Adjunctive Nitrous Oxide During Emergency Department Propofol Sedation in Adults, a Pilot Study
Phase: NA
Conditions: Joint Dislocation, Perianal Abscess, Abscess
Sponsor: Albert Einstein Healthcare Network

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Adjunctive Nitrous Oxide during ED propofol sedation in adults,  
a pilot study. 
NCT02410707 
Version: 7/1/14 
Investigator(s): Joeseph Herres, DO; Kenneth Deitch, DO; Carl Chudnofsky, MD; Kathia 
Damiron, CCRC 
Objectives 
       
To describe the safety and efficacy of adjunctive nitrous oxide pre-propofol 
administration for analgesia and pre-procedure anxiolysis during ED procedural sedation and 
analgesia in adults. 
Background 
Specific Aims 
       
To measure the rates of hypoxia and respiratory depression requiring a physician 
intervention in adult patients receiving 50% demand valve nitrous oxide pre-propofol 
administration during ED procedural sedation and analgesia. Secondary aims include patient, 
nursing, and physician post procedure satisfaction scores, Ramsay sedation scores, total propofol 
dose given, length of time spent using nitrous oxide, patient recall of procedure. 
Significance 
Procedural sedation is the use of sedative, analgesic, and/or dissociative agents to relieve 
anxiety and pain associated with diagnostic and therapeutic procedures.  Propofol has become 
one of the most commonly used agents for ED procedural sedation.1,2 Propofol crosses the 
blood-brain barrier rapidly. The drug takes effect within approximately 40 seconds, and its 

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duration of action is approximately six minutes 2,3 Multiple randomized trials and prospective 
observational studies have found propofol to be safe and effective for PSA in the emergency 
department 3,4,5, Propofol acts as a sedative and amnestic, but provides no analgesia.  
A possible approach is pretreatment with short-acting opioids (eg, fentanyl). 
Unfortunately, the addition of opioids increases the likelihood of respiratory complications. As 
an example, fentanyl at a dose of 1.5 mcg/kg increases the risk of respiratory depression. In 
another study, patients given both alfentanil and propofol required stimulation to induce 
respiration more often than those given only propofol.7 Another alternative to pretreatment with 
short-acting opioids is to use sub-dissociative doses of ketamine (0.3 mg/kg). Ketamine appears 
to provide comparable analgesia with less risk of respiratory depression. However, there is no 
literature that has shown that there is a decreased risk of respiratory depression than with 
propofol.8  
The optimal agent for analgesia before procedural sedation would have effect that is short 
acting, easy to administer, and with minimal risk to the patient.  Nitrous oxide may fit this 
profile. In pediatric emergency departments, inhaled nitrous oxide was found to be the most 
common agent for procedural sedation and analgesia.8  There is a great deal of literature 
supporting the use of nitrous oxide in the pediatric population, and the safety and efficacy of its 
use as a single agent or in concert with a parenteral sedative and/or analgesic is excellent. 
However, there is a paucity of literature to support or refute the use of nitrous oxide in adults for 
ED procedural sedation and analgesia.  
 
 Nitrous oxide is a colorless gas that diffuses rapidly across the pulmonary alveoli 
providing analgesia and anxiolysis with minimal sedative effects, rapid induction, and 
emergence.9 Nitrous oxide is a weak sedative agent with the potential for significant analgesic 

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effects.  Noncompetitive antagonist activity at the NMDA receptor along with activation of 
opioidergic receptors contributes to its anesthetic mechanism.10  In an RCT (ENIGMA 1) using 
anesthesia with and without nitrous oxide, there was a small increased risk of myocardial 
infarction in the nitrous oxide group.11 However, there were patients getting general anesthesia 
for over two hours; our patients will be receiving 50/50 nitrous oxide for 5-10 minutes 
maximum, and there are no known cardiac side effects reported during short-term sedation in the 
literature.11 There are rare adverse events, most often cited as case reports of chronic or acute 
toxicity causing myeloneuropathies and polyneuropathies.12-15   
 Nitrous oxide has been used in general anesthesia for over 2 centuries, but its use outside 
of the operating room began when Tunstall introduced the nitrous oxide/oxygen mixture as an 
analgesic agent during labor.16  Since this inception, the nitrous oxygen/oxygen mixture has been 
used readily in the fields of dentistry, gastrointestinal procedures, and children’s procedural 
sedation.  Nitrous oxide is often administrated via continuous flow or on-demand at a 
concentration of 50-70%. 
 
