A Randomized Controlled Trial of an Intervention to Reduce the Incidence of Hypoxia With Nasal Continuous Positive Airway Pressure Versus Standard Care During Procedural Sedation for Gastrointestinal Endoscopy
Phase: NA
Conditions: Hypoxia, Endoscopy, Anesthesia Morbidity
Sponsor: Johns Hopkins University

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Date:  November 16, 2017         NCT03369197  
Principal Investigator: Laeben Lester, MD  
Application Number: IRB00118466  
  
  
  
JHM IRB - eForm A – Protocol  
  
  
  
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1.  
Abstract  
a. Provide no more than a one page research abstract briefly stating the problem, the research 
hypothesis, and the importance of the research  
  
Monitored anesthesia care with procedural sedation has increased dramatically over the past 15 
years, driven by increased utilization in gastrointestinal endoscopy, cardiology (both interventional 
and electrophysiology), and interventional radiology.  Despite the increase in the number of patients 
receiving procedural sedation, current monitors of respiratory depression are inadequate to 
determine the degree of anesthetic induced hypoventilation.  Underappreciated hypoventilation puts 
patients at risk for hypoxia, respiratory arrest, cardiopulmonary arrest, and other adverse events.   
While pulse oximetry is an outstanding and required monitor of oxygen saturation, it is a poor 
monitor of ventilation in patients receiving supplemental oxygen.  The American Society of  
Anesthesiologists Monitoring Standards recognizes the underlying contribution of hypoventilation to 
hypoxia and adverse events by mandating the use of end-tidal capnography for procedural sedation.  
While well intentioned, end-tidal capnography is helpful in determining respiratory rate, it appears 
to be insufficient for detection of hypoventilation during procedural sedation.  In fact the quantitative 
value may paradoxically decrease as the degree of hypoventilation increases.  Further, the 
mechanism of anesthetic induced hypoventilation during monitored anesthesia care with procedural 
sedation is not entirely understood or appreciated.    
  
Fortunately, other FDA approved monitors are available that can non-invasively monitor additional  
respiratory parameters and hypoventilation.  The ExSpironTM respiratory monitor is an FDA-cleared 
device that allows acquisition of quantitative values of respiratory rate (RR) tidal volume (TV), and 
minute ventilation (MV), and has a signature pattern to identify episodes of airway obstruction 
(Respiratory Motion, Inc. Waltham, MA).  Transcutaneous CO2 (PtcCO2) monitoring is a non-invasive 
method for continuous monitoring of overall ventilation that closely approximates arterial carbon 
dioxide values (PaCO2) obtained from blood samples (SenTec, Bern, Switzerland).  Further, 
processed electroencephalography (EEG) using bispectral index (BIS) is a non-invasive monitor that 
has been described as a marker for depth of anesthesia during general endotracheal anesthesia GETA 
and procedural sedation (Medtronic, Minneapolis, MN.   Together, these devices will allow a more 

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precise understanding of the respiratory effects of monitored anesthesia care and procedural 
sedation.    
  
This study will use this innovative combination of respiratory monitors to better understand the 
magnitude and mechanism of respiratory depression during MAC with procedural sedation at 
different anesthetic levels.  For example, we will be able to distinguish the decrease in minute 
ventilation due to loss of motor tone and subsequent airway obstruction from that caused by 
decreased respiratory drive minute ventilation due to changes in tidal volume, respiratory rate, or 
both.  Likewise, these devices have the potential to improve the monitoring of respiration and the 
quantification of hypoventilation, making it a potentially valuable tool for clinical care in the future, 
as well as further studies to determine anesthetic regimens that may cause less respiratory 
depression.   Further, if the addition of CPAP does in fact alleviate obstruction and decrease 
hypoventilation, it is a potentially very important finding for patient care.   
  
