital facilities, a protocol for ready access to ambu- parameters and to assist in any supportive or resusci-
lance service and immediate activation of the emer- tation measures, if required. This individual may also
gency medical services) (EMS) life-threatening com- be responsible for assisting with interruptible patient-
plications must be established and maintained. It related tasks of short duration. This individual must
should be understood that the availability of EMS does be trained in and capable of providing pediatric basic
not replace the practitioner’s responsibility to provide life support. The support person shall have specific
initial rescue in managing life-threatening complica- assignments in the event of an emergency and current
tions. knowledge of the emergency cart inventory. The prac-
On-Site Monitoring and Rescue Equipment titioner and all ancillary personnel should participate
in periodic reviews and practice drills of the facility’s
An emergency cart or kit must be immediately emergency protocol to ensure proper function of the
accessible. This cart or kit must contain equipment to equipment and coordination of staff roles in such
provide the necessary age- and size-appropriate drugs emergencies.
and equipment to resuscitate a non-breathing and
unconscious child. The contents of the kit must allow SUMMARY
for the provision of continuous life support while the
It is generally agreed that most fearful and unco-
patient is being transported to a medical facility or to
operative children can and should be managed with
another area within a medical facility. All equipment
behavioral (nonpharmacologic) management tech-
and drugs must be checked and maintained on a
niques such as tell show do, positive reinforcement,
scheduled basis. Monitoring devices such as pulse
distraction, modeling etc. Unfortunately, there are a

Pakistan Oral & Dental Journal Vol 32, No. 3 (December 2012) 452
 Use of Oral Midazolam Sedation in Pediatric Dentistry: A Review

small percentage of pediatric patients that cannot be 8 Ozen B, Malamed SF, Cetiner S, Ozalp N, Ozer L, Altun C.
Outcomes of moderate sedation in paediatric dental patients.
successfully managed solely through behavioral man- Aust Dent J 2012; 57: 144-150.
agement techniques. When behavioral management
9 Curran HV. Tranquillizing memories: A review of the effects of
strategies fail, some form of pharmacologic sedation or benzodiazepines on human memory. Biol-Psychol 1986; 23:
anesthesia becomes a valuable and necessary alterna- 179-213.

tive. Various sedative agents and combination of these 10 Smith BM, Cutilli BJ, Saunders W. Oral midazolam: pediatric
conscious sedation. Compend Contin Educ Dent 1998; 19:
agents have been used to reduce anxiety and fear
586-588.
associated with dental treatment, producing variable
11 Kain ZN, Hofstadter MB, Mayes LC, Krivutza DM, Alexander
results in terms of efficacy and safety. Midazolam, one G, Wang SM. Midazolam: Effects on amnesia and anxiety in
of the commonly used oral sedation agent in children children. Anesthesiology 2000; 93: 676-684.
has several characteristics such as safety of use, rapid 12 Kupietzky A, Houpt MI. Midazolam: a review of its use for
onset and some degree of amnesia that make it a conscious sedation of children. Pediatr Dent 1993; 15: 237-241.

desirable sedation agent in children. On the other 13 Dionne R. Oral midazolam syrup: A safer alternative for pedi-
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meperidine for management of the difficult young pediatric
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international professional bodies must be followed. peutic procedures. Pediatr Dent 2011; 33: 185-201.
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16 American Society of Anesthesiologist. Standards, Guidelines,
appropriate training and place must be amply equipped Statements and Other Documents. Standards, Guidelines, State-
before any sort of sedation is utilized for dental treat- ments and Other Documents. Continuum of deep sedation:
Definition of general anesthesia and levels of sedation/analge-
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