There is some early data describing a favorable adverse event profile with nitrous oxide 
as a single agent in adults.  Hennequin et al. (2012) demonstrated support for the efficacy of 
nitrous oxide with no major adverse cardiorespiratory events. Although approximately 10% of 
participants received mild gastrointestinal and behavioral side effects (e.g. agitation).  Greater 
than 90% of the study participants stated they would receive nitrous oxide again.17  In a large 
prospective trial, Babl et al. (2008) found there to be only 2 patients out of 655 who suffered 
serious adverse events (i.e., chest pain and oxygen desaturation).  Both patients had been 
administered 70% nitrous oxide compared to the more conservative 50% concentration.  
Additionally, there was an increased incidence of minor adverse events (i.e., emesis and 

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agitation) with the higher concentration of nitrous oxide.18 Kariman et al. (2011) compared 
nitrous oxide versus parental fentanyl as an analgesic after long bone fracture and found similar 
pain scores and a more rapid decrease in the pain score in the nitrous oxide group when 
compared with the opiate group.19   
  
Nitrous oxide has been shown to be a safe and effective agent for procedural sedation in 
children, including work that has combined opiates and benzodiazepines with nitrous oxide 
continuously. Burton et al. (1998) conducted a small, randomized controlled trial studying the 
effectiveness of nitrous oxide on anxiety scores in children during laceration repairs.  They found 
a significant decrease in the group that used nitrous oxide compared to the placebo group.20  This 
finding was further validated by Luhmann et al. (2001) with 50% continuous flow of nitrous 
oxide resulting in less distress and anxiety as well as increased patient satisfaction compared to 
midazolam or topical anesthetic agents 21. The study also showed that the main adverse event 
associated with nitrous oxide was nausea and vomiting, whereas the midazolam group had 
significant ataxia and dizziness.  There was no demonstrable advantage of the combination of 
midazolam and nitrous oxide in regard to patient satisfaction versus nitrous oxide alone, but 
there was an increase in adverse events when midazolam was included.21  A study performed by 
Evans et al. (1995) demonstrated that the pain and memory of the procedure between children 
receiving either nitrous oxide versus children receiving intramuscular meperidine in combination 
with promethazine for fracture reduction was similar, but there was increased satisfaction and 
decreased length of stay in the nitrous oxide group.22   Seith et al. (2012) demonstrated that the 
addition of intranasal fentanyl to nitrous oxide in children resulted in deeper levels of sedation 
when compared to nitrous oxide alone; however, there were no serious adverse events.23   

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Nitrous oxide as an adjunct to propofol may an ideal agent to decrease pre-procedure 
anxiety before deep sedation of adults in the ED. Nitrous oxide has some analgesic and 
anxiolytic qualities, with an excellent cardio-respiratory profile. The anxiety and pain 
surrounding procedural sedation is not limited to the procedure itself, but the elapsed time from 
the time the patient enters the ED to the time spent in preparation for the procedure can be 
significant and lead to increased anxiety. This may lead to increased time and difficulty in 
sedating a patient to an appropriate level for a procedure. These patients may require higher 
levels of propofol to appropriately sedate, which is associated with increased rates of adverse 
respiratory events. 
  
We believe that pre procedure adjunctive nitrous oxide may provide a level of 
anxiolysis and analgesia before propofol is administered, leading to a smoother and more 
satisfactory sedation and procedure, with  fewer adverse respiratory events and less overall 
propofol dose than propofol alone. Since this is a novel concept, we believe that a pilot study to 
evaluate the safety and efficacy of pre-procedure adjunctive 50/50 nitrous oxide administration 
with adult propofol administration is warranted. 
Setting of the Research 
       
Patients will be recruited from the Emergency Department of Einstein Medical Center 
Philadelphia. The Einstein Medical Center Philadelphia is an urban teaching hospital, level one 
trauma center with 500 beds and an annual ED census of 100,000 subjects.  
Resources Available to Conduct this Research 
       
