SCIENTIFIC ARTICLE Evaluation of two dosages of oral ...

SCIENTIFIC ARTICLE

Evaluation of two dosagesof oral midazolamas a conscioussedation
for physically and neurologically compromisedpediatric dental patients

ThomasSilver, DDS, MSCarolyn Wilson, DDS,MSDMichael Webb,DDS

Abstract

Physically andneurologicallyhandicappedpediatric dental patients are often a challengeto treat andmayrequire the use of
pharmacologicaalgents for behaviormodification. Thepurposeof this study wasto investigate the safety, in termsof vital sign
changesandcomplications,andthe effectiveness, in terms of behavioralchanges,of twodosagesof oral midazolamas a conscious
sedative agent for this unique population. Participating in this study were31 patients of TexasScottish Rite Hospital for
Children, whowereuncooperative(as rated on the Franklscale) at a previousdental appointment.Thepatients, 3-18 years old,
were randomlyselected to receive one of the two dosageregimens; GroupA received 0.3 mg/kgoral midazolamand GroupB
received 0.5 mg/kg. Physiologic parametersand behavior were recorded throughout the appointmentand overall safety and
success were determined. Althoughclinically insignificant, GroupA’s pulse rates 20 rain into treatment weresignificantly
higher than at baseline or treatment start, and oxygensaturations werelower during treatment than at baseline and start of
treatment. Intratreatment systolic anddiastolic blood pressures andpulse rates of GroupB weresignificantly higher than the
baseline figures; however,these changeswerenot clinically significant. Noclinical or postoperativecomplicationswerenoted
for either dosage. The regimenof 0.3 mg/kgof oral midazolamwassuccessful 75%of the time, andthe regimenof 0.5 mg/kgof
oral midazolamwas successful 60%of the time in providing adequate sedation to allow operative treatment to be safely and
efficiently performed.Therewasno statistically significant difference in the effectiveness of the two regimenswhenoverall
success rates wereanalyzed. (Pediatr Dent 16:350-59, 1994)

Introduction dures lasting longer than 20 min needs to be evaluated.
There are no documented studies reporting the effec-
Providing dental care to patients with neurological tiveness of oral midazolamin pediatric dentistry.
disorders can be very challenging because they are
often noncommunicative, negating the effectiveness of Midazolam is a potent imidazobenzodiazepine used
many age-appropriate behavior-modifying or behav-
ior-shaping techniques. For many physically, neuro- as a premedicant and as an anesthetic induction agent.
logically, or developmentally compromisedchildren a The pharmacokinetics are similar to other benzodiaz-
sedative agent is effective and indicated to reduce fear epines in possessing hypnotic, anticonvulsant, muscle
and improvethe child’s ability to cooperate, and thereby
improve the quality of care delivered. relaxant, antegrade amnesic, and anxiolytic activity. It
is rapidly absorbed from the gastrointestinal tract and
For the "well" child, meperidine is one of the most short acting, s The hypnotic potency of midazolamcom-
commonly used sedatives. However, concerns have
recently been expressed regarding meperidine use in pared with diazepam is 1.5-2.1 times more potent.
patients with a history of seizure activity/disorders However, recovery characteristics are comparable for
because of the possible risk of inducing seizure activ-
ity. Precautions should be taken because meperidine the two agents. Midazolam has a high affinity, ap-
mayaggravate pre-existing convulsions in patients with proximately twice that of diazepam, for the benzodiaz-
seizure disorders. 1 Also, animal studies have indicated
that narcotics can reduce the convulsive threshold of epine receptors, which occur mainly in the CNSand
local anesthetics and increase their CNSdepressant account for its increased potency and hypnotic effects
effects. 2-~ The reported success and widespread use of compared with that of diazepam. 6 The anxiolytic and
oral midazolam as a preoperative sedative agent for
pediatric patients has brought this medication to the muscle relaxant properties of midazolam are attrib-
forefront as a prospective replacement. Most docu- uted to its ability to increase glycine-inhibitory neu-
mented studies have reported favorable results for its rotransmitters in the brain stem and spinal cord. 7 The
effectiveness as a preoperative agent for general anes- half-life activity of midazolam-- both in distribution
thesia cases. However, the use and effectiveness of
midazolam in providing modified behavior for proce- (6-15 min) and in elimination (1-4 hr) -- is the
favorable of the benzodiazepines,s, 8

Midazolam is the most lipid-soluble memberof the
benzodiazepines. The lipophilic nature of midazolam

accounts for its rapid absorption and metabolism by
the gastrointestinal tract, as well as its efficient entry

into brain tissue. This property produces rapid onset
and recovery.

