Clinical trial NCT03085563
Conditions: Conscious Sedation Simple Lacerations Less Than 4 cm Lumbar Punctures Minor Incision Drainage of Abscesses Not Requiring Extensive Debridement
Sponsor: University of Colorado, Denver
Start date: 2017-05-24; Completion date: 2018-11-08
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this project is to compare the sedative effects of intranasal midazolam versus inhaled nitrous oxide (N2O) for minor procedures in the pediatric emergency department. The primary outcome will be length of stay (LOS) in the emergency department (ED) stay for minor procedures. Secondarily the investigators will compare patient/family and provider satisfaction while using either intranasal midazolam or N2O for minimal sedation. The investigators hypothesize that the total length of stay for children undergoing minor procedures in the ED will be lower for N2O, as compared to intranasal midazolam. The investigators also hypothesize that patient/family and provider satisfaction will be higher with N2O and adverse effects will not differ between N2O and intranasal midazolam. Patients will receive either intranasal midazolam or N2O for minor procedures. Following the enrollment period, data will be analyzed and the two will be compared. Total length of stay, patient/family and provider satisfaction will be studied.

Detailed description:

Arms: arm 1: Nitrous oxide will be delivered in one of two ways, using the titration method or rapid infusion method. arm 2: Intranasal midazolam with mucosal atomizer device administration will follow the Children's Hospital Colorado (CHCO) established policy 'Intranasal Administration (atomization) of Medications'.
Interventions: intervention 1: Nitrous Oxide intervention 2: Midazolam
Intervention descriptions: intervention 1: Nitrous oxide will be delivered in one of two ways, using the titration method or rapid infusion method. Which ever method is used will be recorded. When using the titration method, starting at 20%, nitrous oxide will be added in 10% increments every 60 seconds until the ideal level of sedation has been met (not to exceed 70% nitrous oxide). Using the rapid infusion method, after the proper flow rate has been achieved with oxygen, the flowmeter will be increased to obtain 50% concentration of nitrous oxide. After 2-3 minutes if the patient does not have adequate sedation, nitrous oxide concentration will be increased to 70%. intervention 2: Intranasal midazolam with mucosal atomizer device administration will follow the Children's Hospital Colorado (CHCO) established policy 'Intranasal Administration (atomization) of Medications'. As per standard of care, each patient will receive a standardized dose of 0.4mg/kg (maximum dose of 10mg) of intranasal midazolam with the mucosal atomizer device for all procedures.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 11 
COMIRB# 16-1909 
PI: Paul Szefler, MD 
Protocol version: 8/24/17 
 
 
 
w 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #: 16-1909 
Project Title: A comparison of intranasal midazolam and Nitrous Oxide (N2O) 
minimal sedation for minor procedures in a pediatric emergency 
department.   
 
 
 
 
 
Principal Investigator:  Paul Szefler, MD 
Version Date: 8/24/17  
 
 
 
 
  
 
I. Hypotheses and Specific Aims:   
 
The objective of this project is to compare the sedative effects of intranasal midazolam 
versus inhaled nitrous oxide for minor procedures in the pediatric emergency 
department. Our primary outcome will be length of stay (LOS) in the emergency 
department (ED) stay for minor procedures. Secondarily we will compare 
patient/family and provider satisfaction between these two sedative agents.  We 
hypothesize that the total length of stay for children undergoing minor procedures in 
the ED will be lower for nitrous oxide, as compared to intranasal midazolam.  We also 
hypothesize that patient/family and provider satisfaction will be higher with nitrous 
oxide and adverse effects will not differ between N2O and intranasal midazolam.   
 
II. Background and Significance:  
 
Every day, infants, children, and adolescents undergo procedures in the pediatric ED 
that are anxiety producing, painful, or cause significant distress1.  Providers must be 
cognizant of the anxiety, pain and significant distress caused by undergoing 
procedures; thus, the use of appropriate analgesia and sedation should always be 
considered.  Not only will the use of appropriate analgesia and sedation reduce anxiety 
and emotional distress, but it may also improve the overall effectiveness and ease of 
the procedure. The use of mild to moderate sedation for minor ED procedures, such as 
fentanyl, midazolam, or ketamine has been well studied and shown to be safe in the 
pediatric population.  Consequently, these medications are the typical sedative agents 
used for minor procedures in the pediatric ED.   
 