The Einstein Medical Center Philadelphia ED sees approximately 300 patients a day, of 
which 5% are emergencies that require procedural sedation and analgesia, and thus will be 
available as potential subjects in this study. The Division of Clinical Research of the Department 

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of Emergency Medicine has extensive experience in both investigator led and pharmaceutical 
research. This will be the seventh trial we have conducted in our ED in procedural sedation and 
analgesia in the last 7 years, and each of these studies has recruited 100-200 patients. We have a 
research associate 7 days a week who will consent and enroll eligible patients. The division also 
has 2 full time coordinators and a full time division director, as well as biostatistician support. 
We have two well-equipped offices, one in the ED where the research associate is based and one 
in our department where our division director works. The lead investigator will lead 10% of their 
non-clinical time to this endeavor.  
Study Design 
       
This pilot study will be conducted in a prospective, non-randomized fashion using a 
convenience sample of 100 subjects undergoing sedation for ED procedures. 
1. Recruitment Methods 
 
The research associates as well as the heath care team (both residents and attending 
physicians) will screen patients who may need procedural sedation in the ED and may qualify for 
the study. Research associates will use the Cerner/AeCIS System for screening, and they will be 
in charge of informed consent, enrollment, placement of the capnography monitor, as well as 
data collection. The health care team will be in charge of the procedural sedation and all other 
management.  
2. Inclusion and Exclusion Criteria 
i. Inclusion criteria: All spontaneously breathing subjects, 18 years of age and 
older, with an American Society of Anesthesiologists (ASA) Physical Status 
Classification 1 or 2, who will be receiving sedation for an ED procedure. 
Written informed consent will be obtained from all subjects. 

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ii. Exclusion criteria: Subjects with underlying conditions that could affect 
ventilation, perfusion, or metabolism including intubated subjects, subjects 
with clinical signs of cardiopulmonary instability, major trauma, shock, 
sepsis, ASA class 3, 4, and 5. Also those unable to provide informed consent, 
nursing home residents, age less than 18 years, non English speaking, 
pregnant women, subjects under police custody, or physician discretion. 
3. Study Endpoints 
i. Primary: 
1. ETCO2 measured q 20 miliseconds seconds 
2. SpO2 measured q 20 miliseconds seconds 
ii. Secondary Endpoints 
1. A baseline reading of the vital signs (heart rate, respiratory rate, 
peripheral SaO2 and ETCO2)  
2. Physician interventions (verbal or physical stimulation, airway 
repositioning, additional oxygen, positive pressure ventilation, 
endotracheal intubation) 
3. Level of sedation (Ramsay Score) 
4. Patient Demographics  
5. Patient recall of procedure 
6. Total propofol dose 
7. Total elapsed time of nitrous oxide use 
8. Patient and physician procedure satisfaction score 
4. Procedures Involved in the Research 

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Initial medical assessment will be made in accordance with established clinical 
procedures, including the history, physical examination, and vital signs. If by clinical assessment 
the patient meets eligibility criteria, then they will be approached by a research associate for 
enrollment in the study. After informed consent is obtained and prior to starting the sedation, 
standard vital sign monitoring will be placed on the patient (electrocardiogram, non-invasive 
blood pressure monitoring, pulse oximetry, and capnography). Level of consciousness will be 
determined using the modified Ramsay scale, which will be assessed at baseline.  The 
Capnostream 20 ETCO2 monitor will be used as the primary device to measure ETCO2, with a 
nasal cannula capable of delivering supplemental oxygen and measuring ETCO2 (Oridion 
Medical, Needham, MA).  
 
The SEDARA gas mixer system [Linde Gas North America LLC] will be used as 
our primary nitrous oxide delivery device. It will mix and deliver nitrous oxide and oxygen in a 
1:1 ratio, at a fixed concentration of 50%/50%. It uses a patient driven demand valve system that 
is hand held. This device provides a consistent, fixed 50%/50% blend of nitrous oxide (N2O) and 
oxygen (O2), eliminates the need to titrate, and provides fixed concentrations for controlled and 
consistent dosing. The device comparator detects dosing imbalance to protect against hypoxic 
mixtures, it cannot deliver nitrous gas without concurrent oxygen, and the device has an anti-
asphyxia valve override. The on demand valve requires patient inspiration to trigger dosing. This 
portable device scavenges exhaled waste gases for environmental safety, as well as a key 
mechanism that renders the system inoperable without it for security. 
 
