A Comparison of Oral Sedation-related Events of Three Multiagent Oral Sedation Regimens in Pediatric Dental Patients
Phase: PHASE3
Conditions: Anxiety, Dental, Dental Decay
Sponsor: Loma Linda University

Title page:                   
 
Title: A Comparison of Oral Sedation-related Events of Three Multiagent 
Oral Sedation Regimens in Pediatric Dental Patients 
 
 
NCT 05126459                           Unique Protocol ID: 5190213 
 
Document Date: October 24, 2019 
 
 
 

 
Statement of the Problem:  
 
Providing safe and effective dental care while managing patients’ behavior of 
is a continuous challenge for pediatric dentists. Many resources are available for 
pediatric dentists to aid in guiding patients’ behaviors in order to provide quality 
dental care. These tools range from non-pharmacological methods to more 
advanced techniques that include oral sedation and general anesthesia.4 Recent 
changes in parenting styles have led to a shift in treatment preferences favoring 
pharmacological management.5,6 
Conscious sedation is a state of drug-induced depression of consciousness in 
which patients respond purposefully to verbal commands, either alone or 
accompanied by light tactile stimulation.4 There is no intervention necessary to 
maintain an open airway, and spontaneous ventilation is adequate while 
cardiovascular function is maintained.4,7  
The purpose of sedation is to significantly reduce anxiety, provide analgesia 
and allows the delivery of safe and successful dental treatment that may otherwise 
would be compromised.8 This prevents negative experiences for the patient, the 
family and the dental team.  It is also used to encourage change in the child’s 
behavior, to help children develop their own coping skills and to promote 
acceptance of the dental environment.9  
Although oral sedation can be very beneficial in obtaining patient’s 
cooperation and facilitating dental treatment, some limitations exist. A major draw 
back of oral sedation is the inability to titrate the medications to the desired effect 

given and unpredictability due to variable individual absorption and first pass 
effects.2-3,7,10 The  adverse events associated with oral sedation  can occur during at 
any time, from the time of administration of medication,  during  the sedation 
procedure itself,  and after the patient has been discharged from the controlled and 
monitored environment of the health care facility.6  Nausea and vomiting are 
frequently seen when using sedation agents. Adverse events like frequent sleeping, 
gastrointestinal side effects, diminished activity, residual central nervous system 
alterations, respiratory depression and the existence of a paradoxical reaction were 
also observed in the literature.11,12 Some of the most dramatic adverse sedation 
related events that have been reported are brain damage and death mainly due to 
respiratory depression in the sedated patients secondary to over sedation and the 
unintentional introduction of general anesthesia.13 
A wide array of medications can be used in oral sedation. One drug regimen 
in use is a “triple-agent cocktail” that combines Midazolam (MZ), Meperidine (M), 
and Hydroxyzine (H).11,14 Although several authors have claims of safety and 
efficacy of the MZ/M/H triple-agent cocktail, some concerns with use multi-agent 
regiments sedative effect on children exist. Use of multi-agent regimens may lead to 
a synergistic effect of all medications that potentially prolong the duration of the 
sedative effect which can be highly inconsistent and unpredictable.11 This study will 
compare the adverse sedation-related events among three different sedation 
regimens (MZ/M/H, MZ/H, and M/H) in order to provide pediatric dentists with 
data that will aid them in their efforts to minimize adverse events during sedation 

and using the least amount of medication necessary to provide quality dental care. It 
will also assess the potential adverse effect over time among the three regimens.  
 
Introduction: 
Cooperation is imperative to successful treatment in the pediatric dental 
patient. While the majority of children are able to cooperate with the use of non-
pharmacologic behavior guidance techniques, such as tell-show-do, positive 
reinforcement and modeling that are carefully selected for each child, a small but 
significant percentage of children are unable to accept dental treatment.1,15 This is 
especially true for pediatric patients under five years of age, who commonly fall into 
this category and can be some of the most difficult patients to manage.4 These 
difficulties in management and absence of cooperation can be due to lack of 
psychological or emotional maturity and/or the existence of a mental, physical, or 
medical disability.4,15 Unlike an adult, a child does not understand that cooperation 
during treatment may produce faster and more favorable results.3    Ultimately, the 
lack of cooperation can lead to a diminished quality of dental care or even injury to 
the patient. In addition to inherent difficulties in patient cooperation, changes in 
parenting styles and the decreasing acceptance by parents of assertive behavior 
management techniques, such as hand-over-mouth and protective stabilization 
(papoose board), have resulted in the continuing search by pediatric dentists for 
other methods for facilitating treatment of uncooperative young patients.16  When 
behavior management strategies are unsuccessful, some form of pharmacological 
sedation or general anesthesia may be indicated.1  High levels of dental disease in 

