Hypercapnia Clinical Efficacy by NIPPV v HVNI: A Randomized Control Trial in the Stabilization of Acute Hypercarbic Respiratory Failure
Phase: NA
Conditions: Hypercapnic Respiratory Failure, Chronic Obstructive Pulmonary Disease, Dyspnea, Hypercapnic Acidosis
Sponsor: Vapotherm, Inc.

 
 
 
Vapotherm 
Clinical Stabilization of 
Hypercapnia NIPPV v 
HVNI     
 NCT04709562  
Dec 23 2020 
 

            
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Protocol Title: 
Hypercapnia Clinical Efficacy by NIPPV v HVNI: A Randomized Control 
Trial in the Stabilization of Acute Hypercarbic Respiratory Failure 
(HYPERACT)  
Protocol Number: 
 
RP-VTPF2020001Sci  
 
 
Revision: 
 
 
Rev 1.2 – 23 December 2020 – STERLING IRB SUBMISSION 
 
 
Principal Investigator: 
Andrew Melzter, MD 
 
 
 
 
Co-Investigators: 
 
TBD 
 
 
 
Sponsor: 
 
 
Vapotherm, Inc 
100 Domain Drive 
Exeter, NH  03833 
1 (603) 658-0011 
http://www.vtherm.com 
 
Site Monitor(s):  
 
Sohrab Mayar MSc RRT, Clinical Trial Manager 
                                                           Amanda DeBellis MSc, Clinical Research Associate 
                                                           Alison Branitsky MSc, Clinical Research Associate 
Leo Volakis MS PhD, Research Scientist 
 
 
 
 
Ronald DeBellis PharmD FCCP, Director of Clinical and Scientific Affairs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
 
Study site should keep protocol, all contents and related information confidential. 
 
 
 

            
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Protocol Approval 
 
 
Investigator Statement 
 
As Investigator of the study titled “Hypercapnia Clinical Efficacy by NIPPV v HVNI: A Randomized Control 
Trial in the Stabilization of Acute Hypercarbic Respiratory Failure” (the “Study”), I agree to:  
 
(i) conduct the Study in accordance with: this Investigator Agreement; the Study’s Protocol as approved by 
the IRB (the “Protocol”); all applicable laws and regulations; and any IRB or FDA conditions of approval;   
(ii) await IRB approval for the Protocol before obtaining informed consents (if applicable); 
(iii) ensure that all requirements for informed consent are met and not let any subject participate in the 
Study before obtaining that subject’s informed consent (if applicable);  
(iv) not make modifications to the Protocol without first obtaining consensus from the Vapotherm Science 
and Innovation team and necessary IRB approval;  
(v) maintain Study documentation for the period of time as required by appropriate regulations; and 
(vi) supply to the Sponsor, as part of this Investigator Agreement, my curriculum vitae. 
 
 
INVESTIGATOR 
 
 
 
 
 
 
Signature: 
_________________________________________________ 
 
Printed Name:    ________________________________________________ 
 
 
 
Date: 
 
____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

            
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GLOSSARY OF DEFINITIONS AND TERMS .............................................................................................. 4 
I. BACKGROUND AND SIGNIFICANCE ...................................................................................................... 6 
II. OVERALL STUDY OBJECTIVE ............................................................................................................... 8 
III. SUBJECT SELECTION ............................................................................................................................ 9 
IV. STUDY DESIGN ..................................................................................................................................... 10 
V. SUBJECT ENROLLMENT ....................................................................................................................... 12 
VI. STUDY PROCEDURES.......................................................................................................................... 13 
VII. DATA COLLECTION ............................................................................................................................ 19 
VIII. STATISTICAL ANALYSIS .................................................................................................................. 20 
IX. RISKS AND DISCOMFORTS ................................................................................................................ 20 
X. POTENTIAL BENEFITS ......................................................................................................................... 21 
XI. MONITORING AND QUALITY ASSURANCE ...................................................................................... 21 
XII. PROTOCOL DEVIATIONS .................................................................................................................. 21 
XIII. ADVERSE EVENT REPORTING ........................................................................................................ 21 
XIV. CONFIDENTIALITY ........................................................................................................................... 22 
XV. REFERENCES ....................................................................................................................................... 22 
 
 
 
 
 

            
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Glossary of Definitions and Terms 
 
High Flow Nasal Cannula (HFNC): Nasal cannula system that delivers flow rates of respiratory gas meeting or 
exceeding a patient’s normal spontaneous inspiratory flow demand.  HFNC systems must maintain adequate 
heating and humidification of the delivered gas to protect the airway tissues from dryness. 
 