After informed consent, the patient will fill out a pre procedure questionnaire and a 
100 mm VAS baseline pain scale. The patient will be given the mask for delivery of nitrous 
oxide, and instructed on its use. The research associate will mark the time the patient began using 
the device electronically on the capnostream 20. Once IV access is established, and the team and 

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patient are ready to begin the procedure, the nitrous oxide mask will be removed, and a 100% 
NRB mask delivering 15 liters a minute of supplemental oxygen will be placed on the patients 
face. The loading dose of propofol will then be administered immediately. All sedations in this 
trial will use propofol 1.0 mg/Kg initial dose, with 0.5 mg/Kg doses titrated to deep sedation. 
Once the patient is deeply sedated, the procedure will begin. 
 
The subject’s clinical data and sedation information (refer to data management) will 
be entered into a standardized data collection form. The data will be continuously recorded 
throughout the sedation and recovery periods. Study will end when the subjects recovers back to 
baseline mental status.  
 
Vital signs will be flagged electronically when a physician intervenes for clinical 
respiratory depression. Respiratory depression will be defined as peripheral SaO2 below 92%, 
ETCO2 level above 50, a rise or decrease of 10% above or below baseline, the loss of the ETCO2 
waveform for more than 15 seconds. Level of consciousness will be determined using the 
modified Ramsay scale, which will be recorded at baseline and at the point of deepest sedation. 
Once the procedure is complete, and the patient is deemed back to their mental status baseline, 
they will fill out a post procedure satisfaction questionnaire, and a 100mm VAS scale. They will 
be asked about procedure recall. The physician will also fill out a post procedure questionnaire. 
5. Data Management 
A standardized data collection form will be used to collect clinical data and a USB drive 
to collect electronic vital sign data. Initial data gathered will include age, gender, weight, and 
baseline vital signs (BP, HR, RR, peripheral SpO2, and ETCO2). Other information collected 
will be the elapsed time of nitrous oxide use, start time (when protocol was given), time (when 
patient returns to baseline), elapsed time in seconds under sedation (from start time to end time), 

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medications administered, repeated doses and times for every administered medication, total 
dose of each medication administered, adverse events, and interventions aimed at correcting 
respiratory depression. Level of consciousness using the modified Ramsay scale will also be 
recorded at baseline and at set intervals during sedation.  
The electronic monitoring data will be continuously recorded into the USB drive 
throughout the sedation and recovery periods. The Capnostream 20 ETCO2 monitor (Oridian 
Medical, Needham, MA) is capable of sampling and recording ETCO2 and pulse SaO2 every 5 
seconds. A patient identifier will be recorded to link the subject and the electronic monitoring 
data without compromising his/her confidentiality. At the completion of the sedation, all device 
data will be transmitted to a password-protected Excel/SPSS spreadsheet for analysis. The 
research associate is responsible for recollection and storage of the data. Only the primary 
investigators, the study coordinator, and the research associates will have access to such.  
To assess these outcomes, we will download electronic data from each sedation into a 
Microsoft Excel database, checked and adjudicated any discrepancies with research associate 
notations, and generate a graph of the subject’s sedation with the X-axis showing time and the Y-
axis depicting ETCO2, SpO2, respiratory rate, and heart rate. Electronic time stamps noted 
propofol administration, procedure initiation and completion, adverse events, and physician 
interventions.  
           Before study blinding is broken, three investigators will evaluate each graph to code the 
presence or absence of cerebral hypoxia, peripheral hypoxia and respiratory depression. We will 
disqualify graphs if they had >35% data loss, unless all three evaluators agreed that there was 
unequivocal evidence of hypoxia (cerebral and or peripheral) and/or respiratory depression.     
 