the pediatric population, increasingly difficult child behavior and parent 
expectations support the need for sedation services.10  Additionally because general 
anesthesia in a hospital environment is an expensive alternative, pharmacologic 
sedation in the dental office is is often selective as a more cost effective  option if the 
provider has the necessary clinical anesthesia-related skills and if the patient’s 
health/comorbidities allow its utilization.13,16 
While oral conscious sedation enables the dentist to perform necessary 
dental treatment that may not, otherwise, have been possible, some risks do exist.2 
Drug responses are unpredictable and can produce a variable range of adverse 
outcomes.3 Due to the presence of these adverse outcomes, the search for an 
efficacious sedative regimen with the least amount of risk to the patient continues.  
The Pediatric dental literature contains numerous reports on various medications 
that have been administered alone or in combination for children as oral sedation.8-
11,14 Some examples include, but are not limited to, nitrous oxide, opioids, 
barbiturates, antihistamines, chloral hydrate and benzodiazepines.9,18 Some of the 
commonly used medications for oral sedation in pediatric dental patients that can 
be used individually or in combination are Midazolam (Versed), Miperidine 
(Demerol) and Hydroxizine (Vistaril).  
The efficacies of the (MZ/M/H) drug regimen during treatment have been 
investigated.14,19-20 However, when choosing a drug regimen, it is important to not 
only look at the efficacy of the regimen, but also check its risks for adverse events. 
Adverse events can happen not only during treatment, but also from the time the 
drug administration prior to treatment, as well as after the patient has been 

discharged from the health care facility.11,14 Understanding of events occurring after 
discharge may influence future sedation protocols or discharge criteria and add a 
margin of safety if practitioners and parents are alert to them.  
The purpose of this study is to compare the incidence of adverse sedation-
related events for the three sedation regimens.  The observation period will start at 
the time of drug administration and will continue until 24 hours after drug 
administration.  
 
 
 
 
 
 
Review of Literature: 
The concept of oral sedation use in pediatric dentistry is not new. Oral 
sedation involves using either a single medication or combination of drugs to 
achieve a state of altered consciousness in order to obtain a child’s cooperation, 
reduce anxiety, provide analgesia and allow the delivery of safe and quality dental 
care.8-9 For over 30 years oral sedation has been used in dental practices all across 
the country.12 In a survey in 1988, the authors found that as many as 76% of 
surveyed pediatric dentists indicated that they used oral sedation in their 
practices.21 Another survey in 1996 of 1,758 AAPD members reported using oral 
sedation 1 to 5 times every week, with 20% using it even more than 5 times per 

week.22  A more recent survey by Houpt comparing previous surveys taken in 1985, 
1991, and 1995, found an increased use of sedation by pediatric dentists in the year 
2000. This survey showed the total number of patients sedated with agents other 
than nitrous oxide in a three-month period had substantially increased in the year 
2000, with 77,112 sedations conducted in that year, as opposed to only 33,683 in 
the year 1985.18  
Various factors have led to the recent popularity of pharmacological, or 
advanced, management techniques in dental treatment of children. One factor is 
related to changes in parenting styles that led to a shift in treatment preferences 
favoring pharmacological management. In a study by Eaton et al. in 2005 found that 
parental acceptance of general anesthesia and sedation has increased over time. In 
their study, sedation was ranked as the fifth most acceptable behavior management 
technique after tell-show-do, nitrous oxide, general anesthesia and active restraint.5 
A more recent study by Patel in 2016 evaluating parental attitudes toward advanced 
behavior guidance techniques used in pediatric dentistry reported that oral sedation 
was rated as the most acceptable advanced technique in a survey of 105 parents, 
followed by general anesthesia.6 Other possible consideration for favoring oral 
sedation include limited access to hospital operating rooms for general anesthesia, 
or GA. 5,13,16 General anesthesia has some disadvantages that may decrease its 
popularity. This is illustrated by Camm et al. who found that while children who had 
dental treatment under oral sedation and general anesthesia both experienced 
behavioral changes, those under general anesthesia were reported to have 
significantly more stress.23 Another limitation with general anesthesia is possible 

adverse anesthetic drug reactions, as demonstrated by Becker et al. who concluded 
that 10-20% of hospitalized patients experience such reactions his study.24  
Oral conscious sedation is also not without risks. Two serious complications 
of oral sedation are respiratory suppression or depression and airways obstruction, 
which can lead to brain damage or death.2,25 In a systematic investigation performed 
by Cote and colleagues, the authors investigated adverse events with regard to the 
medications used in sedation. In 28 of the 95 cases, death or permanent neurologic 
injury was associated with drug overdose.20 Deaths and injuries after discharge 
were more commonly associated with sedatives with long half lives of elimination, 
often chloral hydrate but pentobarbital, promazine, promethazine, and 
chlorpromazine have also been reported.  These medications with prolonged half 
lives account for nearly 80% of the devastating adverse events reported. They found 
no relationship with regard to outcome and drug class (opioids; benzodiazepines; 
barbiturates; sedatives; antihistamines; and local, intravenous, or inhalation 
anesthetics) or route of administration (oral, rectal, nasal, intramuscular, 
intravenous, local infiltration, and inhalation). Additionally, the authors reported 
that respiratory compromise accounted for most of the deaths/injuries that 
occurred in automobiles or at home after a procedure. Some children were injured 
in their car seats on their way home after a procedure.  A possible mechanism for 
the injury was the child falling asleep with the rhythmic motion of the automobile 
and the head falling forward, thereby obstructing the upper airway.  In the presence 
of residual drug effect, the child may be unable to aroused or be unable to reposition 
the head to relieve the airway obstruction.20 This highlights a major concern with 