Nitrous Oxide (N2O) has had limited use in the pediatric ED despite being used for 
many years in pediatric dental clinics2.  Nitrous oxide is a colorless gas, and has been 
described as odorless or having a pleasant, sweet odor and taste 2.   Given its favorable 
adverse effect profile, its ease of administration, and its ability to provide amnesia and 
analgesia, it is an attractive sedative for use in minor procedures 2.  It also provides 
rapid onset and rapid offset 3.   
 


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Protocol version: 8/24/17 
 
 
 
Intranasal midazolam is well studied and has been shown to be safe and effective for 
sedation in the pediatric ED.  It is a short acting benzodiazepine that has anxiolytic, 
sedative, hypnotic, anticonvulsant, and anterograde amnestic effects4,5. Midazolam is 
most commonly favored for sedation, having a fast onset, short half-life (2 – 4 hours), 
steepest dose-response curve and a >50% incidence of amnesia6.  It has a wide 
toxic/therapeutic ratio and safety margin and does not produce prolonged sedation 
associated with other benzodiazepines7. Respiratory depression is rare, as is 
cardiovascular depression with the exceptions of patients that have a history of 
hypovolemia or heart failure6.   Paradoxical reaction to midazolam has been previously 
described in the literature.  These may include hallucination, disorientation, 
uncontrollable crying or verbalization, agitation, restlessness, involuntary movement, 
self-injury, and aggressive or violent behavior, which sometimes require restraints15. 
 
Nitrous oxide has potential for safe and effective administration as a sedative agent for 
ED minor procedures that is superior to intranasal midazolam. Therefore, the primary 
objective of our study is to compare the total length of ED stay when using intranasal 
midazolam or nitrous oxide for minimal procedures.  Secondary objectives include 
comparing patient/parent and provider satisfaction between intranasal midazolam 
and nitrous oxide and assessment of safety profile as measured by the rate of adverse 
effects. 
 
III. Preliminary Studies/Progress Report:   
 
There have been no previous studies comparing nitrous oxide and intranasal 
midazolam for mild sedation/anxiolysis in children requiring minor procedures. 
 
Both intranasal midazolam and nitrous oxide have been well studied individually.  
Midazolam is a GABA receptor agonist and has been shown to be safe and effective for 
use in children to provide anxiolysis and pre-anesthetic sedation8.  Studies evaluating 
midazolam have shown improvements with anxiety and crying, as well as need for 
restraint9.  The most common complaint with intranasal midazolam is that it is 
noxious and painful to the nasal mucosa10. It also has a relatively low drug 
concentration (5mg/mL) leading to a respective large volume required for intranasal 
dosing.  Primary adverse effects include respiratory depression.  Cardiovascular 
depression is rare, except in patients with hypovolemia or heart failure6.  
 
Although classified as an anesthetic gas, the potency of nitrous oxide is significantly 
less than other inhaled drugs used to provide general anesthesia11.  Several studies, 
one with >35,000 patients, have shown nitrous oxide delivered at fixed 
concentrations of 50% to 70% is safe and effective for minimal sedation11-14.  Nitrous 
oxide has been shown to have a very rapid onset and rapid offset, with a very short 
half-life, thus making it an ideal sedative for minor procedures3.  Numerous studies 
have shown that it provides anxiolysis and is a safe pre anesthetic sedation.  It has 
also been shown to improve anxiety, crying and need for restraints.  
 


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IV. Research Methods 
 
A.  Outcome Measure(s):  The primary outcome measure of this study is to 
compare length of ED stay between intranasal midazolam and nitrous oxide, 
when used as minimal sedation for minor procedures.  The total length of ED 
stay will be defined as time from intranasal midazolam or nitrous oxide 
administration to time of discharge readiness, collected by the research 
assistants. Additional time periods measured will include: time from 
anxiolytic/sedative given to time of procedure completion, and total time for 
recovery. 
 
 Secondary outcome measures will include patient/parent and provider 
satisfaction with sedation and adverse events with anxiolytic/sedative.  
Adverse events will be classified and defined as hypoxia, need for 
administration of reversal agent, nausea, vomiting, paradoxical reaction, 
airway obstruction, laryngospasm, inadequate sedation, allergic reaction, and 
cardiac arrest.   
 