In addition, this study aims to explore a novel mechanism that may account for individual variability 
in the respiratory response to anesthesia.  Short chain fatty acids are produced by the gut 
microbiome (non-pathological bacteria in the gastrointestinal tract).  Low levels of these compounds 
have been associated with hypertension and obesity, as well as hypertension in people with sleep 
apnea.  Receptors that are activated by these compounds are found in high concentration in the 
carotid body, where their activation appears to stimulate respiration.  We will measure serum levels 
of short chain fatty acids, and hypothesize that lower concentrations will be associated with greater 
anesthesia induced respiratory depression and higher levels will be protective.  If short chain fatty 
acids are shown to be associated with a protective affect on respiratory depression, this could open 
the door to an entirely new understanding of the mechanisms that contribute to respiratory 
depression during anesthesia, but also those involved with obstructive sleep apnea.  In addition, it 
could raise the possibility that short chain fatty acids could be administered as a protective 
treatment.  
  
2.  
Objectives (include all primary and secondary objectives)  
  
Specific Aim 1: To test whether nasal CPAP reduces the incidence of hypoxia during procedural sedation 
with propofol as compared to usual care.  Hypothesis: A randomized clinical trial of an intervention to 
reduce airway obstruction (nasal CPAP) will decrease the incidence of hypoxic events (<90% ≥ 15s)  
compared to usual care in patients undergoing procedural sedation.  
  
Specific Aim 2: To determine the duration, magnitude and mechanism of hypoventilation and its 
association with hypoxia in subjects undergoing procedural sedation. Hypothesis: By determining minute 
ventilation, transcutaneous CO2 and sedation depth while measuring end-tidal CO2, it will be possible to 
relate ventilation to hypoxic events, sedation depth and airway obstruction.  Further, reductions in the 
incidence of hypoxia in the intervention group will be consistent with the hypothesis that loss of airway 
motor tone underlies hypoventilation and associated hypoxia.  
  
Specific Aim 3: To characterize the physiologic state when end-tidal capnography is insufficient for 
detecting hypoventilation.  Hypothesis: The amplitude of the capnographic signal is not representative of 
the adequacy of ventilation due to artifact from loss of airway motor tone during procedural sedation.  
  
Specific Aim 4: To determine if there short chain fatty acid serum concentration is protective for 
procedural sedation induced hypoventilation, obstruction and hypoxia:  Hypothesis: Higher concentration 

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of short chain fatty acids will be reduce the risk of hypoventilation, obstruction, and hypoxia and suggests 
a link between respiratory function and gut microbiome.    
  
3.  
Background (briefly describe pre-clinical and clinical data, current experience with procedures, 
drug or device, and any other relevant information to justify the research)  
  
There has been an explosion in the number of anesthetics administered outside of traditional operating 
rooms in the last decade.  The rise in such non-operating room anesthetics (NORA) has been driven by 
increased demand in gastrointestinal endoscopy (GE), interventional radiology, and cardiology.1 Increased 
anesthesia support for GE procedures appears to be the primary driver for the rise in NORA.1 The increase 
is huge – between 2003 and 2009, anesthesia support for GE for Medicare patients grew from 13.5% to 
30.2%, while anesthesia support for patients undergoing GE procedures with private insurers increased 
from 13.6% to 35.5%.2 In 2009, an estimated 18.6 million gastrointestinal endoscopies were performed in 
the United States, of which 6.9 million were upper, 11.5 million lower, and 228,000 biliary.3 Together, 
these studies suggest that more than 6 million anesthetics were administered for GE in 2009.  Further, 
previous projections have indicated that anesthesia services would be used in over half of all GE 
procedures by 2015.4  These predictions appear to be reflected in reports of increased NORA for GE at 
tertiary medical centers.5,6  In the endoscopy suite at the Johns Hopkins Hospital, nearly all GE procedures 
are performed with anesthesia involvement, with an increase in annual cases from from approximately 
4000 in 2007 to nearly 12,000 in 2015.    
  
