A Retrospective Evaluation of the Safety Profile of Dexmedetomidine

and Nitrous Oxide for Pediatric Dental Sedation

John H. Unkel, Carson Cruise, Adam Rice, Jennifer Macdonald, Elizabeth J.

Berry, Judy Reinhartz, Dennis Reinhartz.
Pediatr Dent 2021;43(2):129-32.

Presented By: Dr. Shraddha Patil

(1st year PG)
Guided by: Dr. Rashmi Jayanna
Dr. Swapnil Mhatre
Dr. Priyanka Razdan
 Introduction

• Over the past several decades, there has been an increase in the need for completing pediatric
dental procedures outside the operating room.

• Sedation is the modality of choice for many pediatric dentists for the safe treatment of children
who are unable to tolerate a standard dental procedure due to dental fear, uncooperative behavior,
or medical and/or developmental history.

• Sedation can help provide anxiolysis, amnesia, and behaviour modification for a patient who
otherwise would be unable to get the treatment completed.
• Combinations of nitrous oxide and midazolam with or without hydroxyzine are
traditionally accepted and common sedation regimens in pediatric dentistry.

• The oral route (PO) of Midazolam has several limitations, such as delayed onset due to
first-pass hepatic metabolism and lack of titration capacity.

• Intranasal (IN) administration of midazolam is a noninvasive alternative that likely utilizes

direct transport of the medication to the brain via vessels, avoiding first-pass metabolism,
therefore resulting in quicker onset time and recovery.

• It is safe and effective in short dental procedures; however, it is associated with mucosal
irritation that affects patient compliance and hinders use.
• Hydroxyzine, an antihistamine, is also a popular drug for procedural sedation in pediatric
dentistry.

• It is often combined with midazolam, with the thought that it enhances midazolam’s
sedative effect; however, evidence supporting this is mixed.

• There is evidence that hydroxyzine alone does not provide adequate sedation levels to be
useful in pediatric dentistry, and it has a long time of onset and duration of effect.
• Dexmedetomidine (DEX) is a selective a-2 agonist that produces sedation, mild analgesia,
and anxiolysis, with minimal respiratory depression.

• Its primary effect in the central nervous system is to stimulate receptors in the vasomotor
centers of the medulla decreasing sympathetic tone.

• The sedative and analgesic properties of the drug are a result of decreased sympathetic
outflow from the locus ceruleus of the brainstem.

• Arousal reactions are in part controlled by the locus ceruleus; therefore, suppression by an
a-2 agonist causes a state that mimics natural sleep.
• The most commonly documented adverse effects of DEX are hypotension and bradycardia,
which are a result of this decrease in sympathetic activity.

• DEX can be administered via a variety of routes: IN, PO, buccal, intramuscular (IM), and
intravenous (IV).

• When given IN, DEX has a reported range of bioavailability from 65 percent to 93 percent.
(Lihora T et al)

Iirola T, Vilo S, Manner T, et al. Bioavailability of dexmedetomidine after intranasal administration. Eur J Clin Pharmacol 2011;67(8):825-31.
• Studies involving IN DEX report effective doses ranging from 0.5 mcg/kg to four mcg/kg.
DEX is gaining popularity for procedural sedation due to its ability to preserve respiratory
drive and spontaneous ventilation while at sedative levels.

• DEX is often used as a sedative in pediatric medicine, with research showing DEX to be a
safe and effective drug that may produce more sedative effects than medications like
midazolam and less respiratory depression than medications like propofol.

• DEX is used for sedation with imaging procedures and is a useful drug for sedation in
pediatric electroencephalogram (EEG) studies.

• Yuen VM, Hui TW, Irwin MG, et al. A randomised comparison of two intranasal dexmedetomidine doses for premedication in children. Anaesthesia 2012;67(11):1210 -6.
• Reynolds J, Rogers A, Medellin E, Guzman JA, Watcha MF. A prospective, randomized, double-blind trial of intranasal dexmedetomidine and oral chloral hydrate for sedate auditory
brainstem response (ABR) testing. Pediatr Anesth 2016;26(3):286-93.
• Comparatively, limited research exists on the use of IN DEX in children for more intrusive,
stimulating procedures

• The use of IN DEX is safe and effective for anxiolysis when used with local analgesia for
laceration repair and pediatric dental procedural sedation, but more research needs to be
completed on stimulating procedures.

