Carbon Dioxide (CO2) Clearance From Various Face Masks in Normal Volunteers at Various Level of Expiratory Positive Airway Pressure (EPAP) When Using a Non-Invasive Positive Pressure Ventilation (NIPPV)
Phase: NA
Conditions: CO2 Clearance, Mask Comfort, Rebreathing Exhaled Gas
Sponsor: Rush University Medical Center

Student Research Project Proposal
Title:
Carbon Dioxide (CO2) Clearance from various face masks in Normal Volunteers 
at various level of Expiratory Positive Airway Pressure (EPAP) when Using a 
Non-Invasive Positive Pressure Ventilation (NIPPV)
Investigators:
Mentor:
DAVID VINES, MHS, RRT, FAARC, FCCP
Graduate Student: 
Ahmed Al Hussain, Respiratory Care Department, Rush University.
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

Study aim:
Determine the EPAP (baseline pressure) required to effectively wash out CO2 for current 
available masks, and assess perceived level of comfort with each mask with using 
noninvasive ventilator.
1- Abstract:
Background: Noninvasive positive pressure ventilation (NIPPV) can be delivered via 
single limb circuit or double limb circuit ventilators. There are many advantages to 
NPPV. However, a reasonable number of questions remain unanswered, such as mask 
impact on carbon dioxide (CO2) clearance based on EPAP level.
Objective: Determine the EPAP (baseline pressure) required to effectively wash out CO2 
for each mask, and assess perceived level of comfort with each mask with ICU ventilator.
Method: This study will be a randomized crossover trial that will be conducted at Rush 
University. The study will be conducted with 20 healthy volunteers who will be placed 
on ICU ventilator operating in the NIPPV mode. All subjects will perform 15 minutes of 
breathing on NIPPV on each mask of the 4 different masks (2 oronasal and 2 full face 
masks) that are randomly selected. Breathing through each mask will be followed by a 5-
minute wash out period between masks. End tidal Carbon Dioxide (EtCO2) will be 
sampled nasal/oral. Different levels of EPAP will be set and CO2 clearance will be 
monitored. Additionally, subjective mask comfort will be assessed via visual analog scale 
(VAS) with 1 referring to least comfortable and 5 being the most comfortable.
2- Introduction
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

Noninvasive positive pressure ventilation (NIPPV) is a form of ventilatory support for 
spontaneously breathing patients without the need of an artificial airway.1 NIPPV is 
recommended for patients with chronic obstructive pulmonary disease (COPD) 
exacerbation as well as cardiogenic pulmonary edema.2 The use of NIPPV has reduced 
the need for intubation and improved mortality.2 Some studies have demonstrated a 
decrease in mortality rate in individuals with acute hypoxemic respiratory failure and 
immunosuppression with the use of NIPPV.2 Issues that exist with NIPPV is patient 
compliance or tolerance.3 NIPPV failure rates can exceed 40%. Mask intolerance remains 
a major hindrance to NIPPV success.3,4 
NIPPV uses external interfaces such as nasal mask, facial mask, mouthpiece, or helmet.1 
Noninvasive ventilation (NIPPV) can be delivered by a dedicated NIPPV ventilator 
which utilizes a single limb circuit requiring an expiratory port to allow for carbon 
dioxide clearance. This NIPPV ventilator has the ability to adjust for leak and continue to 
function properly without the mask fitting tightly to the face.3,4 NIPPV can also be 
delivered by ICU ventilators which utilize a dual limb circuit and these circuits usually 
have no leak to properly function. NIPPV interface fitting is another key factor, however, 
to minimize leak the interface may be over tighten and cause patients discomfort. Patients 
may complain of NIPPV due to multiple factors, it can be facial discomfort, massive air 
leak or pressure sores.5 It has reported that oronasal mask to perform worse with pain at 
nose bridge in comparison to total face mask.6 While cheeks’ pain was more prevalent in 
the oronasal mask in comparison to total face mask7, oronasal dryness and claustrophobic 
were reported higher with total face mask.6 It is fair to state that success of NIPPV is 
dependent on many factors, one of them is mask characteristics.8 These issues may 
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