High Velocity Nasal Insufflation (HVNI): HVNI exists as a refined form of HFNC, a system consisting of heated 
and humidified gas mixtures of varying FiO2 delivered to a patient using a small-bore nasal cannula, at 
generally high flow rates imparted with increased velocity as compared to other standard large-bore 
cannulae. The flow rates of respiratory gas generally exceed a patient’s normal spontaneous inspiratory flow 
demand.  HVNI systems must maintain adequate heating and humidification of the delivered gas to protect 
the nasal tissues from dryness and provide patient comfort.   
 
Non-Invasive Positive Pressure Ventilation (NIPPV): Breathing assist where a mask is strapped tightly to a 
patient’s face and bi-level positive airway pressure is administered at an established frequency to support 
patient ventilation.  NIPPV may also refer to Continuous Positive Airway Pressure (CPAP). 
 
Intubation: The placement of an endotracheal tube to facilitate respiratory support and provide airway 
protection. 
 
Respiratory Failure: The inability to maintain sufficient arterial blood oxygen saturation and/or retention of 
carbon dioxide levels during unassisted spontaneous breathing. 
 
Pulse Oximetry Reading (SpO2):  Indirect measure of a patient’s arterial blood oxygen saturation using pulse 
oximetry technology that utilizes oxygen/hemoglobin concentrations. 
 
Resting SpO2:  SpO2 value the patient demonstrated at rest, while sitting upright and connected to the pulse 
oximetry monitor prior to the start of the study session.  This value will be patient specific and reflect oxygen 
saturation. 
 
Desaturation SpO2: The SpO2 value considered to be the point of desaturation where the value drops below a 
specified threshold.  This value is based on the desaturation requirement for reimbursement of oxygen 
therapy. 
 
Ventilatory Work Effort / Work of Breathing (WOB):  The physical, physiologic muscular demands of 
breathing manifested through signs and symptoms of increased physical exertion, manifested through 
pulmonary changes leading to the use of accessory muscles for inspiration or exhalation. 
 
Fraction of inspired oxygen (FiO2%): The percent of the delivered respiratory gas mixture that is oxygen, 
expressed as a fraction. 
 
Ventilatory Rate (Respiratory Rate; RR, BPM): The number of breaths a patient takes per minute 
(breaths·min-1). 
 
Blood Pressure (BP): as measured by systolic and diastolic pressures of the blood contained in the 
circulatory system, measured for this study in mmHg.  

            
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Heart Rate (HR): The number of heart beats per minute (beats·min-1). 
 
Modified Borg Scale (Borg): Dyspnea is an important measure of patient respiratory distress & pulmonary 
functional status. The rate of perceived dyspnea (RPD), an accepted and well-published form of measuring 
breathlessness, is determined by patients and clinicians to using specific descriptors, on a scale of 0 (no 
dyspnea) to 10 (unbearable dyspnea).  
 
Standard of Care (SOC): Site standard practices for the medical care of patients presenting with specific 
symptoms.  
 
Case Report Form (CRF): The form used to record pertinent patient data to address the study aim(s).  CRFs 
do not contain patient names or medical record numbers; rather they will be coded with a patient number 
and the site principal investigator at each center will maintain the key.  CRFs may be digitally compiled. The 
CRFs are the property of Vapotherm. 
 
 
 

            
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I. Background and Significance 
  
Patients with Chronic Obstructive Pulmonary Disease experience a complex physiologic derangement 
marked by various levels of chronic increased mucus production and chronic alveolar destruction.  
Ultimately, this leads to impaired ventilation and difficulties with gas exchange, producing hypercapnia, and 
in some cases leading to hypoxia. While the chronic disease typically progresses gradually over many years, 
patients experience several intermittent rapid decompensations per year, in the form of acute exacerbations. 
The etiology of these acute exacerbations is multi-factorial, but they are often hallmarked by increased work 
of breathing, discomfort/shortness of breath, and the more severe exacerbations progress to hypercapnic 
respiratory acidosis, hypoxia, and ultimately respiratory failure.1  
 