350 Pediatric Dentistry: September/Octobe1r994 - Volume16, Number5

Midazolamacts to protect against cerebral hypoxia The majority of studies on pediatric patients have
-- useful for patients whohave decreased intracranial been performed utilizing rectal, nasal, IV, or IMadmin-
compliance9. Data investigating cerebral effects of vari- istration. In pediatric patients, peak serum concentra-
tions for the IM, rectal, and oral routes are 15, 30, and 53
ous induction agents have showna decrease in cerebral min, respectively. Bioavailability was 87, 18, and 27%,
blood flow, cerebral perfusion pressure, cerebral meta- r1e6spectively, at a dosage of 0.15 mg/kg.
bolic rate of oxygen, intracranial pressure, and intraocu-
lar pressure with midazolam2° These actions help to Oral preanesthetic medication with midazolam in
prevent episodes of cerebral hypoxia and also protect the pediatric population has shownfavorable results,
although the data on effectiveness have been sketchy
the brain against episodes of ischemic insult. Midazolam and inconclusive. Three different dosages of oral
midazolam were evaluated in combination with atro-
doses of 10 and 15 mg, compared with diazepam in pine prior to surgery27 Results in children 1-10 years
similar doses, produced significant pharmacological old, indicated that 0.75 mg/kg of midazolam produced
more significant sedation at 30 min compared with
effects in preventing seizure activity as measuredby an dosages of 0.25 and 0.50 mg/kg. In children 1-6 years
EEG1.1 The cerebral effects of most sedative agents are old undergoing elective cardiac surgery, 0.75 mg/kgof
oral midazolam was more effective in reducing anxiety
of concern in a patient with a history of seizure disor- and increasing sedation at separation from the parent
and at application of the face mask than 2.0 mg/kg
der and/or developmental delay because many cause pentobarbitone or 0.2 mg/kg each morphine and atro-
increased intracranial pressure and decrease oxygen to pine28 However, in children 0.5-4 years old undergo-
the brain. ing day surgery, 0.3 mg/kg oral midazolam produced
the sameanxiolytic effect as the placebo29Theeffect of
Benzodiazepines’ depression of respiration has con- oral midazolamon anxiety levels of preschool children
cerned dental professionals. A comparisonof the respi- during emergency laceration repair was evaluated in
another study; 2° 70%of the children in the midazolam
ratory effects of diazepam and midazolam demon- group had at least a 2-point decrease in anxiety level
strated that intravenous (IV) administration of 0.15 mg/ compared with 12%of the placebo group.

kg of midazolam and 0.3 mg/kg of diazepam pro- The clinical implications in pediatric dentistry are
duced comparable and significant respiratory depres- favorable. Antegrade amnesia, muscular relaxant ca-
sion. 12 Theresults also indicated that these effects are pabilities, and anxiolytic properties provide the pa-
due to direct depression of the central respiratory drive. tient and parent with a more pleasant dental experi-
ence. Rapid absorption and onset, short duration of
Although midazolam does not appear to produce less action, and potency have given this agent further cred-
respiratory depression than diazepam, it does have the ibility as a sedative agent. However, studies on oral
advantage of a shorter duration of action. midazolamhave failed to address the safety and effi-
cacy of this agent for prolonged time periods and post-
Oral administration is a beneficial and atraumatic operative complications.
means of consciously sedating patients in a private
practice setting. As opposed to intramuscular (IM) and The purpose of this study was to investigate the use
of oral midazolam to sedate the emotionally, neuro-
IV administration, this route alleviates a child’s fear of logically, and physically compromisedpediatric den-
an injection and does not sensitize the patient to injec- tal patients in two parameters. The first was to evaluate
and compare two dosages, 0.3 and 0.5 mg/kg, of orally
tions prior to beginning the proposed dental treatment. administered midazolamin terms of safety by evaluat-
ing their effects on vital signs and clinical and postop-
Rectal and nasal administration are invasive and may erative complications. The second purpose was to evalu-
ate patient cooperation at specific intervals during the
also have long-term negative effects on the child. The appointment and as an overall rating to determine and
efficacy of orally administered sedatives has been stud- compare effectiveness of the two dosages.
ied in comparisonto IMadministration. 13 The results of
Methodsand materials
this study indicate that oral preanesthetic dosages may
be just as effective as IMadministration. Another in- All 32 subjects selected werepatients of record at the
Texas Scottish Rite Hospital for Children in Dallas,
vestigation found that the rapidly acting benzodiaz- Texas, a facility limited to treatment of orthopedically
and/or neurologically involved pediatric patients. One
epines, such as midazolam, produced a safe and effec- patient was eliminated from the study when it was
tive alternative to IV diazepamfor minor dental surgical discovered that the child had been inappropriately
p~r4ocedures in adults.

The use of oral midazolam as a premedication in-
volves different pharmacokinetics than all other routes

of administration. Following oral administration, peak
plasma concentrations generally are achieved within 1

hr of ingestion, and the clinical onset is correspond-
ingly rapid. There is an extensive first-pass hepatic
extraction of oral midazolam. In reported cases, 30-

41%of the unmetabolized form of an oral dose reaches
the systemic circulation, z, 15 This high rate of hepatic

extraction makes the need for an oral dose two times
greater than the IV dose to obtain similar clinical ef-

fects. Interestingly, the elimination half-life is indepen-
dent of the administration route.

Pediatric Dentistry: September/Octobe1r 994 - Volume 16, Number5 351

Table1. ComparisoofnFranklScaleandModifiedBehavioSrcale dosages used in previous stud-
ies27, 20 Anecdotal success was

FranklScale ModifiedBehaviorScale high with oral dosages of 0.3-

Category#1 Definitely negative. Child refuses Combative,thrashing, 0.8 mg/kg prior to induction of
treatment,cries forcefully, fearfully, or general anesthesia. Pilot stud-
displays any overt evidence of extreme agitated, verbal, unableto ies were performed using vari-
negativism. ous dosages to determine which
be restrained, needto produced adequate conscious
terminate procedure.