decrease patient tolerance of NIPPV.5 A properly fit mask may increase patient 
compliance. Moreover, health care providers (HCPs) must have an excellent 
understanding of NIPPV and the skills to execute the task successfully.5 However, a 
concern remains that a single limb circuit with NIPPV ventilators may cause carbon 
dioxide (CO2) rebreathing.9 This CO2 rebreathing can lead to NIPPV failure.
  Samolski et al, studied the CO2 rebreathing while using a portable ventilator 
which uses a single limb circuit. They studied the effect of expiratory port location, 
different sites of the port (i.e. in the mask, before the mask), and the addition of dead 
space between the circuit and mask on CO2 rebreathing. They found no CO2 rebreathing, 
and baseline pressure as low as 4 cm H2O was effective in preventing CO2 rebreathing.9 
However, this study has limitations. First, they used three different nasal masks and 2 
different facial masks. Currently there are newer masks available that need testing. Last, 
they measured fraction of inspired CO2 (FiCO2) via a sampling line located in the mask.9 
The site of sampling can significantly affect the accuracy of end tidal CO2 (EtCO2) 
measurement. Sampling line at the oral/nasal site may be the most reliable sampling site 
for EtCO2 and determining rebreathing of exhaled gas. 
NIPPV interface choice is crucial to achieve a good clinical outcome with the use 
of NIPPV. Common interfaces are nasal mask which covers the nose only, facial mask 
known as oronasal mask which covers the nose and mouth. Total face mask and helmet 
are gaining popularity. Generally, nasal mask is better tolerated, while oronasal mask is 
more effective for improving gas exchange. The perfect mask should be lightweight, 
comfortable, easy to apply, transparent in color, latex-free, have small internal volume 
and low airflow resistance.1 
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

The total face mask which covers the entire face was designed with the aim of 
enhancing patient tolerance. Newer generation of NIPPV full face masks are available on 
the market (e.g. PerforMax) which also covers the eyes, nose, and mouth. The mask also, 
has advantages by minimizing gas leakage. Furthermore, due to its shape, it helps to 
minimize pressure sores on the face as there is no contact with the nose bridge. On the 
other hand, the mask has disadvantages such as adding a large dead space, which varies 
from mask to mask based on different manufacturers. Unlike the larger older generation, 
this mask comes without the two orifices for CO2 washout.3,6 To accommodate both 
types of ventilators (NIPPV and ICU ventilators) this mask comes with two options of an 
elbow, a standard elbow for use with double circuit ICU ventilators or an entrainment 
elbow for NIPPV ventilators.3 It is worth mentioning that the total face mask costs more 
than the nasal mask or oronasal mask.10 Despite total face mask’s large internal volume, 
the mask doesn’t affect patients’ gas exchange during short term of NIPPV using ICU 
ventilator.10
 
NIPPV masks were developed with an intentional leak to remove CO2 from the 
interface.8 A comparison of three different masks (mask A, mask B, mask C) on healthy 
volunteers to investigate CO2 wash out hypothesized that in NIPPV masks with lower 
rates of intentional leaks, CO2 rebreathing might occur. 8 Transcutaneous capnography 
(PtcCO2) was measured. IPAP level of 14 cm H2O, EPAP of 4 cm H2O was applied to 
all masks. Each subject was placed on NIPPV, and tried all three masks consecutively. 
Each mask was tested for 10 minutes followed by 5 minutes break in between masks. 
They found no differences in PtcCO2 between masks. 8 Despite accuracy of PtcCO2 
measurement, this study has some limitations. It did not assess CO2 clearance at the mask 
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