Fundamentally, the shift to anesthesia involvement in gastrointestinal endoscopic procedures represents a 
change from gastroenterologist directed, nurse administered sedation with fentanyl and midazolam, to a 
propofol-based anesthetic.7   This change has been driven by several factors, including patient preference 
and satisfaction, risk aversion on the part of the proceduralist, perception of better procedural conditions, 
and evidence of decreased length of stay in the post anesthesia care unit and faster throughput.8,9  The use 
of propofol sedation compared to midazolam and fentanyl appears to be associated with deeper levels of 
anesthesia.10  In fact, when propofol is used for procedural sedation, electroencephalographic monitoring 
such as BIS suggests anesthetic depth often associated with general anesthesia.11  Some retrospective 
studies have suggested higher rates of complications with propofol-based anesthetics compared to 
midazolam and fentanyl, including cardiorespiratory arrest, aspiration, and hypoxia.12  In contrast, other 
studies have suggested no difference or improved outcomes with anesthesia involvement, and patients were 
generally sicker with longer cases.13,14  
  
The large and growing number of GE procedures with anesthesia services underlies the importance of 
delivering safe care, as even a low rate of sedation related adverse events may affect a large number of 
patients.  In several retrospective studies, cardiopulmonary events occurred in up to 11.7/1000 events, and 
hypoxia was the most common.13   While the full implication of mild transient hypoxia on outcomes is 
unknown, significant hypoventilation with hypercarbia and hypoxia commonly proceeds cardiopulmonary 
arrest.15 Respiratory depression from oversedation is an important mechanism of patient injury during 
monitored anesthesia care.16  The rate of hypoxia is considered as a marker for unsafe sedation practices in 
endoscopy suites.17  However, the true rate of hypoxia associated with sedation for endoscopic procedures 
is unknown and ranges from 1% to 70% in the literature.18,19,20  The variability may be related to adequacy 
of surveillance as well as differences in the definition of hypoxia. For instance, lower rates of hypoxia in 
manually and electronically recorded pulse oximetry data during clinical care have been reported.21  A 
recent study from the Netherlands reported a hypoxia rate in average risk patients during sedation for 
colonoscopy without oxygen supplementation of 55.6%.22  A recent study from Germany  
pseudorandomized patients undergoing upper, lower, or combined endoscopic procedures with 
propofolbased anesthesia to nasal cannula alone or with a nasopharyngeal airway and found rates of 

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hypoxia of 1.8% versus 13.5%.23  In another study from the Cleveland Clinic evaluating the STOP-BANG 
sleep apnea scoring system, subjects with STOP-BANG score >3 had a rate of hypoxia of 16.9% versus 
11.2% in the STOP-BANG score <3 group, but this did not reach significance in this underpowered 
study.24  However, higher BMI was associated with more sedation-related adverse events (SRAE).     
  
Hypoxia is related to both centrally mediated changes in respiratory drive caused by sedative drugs, direct 
effects of the anesthetic agents on motor function, and diminished airway tone due to sleep or sedation 
(change in state). Furthermore, sedative agents decrease airway tone and increase the risk of obstruction, 
while blunting the normal arousal that occurs in response to hypercarbia and hypoxia during obstruction 
events during natural sleep.25,26   Obstructive sleep apnea and obesity are risk factors for airway obstruction 
during sedation.14,25  Use of nasal CPAP has been demonstrated to improve ventilation, alleviate upper 
airway obstruction, and reverse hypoxia in women undergoing spinal anesthesia with sedation for 
gynecological procedures.27  Continuous positive pressure stents the airway, alleviating the obstruction 
from oropharyngeal soft tissue that occurs during sleep and under sedation, and has been advocated in 
patients with obstructive sleep apnea on CPAP at home.28  Positive pressure ventilation using a nasal mask 
has also been shown to be effective.29  The Supernova mask (RMD medical, Tucson, AZ) is FDA approved 
commercially available nasal mask that can  be attached to a standard anesthesia circuit or Jackson Reese, 
and allows for up to 30 l/min of oxygen delivery, making it convenient for use in procedural sedation.  It 
can supply CPAP as well as supplemental positive pressure breaths by closing the mouth or applying gentle 
cephalad directed submandibular pressure to push close the oropharynx by approximation of the tongue and 
palate.  
  