• Additionally, no studies have been published detailing the combination of nitrous oxide
with IN DEX in pediatric dental sedation.
 AIM :

To investigate the safety of intranasal dexmedetomidine when paired with

nitrous oxide in comparison to the more commonly used drug combination
involving midazolam ± hydroxyzine.
 MATERIALS :

• Records of 158 healthy children’s charts were randomly chosen for review,
with 149 patients’ charts meeting the inclusion criteria:

 American Society of Anesthesiologists (ASA) I or II

 between the ages of three and six years who underwent inoffice pediatric
dental procedural sedation between January 2014 and December 2019 at St.
Mary’s Hospital of Richmond with Institutional Review Board approval.
 Three different sedation regimens were analyzed and compared for safety:

(1) dexmedetomidine (DEXNO);

(2) midazolam (MIDNO); and

(3) midazolam with hydroxyzine (MIDHYNO)–all regimens with nitrous oxide.

• The following were used as exclusion criteria when determining if a patient was a
candidate for in-office sedation:

 a body mass index greater than or equal to the 95th percentile;

 patients weighing less than 10 kg;

 patients who were deemed unsuitable for sedation by a physician based on their
preoperative history and physical;

 patients who had an ASA classification greater than II, Mallampati score greater than 2, or
Brodsky tonsil score greater than 2;
 patients with sleep apnea;

 patients with a history of an unfavorable reaction to DEX or clonidine;

 patients with pulmonary hypertension; and

 patients with gastroesophageal reflux disease or

 patients with cardiac arrhythmia

• Vital signs, including blood pressure (BP), oxygen saturation (SpO2), heart rate (HR),
respiratory rate (RR), end-tidal carbon dioxide (EtCO2), electrocardiogram (ECG), from the
same monitoring machine were collected for analysis.

• A pediatric attending dentist remained in the room to assist with recordings during the
sedation to ensure consistency (two total attending pediatric dentists), while pediatric
dental residents completed the dental treatment.
 159 records
Excluded 9
Excluded-9
insufficient recordings of vital signs

149 records

(49) (47) (53)

DEXNO MIDNO MIDHYNO

0.5-0.7 mcg/kg PO MID

0.5-0.7 mcg/kg PO
3 mcg/kg IN DEX +
MID
1 mg/kg PO
hydroxyzine
• Nitrous oxide concentration for IN DEX was 65%; for other regimens, it ranged from 50%
to 70%.

• Local anesthetic was administered for operative analgesia.

• Dental procedures performed consisted of restorations, pulp therapy, extractions, and

sealants.
• After the procedure, all patients were given 100 percent oxygen for at least five minutes
and continued to recover for a minimum of 20 minutes while being assessed using
Aldrete’s scoring system before they were discharged.

• Demographic data, procedural times, and major and minor adverse events were recorded
from each chart.

• Major adverse events were defined as death, aspiration, cardiac arrest, unplanned
hospital admission, and level-of-care increase.
• Minor events were defined as apnea, desaturation (up to 92 percent Sp02), airway
obstruction, bradycardia, and hypotension.

• Bradycardia was defined using Pediatric Advanced Life Support (less than 60 beats per
minute).

• Hypotension was defined using both the PDLS (systolic blood pressure less than 70 mmHg
plus [age in years times two] mmHg) and Aldrete criteria (systolic blood pressure ±20
mmHg of preprocedure range).
• Data were summarized using descriptive statistics of the number of patients and
percentages for categorical data.

• Continuous data are presented as mean and standard deviation.

• Chi-square tests or Fisher’s exact test were used for categorical data as appropriate, with
the odds ratio calculated with 95 percent confidence intervals.

• P-values less than 0.05 were considered statistically significant.

RESULTS
• No children experienced major adverse events, apnea, desaturation, or obstruction.

• None of the guardians called on return home or next day reporting sedation concerns.

• No arrhythmias were noted on the ECG.

Every instance of
bradycardia or hypotension self-
corrected without the need for
intervention by the operating
clinician.
 Discussion

• DEX is routinely used for pediatric procedural sedation but it has been rarely studied as a
sedative for invasive procedures.

• The current literature on DEX in the pediatric population details its success during imaging
procedures during dental and medical procedural sedation and as a premedication before
general anesthesia or procedural sedation using other sedatives.
• N2O is useful during pediatric dental sedation as an adjunct to other sedative medications to
safely achieve improved patient behavior.

• To the authors’ knowledge, there is a lack of published research regarding the safety of IN DEX
combined with N2O inhalation for pediatric sedation.
• The present study’s results paralleled the current literature regarding the safety of IN DEX as a
sedative agent, demonstrating that dexmedetomidine combined with N2O is a safe drug
regimen for pediatric dental procedural sedation.

• PO MID paired with N2O has a robustly documented reputation as a safe and effective sedative
combination.