 

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6.       Withdrawal of Subjects 
  Participation is voluntary. Subjects may withdraw from this study at any time. If this is the 
case their data will be deleted. We will record the number of patients that withdraw. Subjects 
may be withdrawn without their consent if the electronic data cannot be recorded.  
Statistical Plan 
1. Sample Size Determination 
As this is a pilot, prospective, observational trial, no power calculation will be used to 
measure a difference. In previous propofol studies, approximately 10-30% of patients develop 
hypoxia, and approximately 50% of patients meet criteria for respiratory depression. Thus, we 
believe enrolling 100 patients in this observational trial will allow for approximation of any 
correlations that are measured. 
2. Statistical Methods 
All clinical observations and demographic data will be summarized using medians with range 
or means with standard deviations as appropriate. Rate of detection of respiratory depression and 
hypoxia and timing of these events for each instrument (near-infrared spectroscopy, pulse 
oximetry, capnography) will be summarized descriptively. Associations among SaO2, and 
ETCO2 will be estimated using spearman’s rank correlation coefficient, using within-cluster 
resampling algorithm. This will allow for estimation of the marginal correlation in the presence 
of clustered data. Correlations not involving repeated measures data will be estimated with 
Spearman’s rank correlation coefficient. All analysis will be conducted using SPSS software 
(IBM, Armonk, NY).  
 

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Risks to Subjects 
There are no risks to the subjects other than the normal risks associated with the standard 
procedural sedation and analgesia, which may vary depending on the agent used, but in general 
include hypoxia, respiratory depression, hypotension, etc.  
Potential Benefits to Subjects 
There is no direct benefit for the subject. There will be no reimbursement to 
subjects for their participation in the study. 
Provisions to Protect the Privacy Interests of Subjects 
All data will be de-identified. Data that is loaded into the computer will be password 
protected and only available to the research associates and the investigators. Patients will be 
approached at their bedside by trained associates that will establish a private environment to 
disclose the information about this study and recollect the data. There will be no undue pressure 
placed to participate. All questions about the study may be answered by the research associates 
and the investigators prior, during and after informed consent is given. 
Provisions to Maintain the Confidentiality of Data 
 
Each subject will be given an identification number in the monitors and database in order 
to de-identify data for analysis. Study data will be stored for a minimum of 3 years in a secure 
and password protected file only accessible to study staff. Hard copy of data collection form will 
be kept in the research office under lock and only accessible to study staff. 
Medical Care and Compensation for Injury 

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This is an observational study. No injuries can be consequence from participating in it. 
The procedural sedation and analgesia carries some risk that does not go beyond the standard ED 
protocol.  
Cost to Subjects 
          There will be no cost to the subjects from participating in the study. Aspects that 
are part of standard clinical care will be responsibility of the subjects and their insurance 
companies.  
Consent Process 
Formal written consent will be completed by the patient with a trained research 
associate, who has extensive experience in research recruitment and consent. The consent 
discussion will be hold at the patient’s bed side, and will last until the patient understand 
what is being told. Patient can ask any question related to the study and can take the time 
they consider necessary to consent. No coercion or undue influence will be placed to 
participate.  
The signed documents will be stored in the study binder inside the research office 
and a copy will be given to each subject for their files.  
Vulnerable Populations 
Only eligible adult patients who can give informed consent in writing will be enrolled, no 
children, incarcerated, pregnant, or mentally incapacitated patients will be enrolled. 
Sharing of Results with Subjects 
      Results will not be shared with subjects. 
References 
 

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1. Gan TJ. Pharmacokinetic and pharmacodynamic characteristics of medications 
used for moderate sedation. Clin Pharmacokinet 2006; 45:855. 
 
2. Swanson ER, Seaberg DC, Mathias S. The use of propofol for sedation in the 
emergency department. Acad Emerg Med 1996; 3:234. 
 
3. Miner JR, Burton JH. Clinical practice advisory: Emergency department 
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4. Newstead B, Bradburn S, Appelboam A, et al. Propofol for adult procedural 
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5. Black E, Campbell SG, Magee K, Zed PJ. Propofol for procedural sedation in 
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13. Hsu CK, Chen Y, Lung V, His SC, Lo HC, Shyu HY.  Myelopathy and 
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14.Alt RS, Morrissey RP, Gang MA, Hoffman RS, Schaumburg HH.  Severe 
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15.Richardson PG.  Peripheral neuropathy following nitrous oxide abuse.  
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21. Luhmann JD, Kennedy RM, Porter FL, Miller JP, Jaffe DM.  A Randomized 
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Attachments 
A) Sedara Gas Mixer System Quick Reference Guide 
B) Data Collection Form 
C) Ramsay Scale 
D) Patient and physician procedure satisfaction score