oral sedation, which is the child who falls asleep in the car seat, can develop airway 
obstruction due to head and tongue position. The child is unable to spontaneously 
correct their position and unobstruct, which can lead to devastating outcomes.26 
Other perhaps less serious but more common complications of sedation 
include allergic reaction, lethargy, nausea and or vomiting, behavioral changes, 
headaches, balance and gait disturbances, sleep disturbances, nightmares, 
hallucinations and ear pain. Some patients may experience nausea and vomiting 
while under the influence of oral sedation.2,12 In other patients, certain medication, 
e.g. Midazolam, may activate paradoxical side reaction that results in yelling and 
fighting.27-28 Some of the drugs used in may also induce gastro-intestinal issues such 
as diarrhea.29 A 2010 study by Heard et al. found the prevalence of nausea and 
vomiting to be 8.8% and hemoglobin desaturation to be 6% during conscious 
sedation for dental procedures in 102 children aged 2-4 years. The authors used one 
of four regimens that include midazolam alone or in combination as follows: oral MZ 
(1 mg/kg), intranasal (0.7 mg/kg), intranasal MZ (0.5 mg/kg) with oral 
transmucosal fentanyl citrate, intranasal MZ at 0.3 mg/kg with intranasal 
sufentanil.30 In addition to complications described earlier, dental procedure and 
use of local anesthesia can result in pain and/or lip, cheek or tongue biting.12 
Martinez and Wilson examined adverse events within the 24 hour post sedation 
period in 30 children aged 2-5 years. Parents were called 24 hours after the 
sedation and given a questionnaire. This pilot study compared Combination of CH 
(20.0-30.0 mg/kg), meperidine (1.0-2.0 mg/kg), and hydroxyzine (1.0-2.0 mg/kg) to 
midazolam alone (0.5-0.75 mg/kg). The authors demonstrated that children sedated 

for dental procedures with a triple combination of chloral hydrate, meperidine and 
hydroxyzine were more likely to sleep on the drive home and were more difficult to 
wake than children sedated with midazolam alone. Only 20% of the patients 
reported post operative pain, 30% reported having a “fat lip, cheek or jaw”, and 
none vomited. There was no difference between the two regimens in terms of 
postoperative pain, vomiting, eating, evening sleep or memory.31 A prospective 
study by Huang et al. comparing combinations of a narcotic, a sedative-hypnotic, a 
benzodiazepine, and/or an antihistamine found that that post-discharge excessive 
somnolence during transit and while at home as well as nausea and vomiting were 
frequent complications with oral sedation. Specific findings from this study include 
that 60.1% of patients slept in the car on the way home, while 21.4% of that group 
was difficult to awaken upon reaching home. At home, 76.1% of patients slept. 
Additional findings were that 85.7% of patients who napped following the dental 
visit slept longer than usual. After the appointment, 19.6% exhibited nausea, 10.1% 
vomited, and 7.0% experienced a fever.31 
Currently, various oral sedation regimens exist. This is largely because of the 
the different types of drugs that can be used alone, or in conjunction with other 
drugs, to create a diverse range of outcomes and side effects. Narcotics, 
antihistamines and benzodiazepines have all been used separately, and in 
combination, in an attempt to find the ideal sedation regimen which could be used 
for most clinical situations.33  However, no single agent or regimen has yet to be 
recognized as the standard for dental procedures.16  The ideal oral sedation regimen 
is one that would provide safety for the patient, minimum respiratory depression, 

adequate sedation, minimal patient movement, early and rapid onset of drug 
reaction, and adequate working time.33   
Complicating the process of determining the optimal oral sedation regimen 
are the different needs of each patient as well as the different drug interactions 
within each patient. Typically, the less cooperative a patient, the stronger the 
regimen that is required to accomplish the desired sedation level by the dentist. The 
stronger regimens are often created by mixing different medications together, 
allowing dentists to target patients’ specific needs taking advantage of the 
synergistic effect of combining these drugs.34-36 The increase in the strength in the 
form of mixing different drugs may, however, lead to an increase the likelihood for 
adverse effects.20,25,31 This is shown in an investigation by Cote et al. who found that 
the use of three or more sedatives was strongly associated with adverse outcomes 
(18/20) as compared to one or two medications (7/70), even when given within 
acceptable doses.25 An important point to consider when using oral sedation 
medication is that adverse reactions can occur at multiple time points during the 
oral sedation appointment.  Adverse events can be seen immediately after 
administering the oral sedation medication, before, during and after treatment has 
been completed.20 A major risk with using multi-drug regimens is the possible 
increased sedative effect of such regimens which might extend the working time of 
the drug beyond the time needed for completion of dental treatment. In these cases, 
patients who appear awake during treatment may become excessively sleepy and 
drowsy after stimulation has ceased, thereby rendering them more deeply sedated 
after the procedure is over.  This creates a risk for adverse events after discharge 