Category#2 Negative. Reluctant to accept treatment Slightly combative,verbal, sedation while maintaining the
and someevidence of negative attitude slightly agitated, able to be patient’s protective reflexes.
restrained and procedure From these communications
(not pronounced). safely completed. and pilot studies, the two dos-
ages -- 0.3 mg/kg and 0.5 mg/

Category#3 Positive. Thechild accepts treatment Quiet, not combative, kg -- were selected and incor-
but maybe cautious. Thechild is cooperative, nonverbal. porated into the protocol. At the
willing to complywith the dentist, direction of the anesthesiolo-
but mayhave somereservations. gists, all doses administered
were based on an estimated lean

Category#4 Definitely positive. This child has a N/A body weight of the child. Lean
goodrapport with the dentist and is body weight was calculated as
interested in the dental procedures. follows: weight in kg x dosage x
0.8 for a lean child or 0.7 for an

obese child.

stimulated during the onset of sedation. The remaining Acceptable patients were scheduled for an appoint-

31 patients, ranging in age from 3 to 18 years, had ment and given preoperative instructions regarding

exhibited uncooperative behavior at a previous dental NPOorders prior to the appointment. The patients

appointment. One of the primary investigators, a fac- were not to have any solid food after midnight the day

ulty memberpreviously calibrated for participation in before the appointment and no liquids 4 hr prior to

numerous sedation studies, selected patients based on treatment. An exception was made for regular medica-
a score of I or 2 on the Frankl Scale (Table 1). 21 Accep- tions to be taken on schedule with minimal liquid. The

tance into the study required that patients need treat- parents were told to cancel the sedation appointment if

ment involving local anesthesia. Most patients were the child had a cold or any other acute illness.

selected for this study at either a recall or newpatient Study conduct
exam appointment. However, some patients’ behav-

iors did not becomenegative until a subsequent opera- Prior to drug administration, vital signs including

tive appointment. hemoglobin oxygen saturation, pulse rate, respiratory

Due to the unique patient population and their mul- rate, and blood pressure were taken to establish a

tiple medical diagnoses, medical charts were reviewed baseline reading, and cooperation was noted. A pulse
and consultations with the neurologist and/or anes- oximeter (Nellcor N-200®, Nell Corp, Hayward, CA; or

thesiologist were obtained prior to acceptance into the Invivo 4500TM, Invivo Research Inc., Broken Arrow,

study. Contraindications for acceptance into the study TOMK) and automatic blood pressure monitor (Dinamap

included patients who were presently taking monoam- -- Critikon, Tampa, FL) were attached to the child’s

ine oxidase inhibitors, benzodiazepines, or other drugs upper limbs. Either oral or axillary temperature was
that could change or exaggerate the therapeutic re- taken by an electronic thermometer (Survalent ® -- Pa-
sponse to benzodiazepines. tient Technology Inc, Hauppauge, NY). A stethoscope

Uponidentifying a candidate for the study, the pro- was used to assess breath sounds for any signs of con-
cedures, possible discomforts or risks, as well as pos- gestion.

sible benefits were explained fully to the parents and The randomly selected dosage was administered in

their informed consent was obtained prior to the inves- the following manner. The midazolam, as prepared by
tigation. At the time of selection, the patients were the manufacturer for IM or IV use, was drawn from the

divided randomly into two groups. Group A received vial by syringe and mixed in a medication cup with
0.3 mg/kg midazolam HC1(Versed ®, Roche Laborato- approximately 5 cc of a grape-flavored suspension
ries, Nutley, NJ) and Group B received 0.5 mg/kg (Syrpalta ®, Emerson Laboratories, Texarkana, TX) to

midazolam. The selection of the dosages used in this provide a more palatable oral administration. Behav-

investigation was determined in part by the recom- ior, dose, and administration time all were recorded.

mendation and personal experiences of two pediatric The patient was allowed to return to the waiting area
anesthesiologists at TexasScottish Rite Hospital22, 23 and under close supervision until onset of sedation. The

352 Pediatric Dentistry: September/Octobe1r994 - Volume16, Number5

clinical signs of onset included a glazed look or de- corded by one of two faculty membersstandardized in
layed eye movements, lack of muscle coordination, the use of the behavior scale developed for this study.
slurred speech, or sleep. Uponinitial signs of sedation, These faculty members were familiarized with the
the child was brought to the operatory and the time modified scale by an oral and written review of the
was noted. Appropriate vital sign monitors were placed, three categories and by viewing a taped example of
and recordings made every 10 min, in accordance with each category. They then viewed multiple taped sce-
the sedation/anesthesia policy of the hospital, until the narios depicting a variety of patient behaviors and made
patient was dismissed. Behavior was recorded upon ratings separately and independently. Ratings were
placement of monitors and every 10 min thereafter coincident for 18 of the 19 scenarios for an inter-rater
until dismissal. reliability of 95%. The scenario in which there was
disagreement received ratings of 2 and 3, both of which
Topical mucosal anesthetic was applied prior to in- were considered to be successful ratings for the pur-
jecting local anesthesia. After achieving adequate anes- poses of this study. In addition to the ratings, com-
thesia, a rubber dam was placed whenever possible ments were written regarding procedures and behav-
and operative treatment was performed. A bite block iors during various intervals.
was used (with parental permission) if the patient was
unable to keep his or her mouth open. If a child was Data interpretation
athetotic or unable to remain still for treatment, a re-
straining device was used (with parental permission). Behavior scores were evaluated using descriptive
A combative child was not placed in a restraining de- statistics due to the nature of the behavior rating scale.
vice. In those patients in which the sedation was con- To aid in analysis, ratings taken during local anesthesia
sidered unsuccessful, treatment was terminated, tem- administration were eliminated from the criteria to
porary restorations placed if appropriate, and the evaluate success. The operative phase of treatment was
treatment was completed at another appointment considered the most critical as it is usually the longest
through other means, either in the operating room or phase and the most technique sensitive with regard to
under an alternative sedation. Following treatment, the quality of dentistry performed. That is, the quality
the patient was allowed to return to the waiting area of the dentistry performed maysuffer if the patient’s
with the parents until responsive to verbal stimulation, struggling or movement leads to inadvertent move-
awake, exhibited no sign of compromised respiration ment of the handpiece and/or contamination of the
and, according to the accompanyingadult, appeared to preparations and dental materials. Therefore, if the
behave in the usual manner. All patients in the study patient’s behavior dropped to a rating of 1 after local
wererequired to remain in the clinic or waiting area for anesthesia administration, the sedation was consid-
at least 90 min after drug administration. Postopera- ered a failure due the need for restraint or other aggres-
tive instructions were discussed with the parents re- sive behavior managementtechniques required to ren-
garding the after-effects of the conscious sedative, local der treatment during this time period. Behavior ratings
anesthesia, or any other precautionary measures con- of 2 or 3 on the modified scale during operative treat-
cerning the actual dental treatment. An emergency ment were considered successful since treatment was
phone number was made available for questions or rendered with minimal patient trauma. The
problems. A post-treatment follow-up phone call was success:failure ratios were considered as the overall
made the next day to obtain additional information success of the two regimens and were used to compare
regarding the overall well-being and conscious state of the effectiveness of the two different dosages.
the child.
Vital signs, including systolic and diastolic blood
Behaviorevaluation pressures and pulse rates, were examined at various
time intervals using the ANOVAfor repeated mea-
Due to manyof the patients’ severe neurological sures to determine if significant changes were observed
handicaps, developmental delays, and inability to com- during the sedation appointment. Respiration rate data
municate, a modified scale was devised to more accu- were evaluated using descriptive statistics.
rately describe the level of cooperation (Table 1). The
cooperation scale used to evaluate behavior during Results
midazolam sedation was independent of the Frankl
scale. A behavior rating of 1 indicated a total lack of Of the 31 patients available for data analyses, 16
cooperation, combative nature, and ineffectiveness of received a midazolam dosage regimen of 0.3 mg/kg
the medication. A rating of 2 was indicative of a some- (Group A) and the other 15 received a dosage regimen
what cooperative patient exhibiting periods of anxiety of 0.5 mg/kg (Group B). There were no statistically
or crying in a noncombative manner. A rating of 3 was significant demographic differences between the two
considered very favorable cooperation for dental treat- groups. Demographics are shown in Table 2.
ment. Clinical assessments of cooperation, measured
at 10-min intervals during the appointment, were re- All patients’ vital signs were measuredand behavior
rated (using the modifiedscale) at the following times:

Pediatric Dentistry: September/Octobe1r994 - Volume16, Number5 353

Table2. Patientdatafor groupAs andB Table3. Behavioradlatafor groupAs andB

Demographics GroupA GroupB Results Group A Group B
N = 16 N = 15
Sex 87
Male 88 No. of patients cooperative 13 10
Female in taking medication 30 25-30
7
Agesin years 4-17 3-18 Averageclinical onset of 12 4
(Mean9) (Mean9) sedation in min 1 9
1° 2
Diagnosis No. of patients cooperative 0
for local anesthesia
Static encephalopathy 6 5
2 No. of successful sedations
Developmental delay 3 1 for operative treatment
1
Spina bifida 1 1 No. of patients whoslept
1 during treatment
Left hemiparesis 1 0
1 Postoperative complications
Hypothyroidism 1 0
0
Chomosomedeletion 1 1
1
Status post-meningitis 1 1 ¯ Prolongesdedation

Hydrocephalus 0 6

Multiple congenital anomalies 1 remaining three patients were unable to remain still or
were combative.
Sturge-Weber syndrome 1
In Group A, 12 of 16 patients (75%) cooperated suf-
Tuberoussclerosis 0 ficiently during operative treatment to be considered

Leukodystrophy 0 successful sedations and four patients were considered
failed sedations. Of the 12 successful sedations, six were
Status post-skull trauma 0
cooperative during a major portion of the appoint-
Anabove diagnosis with 7 ment with a favorable experience and outcome of clini-
seizure disorder
cal treatment. These patients, receiving ratings of 3,
1. Presedation for baseline values (B)
2. Immediately before treatment (T) for the effect had no episodes of poor behavior and would be con-
sidered successes in any study population. During the
of the drug alone on these parameters treatment phase, the other six successful patients ex-
3. Every 10 min intratreatment for effect of the
hibited short periods of lack of cooperation that either
drug while undergoing treatment prolonged or complicated treatment. These patients
4. At the end of treatment prior to the child exiting
received a combination of ratings of 2 and 3. The re-
the operatory (E). mainingfour patients, receiving ratings of 1, were evalu-

GroupA: 0.3 mg/kgmidazolam ated as failed sedations either due to a total lack of
cooperation or loss of cooperation during the treat-
Sixteen patients were evaluated for cooperation
during medication administration, clinical onset, co- ment phase, causing an increased risk of patient injury.
operation during injection of local anesthetic, compli- In one failed case, the operator was unable to adminis-
cations, overall clinical success, and postoperative
problems (Table 3). In GroupA, 13 of 16 patients (81%) ter local anesthetic. In the second failed sedation, the
were cooperative when taking the oral medication. patient became so combative after treatment had be-
The remaining three patients required coaxing and/
or more forceful actions with the concurrent use of a gun that temporary restorations had to be placed and
head and/or body restraint to get the child to take the the patient was rescheduled for completion of treat-
oral sedation.
ment under general anesthesia. The remaining two
Averagetime for clinical onset of sedation after ad- patients in whomsedations failed became so combat-
ministering the 0.3 mg/kg dosage of midazolam was
30 min. One child exhibited clinical signs after 20 min. ive and aggressive that restraining techniques were
required to complete treatment.
Goodbehavior (rating of 3) was exhibited by seven
of 16 patients (44%) during the local anesthetic injec- Onechild of 16 in the 0.3 mg/kg group slept but was
tion phase of treatment while the other nine patients easily arousable by verbal stimulation throughout the
were uncooperative. Of these uncooperative patients, appointment; the others remained awake and fully con-
six cried forcefully throughout the injection and the
scious for the duration of the appointment.