via EtCO2. Masks B & C both had higher rate of total leaks due to higher rate of 
unintentional leaks which may improved CO2 wash out, hence, led to no differences in 
PtcCO2. 8 Another study compared total face mask against oronasal mask impact on gas 
exchange (PvCO2) favors total face mask in the first 6 hours and during the acute phase 
of respiratory failure using NIPPV.7 Both Medrinal and Sadeghi assessed gas exchange 
not masks’ CO2 clearance. Since the intentional leak impacts CO2 clearance, and the 
intentional leak level depends on the level of pressure. 8 The previous studies didn’t study 
different level of EPAP (baseline pressure). One level of EPAP pressure of 4 cm H2O 
was used in Medrinal study based on Samolski’s finding. 8 While in Sadeghi’s study, 
IPAP started at 10 cm H2O and EPAP started at 4 cm H2O. IPAP and EPAP were 
increased gradually based on subjects’ need, therefore it lacked consistency in EPAP 
level.9
 ICU ventilators using double limb circuit is an alternative to deliver NIPPV, however, 
researches on minimum baseline pressure required to prevent CO2 rebreathing is not 
clear as well. In a study that compared 3 types of masks (2 ONM and 1 FFM) to helmet 
in acute hypercapnia respiratory failure. NIPPV in both group improved arterial blood 
gases. ICU ventilators settings in masks group used positive end expiratory pressure 
(PEEP) referring to baseline pressure that ranged from 3 – 5 cm H2O (mean 4.26 ± 1.92); 
and inspiratory pressure adjusted to achieve tidal volume of 6-8 ml/kg (16.37 ± 4.19). On 
the other hand, settings for helmet groups were ~ 30%.11
The answer regarding effective EPAP level to wash out CO2 remains uncertain. 
The purpose of this study is to compare the efficacy of CO2 clearance between different 
NIPPV interfaces (oronasal and full face masks) when using double limb circuit ICU 
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

ventilator at lower levels of EPAP. The aim of this study is to determine the EPAP 
(baseline pressure) required to effectively wash out CO2 for each mask and assess 
perceived level of comfort with each mask.
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

3- Methods:
This study will be a randomized crossover trial that will be conducted at Rush University. 
Normal volunteers will be recruited from Rush University Medical Centers. Volunteers 
will be screened with inclusion and exclusion criteria and an informed consent is required 
in order for them to participate. Demographic (age, gender, ethnicity) will be obtained. 
Also, initial baseline vital signs (heart rate, blood pressure, respiratory rate, and oxygen 
saturation) will be obtained. EtCO2 will be obtained at baseline and periodically using an 
oral/nasal sample line with the CapnostreamTM 20p monitor (Medtronic, Minneapolis, 
MN). The study will use a double limb circuit ICU ventilator Puritan Bennett™ 
(Medtronic, Dublin, Ireland). 
We will evaluate 4 NIPPV masks (2 oronasal masks and 2 full face masks). 
Oronasal masks will be labeled as group A and numbered as A1 and A2; while full face 
masks will be labeled group B and numbered as B1 and B2. Order of the masks will be 
randomly chosen in two steps. First steps will be choosing A or B then randomly assign 
mask in each of these groups. We will randomly assign mask in group A or B by drawing 
an initial mask from the group and then continue the sequence of masks from that point. 
For example, we randomly chose group A, then randomly chose A2, the sequence will be 
A2, A1. Then we would randomly choose B2, then the sequence would be B2, B1. 
All subjects will perform 15 minutes on each mask followed by 5 minutes wash 
out interval between masks. EPAP levels will be 0, 2, 4, & 5 while IPAP remains at 5 
higher than EPAP. EtCO2 will be collected at 4:00, 4:30 and 5:00 minute mark. These 
three measures should differ by less than 20% of their average.  Also, subjective mask 
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

comfort will be assessed via visual analog scale (VAS) with 1 referring to least 
comfortable and 5 being the most comfortable after 5 each EPAP setting. 
Procedure figure:
      
   
Randomization of the order of using masks
Data will be collected and analyzed
Consented subject
Application of NIPPV:
Mask 1 for 15 min with different level of EPAP (Vitals, EtCO2 
will be recorded before and during) and VAS for mask comfort 
will be obtained. 
5 minutes break (Interval wash out)
Mask 2 for 15 min with different level of EPAP (Vitals, EtCO2 
will be recorded before and during) and VAS for mask comfort 
will be obtained.
5 minutes break (Interval wash out)
Last mask for 15 min with different level of EPAP (Vitals, 
EtCO2 will be recorded before and during) and VAS for mask 
comfort will be obtained.
End  
Obtain baseline vital signs and EtCO2 (Calibration as needed)
The process will repeat itself until 
each mask is tried 
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

4- Subject Population:
4.1.  Population
Normal volunteers from Rush University.
4.2. Sample Size
20 healthy subjects. 
4.3. Inclusion criteria:
4.3.1. Age > 18 years’ old
4.4 Exclusion criteria:
4.4.1. Prior history of NIPPV as a patient.
4.4.2. Facial surgery or deformity
4.4.3. Ear infection
4.4.4. History of pulmonary or cardiac disease
5- Research recruitment and Consent Procedures: 
5.1. Subjects will be recruited from students enrolled, faculty, and staff at 
Rush University.  
5.2. An informed consent will be obtained by the investigators for all 
eligible candidate that meet the criteria.
 