During general endotracheal anesthesia (GETA), airway obstruction is bypassed by the endotracheal tube 
and the closed system allows for minute ventilation to be continuously monitored and end tidal carbon 
dioxide (EtCO2) generally approximates arterial carbon dioxide (PaCO2).  During monitored anesthesia 
care, end tidal carbon dioxide (EtCO2) monitoring is routinely utilized as a qualitative marker of respiratory 
rate, but quantitative evaluation to identify hypoventilation is usually not possible by nasal cannula or 
standard mask (“green mask). Likewise, minute ventilation is not routinely monitored. In fact, ETCO2 
reading often decreases during hypoventilation with opioids and sedatives, while respiration paradoxically 
decreases (see figure, attached).30  Still, ETCO2 monitoring remains an important  measure of respiratory 
rate, and has been shown to decrease the rate of hypoxia during procedural sedation for colonoscopy from 
32% to 18%.31 Prevention of hypoxia by administering supplemental oxygen may blunt the potential 
increase in respiratory drive stimulated during opioid and sedative administration.32  However, prevention 
of hypoxia during procedural sedation using oxygen allows for airway interventions prior to the onset of 
hypoxia when ventilation is being carefully monitored.  Current standard of care for monitored anesthesia 
care with sedation includes use of qualitative EtCO2 as a marker of respiration, but does not include 
quantitative monitoring of minute ventilation or the degree of hypoventilation.   
Impedence based respiratory volume monitoring has been used to assess adequacy of ventilation and 
airway obstruction in patients undergoing endoscopic gastrointestinal procedures.33,34  In fact, such studies 
also suggest that EtCO2 often decreases as minute ventilation decreases.  In this study, changes in minute 
ventilation from baseline, and episodes of upper airway obstruction will be assessed using the 
commercially available ExSpironTM (Exspiron, Respiratory Motion Inc, Waltham MA).  Previous studies 
using the ExSpironTM have suggested that decreased minute ventilation during sedation for GE procedures 
is primarily due to decreased tidal volume rather than respiratory rate.33 Transcutaneous carbon dioxide has 
proven to closely approximate to arterial carbon dioxide (PaCO2), and in fact more closely reflects PaCO2 
then end tidal carbon dioxide (EtCO2).35 Transcutaneous carbon dioxide (TcCO2) has been shown to 
closely correlate with paCO2.  After approximately 5 minutes of calibration time, it appears to track 
changes in PaCO2 with a lag time of 30 seconds to 2 minutes.  In our experience using the TcCO2 monitor 

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for clinical application during jet ventilation, we have found the device to consistently track within 5 points 
of the PaCO2. (Sentec, Therwil, Switzerland).   
  
Depth of anesthesia using processed electroencephalography has been described as a marker for depth of 
anesthesia during GETA and MAC with sedation.  Depth of anesthesia using bispectral index (BIS) has 
been relatively well established and is known to correlate well with other measures of depth of 
anesthesia.36,37  We will use bispectral index (BIS) (Medtronic, Minneapolis, Minnesota) as a marker of 
state.  In addition, all clinical data utilized in routine practice will be recorded, including drug dosing, 
method of drug administration, and length of stay in the recovery area.   
  
Recently, alterations in the gut microbiome have been implicated in obesity, hypertension, obstructive sleep 
apnea induced hypertension, and airway smooth muscle  tone that may relate to reactive airway disease.38-40  
In general, lower short chain fatty acid levels are associated with pathology, and higher levels appear to be  

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protective.  Olfactory receptors located in vascular endothelium are activated by short chain fatty acids, 
causing smooth muscle relaxation, vasodilation, and protection from hypertension, with some feedback 
mechanisms that may prevent significant hypotension as well.  Interestingly, these receptors are also highly 
expressed in the carotid body, where activation by short chain fatty acids increases respiratory drive.41  This 
is an intriguing possible mechanism for individual variability in susceptibility to anesthesia induced 
hypoventilation and may also be a contributing mechanism for hypoventilation in patients with sleep apnea.  
We hypothesize that lower serum concentration of short chain fatty acids will be associated with more 
respiratory depression and higher levels will be protective. Further, we suspect that patients with known 
obstructive sleep apnea, hypertension, and high BMI will have lower short chain fatty acid levels.   
  
 
with minute ventilation and transcutaneous CO2 to better understand the total effects of sedation on 
respiration.  Thus, the study will also serve  to evaluate which mode(s) of respiratory monitoring might be 
the best possible intervention to enhance safety during procedural sedation.  Further, we suspect that the 
amplitude of ETCO2 will not predict the degree of respiratory depression seen with other monitors.  In 
addition, we will measure serum short chain fatty acid concentrations as a predictor and possible 
mechanism for differences in individual variability in anesthesia induced respiratory depression.   
  