• However, PO MID has several disadvantages, including bad taste, the potential for paradoxical
reactions, risk of respiratory depression, and lack of analgesic effect.
• Unlike IN MID, IN DEX does not cause an unpleasant sensation upon administration and
produces dose-dependent analgesic effects.

• DEX does not interact with GABA receptors and causes little to no change in airway tone and
the respiratory drive; however, it does not have an approved reversal agent and its amnesia
effect is possibly limited.
• Filho et al. reported a 15 percent incidence of bradycardia following IN administration of
2.5mcg/kg DEX.

• In the present study, one patient experienced intraprocedural bradycardia, which was not
significantly different and did not require clinical intervention to return to an adequate heart
rate.

• The bradycardia and hypotension seen with the use of DEX are rarely clinically significant and
typically require no intervention.

• Additionally, it was also noted that bradycardia and hypotension were corrected with
stimulation during sedation (for example seating a crown).
Mekitarian Filho E, Robinson F, de Carvalho WB, Gilio AE, Mason KP. Intranasal dexmedetomidine for sedation for pediatric computed tomography imaging. J Pediatr
2015;166(5):1313-5.
• Behrle et al.(2017) and Yuen et al.(2012) both found no statistical difference between IN DEX
and non-DEX regimens regarding the occurrence of hypotension.

• In the present study, however, 17 patients in the DEXNO group (35 percent) experienced some
degree of intraoperative or postoperative hypotension, which was significantly more than in the
other groups, but all hypotension self-resolved without clinical intervention.

• The medication regimen chosen for each patient may have been influenced by the patient’s
past medical history, the time needed for treatment, or prior experiences with a specific
medication.

• Behrle N, Birisci E, Anderson J, Schroeder S, Dalabih A. Intranasal dexmedetomidine as a sedative for pediatric procedural sedation. J Pediatr Pharmacol Ther 2017;22(1): 4-8.
• Yuen VM, Hui TW, Irwin MG, et al. A randomised comparison of two intranasal dexmedetomidine doses for premedication in children. Anaesthesia 2012;67(11):1210 -6.
• Additionally, the DEXNO group may have been more deeply sedated and, thus, less stimulated
than the other groups, hence the decrease in blood pressure.

• The medication regimen chosen for each patient may have been influenced by the patient’s
past medical history, the time needed for treatment, or prior experiences with a specific
medication.
 MERITS
 Pioneer study
 safety of IN DEX combined with N2O inhalation for pediatric sedation.
 DEMERITS
 Variation existed from 50 percent to 70 percent N2O used during MIDNO and MIDHYXNO cases
per clinician preference, but the DEXNO group was maintained at 65 percent.
 MIDHYXNO and MIDNO groups received a variation of 0.5 to 0.7 mg/kg of midazolam.
 LIMITATION
 Lack of standardization in the groupings.
 CONCLUSION

• Intranasal dexmedetomidine with nitrous oxide appears to be a safe method for achieving
sedation in the pediatric dental setting, as no adverse events were reported.
• DEX use resulted in significantly more hypotensive events than either of the other regimens
but did not require intervention.
• Larger, prospective, randomized control trials should be performed to further elucidate the
safety profile of intranasal DEX with nitrous oxide.
 Aim Methods Conclusion
To characterize the Nitrous oxide and Addition of
mechanisms for the dexmedetomidine given dexmedetomidine to nitrous
2004 interaction between both intraperitoneally and oxide is likely to provide
α2agonists and nitrous intrathecally in rats enhanced and more durable
oxide on nociceptive analgesia in settings in
processing. which nitrous oxide is
currently used alone (e.g.,
dental surgery).
 Aim
To identify the safest and
most effective sedative
2016 drugs so as to ensure
successful sedation with as
few complications as
possible.
Methods
21 studies were selected
due to their rigorous study
design and conduciveness
to further, more exhaustive
analysis
Conclusion
Midazolam-most common.
Others like ketamine,
dexmedetomidine and
propofol have also been
proven safe and effective;
however, further
comparative clinical studies
are needed to better
demonstrate which of these
are the safest and most
effective.
 Aim Methods Conclusion
To evaluate the efficacy Group IN DEX(50/50 N2O) Phase IV trial
and safety of intranasal Group MIDDEX ClinicalTrials.gov identifier
2017 dexmedetomidine when Group NOMIDDEX(50/50 : NCT02985697
used in combination with N2O) (not updated)
oral midazolam and/or
nitrous oxide for moderate
sedation during pediatric
outpatient dental
procedures.
Thank you!