Treatment of acute exacerbations of COPD is multimodal; these modalities often include bronchodilators, 
steroids, and antibiotics. Respiratory support and treatment of acute hypercapnic respiratory failure (AHRF) 
secondary to an Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) is most commonly 
provided through non-invasive positive pressure ventilation (NIPPV), or in some cases mechanical 
ventilation (MV). A recent Cochrane meta-analysis by Osadnik et al 2017 compared the efficacy of NIPPV 
when applied in conjunction with usual care practices versus usual care without MV in adults with AHRF 
secondary to AECOPD.2 Data from 17 randomized controlled trials containing 1264 patients, this Cochrane 
meta-analysis demonstrated that NIPPV decreased the risk of mortality by 46% and decreased risk of 
requiring intubation by 65%, which resulted in an associated reduction in hospital LOS, reduced incidence of 
complications, and improvement in pH & PaO2 within 1-hour. The improvement in PaCO2 was shown to 
trend but was not found to be statistically significant. Further post hoc analysis showed a positive statistical 
result. The authors concluded that NIPPV  is “beneficial as a first-line intervention in conjunction with usual 
care for reducing the likelihood of mortality and intubation in patients admitted with AHRF secondary to 
AECOPD,” and the benefits “appear similar for patients with mild acidosis (pH 7.30 to 7.35) versus a more 
severe nature (pH < 7.30), and when NIV is applied within the intensive care unit (ICU) or ward setting.” 
 
Ventilatory therapy has historically been delivered via various devices that provide positive pressure (MV, 
NIPPV, and continuous positive airway pressure [CPAP]).  The goal of using these devices is to have an effect 
on the volume component of the alveolar ventilation equation:  Alveolar ventilation = (Volume-Dead Space) 
X Respiratory Rate.   Flow-based therapy, particularly High-Velocity Nasal Insufflation [HVNI],  supports 
oxygenation and ventilation by flushing the dead space component of the alveolar ventilation equation.3,4 
Furthermore, it has been demonstrated that NIPPV & HVNI provide comparable therapeutic support. 5-7 Two 
separate mechanisms of action are available which influence alveolar ventilation.  HVNI has been shown to 
be a therapeutic alternative to NIPPV.5  
 
Vapotherm HVNI therapy, is premised on the technical ability to create ideally conditioned medical grade 
vapor, which is delivered nasally with an intent to support spontaneous ventilation. 3,8 Vapotherm 
technology is unique in its ability to provide this optimally conditioned gas through a small-prong nasal 
cannula resulting in a high velocity, physiologically warmed humidified gas without the well-known adverse 
effects related to drying and cooling of the nasal mucosa that occurs with simple oxygen therapy. 9  In 
addition and uniquely, the high velocity nasal flow facilitates a well described mechanism of improving 
ventilatory efficiency by way of eliminating carbon dioxide traditionally stacked in anatomical dead space of 
the upper airway.3 Upper airway purge is important to alveolar gas exchange as the gas that is drawn to the 
respiratory regions of the lungs comes from the dead space or anatomical reservoir created by the flush. This 
mechanism operates similarly to that of oxygen conservation masks (re-breathers).  These masks create an 

            
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artificial reservoir through bags to reduce the bulk flow requirements from the oxygen source to achieve the 
same oxygenation effect. 3,10  HVNI uses the anatomic dead space as a natural reservoir for oxygen to support 
patients who require oxygenation when needed as well as utilize anatomic dead space to flush CO2 from the 
respiratory stack.4  Based on mathematical modeling of standard anatomy, physiologic studies and clinical 
observations, a flow rate of 4 to 8 L·min-1 through Vapotherm’s neonatal cannulae, or 25 to 40 L·min-1 
through Vapotherm’s adult cannulae, would purge the anatomical reservoir of the upper airway of CO2 in the 
window of time between breaths. 4,11-13  
 
Vapotherm’s humidification system is specifically designed to tolerate a high back pressure in the 
humidification cartridge that is generated by passing these high flow rates through small bore cannulae that 
result in the appropriate flow velocities (turbulent energy). 10  Since 2000, Vapotherm HVNI has been used 
extensively and has been well studied and the clinical impact of this ventilation effect using Vapotherm’s 
conventional cannula line is well described. 3,9,10,14,15   A multi-center randomized clinical trial also 
demonstrated the noninferiority of HVNI to NIPPV in the treatment of undifferentiated respiratory distress 
for patients presenting to the Emergency Department. 5 The current study is an extension of the prior 
published studies’ outcomes. The goal of this randomized control trial is to evaluate, the relative efficacy of 
HVNI or NIPPV to clinically stabilize & relieve the patient’s moderate-to-severe hypercapnic respiratory 
distress, through oxygenation and ventilation, upon presentation. 
 