6- Compensation: 
Volunteers will be compensated with $ 25 Visa gift card
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

7- Special precautions:
7.1. Subjects refrain from eating at least 60 min before the study
7.2. Study will be stopped if HR change by 20% from baseline for more than 1 
min.
7.3. Study will be stopped if subjects complain of shortness of breath
8- Confidentiality:
 Subject names, date of birth, and contact information (email) will be in stored in 
REDCap. However, only de-identified data will be used for analysis.
9- Data Collection Instruments/ Data Collection Procedures/Data Analysis Plan:
Data for each subject will be recorded in REDCap 
10- Variables:
Dependent: CO2 clearance, level of comfort 
Independent: NIPPV interface, level of EPAP
11- Limitation:
It is performed on healthy subjects.
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

12- Analysis:
Data will be recorded in REDCap. Demographics data age (interval), gender (nominal), 
ethnicity (nominal) will be collected. HR (continuous), RR (continuous), SpO2 
(continuous), ETCO2 (continuous), EPAP (ordinal), IPAP (ordinal) will be collected. 
Means and Standard deviations will be calculated for aforementioned data. NIPPV 
interfaces number, sizes will be collected. Level of comfort will be collected; median and 
interquartile ranges will be calculated. Relationship between dependent variable ETCO2 
and independent variable EPAP level will be analyzed by a Kruskal-Wallis test to 
determine if a significant difference exists. If a significant difference is found a Mann-
Whitney U Test will be used to determine which EPAP levels significantly differ. 
Relationship between dependent variable comfort level and independent variable NIPPV 
interfaces will be analyzed a Kruskal-Wallis test to determine if a significant difference 
exists. If a significant difference is found a Mann-Whitney U Test will be used to 
determine which masks were significantly more comfortable.
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018

Literature cited:
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JV, et al. Preventing facial pressure ulcers in patients under non-invasive 
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136.
2- Thille AW, Contou D, Fragnoli C, Cordoba-Izquierdo A, Boissier F, Brun-
Buisson C. Non-invasive ventilation for acute hypoxemic respiratory failure: 
intubation rate and risk factors. Crit Care 2013;17(6):R269.
3- Nakamura MA, Costa EL, Carvalho CR, Tucci MR. Performance of ICU 
ventilators during noninvasive ventilation with large leaks in a total face mask: a 
bench study. J Bras Pneumol 2014;40(3):294-303.
4- Ozsancak A, Sidhom SS, Liesching TN, Howard W, Hill NS. Evaluation of the 
total face mask for noninvasive ventilation to treat acute respiratory failure. Chest 
2011;139(5):1034-1041.
5- Brill AK, Moghal M, Morrell MJ, Simonds AK. Randomized crossover trial of a 
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6- Holanda MA, Reis RC, Winkeler GF, Fortaleza SC, Lima JW, Pereira ED. 
Influence of total face, facial and nasal masks on short-term adverse effects 
during noninvasive ventilation. J Bras Pneumol 2009;35(2):164-173.
7- Sadeghi S, Fakharian A, Nasri P, Kiani A. Comparison of Comfort and 
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Pressure Ventilation in Patients with Acute Respiratory Failure: A Clinical Trial. 
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8- Medrinal C, Prieur G, Contal O, Villiot-Danger E, Doyle C, Reychler G, et al. 
Non-invasive ventilation: evaluation of CO2 washout by intentional leaking in 
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532.
9- Samolski D, Calaf N, Guell R, Casan P, Anton A. Carbon dioxide rebreathing in 
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Physiological effects of different interfaces during noninvasive ventilation for 
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11- Pisani L, Mega C, Vaschetto R, Bellone A, Scala R, Cosentini R, et al. Oronasal 
mask versus helmet in acute hypercapnic respiratory failure. Eur Respir J 
2015;45(3):691-699.
ORA: 18011502-IRB01   Date IRB Approved: 3/30/2018   Amendment Date: 5/11/2018