B. Description of Population to be Enrolled:   
 
Inclusion criteria: 
1. Patients ≥2 years of age and <18 years of age and Parent/legal 
guardian age ≥18 years of age to <80 years of age 
2. Patients with an American Society of Anesthesiologists (ASA) Physical 
Status Classification System level 1, 2, and 3   
3. Patients requiring anxiolysis and mild sedation for minor procedures 
a.    Minor procedures will include simple lacerations less than 4 
cm 
b. Lumbar punctures 
c.    Minor incision and drainage of abscesses that do not require 
extensive debridement or require moderate sedation or 
surgical consultation. 
d. Must receive the standard of care dosing for either nitrous oxide 
or intranasal midazolam.   
e. Nitrous oxide up to 70% nitrous concentration will be allowed 
f. Intranasal Midazolam 0.2-0.5mg/kg with a max dose of 10mg  
 
    Exclusion criteria will include the following:  
1. Nasal injury with deformity, nasal obstruction or significant 
congestion, which would make delivery of medication difficult or 
unpredictable.  
2. Laceration that involves the nose and ears or come into contact with 
the scavenger device or nitrous oxide tubing  
3. Allergy to benzodiazepines 
4. Benzodiazepine dosing for any reason 24 hours prior to procedure 


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5. Epistaxis that causes significant obstruction that would make delivery 
of medication difficult or unpredictable.  Or does not stop with direct 
pressure and requires other interventions for hemostasis.  
6. Facial or nasal deformity that cause significant obstruction limiting 
delivery of anxiolytic medications. 
7. Copious mucous  
8. Recent (less than 1 week) tympanic membrane graft or middle ear 
surgery 
9. Patients undergoing bleomycin therapy.  
10. Patients known to be pregnant at time of enrollment  
11. Patients with severe behavior problems, personality disorders or 
other mind-altering conditions as determined by administering 
provider. This would include a patient unable to cooperate with 
having nasal device on nose, or significantly distressed with device 
not allowing for proper use. 
12. Closed space situations such as pneumothorax, air embolus, 
pneumocephaly or craniotomy in the last 3 weeks, intraocular 
surgery with retained gas, pulmonary bullae, severe emphysema, or 
bowel obstruction. 
13. Patients with significant co-morbidities: severe pulmonary disease, 
cardiac disease, hematologic diseases associated with B12 deficiency, 
sickle cell disease. 
14. Patients with acute otitis media and/or sinusitis 
15. History of paradoxical reaction to nitrous oxide   
16. Known MRSA (+) patients 
17. Co-administration of additional sedation or analgesic medications 
 
 
C. Study Design and Research Methods   
 
Study Design, Setting, and Subject Enrollment: 
 
We will use a prospective, observational study design with an alternating 
weekly suggested anxiolytic medication.  As we will be encouraging an 
anxiolytic medication on certain suggested weeks, this study will not be 
strictly observational.  The study however, is not intended to be an 
interventional study as both the administration of nitrous oxide and 
intranasal midazolam in the pediatric ED for anxiolysis intended for minor 
procedures is standard of care. We are not attempting to randomize the 
groups but are encouraging providers to consider nitrous oxide on certain 
weeks or intranasal midazolam administration on certain weeks in order to 
obtain patients in each arm to gain power in the study to show possible 
statistical significance.  This study will take place in a large urban tertiary care 
Children’s Hospital in Aurora, CO with over 72,000 visits annually.  This is an 
academic institution and a multi-state referral center. Patients participating 


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will be enrolled over a one-year period. Trained research staff will obtain and 
collect data needed by enrolling patients meeting inclusion criteria as stated 
above.  
 
Both nitrous oxide and intranasal midazolam are considered standard of 
care in the Children’s Hospital Colorado (CHCO) ED.  Although Nitrous Oxide 
is relatively new to the CHCO ED, greater than 20 providers have been 
trained on its use, and it has become a very popular method for anxiolysis for 
procedures to date.  In coordination with our statistician, in order to ensure 
that there are evaluable numbers of subjects receiving each sedative agent, 
we will designate one medication as the primary agent for alternating weeks.  
For example, the first and third week of the month would be designated a 
nitrous oxide week and the other weeks of the month would be designated 
an intranasal midazolam week. However, if the patient/caregiver or provider 
is not comfortable with the minor sedative recommended for that week they 
may choose the one they wish to use.   
 
Medication Administration: 
 
Clinical pain management will not be restricted or limited in any way whether 
a patient receives intranasal midazolam or nitrous oxide. Analgesia will be 
provided per standard of care whether a patient is in the nitrous oxide arm or 
the intranasal midazolam arm. For example, for a laceration, local anesthetic 
will be applied per standard of care if either enrolled in the nitrous arm or the 
intranasal midazolam arm.  If a patient complains of pain prior to any 
procedure requiring anxiolysis, Tylenol or Ibuprofen will be made available to 
the patient. 
 