and they are no longer under the direct supervision of trained clinicians.25,31 This is 
illustrated by the previously mentioned critical review by Cote and colleagues in 
which they reviewed 95 adverse sedation events in pediatric patients using critical 
incident analysis of case reports. The authors found that nearly 80% of the events 
presented initially as respiratory depression. Additionally, negative outcomes were 
associated with multiple drug combinations and interactions. Dental specialists had 
the greatest frequency of adverse sedation related events when associated with the 
use of 3 or more sedating medications.25   
Historically, Chloral hydrate, CH, has been a main component in the triple 
combination, or cocktail, sedation medication, along with hydroxyzine and 
Meperidine.7,11,32 A recent and comprehensive retrospective review of 195 pediatric 
conscious sedations using multi-agents regimen containing Hydroxyzine, Chloral 
hydrate and Meperidine, as the following regimen CH/M/H: 50 mg/kg, 1.5 mg/kg,25 
mg, reported that 72% of the sedations were satisfactory and that adverse outcomes 
were few and minor under a strict protocol and use of oxygen supplementation.12 
Despite the widely stated claims of safety and efficacy of this triple-drugs cocktail, 
there are expressed concerns with CH as a sedative agent for children.14  The 
sedative properties of chloral are attributed to the active metabolite 
trichloroethanol.  Alcohols, such as trichloroethanol, follow zero-order kinetics and 
have no definitive half-life, leading a to a prolong sedative effect that can reach up to 
10 hours, while the inactive metabolite like trichloroacetic acid the half-life ranged 
from 89 to 94 hours.37 Consequently, the duration of the sedative effect can be 
highly variable and unpredictable.2  Since the half-life of chloral hydrate is fairly 

long and variable, an extended period of observation for recovery is often required 
and residual effects may persist for up to 24 hours. More recently, Chloral Hydrate 
has been replaced with Benzodiazepines, mainly Midazolam. In a study by 
McCormack et al, the authors found that patients who took chloral hydrate had 
more somnolence and less talking, while those who took Midazolam had more 
difficulty walking and slurred speech. Most adverse events occurred within the first 
8 hours of discharge. The authors compared combinations of CH/M/H (dosages of 
30 mg/Kg, 2 mg/kg and 2 mg, respectively to MZ/M/H (doseages 1 mg/Kg, 2 mg/kg 
and 2 mg/Kg) in 40 children aged 3-6 years.11 Similarly, Ritwik et al. reported 
comparable adverse effects 8 hours, and even up to 24 hours, after oral sedation in 
46 children aged 3-9 years. The regimens compared were MZ/H (each with a dosage 
of 1-2 mg/Kg) compared to MZ alone (0.5-0.7 mg/Kg). They found that a 
significantly larger proportion of children in the meperidine and hydroxyzine group 
experienced prolonged sleep at home, while more children in the midazolam group 
exhibited irritability in the first 8 hours. They also reported no statistical differences 
between the 2 groups with respect to incidence of pain, fever, vomiting, sleeping in 
the car, snoring, and difficulty in waking up.38 A 2011 study by Costa et al. compared 
post-discharge adverse events in 103 dental sedation in children aged 1-8 years 
who had received either high dose midazolam 1.0-1.5 mg/kg (maximum: 20.0 mg) 
or chloral hydrate70-100 mg/kg CH (maximum: 2.0 g) for dental sedation. In this 
study, 42 children had 103 dental sedations. Midazolam 1.0 mg/kg was used for the 
first sedation. If the child was cooperative, the same regimen was used for the 
subsequent sedation. If not, the dosage was increased to 1.5 mg/kg midazolam, 