 
 

            
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II. Overall Study Objective 
 
The overall objective of this randomized study is to evaluate the efficacy of HVNI, in comparison to NIPPV, 
to clinically stabilize and provide respiratory therapy to patients who have COPD with moderate-to-severe 
hypercapnic respiratory distress upon presentation.  
 
The hypothesis: HVNI is comparable to NIPPV in the stabilization and relief of moderate-to-severe 
hypercapnic respiratory distress upon presentation, by relieving the patient’s dyspnea (breathlessness) 
within 4 hours to a comparable degree to NIPPV.  
Ho: µT <= µC – 1 
Ha: µT > µC – 1, 
where µT and µC are the improvement in modified BORG at 4 hours for treatment (Vapotherm) and 
control (NIPPV), respectively, and the non-inferiority margin is 1. 
 
To test this hypothesis, the study will be conducted with the following specific aims:  
 
Aim #1: Primary Outcome. The primary endpoint is to evaluate the patient’s relief of dyspnea, as measured 
by the modified Borg, rated perceived dyspnea [RPD 0-10], during the 4-hour post-therapy initiation 
interval.  These measurements will be compiled over the time course of the study – baseline, 30min, 1h, and 
4h. 
 
Aim #2: Secondary Outcomes. The secondary endpoints evaluate treatment failure (need for intubation), 
indices of Work of Breathing (patient vitals [HR, RR, SpO2]), patient’s clinical stability during hypercapnic 
respiratory distress, as measured by an index of patient communication capability [Patient Stability Index: 0-
10], venous blood gases (pH, PCO2, PO2, bicarbonate, base excess), basic metabolic panel* (lactate, Na+, K+, Cl-, 
glucose), and patient disposition (length of stay [LOS]). These measurements will be compiled over the time 
course of the study – baseline*, 30min, 1h, and 4h. The Patient Stability Index is described in the protocol. 
 
*Basic metabolic panel (BMP) will be collected at baseline only. 
Aim #3: Tertiary Outcomes. The tertiary endpoints evaluate patient and clinician assessment of therapy. 
For the patient perception/satisfaction these include: (1) relief of symptoms, and (2) comfort/tolerance. For 
the clinician perceptions these include: (1) expected/perceived patient outcomes, (2) patient comfort & 
tolerance, and (3) ease of use.  
 
These endpoints will establish comparability of HVNI to NIPPV in Acute Hypercapnic Respiratory Distress. 

            
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III. Subject Selection  
Patients will be identified and recruited by study investigators or research staff trained on this particular 
trial. The study will initiate in an Emergency Department setting, or from an inpatient setting, and transfer to 
an acute-care unit that is sufficiently staffed and skilled in NIPPV and HVNI to support patients presenting 
with moderate to severe hypercapnic respiratory acidosis. Testing during this study will be performed in the 
presence of health care individuals who will provide appropriate supervision and staff training to maintain 
patient safety. The test will evaluate the patient’s relief of dyspnea, clinical stability, WOB indices (vitals, 
RPD, ventilation, oxygenation), patient disposition, and patient and physician perceptions for each study arm 
before and during therapy for hypercapnic respiratory distress. Initial patient contact will be made by study 
investigators or research staff trained on this particular trial. Participants may or may not decide to enroll 
after being consented. Consent in this ED/acute-care-setting-based study will be obtained by a verbal 
consent prior to participation/randomization followed by written consent (when patient is medically 
stable), or a written consent prior to participation/randomization. The verbal consent will be obtained and 
documented in the patient chart along with a witnessed attestation. The written consent will be obtained 
once patient is able to participate in a consent discussion, when their respiratory symptoms are manageable.  
 