Intranasal midazolam with mucosal atomizer device administration will 
follow the CHCO established policy ‘Intranasal Administration (atomization) 
of Medications,’ which is 0.2mg/kg-0.4mg/kg, with providers’ discretion 
when using 0.5mg/kg. Although standard of care is 0.2mg/kg-0.4mg/kg, it has 
been proven to be safe and effective when using 0.5mg/kg and we would like 
to study the normal practice of our providers.  Due to variability in the dosing 
prescribed by providers, we will allow patients to receive a dose of 0.2-
0.5mg/kg (maximum dose of 10mg) of intranasal midazolam with the 
mucosal atomizer device for all procedures.     
 
For nitrous oxide administration, we will use an FDA approved device for 
delivery (Matrx Digital MDM (w/Bag Tee), (DMDM). The nasal hood with 
scavenger device will be placed over the patient’s nose and the patient will 
help adjust the mask for comfort.  The patient will be asked to close their 
mouth and breathe through their nose.  Appropriate flow rate while delivering 
100% (starting at 3L/min and increasing to 5L/min) will be established for 1-
2 minutes while observing the reservoir bag for proper inflation and 


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Protocol version: 8/24/17 
 
 
 
pulsation.  If a mouth breather continues despite instructions to nasal breath 
the nasal hood will be repositioned over the mouth to allow for gas 
administration. 
 
Nitrous oxide will be delivered in one of two ways, using the titration method 
or rapid infusion method.  Whichever method is used will be recorded. When 
using the titration method, starting at 20%, nitrous oxide will be added in 10% 
increments every 60 seconds until the ideal level of sedation has been met 
(not to exceed 70% nitrous oxide). Using the rapid infusion method, after the 
proper flow rate has been achieved with oxygen, the flowmeter will be 
increased to obtain 50% concentration of nitrous oxide.  After 2-3 minutes if 
the patient does not have adequate sedation, nitrous oxide concentration will 
be increased to 70%.   
 
Nitrous oxide concentration can be titrated up and down to meet adequate 
sedation levels at the discretion of the provider.  Adequate sedation will be 
obtained by asking the patient questions (tingling of hands/feet, 
lightheadedness).  Upon completion of procedure, nitrous oxide will be 
terminated and patient will be given 100% oxygen for 5 minutes to flush out 
remaining nitrous oxide.  Once recovered and patient meets discharge criteria 
patient will be discharged. Nitrous oxide delivery will follow the standard 
CHCO standard practice procedures.   
 
Patients will be monitored via standard of care in the CHCO ED.  All patients 
will receive pre sedation vitals and continuous pulse oximetry for the duration 
of anxiolysis and mild sedation.  Airway management equipment will be 
available at the bedside for all patients if needed. 
 
Efficacy and side effects will be observed and recorded by a research assistant 
(RA) on a standard data collection sheet as well as a Standardized Adverse 
Event Reporting Form.  Safety will be assessed by monitoring physiologic 
parameters (heart rate, respiratory rate, blood pressure, and pulse oximetry) 
as well as adverse effects (nausea, vomiting, laryngospasm, apnea, 
desaturation, and paradoxical reactions).  The use of supportive interventions 
including airway re-positioning, supplemental oxygen or assisted ventilation 
will be recorded.  
Data Collection: 
 
Data will be collected by the RA on the total length of stay in the ED for all 
simple procedures using a start time of when sedation was administered to 
time of discharge readiness. Discharge readiness will be determined by a 
standard discharge readiness protocol as defined by our hospital for 
anxiolytic medications administered in the ED.  In general, a patient will meet 
criteria if mental status has returned to baseline, cardiovascular/pulmonary 
and airway stability assured, neurologic stability, able to hold head upright, 


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sit up or ambulate with assistance dictated by age, and adequate hydration 
without excessive vomiting. In typical, the standard process in the ED, the RNs 
will make the provider aware of discharge readiness. We will use Epic time 
stamps to determine when the order placed by the provider for discharge was 
completed.  
 Recovery time from sedation as well as total length of ED stay will also be 
recorded. Procedures will occur within 10-15 minutes following intranasal 
midazolam administration and when adequate sedation with nitrous oxide 
has been met.   All time stamps will be collected by the RA in real time.   
 