followed by chloral hydrate 70mg/kg and chloral hydrate 100 mg/kg as necessary. 
Intraoperative adverse events were recorded. In addition, caregivers were 
contacted 24 hours after the procedure and asked about thing such as agitation, 
nausea, vomiting, dizziness, sickness, difficulty breathing, irritation, hallucination, 
and excessive sleep. The most common adverse events were excessive sleep 
(41.9%) and hallucination (3.9%). Adverse events were more common with chloral 
hydrate than midazolam.39 Another major disadvantage of chloral hydrate is that it 
does not have a reversal agent. Due to these disadvantages and the introduction of 
benzodiazepines and other agents, chloral hydrate is being used less frequently in 
general and not used in the pediatric dental clinic in Loma Linda University, 
therefore, it will not be included as one of the drugs in this study.  
One drug regimen that has become more popular recently for the sedation of 
pediatric dental patients is a triple-agents combination that includes Midazolam, 
Meperidine, and Hydroxyzine (MZ/M/H)8.  Midazolam is a water-soluble short 
acting, high potency benzodiazepine that provides sedative, anxiolytic, amnestic, 
and hypnotic effects. The oral peak onset is 10-20 minutes with a half-life 2.2 to 6.8 
hours.40 The major metabolite is α-hydroxymidazolam and is considered to be just 
as potent as midazolam.40 Benzodiazepines are regarded as being extremely safe in 
clinical use, having a wide margin between therapeutic dose and toxic dose.10  
Midazolam, specifically, is considered one of the safest and most effective sedative 
drugs available.41,42 Its successful use in the pediatric population is well documented 
in the literature.41 Midazolam and other benzodiazepine act centrally at the gamma 
amino-butyric-acid (GABA) receptor in the limbic system to produce anxiolysis and 

profound amnesia.40 A major benefit of utilizing Midazolam is that it is easily 
reversed by flumazenil.2,42 In A 2006 study by Sheroan et al, the authors compared 
behavior and physiological effects of two different sedation regimens; chloral 
hydrate, meperidine and hydroxyzine at doses of 50 mg/Kg, 1.5 mg/kg and 25 mg, 
respectively (regimen A) vs. midazolam, meperidine and hydroxyzine 1 mg/Kg, 1 
mg/kg and 25 mg, respectively (regimen B). Sixteen children who needed two 
sedation appointments each were randomly assigned to receive one regimen for 
their first appointment and the other for the second appointment, a crossover 
design. No significant differences were found in terms of behavior or physiologic 
parameters between the regimens, however 10 episodes of hemoglobin 
desaturation in 2 patients were observed with regimen A, whereas no desaturation 
events occurred with regimen.14 Midozalom has some drawbacks other very short 
working time when used alone. The main disadvantage to using midazolam is that 
some patients may develop paradoxical reactions characterized by restlessness, 
agitation, anxiety and sometimes aggressive behavior.27 These children show an 
extreme inconsolable irritability and agitation, making treatment and discharge 
challenging.28 A 2010 study by Lourenco-Matharu and Roberts examined adverse 
events during 510 pediatric dental sedations with midazolam (0.5 mg/kg). Overall, 
twenty three percent of children experienced side effects including crying/agitation 
(14.5%), hiccups (1.6%), diplopia (1.6% ), and lip biting (1.2%). One child required 
reversal with flumazenil as “he appeared to be over sedated by sleeping deeply”. No 
serious adverse events occurred.43 

         Meperidine is a narcotic, specifically a synthetic opioid analgesic, that causes 
central nervous system (CNS), cardiovascular, and respiratory depression. It is 
commonly used to elevate the pain threshold to control moderate-severe pain. It is a 
mu receptor agonist that primarily produces analgesia and sedation that can lower 
seizure threshold and induce histamine release. Oral Meperidine analgesia can be 
obtained within 30 minutes of administration. Peak analgesia onset is 60-120 
minutes with a half-life of 2.5 to 5 hours. Meperidine can be reversed by Naloxone. 
The recommended therapeutic oral dosage of meperidine for sedation is 1.1 to 2.2 
mg/kg when given orally.42,44-45 Meperidine is absorbed well by all routes but is less 
effective when given orally because only 50% of the drug escapes first-pass 
metabolism to enter the blood stream. However, the oral route is considered by 
most pediatric dentists to be the route of choice when sedating an uncooperative 
pediatric dental patient, and many believe the oral route to be the safest and 
associated with the least potential for overdose.46-47 The side effects of Meperidine 
are many and varied and may be seen with a small dose as well as a large dose. They 
may vary from dizziness, anorexia, nausea and vomiting to flushing, perspiration, 
dry mouth or sleep. 42,44-45 Convulsion has been reported as one of the possible side 
effects of using Meperidine, comorbidities were mainly reported in patients with 
renal impairments which suggested to be related to the accumulation of the inactive 
metabolites (normeperidine).47  
Hydroxyzine is a long acting H1 antagonist providing antihistamine, 
antipruritic, and antiemetic properties. Hydroxyzine is considered a sedative, CNS 
depressant and may provide relief from anxiety, itching, skeletal muscle relaxation, 