Inclusion Criteria – Selection of Inclusion  
1. Adults, 18 years or older with a known or suspected diagnosis of COPD 
a. Suspected diagnosis of COPD defined as a history of smoking or significant second-hand 
smoke, plus clinical history of wheezing, chronic cough, bronchospasm, or exacerbations, 
and/or exposure with hypercapnia 
2. Presentation with acute hypercapnic respiratory failure defined as: 
a. Moderate to Severe patient baseline hypercarbia/hypercapnia, defined as a baseline PCO2 of 
60 mmHg or higher (as measured by venous blood gas) 
3. Venous pH of 7.0 – 7.35   
 
Exclusion Criteria 
1. Severe metabolic derangements, e.g. suspected drug overdose, mixed acid/base disorder 
(bicarbonate at normal or above to be eligible) 
2. Need for airway protection, e.g. neurologic disorder(s) 
3. Primary condition of Congestive Heart Failure, e.g. Acute Severe Decompensated Heart Failure 
4. Need for emergent intubation 
5. Pneumonia diagnosis with significant infiltrate on chest x-ray that is clinically correlated with 
pneumonia 
6. Inability to provide informed consent 
7. Pregnancy  
8. Known contraindication to perform procedures listed, or therapies described in the protocol 
9. Respiratory arrest or significant respiratory depression on presentation 
10. Significant nasal occlusion either unilateral or bilateral 
11. Absence of spontaneous respiration or known contraindication to HVNI 
12. Extreme agitation or uncooperativeness that would hinder either arm of randomized therapy 
13. Determined by the clinician to be sufficiently unstable or unsuitable for this study  
 

            
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IV. Study Design  
This will be performed as a prospective, unblinded (by definition), multicenter, 1:1 randomized non-
inferiority design clinical trial to evaluate the efficacy of HVNI compared to NIPPV (two approved 
interventions for the management of acute respiratory distress) in the clinical stabilization and relief of 
moderate-to-severe respiratory distress requiring ventilatory support upon presentation. Patients deemed 
to fit the criteria for inclusion will perform the study procedures for one of the study arms of the randomized 
study design. Patient completion of either of the study arms will provide an evaluation of the efficacy of HVNI 
or NIPPV in stabilization and relief of respiratory acidosis and will record patient ventilatory/WOB indices, 
treatment failure, disposition, and physiologic parameters during a 4-hour therapy-response window. 
Additionally, tertiary outcomes will provide an evaluation of patient comfort, and therapeutic response, per 
the study aims.  Patients are expected to complete the study in one session, per the noted parameter 
sampling intervals (baseline, 30min, 1hr, 4hr). After the patient completes the randomized study arm (HVNI 
or NIPPV), the clinicians and patients will complete perception score assessments. The clinical management 
will otherwise remain unchanged, based on individual study site standard of care and practice.  
 
This study will utilize two arms.  Patients presenting with acute hypercapnic respiratory failure (per 
Inclusion criteria, in need of clinical stabilization and relief of moderate-to-severe respiratory distress ) who 
are escalated to treatment with a non-invasive respiratory support modality will be randomized to one of the 
following: 
• 
Vapotherm high flow nasal cannula therapy (HVNI) administered as defined below (HVNI arm) 
• 
Non-invasive positive pressure ventilation (NIPPV) delivered via single-limb circuit with a full face 
mask using a pressure support mechanical ventilator system (e.g., Respironics Vision, V60) 
administered as defined below (NIPPV arm) 
 
The study design will focus on six distinct phases for each study arm, which will be identical except for the 
therapy randomization (HVNI or NIPPV): (1) Study Start, (2) Baseline Characterization, (3) Therapy 
Evaluation Interval 1, (4) Therapy Evaluation Interval 2, (5) Therapy Evaluation Interval 3, and (6) Study 
End. Primary, secondary, and tertiary outcomes will be completed upon the completion of all study phases.  
 
The Study Start Phase will follow screening and consent, and will confirm randomization to either study arm, 
and gather the patient background, history, health, demographics, and current respiratory therapies. For 
Phase 2, Baseline Characterization will provide the initial clinical evaluation along with the baseline 
physiologic parameters, ventilation parameters, Patient Stability Index, and blood gases. For Phase 3, the 
Therapy Interval 1 will provide the current patient status at 30minutes post randomized therapy interval 
and will include this interval’s physiologic parameters, ventilation parameters, Patient Stability Index, and 
venous blood gases. For Phase 4, the Therapy Interval 2 will provide the current patient status at 1hour post 
randomized therapy interval and will include this interval’s physiologic parameters, ventilation parameters, 
Patient Stability Index, and venous blood gases. For Phase 5, the Therapy Interval 3 will provide the current 
patient status at 4-hour post randomized therapy interval and will include this interval’s physiologic 
parameters, ventilation parameters, Patient Stability Index, and venous blood gases. Following the 3rd 
Therapy Evaluation Interval at 4hours, Phase 6 will be implemented, which concludes with Study End. Phase 
6 will include Visual Analog Scale (VAS) for both patient and clinician assessment scores. The clinician and 
the patient will complete VAS perception scores for their randomized study arm (HVNI or NIPPV) at 
designated intervals. 
 