   
  
4.  
Study Procedures  
Study design, including the sequence and timing of study procedures (distinguish research 
procedures from those that are part of routine care).  
  
This study is a randomized controlled trial comparing oxygen delivery with nasal CPAP versus 
standard care (delivery via nasal cannula or standard facemask) during propofol-based sedation for 
endoscopic procedures.  The primary outcome will be the rate of oxygen desaturation below 90% 
for ≥ 15 seconds.  Secondary outcomes are the degree of hypoventilation measured by continuous 
transcutaneous carbon dioxide (TcCO2), the change in minute ventilation (MV) and obstructive 
episodes measured by impedence-based respiratory volume monitoring, and depth of anesthesia 
measured by bispectral index (BIS) monitoring.  The adequacy of standard ETCO2 monitoring will 
also be assessed.  In addition, all clinical data utilized in routine practice will be recorded, including 
drug dosing, method of drug administration, blood pressure changes, frequency of interruption of 
procedure for airway maneuvers or rescue, length of stay in the recovery area, and any 
complications that are identified.   
  
Subjects will be recruited from the patient population scheduled for MAC with sedation for 
gastrointestinal endoscopic procedures at the Johns Hopkins Hospital Endoscopy Center on Zayed 
2. Patients scheduled for colonoscopy, EGD (including EGD with biopsy, ultrasound, PEG 

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placement, or enteroscopy ) or combined upper and lower endoscopic procedures predicted to last 
longer than 10 minutes and for which MAC with sedation is the planned anesthetic technique will  
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be considered for the study.  A study team member will screen the endoscopy schedule for potential 
subjects.  We will direct our recruitment to patients with documented OSA or a BMI ≥ 30, but we 
not limit it to just those patients.  Written, informed consent will be obtained from interested eligible 
subjects or their representative.    
  
As part of routine care, all patients undergoing MAC with sedation receive an IV in the preoperative 
area.  During the placement of this IV up to 15 mL of blood will be collected for short chain fatty 
acids measurements and possibly the measurement of biomarkers and other compounds.  The 
written consent form will include permission from the participant to store their blood for future 
research.     
  
All subjects enrolled in the study will have research monitors placed on the skin in a similar fashion 
to the pads for ekg lead placement, with respiratory volume monitoring on the chest, BIS and TcCO2 
on the forehead.  All enrolled subjects will be connected to the ExSpironTM monitor (Respiratory 
Motion, Inc., Waltham MA) and digital respiratory traces of MV, TV, and RR measurements will be 
collected on all 240 patients.  The ExSpiron monitor uses an adhesive, latexfree, adjustable 5 sensor 
strip applied to the chest to measure the amount of air moving in and out of the lung in real time.  
Minute ventilation will also be correlated to transcutaneous CO2 as measured by the SenTec 
Digital Monitor (SenTec AG, Therwil, Switzerland). Transcutaneous CO2 (Ptc CO2) monitoring 
provides a noninvasive technique allowing continuous monitoring of ventilation. It is based on 
arterialization of the capillary bed through the local application of heat and the use of Stow–
Severinghaus electrodes.  The sensor will be calibrated, applied to the patient’s forehead, cheek, 
or chest, and warmed to a constant surface temperature of 42 °C.  In adults, these temperatures 
are safe for up to 24h, and the procedures performed in this study are generally less than 2 
hours.  The BIS monitor is also an adhesive strip with 4 sensors applied to the subjects forehead.    
  