 We will also collect information on patient/parent satisfaction with sedation 
as well as provider satisfaction.  Patient/parent satisfaction will be assessed 
for all patients; child satisfaction will be assessed for patients over 12 years of 
age. Satisfaction will be measured on a scale of 1 to 5 (1 being not satisfied and 
5 being very satisfied). Specifically, parents (and children when applicable) 
will be asked “how satisfied with the means of sedation were you for the 
procedure performed”. Research assistants will then ask the ED providers on 
a scale of 1 to 5 (1 being not satisfied and 5 being very satisfied) “how satisfied 
with the means of sedation were you for the procedure performed”.  
Anxiolysis scores will be assessed and recorded by the RA for both nitrous 
oxide and intranasal midazolam.  We will have the RA document an anxiety 
score and FACES score as reported by the provider prior to anxiolytic being 
given, after anxiolysis is given/prior to procedure (at time of actual procedure 
start time) and 5 minutes after procedure stop time. Complications will be 
observed and recorded, through discharge, by the RA.    
 
List of Variables: 
1) Efficacy 
a) Anxiolysis score (Table 1) 
b) Need for additional sedatives 
c) Ability to complete the procedure  
d) FACES  score (Table 2) 
e) Parent/patient satisfaction  
f) Provider satisfaction  
g) Whether or not child life specialist was present or not 
 
2) List of complications 
a) Hypoxia (<90%) 
b) Paradoxical reaction (increased anxiety, awareness, pain) 
c) Need for administration of a reversal medication  
d) Vomiting with aspiration  
e) Prolonged sedation  
f) Airway obstruction  
g) Inadequate sedation  
h) Allergic reaction  


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Protocol version: 8/24/17 
 
 
 
i) Nasal Reaction  
j) Nasal Irritation  
k) Cardiac Arrest  
 
3) Nothing by mouth (NPO) Status  
 
4) Duration of procedure  
 
5) Patient Demographics 
a) Weight 
b) Age  
c) Gender  
d) Race/Ethnicity 
e) Underlying diagnoses  
f) ASA level  
 
 
Table 1: Anxiety Score  
1 
Agitated, clinging to parent, may or 
may not be crying 
2 
Awake, clinging to parent, whimpering, 
but not crying 
3 
Calm, sitting or lying comfortably with 
eyes closed but responding to minor 
stimulation  
4 
Drowsy, sitting or lying comfortably 
with eyes closed but responding to 
minor stimulation  
5 
Asleep, eyes closed, able to be aroused 
but 
not 
responsive 
to 
minor 
stimulation  
 
Table 2: FACES scoring 
 
 
 
D.   Description, Risks and Justification of Procedures and Data Collection Tools: 


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PI: Paul Szefler, MD 
Protocol version: 8/24/17 
 
 
 
 
Anticipated Risks 
Participation in this study is of minimal risk to study subjects.  There is 
an unlikely risk of loss of confidentiality.   
Intranasal midazolam has the following listed adverse effects: 
Hypotension, drowsiness, headache, over-sedation, seizure like activity, 
nausea, vomiting, myoclonic jerks, nystagmus, apnea, cough, hiccups, 
paradoxical reaction, agitation, amnesia, bronchospasm, emergence 
delirium, euphoria, hallucinations, laryngospasm and rash.  
Nitrous Oxide has the following listed adverse effects: hypotension, 
headache, dizziness, confusion, nausea, vomiting and apnea.   
 
Describe plan to minimize risk  
The risk of loss of confidentiality will be minimized by only allowing 
research personnel to have access to the data and storing data in a HIPAA 
compliant REDCap database.   
 
Justification 
The potential benefit of this study is that by implementing nitrous oxide 
for minimal sedation we can shorten the total length of stay in the ED 
and thus improve patient and provider satisfaction.  We also hope to 
strengthen the support for use of nitrous oxide in the pediatric ED by 
showing it is as safe and effective as intranasal midazolam.  
 
F.   Data Analysis Plan:   
In this study we will measure a clinical significance as a difference in total 
length of ED stay as 15 minutes.  Total length of stay will be measured and 
compared for statistical significance using t-test analysis.  Patients will be 
enrolled over a one-year period.  Based on annual CHCO ED estimates of 
candidate procedures, we estimated a total of 300 patients will be eligible. 
Considering possible attrition from refusals and RA availability we have 
calculated a range of possible samples needed to achieve adequate power to 
find a significant difference in Length of stay (Table 3) 
 
Table 3:  Power Calculation 
 


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Protocol version: 8/24/17 
 
 
 
 
 Patient/parent and provider satisfaction scores will be compared and 
measured for statistical significance by completing chi-squared analysis. 
Demographics and baseline patient characteristics will be measured using 
means and standard deviation for continuous variables and frequency and 
percentage for categorical variables.   We will also attempt to control for 
confounding variables: including tracking if our child life team is present, % 
of nitrous oxide used, use of local anesthetic, age, gender, weight, NPO status, 
ASA status, as well as FACES score and anxiety score.    
 