            
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This study will be conducted in an Emergency Department or Inpatient Critical Care setting, if applicable, 
where patient care and testing can be performed with appropriate supervision and staff training to maintain 
patient safety.  In this acute-care setting study, participants may or may not decide to enroll after being 
consented. Patients may be excluded after randomization, as this study takes place in the ED or inpatient 
critical care unit and patients may need to be randomized and treated immediately to maintain patient 
safety.  All respiratory interventions will be tracked during the study window for each patient.  
 
 

            
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V. Subject Enrollment 
 
Subjects will be solicited by investigators and consented as described above (Section III), due to the 
emergent need for treatment at time of initial presentation. Should subjects provide initial verbal or written 
consent, only then will data be compiled and used as part of the subject participation in this study (Aims 1-
3). Once enrolled, and randomized 1:1 to study arms, the participants and investigators will complete data 
collection in all Aims during the course of the trial timeline.  
 
Sample Size:  
This trial will randomize subjects 1:1 to Vapotherm:NIPPV.  A total sample size of 64 subjects (~32 per arm) 
randomized with endpoint data, and a one-sided alpha of 0.025 will provide at least 80% power to 
demonstrate non-inferiority.  This sample size assumes a difference of 0.9 between treatment and control 
with standard deviation of 2.4 and 2.9 for treatment and control, respectively, and a non-inferiority margin 
of 1.0.   
 
Allowing for up to 20% attrition, approximately 80 subjects (40 per arm) will be enrolled in order to achieve 
64 subjects with an endpoint. 
 
From Doshi et al, comparable moderate-to-severe hypercapnic respiratory distress patient data was 
analyzed, which informed this sample size calculation’s assumed difference and standard deviations in 
treatment (HVNI) and control (NIPPV) for the modified Borg score.5  
Change in modified 
Borg over 4 hours 
Mean 
Standard 
Deviation 
NIPPV arm (Control) 
-3.208 
2.431 
HVNI arm (Treatment) 
-4.143 
2.931 
 
The minimal clinically important difference (MCID) for modified Borg was informed from literature, as a 
difference value of 1.0.16  
 
 
NOTE:  As this is an Emergency Department or inpatient acute care study, and treatment is often 
immediate due to need for maintaining patient safety, there is an expected patient dropout (i.e. 
incomplete or unusable subject number) of randomized & enrolled patients into this study. After 
presenting to the ED or inpatient acute care setting, should the patients be transferred to another 
area of the hospital, the study procedures will continue until complete.     
 

            
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VI. Study Procedures 
This head-to-head non-inferiority randomized control trial is non-blinded by necessity, as the devices are 
different in size, apparatus, and appearance, when viewed by both patients and clinicians. Patients may 
prefer HVNI over NIPPV or NIPPV over HVNI; however, this will not play a role in patient randomization. The 
study is a 1:1 randomized control design trial that will measure & compare the physiologic effect of the 
tested devices, specifically the effect on relieving patient dyspnea, and the stabilization and improvement of 
patient pH and PCO2 (venous blood gas). In addition, patient physiologic outcomes (e.g. HR, RR, BP, SpO2), 
patient disposition (LOS), patient venous blood gases (pH, PCO2, PO2, bicarbonate, base excess ,) and patient 
& clinician assessment scores will be assessed and documented. Figure 1 illustrates a flowchart of overall 
study procedures. Except for the randomized study arm (HVNI or NIPPV device), the study procedures are 
identical.  
 