All subjects will also have standard, routine monitors placed by the treating team, including blood 
pressure, ECG, pulse oximetry, and EtCO2.  Subjects will be randomized to either 1) receive oxygen 
by nasal mask (nCPAP) with CPAP of 10 mmHg or 2) standard oxygen therapy.  Subjects 
randomized to nCPAP will have a nasal facemask (SuperNOVA) placed approximately 5 minutes 
prior to the procedural start.  The mask attaches to the anesthesia circuit, oxygen flow will be set at 
10 lpm, and the CPAP of 10 will be set by turning the “pop-off” valve to 10 mmHg.   Subjects 
randomized to standard care will have oxygen delivered by nasal cannula or simple facemask with 
oxygen level set by the treating providers. The CPAP level of 10 will be chosen because previous 
studies suggest that 95% of airway obstruction can be alleviated with a CPAP of 7.1, and it is 
convenient marked on the anesthesia “pop-off” valve, ensuring standardization.27  For the CPAP 
group, flow below 10 lpm will be allowed in cases in which the patient or provider does not tolerate 
higher flows.  For practicality, providers and patients will not be blinded to the intervention because 
application of the nasal mask is obvious.  While the clinical team will have access to all of the 
routine monitors, they will be blinded to the research monitor data, which will include TcCO2 
monitoring, respiratory volume monitoring (RVM), and BIS.  Researchers analyzing the data will be 
blinded to the intervention.   
  

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All subjects will receive a routine propofol-based anesthetic per the treating clinical team. A study 
team member will record all airway maneuvers or interventions performed by the anesthesia team 
during the procedure, including changes in oxygen flow, ventilatory assistance, jaw thrust, or 
placement of an oral or nasal airway.  Further, the duration of the endoscopic procedure and any 
anesthesia related interruptions will be recorded.  The study duration will be entirely within the time 
period of the patients’ visit to the endoscopy suite.  All study monitors will be removed when the 
participants are discharged to home or transferred to the ward depending on the clinical routine or 
needs.    
  
Each subject will be assigned a study number to allow connection of the demographic data and 
clinical characteristics for comparison with the physiological data.   All analog data for vital signs 
will be digitized using a digital to analog converter and processed using commercially available 
software.  Medication data and length of stay data will be collected directly from EPIC .   
Additionally, data relating to any respiratory events (decreased RR, oxygen saturation, airway 
obstruction, etc.) requiring intervention will be recorded.  Raw data from the ExSpironTM 
monitor, actigraph device, and transcutaneous monitor will be stored in a separate file with 
the file name being the study number assigned above.  There will be no patient identifiers in 
these files.    
  
a. Study duration and number of study visits required of research participants.  
Enrollment and data collection will begin after IRB approval. For each subject, the study will be 
performed entirely within their visit to the endoscopy suite.  No additional visits will be required of 
study participants.    
  
b. Blinding, including justification for blinding or not blinding the trial, if applicable.  
The clinical team will have access to all of the routine monitors, but they will be blinded to the 
research monitor data, which will include TcCO2 monitoring, respiratory volume monitoring 
(RVM), and BIS.  For practicality, providers and patients will not be blinded to the intervention 
because application of the nasal mask is obvious. Researchers analyzing the data will be blinded to 
the intervention.   
  
c. Justification of why participants will not receive routine care or will have current therapy 
stopped.  
Except for the application of study monitors to the skin and nasal CPAP in the treatment group, 
all subjects will receive routine anesthesia care to facilitate the planned procedure.  The 
procedure will not be effected by participation in the study.  
  
d. Justification for inclusion of a placebo or non-treatment group. Not applicable  
  
e. Definition of treatment failure or participant removal criteria.  
If a case is aborted because of procedural problems and no anesthesia was provided or the 
duration of the procedure was too short to obtain data, the participant would meet criteria for 
removal from the study.  However, if an anesthetic requires change to an alternate anesthesia 
plan (such as conversion to general anesthesia) this will be recorded in the analysis.    
  
f. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely.  
If a participant’s participation ends prematurely, they will receive routine care.  
  