 
G.  Summarize Knowledge to be Gained:   
By completing this study, we will better understand the potential benefits of 
using nitrous oxide for minor procedures in the ED.  Because of its fast onset 
and rapid offset we anticipate its use for these procedures will significantly 
decrease the length of stay in the ED, therefore improving work flow, as well 
as improving patient/parent and provider satisfaction.  While more studies 
need to be completed, this study will potentially increase provider’s awareness 
of other anxiolytic methods that are safe and effective in the pediatric ED.   
 
 
 
 H. References: 
 
1. 
Srinivasan M, Carlson DW.  Procedural Sedation by Pediatric Hospitalists: 
Analysis of the Nautre and Incidince of Complications During Ketamine and 
Nitrous Oxide Sedation. Hospital Pediatrics. 2013: 3 (4) 342-347. 
 
 
2. 
Tobias, JD.  Applications of Nitrous Oxide for Procedural Sedation in the 
Pediatric Population. Pediatr Emer Care. 2013; 29: 245-265.  
 
3.  
Babl FE, Oakley E, Seaman C, Barnett P, Sharwood LN.  High-Concentration 
Nitrous Oxide for Procedural Sedation in Children: Adverse Events and Depth 
of Sedation. Pediatrics. 2008; 121; e528-e532.  
 
4. 
Rothman DL. Sedation of the pediatric patient. J Calif Dental Assoc 2013; 41: 
603-11 
 
5. 
Kupietzky A, Holan G, Shapira J. Intranasal midazolam better at effecting 
amnesia after sedation than oral hydroxyzine: a pilot study. Pediatric Dent 
1996; 18:32-4. 
 
6. 
Katzung BG, Masters SB, Trevor Aj: Basic and Clinical Pharmacology. MGGraw-
Hill Medical: MGGraw-Hill, New York 2012. 
 


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7. 
Field LM, Dorrance DE, Krezeminska EK, Barsoum LZ.  Effect of nitrous oxide 
on cerebral blood flow in normal humans. Br J Anasth 1993; 70:154-9 
 
8. 
Rita L, Seleny FL, Mazurek A et al. Intramuscular midazolam for pediatric 
preanesthestic sedation: a double blind controlled study with morphine.  
Anesthesiology 1985; 63: 528-531. 
 
9. 
Theroux MC, West DW, Coddry DH, et al. Efficacy of intranasal midazolam in 
facilitating suturing of lacerations in preschool children in the emergency 
department.  Pediatrics. 1993; 91: 624-627. 
 
10. 
Kogan A, Katz J, Efrat R, et al. Premedication with midazolam in young 
children: a comparison of four routes of administration. Pediatric Anaesth 
2002; 12:685-689. 
 
11. 
Onody P, Gil P, Hennequin M. Safety of inhalation of a 50% nitrous 
oxide/oxygen premix: a prospective survey of 35,828 administrations. Drug 
Saf 2006: 29: 633-40 
 
12. 
Gall O, Annequin D, Benoit G, Glabeke E, Vrancea F, Murat I.  Adverse events of 
premixed nitrous oxide and oxygen for procedural sedation in children. Lancet 
2001: 358: 1514-5 
 
13. 
Annequin D, Carbajal R, Chauvin P, Gall O, Tourniaire B, Murat I.  Fixed 50% 
nitrous oxide oxygen mixture for painful procedures: a French survey. 
Pediatrics 2000; 105: e47 
14. 
Kalach N, Barbier C, el Kohen R, Begon-Lours J, Nyombe-Nzungu P, Sonna M, 
Laurent A, Kremp O. Tolerance of nitrous oxide-oxygen sedation for painful 
procedures in emergency pediatrics: report of 600 cases. Arch Pediatr 2002; 9: 
1213-5. 
 
15. 
Young Eun Moon. Paradoxical reaction to midazolam in children. Koren J 
Anesthesiol 2013; 65(1): 2-3.