Screening, Enrollment, & Management 
Upon screening and fitting subject selection criteria, known at time of presentation to the ED or Acute Care 
unit for treatment, subjects may or may not be able to be asked to be randomized and enrolled into this 
study. In ED or Acute Care settings, there is a need to treat immediately to maintain patient safety. As such, 
consent in this study will take place through verbal consent prior to participation/randomization followed 
by written consent (when respiratory symptoms are manageable), or written consent prior to 
participation/randomization. Patients will be reassured that their medical care will not be impacted in any 
way and their medical providers will not change. All patients randomized, but not included in the final study 
population, will be accounted for in a CONSORT diagram, noting the dropout criteria (i.e. refused consent, 
met exclusion criteria, incomplete dataset, etc.). All study procedures will be explained to the subject.   
 
Subjects will be managed by routine care while study data is captured as shown in the timeline below (Table 
1).  All decision making for patient participation will be made per standard practice/care at the trial site, 
relying on the judgment of qualified medical professionals on staff.  
 
 
 
Figure 1. Framework of the clinical study procedures discussed within this protocol for the two study 
arms: HVNI and NIPPV.  
 

            
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Phase 1 – Study Start/Setup & Patient Background 
Upon enrollment and randomization, the Study Start Phase will confirm inclusion criteria, record 
randomization to either study arm (HVNI or NIPPV), and will collect/record appropriate patient background, 
history, health, demographics, anthropometrics, and current respiratory therapies and respiratory status.  
 
Appropriate Patient Background data will be collected (see below under Data Collection), including patient 
demographics (e.g. age, gender, ethnicity, race), anthropometrics (e.g. weight, height, BMI), COVID-19 status, 
and applicable medical history including a detailed focus on the patient’s current respiratory status (LTOT 
user, positive-airway pressure therapy user, current respiratory therapy). Patient medication data will be 
recorded and tracked for this study. Patient data necessary for calculating the severity index score of BAP-65 
will be recorded at this time.  
 
Phase 2 – Baseline Characterization 
The baseline characterization will provide the initial clinical evaluation. Upon enrollment, randomization, 
and patient background collection, an venous blood gas sample will be drawn to establish the patient 
baseline at the time just prior to placing the patient on either of the study arm therapies (HVNI or NIPPV). 
Patient baseline for physiologic parameters (RR, HR, SpO2, BP, RPD) and venous blood gas parameters 
(PCO2, PO2, pH, bicarbonate, base excess,) will be collected at this time, prior to the initiation of the 
assigned/randomized therapy. A basic metabolic panel (BUN, CO2, Creatinine, Glucose, Chloride, Potassium, 
Sodium, Calcium) will also be collected at this time. For the RPD, the clinician will record patient scores. 
Patient Stability Index evaluation will be evaluated by clinicians and recorded at this time, described as 
follows: to assess patient clinical stability using a continuous VAS score on a scale from unable to speak, due 
to severe respiratory distress, up to speaks in full sentences without severe respiratory distress.  
 
At baseline, only patient perception scores will take place. During the noted study phases, the clinician and 
the patient will complete VAS perception scores (annotated on 100mm line with an “X”) for their 
randomized study arm (HVNI or NIPPV). Patient & Clinician Perception Assessment will be performed by the 
clinician or therapist performing or participating in the testing procedures. The Perception Assessments will 
be completed for each of the three endpoints for clinician assessment and the two endpoints for the patient 
assessment. For the patient perception/satisfaction these include: (1) relief of symptoms, and (2) 
comfort/tolerance. For the clinician perceptions these include: (1) expected/perceived patient outcomes, (2) 
patient comfort & tolerance, and (3) ease of use.  
 
The assigned therapy per randomization will be implemented per the initial settings identified below, after 
which settings will be titrated per standard practice for optimal effect. Patients will be managed by routine 
care while study data is captured as per the timeline given in Table 1.  Note: All decision making for 
intubation, treatment regimen, discharge, and disposition will be made per standard practice at each center 
using the judgment of the PI, Sub-I or their designee.   
 
Initial Settings for Comparative Therapies – HVNI and NIPPV 
The initial settings in the two arms are designed as a standardization of usual medical treatment for the 
respective therapies and were devised to provide critical intervention and rapid abatement of both dyspnea 
and increased work of breathing.  Once the patient has been placed upon the initial settings, the medical staff 
may, and should, manipulate and titrate the settings to optimize effectiveness and subject’s tolerance. Overall 

            
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target should be to lower respiratory rate by 20% or below 24 br/min, while subsequently clinically 
stabilizing and reliving moderate-to-severe hypercapnic respiratory distress.  
 