In only one case did parents describe any form of
postoperative, sedation-related complication. This was
prolonged sedation for approximately 20 hr and then

resumption of normal behavior and activity. There were
no cases of postoperative nausea, seizure activity, or

354PediatricDentistryS: eptember/Oct1o9b9e4r- Volum1e6, Numb5er

Table4. ScheffFe-testforvital signs DIASTOLIC BLOODPRESSURE

GroupA Significance GroupB Significance

Com- Dias Syst Pulse 02 Dias Syst Pulse 02
parison BP BP sat BP BP sat

Bvs. T NS NS NS NS NS NS NS NS
Bvs. 20 NS NS Sig.° Sig.° Sig. ° Sig. ° Sig. ° NS
Bvs. E NS NS NS NS NS Sig. ° Sig.° NS
Tvs. 20 NS NS Sig.° Sig.° Sig.° Sig.° Sig.° NS
T vs. E NS NS NS Sig.° NS NS Sig.° NS
55

20vs. E NS NS NS Sig.° NS NS NS NS 45

B = Baseline Dias BP= Diastolic blood pressure 35
T = Start of treatment Syst BP= Systolic blood pressure B T 10 20 30 40 50 60 E
E= Exit reading
Pulse = Pulse rate 10 MINUTEINTERVALS
20 = 20 min into treatment 02 sat = Oxygen saturation
NS= Nonsignificant Sig. ° = P < 0.05 ...... groupA --. group B

Fig1. Diastolicbloodpressuroef GroupA(0.3 mg/kga)nd
GrouBp(0.5 mg/kga)longwithmeanasndstandarddeviations.
(B-- BaselinReeadinTg-;- Startof TreatmenEt-;- Exit)

other postoperative complications at the time of the GroupB: 0.5 mg/kg midazolam
follow-up phone call.
Fifteen patients were evaluated for cooperation dur-
Vital signs changes were evaluated and statistically ing medication administration, clinical onset of effect,
analyzed at four different time periods: baseline read- cooperation during injection of local anesthetic, com-
ing (B), start of treatment (T), 20 mininto treatment plications, overall clinical success, and postoperative
and the exit reading (E). The 20-min time period was problems (Table 3). In GroupB, 10 of 15 patients (67%)
chosen to be representative of the intratreatment phase were cooperative when taking the oral midazolam. The
of the study. remaining five patients were not cooperative and re-
quired restraint and more forceful actions to get the
Vital sign measurements recorded during the seda- child to take the medication. The average time period
tion appointments showed that respiration rate varied for clinical signs of sedation for the majority of Group
only slightly in all patients at all recorded intervals. An B children was 25-30 min. Onset of clinical signs for
ANOVfAor repeated measures revealed that there were three children was 15 min, while one child did not
no significant differences amongthe various measure- showsigns of sedation until almost 40 min.
ments for the diastolic blood pressures (Fig 1; Table 4).
Similar results were obtained for the measurements of Goodbehavior (3 rating) was exhibited by four of
systolic blood pressure, showingno significant differ- patients during the injection phase of treatment, while
ences (Fig 2; Table 4). Pulse rates differed significantly 11 patients (73%) were uncooperative. Of these pa-
(ANOVAP; < 0.05). Further analysis by a Scheffe F-test tients, five cried forcefully during the procedure and
showed that the mean pulse rate at 20 min differed the remaining six were unable to remain still or were
significantly from those at baseline (B) or treatment combative.
start (T)(Table 4; Fig 3). Oxygensaturation measure-
ments were most significant when statistically ana- In Group B, nine of 15 patients (60%) were consid-
lyzed (ANOVAP; < 0.05). Further analysis by a Scheffe ered successful sedations, and six had failed sedations.
F-test revealed significantly lower O2 readings During the operative phase, five patients were coop-
intratreatment when comparing different time periods erative with virtually no episodes of combativeness or
(Table 4). Differences existed between(B) and (20), undesirable vocal behavior, resulting in a successful
and (20), (T) and (E), and (20) and (E). Oxygen sedation rating of 3. During isolated periods of treat-
tion readings showed fluctuations during treatment ment four patients received ratings of 2; however, the
with one patient dropping to 92%oxygen saturation, overall clinical assessment of behavior was favorable.
another to 93%, and seven patients dropping to 94%for These patients were evaluated as successful sedations
a short period of time (Fig 4). Headrepositioning re- because treatment was completed with minimal be-
sulted in return of oxygen saturations to acceptable havioral complications. The remaining six patients were
levels. All patients registered acceptable (95%) oxy- so uncooperative, receiving ratings of 1, that treatment
gen saturation levels for the majority of treatment and was difficult or impossible to complete. In the unsuc-
were discharged without complications or delays. cessful sedations, half were characterized by a total