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5.  
Inclusion/Exclusion Criteria Inclusion Criteria  
  
Adult patients (≥ 18 years of age) undergoing colonoscopy, EGD, EGD with biopsy and/or 
ultrasound, or combined upper and lower endoscopy procedure anticipated to last longer than 10 
minutes in the Endoscopy Suite in the Sheikh Zayed Tower at the Johns Hopkins Hospital when the 
anesthetic plan is MAC with propofol-based anesthesia with a natural airway.  
  
Exclusion Criteria  
LVAD  
Severe Pulmonary Hypertension (defined by the PI or co-investigators during the screening)  
EF < 35%  
Active CHF  
Planned procedure is Balloon Enteroscopy, ERCP  
Topical lidocaine administration  
Pregnancy  
Previous enrollment in this study   
  
6.  
Drugs/ Substances/ Devices  
a. The rationale for choosing the drug and dose or for choosing the device to be used.   
The ExSpironTM is an FDA-approved device that allows acquisition of quantitative values 
of minute ventilation (MV) (Respiratory Motion, Inc. Waltham).  Unlike currently utilized 
ECG derived RR, the device’s detection algorithm has been tuned to identify not just the 
onset of a new breath (RR) but also to estimate the thoracic size changes to provide a 
measurement of TV.  
  
Transcutaneous CO2 (Ptc CO2) monitoring provides a noninvasive technique allowing 
continuous monitoring of ventilation. It is based on arterialization of the capillary bed 
through the local application of heat and the use of Stow–Severinghaus electrodes.  
Transcutaneous CO2 monitors have been used in patients as young as neonates and a good 
correlation between Ptc CO2 and PaCO2 has been found in adults and children.  
(Berkenbosch JW, Tobias JD. Crit Care Med 2002 30:1024–1027. Herrejo´n A, Inchaurraga 
I, et al. Arch Bronconeumol 2006 42:225–229).  The BIS monitor is an FDA approved, 
noninvasive monitor that can provide a validated monitor for depth of anesthesia and sedation.    
  
The SuperNovaTM is an FDA approved nasal anesthesia mask that can generate CPAP to 
maintain airway patency, provide ventilator support, and provide rescue nasal ventilation during 
procedural sedation and during the perioperative period.  The most likely risk is a red mark on 
the face from the mask, dry nose and mouth, and the very unlikely risk of nose bleed.  (In 
fact, a common rescue during standard therapy is to place a nasopharyngeal airway, which 
carries a higher risk of nose bleed).   CPAP and ventilator interventions associated with the 
nasal mask carry similar risks to interventions that may be required in patients 
undergoing sedation who require additional ventilator support.    
b. Justification and safety information if FDA approved drugs will be administered for non-
FDA approved indications or if doses or routes of administration or participant 
populations are changed. Not applicable  
  
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  Not applicable  

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7.  
Study Statistics  
a. Primary outcome variable.    
The primary outcome will be the rate of hypoxia below 90% for ≥ 15 seconds.  
   
b. Secondary outcome variables. Secondary outcomes will include change in respiratory 
parameters (tidal volume, respiratory rate, minute ventilation, obstructive events), 
hypoventilation by TcCO2, EtCO2, and depth of anesthesia by BIS, as well as demographic 
differneces.  Demographic information to the occurrence of hypoxic events will be analyzed 
with logistic regression.    
  
Statistical plan including sample size justification and interim data analysis.   
Power analysis is based on a previous German study in the literature, of patients undergoing  
upper and lower endoscopy with hypoxia rates of 13.5% with standard care and 1.8% with 
application of nasopharyngeal airway.  Using these figures to perform a power analysis for the 
primary outcome of hypoxia bellow 90%, with alpha 0.05 and power of 0.9, approximately 109 
subjects in each arm or a total of 218 subjects will be needed.  In order to obtain 109 completed 
subjects in each arm and to allow for those participants with incomplete datasets (e.g. monitor 
failure), we will enroll 120 subjects in each arm and a total of 240 subjects.  
  