analgesia, and bronchodilation and antiemetic effects. Hydroxyzine when given 
orally has an onset of 15-30 minutes.48-50 It has been used in conjunction with 
chloral hydrate, midazolam, and meperidine to reduce the incidence of nausea and 
vomiting.50 It does not cause respiratory depression when used in the 
recommended doses and there are no known side effects. 48-50 The bronchodilatory 
effect of Hydroxyzine is in fact favorable during oral sedation.25 
The use of Mz/M/Hx in different combinations has been described in the 
literature.11,14,51-52 In a retrospective study conducted by Lanehan et al, the authors 
reviewed 248 Pediatric Oral sedations utilizing the combination of Meperidine and 
hydroxyzine for dental treatment. All dosages were within the recommended 
guidelines for both drugs. The maximum dosage of meperidine administered was 
2.2 mg/kg with a maximum dose of 50 mg (ranging from 1 mg/kg to 2.2mg/kg). 
Hydroxyzine was typically administered in 12.5 mg increments, ranging from 0.5 
mg/kg to 2.2 mg/kg with a maximum dose of 50 mg. The authors reported that over 
81% of sedations were considered effective or very effective. While Less than 5% of 
sedations were aborted due to behavior.51 When comparing midazolam alone (0.5 
mg/kg)   
and in combination with Hydroxyzine (3.7 mg/Kg and MZ 0.3 mg/kg) in 56 dental 
sedations, Shapira at al. found that the Midazolam group exhibited significantly 
more movement in the first 20 minutes. They also found that during the first 30 
minutes of treatment, more children cried in the Midazolam group, while the 
combination group presented more children asleep or quiet. No significant 
differences were found in behavior as a function of the order the sedative regimens 

were given. Overall success was similar in the two regimens.33 A prospective study 
by Musial et al. compared the use of Midazolam alone (1 mg/ kg )and in combination 
with Meperidine 1 mg/kg, MZ: 0.5 mg/Kg) and found that no difference in 
physiology or behavior between the groups. However, higher heart rates and 
disruptive behaviors occurred more frequently during or after local anesthesia 
administration in this crossover design study of 20 children aged 3- 5 years.53 In a 
study by Dosani et al, the authors investigated combinations of midazolam, 
hydroxyzine, and meperidine orally or intramuscularly in 50 children aged 2-16 
years of age. They found that 66% of children slept in the car; of these 12% were 
difficult to awaken. Agitation was observed in 22%, restlessness in 10%, withdrawn 
behavior in 16%, and soft tissue trauma in 18%. Motor imbalance and restlessness 
was significantly associated with midazolam. Eighty-two percent slept between 
discharge and bedtime, with 16 % sleeping for greater than four hours.52  
As discussed previously, the sedative action of oral sedation medications is 
potentiated when different medications are combined. The action is either 
synergistic or additive in its effect. Much of the sedation research does not address 
the rates of agitation, irritability, intra- operative and post-operative behavior.11,38 
Few studies have been published which investigate events that may occur within 24 
hours of a sedation. 11,38 Adverse events might be expected from the time of drug 
administration to the beginning of treatment, throughout the treatment, during 
early recovery while in the office, and after discharge from the office. Failure to 
properly monitor the patient might lead to early discharge prior to being fully 
recovered, which results in experiencing adverse events at home. This study will 

compare the post sedation events from three different multidrug oral sedation 
regimens in order to help pediatric dentists determine the best course of action for 
their patients and prepare parents appropriately and caution them about the 
expected effects. Patients will be evaluated for adverse effects within two time 
periods at 8 and 24 hours post oral sedation procedure. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Materials & Methods: 
 
In this randomized clinical trial, a sample of 60 healthy (ASA I) patients 
will be studied, with 20 patients randomly distributed for each group primarily. 
Sample size selection was made based on power analysis and previous studies 8. 

These patients are scheduled to undergo oral sedation appointments in a pediatric 
dental clinic for treatment, which involve no more than two quadrants of dentistry.  
These patients have been scheduled for oral sedation due to situational anxiety in the 
dental operatory and will range from 3-6 years of age with no gender, race or ethnic 
restrictions.  Exclusion criteria will leave out children who have taken any medication 
within the two weeks prior to dental treatment, those who presents for emergencies, 
those who have been sedated previously by other providers or in other institution, 
those with a BMI greater than the 95th percentile for their age and gender, and those 
who fail to drink the entire amount of medication dispensed.   
 
Informed consent will be obtained upon arrival for their sedation 
appointment.  The standard sedation protocol and guidelines of the AAPD and will be 
followed in each case. For this study Group 1 will be given the triple combination of 
Midazolam, Meperidine, and Hydroxyzine (MZ/M/H) at a dose of 0.5-0.75 mg/kg, 1.5- 
2mg/kg, and 1.5-2 mg/kg respectively. Group 2 will be given the double combination 
of Midazolam and hydroxyzine (MZ/H) at a dose of 0.5-0.75mg/kg and 1.5-2mg/kg 
respectively. While group 3 will receive Meperidine and Hydroxyzine (M/H) at a dose 
of 1.5-2mg/kg each. On the day of the sedation, the child will be weighed, and the oral 
medications will be dispensed as described after fasting status is confirmed.  If the 
child refuses to drink the medication from a small cup, the medication will be 
administered by feeding syringe with the parents’ assistance.  Nalaxone will be used 
as a reversal agent for Meperidine and it will be used in a calculated doses of 0.1 
mg/kg with maximum dose of 2 mg. Flumazenil will be used as a reversal agent for 
Midazolam and it will be used in a calculated doses of 0.01mg/kg with maximum dose 