Pediatric Dentistry: September/October 1994 -Volume 16, Number 5 355

SYSTOLIC BLOOD PRESSURE PULSE RATES

150 130
140. 115

100

E 120 85
110 70

100 55

B T 10 20 30 40 50 60 E 40
10 MINUTEINTERVALS B T 10 20 30 40 50 60 E
10 MINUTEINTERVALS

,---.---group A --group B ....... groupA -- group B

Fig 2. Systolicbloodpressureof GroupA(0.3 mg/kg)and Fig3. Pulserateof GrouAp(0.3 mg/kga)ndGrouBp(0.5 rag/
GroupB (0.5 mg/kg)alongwith meansandstandarderrors. kg) alongwith meanasndstandarderrors. (B -- Baseline
= BaselinReeadingT;= Startof TreatmenEt;= Exit) ReadingT;= Startof TreatmenEt;= Exit)

lack of cooperation. Treatment was aborted and tem- at (T) than at (20) and at (E). Oxygensaturation
poraries were placed until an alternative treatment vealed no significant differences (ANOVAP; < 0.05;
Fig 4; Table 4). Vital sign measurementsrecorded dur-
method was scheduled. The three unsuccessfully se- ing the sedation appointments showed that oxygen
saturation momentarily dropped to 92%in one child
dated patients required aggressive restraining to com- and to 93%in another. In both instances, the patient
plete treatment. quickly returned to an acceptable oxygen saturation
with head repositioning. All patients recorded an ac-
Twochildren slept during a major part of the treat- ceptable oxygen saturation level (95%) during a ma-
jority of the appointment and were discharged with-
ment period, yet both were easily arousable with ver- out complications or delays.
bal stimulation; the other 13 patients remained awake
ComparingGroupA with GroupB
and fully conscious. None of the children in Group
Overall success, as determined by the ability to com-
B had prolonged sedation. There were no reports of plete treatment, was 75%for Group A (0.3 mg/kg), and
postoperative nausea, seizure activity, or other 60%for Group B (0.5 mg/kg). Chi-square analysis re-
postoperative complications at the time of the follow- vealed no significant difference in these success rates.

up phone calls. Discussion
Vital sign measurements recorded during the seda-
The widespread and successful use of oral
tion appointment revealed that respiration rates varied midazolamas a preoperative sedative in pediatric hos-
only slightly in all patients. Slight decreases in respira- pitals indicates that it is a favorable choice for pediatric
dentists. The initial question posed was which dosages
tions were seen in five patients when compared with of midazolam would be ideal to study. The fact that
this study population consisted of children of various
the presedation rate; however, it was not clinically evi- ages, weights, and degrees of mental compromisemade
dent that the children were in any form of compro- the decision on an appropriate dosage more difficult.
The dosages selected for this study were based on both
mised respiratory status. recommendations by pediatric anesthesiologists who
Diastolic blood pressure readings revealed signifi- used 0.3-0.8 mg/kgof the agent for preanesthetic seda-
tion22, 23 and reports from the literature using 0.25-0.75
cant changes (ANOVA;P < 0.05) when time periods
were compared (Fig 1; Table 4). Further analysis by mg/kg dosages of oral midazolam.17,20 It was unknown
Scheffe F-test showed that diastolic blood pressures whether these dosages would modify the behavior of
uncooperative mentally or physically compromised
differed significantly when comparing (B) and (20), patients sufficiently and for a duration long enoughto
and (T) and (20). Systolic blood pressure statistical analy-

sis using the ANOVaAlso revealed significant differ-
ences (P < 0.05; Fig. 2; Table 4). TheScheffe F-test showed
these differences to be statistically higher during treat-
ment (P < 0.05) than readings at (B) or (E). Significance

was seen between (B) and (20), (B) and (E), and
(20). Pulse rates revealed significant differences
(ANOVAP; < 0.05; Fig. 3; Table 4). Using a Scheffe

test, pulse rates were significantly lower at (B) than
(20), or at (E). Pulse rates were also significantly lower

356 Pediatric Dentistry: September/Octobe1r994 - Volume16, Number5

OXYGENSATURATION safely, effectively, and without psychological or

lOO r" ". ..±, .’i physical trauma to the patient. In the opinion of the
99 investigators, this modified scale was not only success-
X:’"_li"Z
~ 98 ful in its purpose, but provided an easy method to
quickly and accurately rate cooperation during the
g7
course of the appointment.
95 The investigators determined behavioral success of

B T 10 20 30 40 50 60 E the sedation by rating the patient’s cooperation at set
10 MINUTEINTERVALS time intervals during treatment. Overall success was
determined if behavior during operative treatment did
...... groupA -- group B
not drop to a rating of I and the procedure was com-
Fig4. Oxygesnaturationof GroupA(0.3 mg/kga) ndGroup pleted safely and without excessive physical restraint
(0.5 mg/kg)alongwith meansandstandarderrors. (B
BaselinReeadingT; = Start of TreatmenEt;-- Exit) and harsh management techniques. Behavior did not
tend to deteriorate over time to a rating of I -- rather,
allow dental care to be performed safely. Several pilot
studies were performed using various dosages to de- the patients considered to be failed sedations had mul-

termine which produced adequate sedation while main- tiple ratings of 1. Theresults indicate a slight difference
taining the patient’s protective reflexes. It was found in the effectiveness of the two dosages. In general, the
patients were more cooperative and less combative
that dosages > 0.5 mg/kg did not always produce con-
scious sedation and these patients had to be recovered with the lower dosage, yielding a success rates of 75%
for Group A and a 60%for Group B. The higher dosage
and monitored for extended periods of time. Thus, 0.3
mg/kg and 0.5 mg/kg were chosen for this study. The did not result in a greater rate of success, possibly due

results of this study indicate that both of the selected to the small population size. With an increased sample
dosages provided adequate sedation and working time population, a larger dosage mayprove to be equally
or moreeffective. However,the findings of this inves-
for the majority of patients.
Anobstacle to overcomein evaluating the success of tigation support use of the lower dosage of 0.3
mg/kg since the increased dosage did not offer
a conscious sedation is the use and development of an
assessment tool for behavior and cooperation. The study sufficient advantages.
Oral drug administration is considered the route
population was not typical of those seen routinely in
of choice in pediatric dentistry. There were no episodes
private practice. Many of these children
were moderately to severely neurologically handi- of nausea or vomiting and most children found the
medication acceptable. The midazoalm-Syrpalta mix-
capped with ages ranging from 3-18 years. In
addition, many of the children were nonverbal, ture was considered less than palatable by 35%of the
making behavior assessment even more difficult. The
patients; the remaining 22 patients took the medication
scale used in this study had to be standardized and without complaints. Although the oral route has a
provide specific criteria for each rating from good to slower onset of action than other routes and extensive