Frequency data will be analyzed with Fisher’s Exact Test, ordered categorical data will be 
analyzed with the rank sum test, and continuous data will be analyzed with regression or 
equivalent techniques.  Therefore, our primary outcome as to the incidence of hypoxia in each 
arm of the study will be determined using Fisher’s exact test. All time series data from multiple 
sources will be aligned using the associated time stamp with the aid of the program data 
manipulation capabilities in Mathematica 11.  Longitudinal analysis will be performed using a 
mixed model approach, initially with random intercepts alone, with the addition of nonlinear 
terms and interaction as indicated by the resulting model.  Throughout, findings will be  
considered significant for p < 0.05 and p values will be determined using two-sided tests.  
Statistical analysis will be performed with the aid of Stata 13.  An analysis will be performed 
after the first 20 subjects to ensure complete data collection and to run a batched analysis of 
SCFA to evaluate  this aim.  An interim data analysis will be done after ~120 subjects have been 
enrolled.    
  
c. Early stopping rules.   
Stopping will be considered if the intervention shows clear benefit at the midpoint of the study, 
or if it clearly shows no benefit.   
  
8.  
Risks  
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. All 
subjects will have, as a part of routine care, 5 ECG pads.  The ExSpironTM padset adds no more 
risk to the care of the subjects than does the 5 ECG pads routinely applied to the chest.     The BIS 
padset is also very similar to the ECG pads, but will be placed on the forehead.    
In the past, there was a risk of discomfort or skin burning in infants with the use of transcutaneous 
CO2 sensors. However, current monitoring technology differs from previous sensors in the use of 
lower temperatures (42 °C as opposed to 45–47 °C) which has been shown to dramatically decrease 
the risk for skin burning (Storre JH, Steurer B, et al. CHEST 132:1810–1816).  In adults, the 

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recommendation by the manufacturer is to check the site every 24 hours; however, for purposes of 
this study, sensors will be in place for significantly shorter period of time  
The SuperNovaTM is a nasal anesthesia mask that can generate CPAP to maintain airway patency, 
provide ventilator support, and provide rescue nasal ventilation during procedural sedation and 
perioperative period.  The most likely risk is a red mark on the face from the mask.  Dry nose 
and mouth may occur, as can dry eyes, and a very unlikely risk of nose bleed.  (In fact, a 
common rescue during standard therapy is to place a nasopharyngeal airway, which carries a 
higher risk of nose bleed).   CPAP and ventilator interventions associated with the nasal mask 
carry similar risks to interventions that may be required in patients undergoing sedation who 
require additional ventilator support.   b. Steps taken to minimize the risks.  
Transcutaneous CO2 sensors will be maintained and operated on the same site for a maximum 
8 hours after which the site will be assessed for any signs of irritation and the monitor will be 
moved or removed if indicated.  
Careful placement of the Supernova mask will be performed and the fit adjusted as needed. c. 
Plan for reporting unanticipated problems or study deviations.  
If transcutaneous CO2 sensor sites demonstrate any signs of irritation, the sensor will be 
moved or monitoring discontinued as indicated.   
  
Any unanticipated problem or study deviation will be reported to the IRB.  
  
d. Legal risks such as the risks that would be associated with breach of 
confidentiality.  
This study carries a low risk of loss of confidentiality.  Multiple safeguards are in place to 
protect the confidentiality of the medical and demographic data.  Each patient will be assigned 
a randomly generated number that will be linked to the medical record number.  This file will 
be stored in a password protected spreadsheet and backed up to a network drive managed by 
the Department of Anesthesiology and Critical Care Medicine.   Demographic and clinical data 
will be only linked to the random study number.  
  
e. Financial risks to the participants. None  
  
9.  
Benefits  
a. Description of the probable benefits for the participant and for society.  
This study may provide no benefit to any particular patient.  
  
The study may benefit society if a better method of delivering oxygen is demonstrated for a 
procedure that is performed in millions of patients every year.  Further, the study may help 
us to better understand how patients breathe under anesthesia, which may help us to 
improve delivery of anesthesia care in the future.  
  
10. Payment and Remuneration  
a. Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol. None  
  

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11. Costs  
a. Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify who will 
pay for them.  
There will no costs for the monitors (the hospital has a separate supply) or the SuperNova masks 
used in the treatment arm of this study.  Revolutionary Medical Devices will provide the 
SuperNova masks.  
   
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