of 0.2 mg. Reversal drug doses will be set out for use if needed.  Nitrous oxide/oxygen 
(N2O/O2) will be used in all sedations (50% N2O/50% O2 during local anesthetic 
administration and 30% N2O/70% O2 during the remainder of treatment) with 100% 
O2 given for five minutes pre and post-operatively. Patients will be monitored 
continuously using a pulse oximeter which provides a reliable estimate of O2 
saturation of the patient. Detection of airway obstruction and apnea based on 
reduction in O2 saturation.  A precordial stethoscope will be used to monitor airway 
patency throughout the procedure, and visual observation of respiratory function.  
Blood pressure and heart rate will be monitored and recorded automatically every 
fifteen minutes throughout the procedure. Xylocaine (2% lidocaine with 1:100,000 
epinephrine) will be used for local anesthesia in all cases and the total amount given 
will not exceed 4mg/kg lidocaine.  Discharge information and post-operative care 
instructions, including emergency numbers will be given to the parents prior to 
discharge.   
 
The dentist performing the sedation will receive a questionnaire (Survey 
1) regarding the period of time from administration of medications up until discharge 
(Appendix 1). In addition, parents will be instructed to fill out two other surveys 
regarding events and they will receive two phone interviews for data collections.  
These surveys will be filled out at 8 hours (Survey 2) and 24 hours (Survey 3) after 
discharge by the parents (see appendix 2 and 3). The phone interview will be 
performed at the provider convenience to collect the data which will includes the 
answers for the survey’s questions. Surveys consist of questions falling into the 
following categories: (1) amount and frequency of sleeping; (2) discomfort; (3) food 

intake; (4) changes in sleep rhythms; (5) incidence of nausea or vomiting; and (6) 
incidence of paradoxical reaction.  
 
Statistical Analysis: 
The purpose of this study is to compare the incidence of adverse sedation 
related events between three different multi-agent oral sedation regimens in 
pediatric dental patients.   Data will be collected in the form of 3 survey sets: the 
surveys is survey set 1 are written surveys to be completed by the dentist (Survey 1), 
and survey sets 2&3 are phone surveys to be conducted by the researcher with the 
parents regarding the adverse effects that may occur after 8 hours (Survey 2) and 24 
hours (Survey 3) after discharge.  The majority of these survey responses fit into 
predetermined categories. These categories will be compared between the different 
drug regimens, and also between the different survey sets.  
 
 
 
 
 
 
 
 
 
 

 
 
 
Category 
Related Question Numbers 
Paradoxical Reactions 
Survey1: 5, 6, 7, 8 
Survey 2: 1, 2, 3, 4 
Survey 3: 1, 2, 3, 4 
 Sleep disturbances (sleepy) 
Survey 1: 15 
Survey 2: 5, 7,10 
Survey 3: 5, 8 
Behavior changes 
Survey 1: - 
Survey 2: 11,12,13, 
Survey 3:  9, 10, 11,23 
Respiratory effects 
Survey 1: 9,10,11,12 
Survey 2: 5b-c 
Survey 3: 5b-c 
CNS Effects 
Survey 1: 15,  
Survey 2: 5d,14, 15, 18,19 
Survey 3: 5c, 5d, 
6,7,12,14,16,17,18,19, 
Gastrointestinal Upset 
Survey 1: 2, 3, 4 
Survey 2: 19, 20, 21, 22, 25 

Survey 3: 17,18,19, 20, 24 
Amnesia effect 
Survey 2: 16,17 
Survey 3: 14,15 
Physical reaction 
Survey 1: 14 
Survey 2: 24,25,26 
Survey 3:22,24, 25, 
 
 
All responses will be entered into an excel spreadsheet and analyzed using SPSS 16 
(SPSS Chicago, IL).  Data Analysis will include descriptive and inferential statistics. 
The inferential statistics will include incident rate ratios analysis, chi square and one-
way ANOVA . The significance level will be set as p less than 0.05. 
 
 

 
 
 
 
 
 
 
 
Appendix 1 
 
(Survey 1) 

 Patient #     ______________          Weight    ______________  
 Dentist #   ______________ 
Patient Age ______________  
Height     ______________ 
 Date of TX ______________  
Regimen Administered   ________ MZ/M/H     ____________MZ/H      M/H________________  
 
 
Operating Dentist Survey 
 
Please comment on any “Yes” answers from above, providing additional detail 
 
Notes:  
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
Did the patient… 
Yes 
No 
1. Drink the medication without difficulty? 
 