very unfavorable behavior. first-pass hepatic extraction, it is least traumatic
The most commonlyused behavior scale in pediat-
for the child and produces acceptable results for in-
2ri1c dentistry is the Frankl Behavioral Rating Scale,
which assigns four levels of patient cooperation em- office conscious sedation.
The length of time between administering the oral
phasizing patient rapport. It tends to disregard patient
personality and other factors that play an important medication and starting treatment -- varying from 15
to 40 min-- was an important finding. It appeared that
part in assessing the handicapped child patient’s be- the children with the more rapid onset received less
havior. For this reason a modified scale was developed
distraction and stimulation, eliminating factors that
to enable more accurate cooperation ratings by focus- might produce apprehension and allowing the child to
ing on the patient’s verbal intensity and physical ac- relax. In future studies, placing the child in a quiet
tions rather than on verbal communication. The modi-
fiecl scale wassimplifiect so that a clear distinction could room after oral sedation may produce more rapid se-
dation and lead to better cooperation.
be made as to when treatment was accomplished
Monitoringvital signs to determine the safety of oral
midazolamwas the second objective of this investiga-

tion. It was unknownwhat the clinical effect of oral
midazolam would be after the initial 15-30 min re-
ported in the preoperative studies. 17, 22, 23 Analysis of
vital signs was performed to provide a comprehensive
assessment of physiological parameters during the

appointment. These readings were taken preoperatively
uponarriving at the clinic for a baseline (B), and fol-
lowing clinical onset of the medication prior to the

Pediatric Dentistry: September/Octobe1r 994 - Volume 16, Number5 357

actual start of treatment (T), to provide an accurate reported cases of nausea, seizure activity, or any other
assessment of the effects of the oral midazolamwith-
unfavorable reactions at a 24-hr follow-up phone con-
out interference from clinical treatment factors.
The statistical results indicated that there were no versation with the parent. Since the elimination half-
life is from I to 4 hr, this followup wouldallow for any
significant differences in the vital sign measurements adverse reaction to occur. Only one case of residual
in either Group A or B when comparisons were made
sedation effects was seen -- a child in Group A who
between (B) and (T), showing little influence of was overweight. Because midazolam may be stored
orally administered midazolam. In Group A,
intratreatment (20) pulse rates were significantly el- in adipose tissue and slowly time-released, this
may explain the prolonged sedation and secondary
evated and oxygen saturation significantly decreased sedative effects.
compared with (B) and (T) readings. In Group B,
nificant elevations were noted in all the vital sign pa- Personality factors and age also mayplay an role in
assessing candidates for conscious sedation with oral
rameters except oxygen saturation when similar com-
midazolam. Thoughnot an official part of the project
parisons were made. These comparisons indicate that design, patients’ personalities, and the nature of their
the oral midazolam itself was not a major factor in
interpersonal interactions were noted prior to seda-
altering vital signs, but that anxiety-related factors and tion. Children whowere extroverted tended to be more
stimulation were more influential in elevating blood
successful than those individuals whowere timid and
pressure and pulse. Vital signs were, however, moni- introverted or did not relate well with others. These
tored to the completion of treatment to assure that
there were no significant long-term changes from children were difficult to sedate and even more diffi-

baseline readings or delayed effects of midazolamover cult to makecooperate. Interestingly, age did not seem
time. For the majority of patients, treatment lasted only to be related to the success or failure of oral midazolam
sedation. The average age of the uncooperative pa-
30 min and therefore, the decreased numberof patients
in the extended periods resulted in larger standard tients in both groups was 9 years as was the average
age for the groups as a whole.
deviations (Figs 1-4).
A relationship was found between changes in car- Although it was never the intent of the study to
measure parent desire or satisfaction, there were some
diovascular vital signs and success of the midazolam
dosage. The higher dosage (0.5 mg/kg) used in Group anecdotal observations worth noting. Manyparents of
B was clinically less successful and had statistically children with muscle spasticity commentedthat they
had never seen their child so relaxed. Parents whose
significant increases in all three of these parameters --
pulse and diastolic and systolic blood pressures-- when children had been previously sedated with oral
comparing (B) with (20). Similar comparisons for meperidine and promethazine generally considered

more successful Group A (0.3 mg/kg) showed only oral midazolamto be more effective. The vast majority
significantly increased pulse rates.
of parents were pleased that their child returned to
The respiratory effects of oral midazolam, as mea- their normal behavior so rapidly. Andlast, manypar-
ents expressed the desire for their child to be sedated or
sured by oxygen saturation and respiratory rate showed
the only significant change to be a decrease in oxygen relaxed with midazolam for future appointments in-
saturation for Group A. This maybe explained in sev- cluding routine examinations and oral prophylaxis.