 
2. Complain of nausea?                                                   Pre / During / Post 
 
 
3. Vomit                                                                          Pre / During / Post 
 
 
4. Complain of upset stomach                                         Pre / During / Post 
 
 
5. Cry or scream inconsolably?                                      Pre / During / Post 
 
 
6. Exhibit any abnormally aggressive behavior?           Pre / During / Post 
 
 
7. Bite or scratch anyone?                                              Pre / During / Post 
 
 
8. Seem hyperactive?                                                      Pre / During / Post 
 
 
9. Require the use of reversal agents? Which one?        Pre / During / Post 
 
 
10. Saturation level ever drop below 95?                         Pre/ During/ Post 
 
 
11. Saturation level ever drop below 90?                         Pre / During / Post 
 
 
12. Require Head Repositioning?                                      Pre / During / Post 
 
 
13. Slur or have difficulty speaking?                                Pre / During / Post 
 
 
14. Have any abnormal rash? 
 
 
15. Sleep during treatment? 
 
 
a. Was the patient asleep at the end of treatment? 
 
 
b. Was the patient difficult to wake up? 
 
 
16. At any point was treatment aborted. (if yes, why?) 
 
 
At discharge, could the patient? 
 
 
17. Sit unaided? 
 
 
18. Hold their head up on their own? 
 
 
19. Speak age-appropriately? 
 
 
20. Walk on their own? 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 2 
 
(Survey 2) 

  Patient #     ______________  Dentist #  ______________ 
Surveyed    ______________ 
Patient Age ______________ 
Date of TX ______________  
Survey Date ______________ 
 
8 Hour Sedation Follow-up Phone Survey 
 
 
Did anything else happen that you feel is important to mention? 
Notes:  
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
After leaving the dental clinic, did your child…. 
Yes 
No 
1. Cry or scream inconsolably? 
 
 
2. Exhibit any abnormally aggressive behavior? 
 
 
3. Bite or scratch anyone? 
 
 
4. Seem hyperactive? 
 
 
5. Fall asleep on the car ride home? 
 
 
c. Does your child normally sleep in the car? 
 
 
d. Did your child snore? 
 
 
e. Does your child usually snore? 
 
 
f. Was it difficult to awaken your child when you arrived home? 
 
 
6. Act in a way that made you concerned and caused you to pull the car over? 
 
 
7. Sleep soon after arriving home? 
 
 
a. Did your child complain of bad dreams? 
 
 
8. Need help to sit up? 
 
 
9. Have difficulty walking? 
 
 
10. Seem lethargic? 
 
 
11. Play immediately after arriving home? 
 
 
12. Talk less than normal or refuse to talk? 
 
 
13. Talk more than normal? 
 
 
14. Slur or speak incoherently? 
 
 
15. Complain of or seem dizzy? 
 
 
16. Have any memory of what happened at the dental office? 
 
 
17. Talk about the dental appointment? 
 
 
18. Have or complain of a headache? 
 
 
19. Complain of nausea? 
 
 
20. Vomit? 
 
 
a. Did your child consume any liquids or foods before vomiting? 
 
 
21. Have an upset stomach? 
 
 
22. Have diarrhea? 
 
 
23. Take any medication? 
 
 
24. Have any abnormal rash? 
 
 
25. Have a hiccup? 
 
 
26. Did your child develop any fever? 
 
 

 
 
 
 
 
 
Appendix 3 
 
(Survey 3) 

        Patient #     ______________   Dentist # ______________ 
       Surveyed    ______________ 
Patient Age ______________ 
Date of TX ______________  
Survey Date ______________ 
 
24 Hour Sedation Follow-up Phone Survey 
 
 
Did anything else happen that you feel is important to mention? ______________________________ 
 
Notes:  
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________ 
 
Since the 8 hour follow-up, did your child…. 
Yes 
No 
1.  Cry or scream inconsolably? 
2. 
 Exhibit any abnormally aggressive behavior? 
3. 
 Bite or scratch anyone? 
4. 
Seem hyperactive? 
5. 
Sleep more or less than normal? 
a. Did your child snore? 
b. Does your child usually snore? 
c. Was it difficult to awaken your child? 
d. Did your child complain of bad dreams? 
6. 
Need help to sit up? 
7. 
Have difficulty walking? 
8. 
Seem lethargic? 
9. 
Play more or less than normal? 
10. Talk less than normal or refuse to talk? 
11. Talk more than normal? 
12. Slur or speak incoherently? 
13. Complain of or seem dizzy? 
14. Have any memory of what happened at the dental office? 
15. Talk about the dental appointment? 
16. Have or complain of a headache? 
17. Complain of nausea? 
18. Vomit? 
19. Have an upset stomach? 
20. Have diarrhea? 
21. Take any medication? 
22. Have any abnormal rash? 
23.   Act in a way that made you concerned. 
 
 
24. Have a hiccup?  
 
  
25. Did your child develop any fever? 
 
 

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