eral ways. First, the oxygenprobe is sensitive to move- Future studies should be designed to include collection

ment and the muscle relaxant properties maynot have of parental attitudes concerning the drug’s effect.
been as effective at the lower dosage, causing the oxy- This investigation’s primary purpose was to initiate

gen readings to be inaccurately low due to artifact, research on using oral midazolamon the pediatric den-
especially in patients with uncontrolled movementas- tal patient. The scarcity of information on this topic has
sociated with their diagnoses. Second, one of the un- made manypediatric dentists reluctant to incorporate

successful patients in GroupA, with a low saturation, it into their private practices. This study involved some
was breath-holding as well as struggling during a read- of the most challenging dental patients to treat and the
results indicate an acceptable success rate. Future evalu-
ing. Also, because Group B tended to be less coopera-
tive and cry more, their respiratory effort was greater, ation of oral midazolam on the "normal child" would
causing increased oxygen saturation in this group. Re- perhaps yield even more favorable results. Dosage

straints used on the more combative patients in this modification and concurrent use of nitrous oxide with
group mayhave eliminated some of the effect of move- oral sedation are areas of research that could expand

ment artifact expected in the moreuncooperative group. knowledgeof midazolamand its effectiveness and prac-
Although some vital sign changes were statistically ticality in the pediatric dental office. Concerns over
significant, no patients showedany signs of physiologic somechanges in vital signs in this study could also be
compromiseclinically.
addressed in future investigations. Measurement of
The questions and concerns over postoperative com- end tidal carbon dioxide is considered an accurate analy-
plications were answered favorably. There were no
sis of respiratory alteration and could be incorporated
into a study to further evaluate any respiratory depres-

358 Pediatric Dentistry: September/October 1994 - Volume 16, Number 5

sion from oral midazolam. Pulse oximetry also could LimjucoRA,Shader RhEffect of age, gender, and obesity on
be improved to eliminate some distortion from patient
movement through the use of EKGleads wired into the midazolamkinetics. Anesthesio161:27-35,1984.
6. Mohler H, OkadaT: Benzodiazepine receptor: demonstration
pulse oximetero
in the central nervoussystem. Science198:849-51,1977.
Conclusions 7. Marshall BE:Current theories about the mechanismsof benzo-

1. Orally administered midazolam was successful diazepines and neuroleptic drugs. Anesthesio154:66-72,1981.
8. DundeeJ, Halliday NJ: Midazolam-- a review of its pharma-
75% of the time at a dosage of 0.3 mg/kg and
cological properties and therapeutic use. Drugs28:519-43,1984.
60% of the time at a dosage of 0.5 mg/kg in
9. Nugent M,Artru AA,Michenfelder JD: Cerebral, metabolic,
providing adequate sedation to allow operative vascular and protective effects of midazolammaleate: com-

treatment to be safely and efficiently performed parison to diazepam.Anesthesiol 56:172-76,1982.
10. Fragen RJ, AvramMJ: Comparative pharmacology of drugs
for the moderately to severely physically and
used for the induction of anesthesia. Advancesin Anaesthesia
neurologically compromised pediatric patient. 3:103, 1986.
11. Jawad S, Oxley J, Wilson J, Richens A: A pharmacodynamic
2. There was no statistically significant difference evaluation of midazolamas an antiepileptic compound.J

in the effectiveness of the two oral regimens Neurol, NeurosurgPsychiatry 49:1050-54, 1986.
12. Forster A, GardazJP, Suter PM,GemperleM:Respiratory de-
when either overall success rates or
pression by midazolamand diazepam. Anesthesio153:494-97,
intratreatment ratings were analyzed. 1980.
13. NicolsonSC,Betts EK,Jobes DR,Christianson LA,Walters JW,
3. Although clinically insignificant, Group A (0.3 MayesFR, Korevaar WC:Comparisonof oral and intramuscu-

mg/kg) showed a statistically significant in- lar preanesthetic medicationfor pediatric inpatient surgery.
Anesthesiol71:8-10, 1989.
crease in pulse rate and decrease in oxygen satu- 14. O’BoyleCA,Harris D, Barry H, McCrearyC, BewleyA, Fox E:

ration and Group B (0.5 mg/kg) showed statisti- Comparisonof midazolamby mouth and diazepamIV in out-
patient oral surgery. Br J Anesth59:746-54,1987.
cally significant increases in pulse rate and
15. Crevoisier C, Ziegler WH,Eckert M, HeinzmannP: Relation-
diastolic and systolic blood pressures during ship between plasma concentration and effect of midazolam

treatment compared with readings at baseline after oral and intravenous administration. Br J Clin Pharmacol
16:51S-61S,1983.
and the start of treatment.
16. PayneK, MattheyseFJ, LiebenbergD, DawesT: The pharmaco-
4. No clinical signs of a compromised respiratory kinetics of midazolamin pediatric patients. Eur J Clin Pharmacol

rate were noted with use of either dosage of the 37:267-72,1989.
17. Feld LH, NegusJB, White PF: Oral midazolampreanesthetic
oral midazolam.
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5. Neither sedation regimen caused any postop-
18. Levine MF,Hartley EJ, MacphersonBA, BurrowsFA, Lerman
erative complications. J: Oral midazolampremedicationfor children with congenital

Dr. Silver is private practitioner in ClearwaterF, lorida. Dr. Wilsonis cyanotic heart disease undergoingcardiac surgery: a compara-
associate professor, pediatric dentistry, and Dr. Webbis assistant tive study. CanJ Anaesth40:934-38,1993.
19. Anderson BJ, Exarchos H, Lee K, Brown TCK: Oral
professor, pediatric dentistry, both at BaylorCollegeof Dentistry, premedicationin children: a comparisonof chloral hydrate,
Dallas, Texas.
diazepam, alprazolam, midazolamand placebo for day sur-
1. Demerol.In Physicians DeskReference. Montvale,NewJersey:
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Medical Economics,1993, pp 2142-43. 20. Hennes HM,WagnerV, Bonadio WA,Glaeser PW, Losek JD,
2. MoorePA, GoodsonJM:Risk appraisal of narcotic sedation for
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5. Greenblatt DJ, Abernathy DR, Lochniskar A, Harmatz JS,

Pediatric Dentistry: September/Octob1e9r94- Volume16, Numbe5r 359