HVNI will be initiated per the settings identified here, after which settings will be titrated per 
standard practice for optimal effect.  Patients will be fitted with a Vapotherm nasal cannula that will 
be applied by a respiratory therapist or other clinician skilled in management of HVNI (not to exceed 
50% occlusion of the nares). When appropriate cannula are placed, the HVNI initial settings will be 
the following: FiO2 = 0.50 (unless the patient is receiving supplemental O2, and then FiO2 will reflect 
amount of O2 patient is receiving provided that the SpO2 monitor reflects sufficient oxygenation), 
Flow = 30 L/min, and Temperature = 37°C. The flowrate can be decreased/increased as rapidly as 
necessary to optimize patient response and comfort, after a 5min acclimatization. Starting 
temperature will be 37°C; if patients find the gas temperature to be uncomfortable (warm), it can be 
lowered as necessary down to 33°C to enhance tolerance. The FiO2 will be set initially to approximate 
the likely previous dosage (if any) to initially to assure adequate oxygenation, but this should be 
adjusted (range 0.21 to 1.0) to maintain an SpO2 88-94%, per normal clinical management. If 
possible, FiO2 should be weaned to 0.30 or lower while maintaining SpO2 88-94%. NOTE: The flow 
rate is expected to be increased to the maximum rate of 40 L/min before a patient is removed from 
HVNI therapy.   
 
NIPPV will be initiated per the initial settings identified here, after which settings will be titrated per 
standard practice for optimal effect. When patients are placed, the NIPPV initial settings will be the 
following: 12 cmH2O / 6 cmH2O (IPAP/EPAP), such that IPAP is 6 cmH2O above EPAP, with Backup 
Ventilation Rate = 0-4 breathes/min (lowest), and applied at the site’s standard of care (SOC) for 
humidification (settings to be recorded). Patients will be fit with an oronasal mask using a fitting 
gauge that will be applied by a respiratory therapist or other clinician skilled in management of 
NIPPV. Initial pressures will be at low end of suggested range but can be increased as rapidly as 
necessary to alleviate respiratory distress. Targeted tidal volumes of 6-8 ml/kg ideal body weight 
will be the volume goal. If patients find pressures uncomfortably high/low, they can be adjusted as 
necessary by 1 to 2 cmH2O decrements to enhance tolerance. EPAP (PEEP) can also be adjusted 
upward as needed to reduce triggering effort (by counterbalancing auto-PEEP) or to improve 
oxygenation.  FiO2 will be 0.50 initially to assure adequate oxygenation (unless the patient is 
receiving supplemental O2, and then FiO2 will reflect amount of O2 patient is receiving provided that 
the SpO2 monitor reflects sufficient oxygenation), but should be adjusted promptly to maintain an 
SpO2 88-94%, per normal clinical management. If possible, FiO2 should be weaned to 0.30 or lower 
while maintaining SpO2 88-94%.  
 
Treatment failure will be defined as:  
1. Failure to tolerate device if the patient is unable to tolerate the mask, nasal prongs, air flow or 
pressure, has persisting asynchrony and is unable to cooperate with the therapy. 
2. Failure to oxygenate if the modality is unable to sustain an SpO2 sat > 88 - 92% or PaO2 > 60 – 65 
mmHg despite maximal treatment with FiO2=100% and optimal manipulations of flow rate and/or 
airway pressures, in spite of maximal settings per institutional standard. 
3. Failure to ventilate if patients remain acutely hypercapnic and acidemic with lack of reduction in 
PCO2 or improvement in pH, in spite of maximal settings per institutional standard.  
4. Deteriorating medical status correlating to worsening venous blood gases related to respiratory 
distress, manifested by worsening mental status or hemodynamics, manifested by hypotension 

            
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(systolic BP < 90 mmHg), unremitting tachycardia (>140 or increase by >20% during therapy) or 
other conditions interpreted by the patient’s clinicians as constituting evidence of deterioration.  
 
Intubation Criteria will be at the discretion of the treating physician. Researchers will not interfere with 
clinical management decision. Researchers will attempt to ascertain the physician’s rationale for intubation 
and categorize as one of the following: (may include multiple reasons, or other): 
1. Intubation will be undertaken for unremitting respiratory failure despite maximal use of initial 
and/or crossover therapy as manifested by failure to maintain > 88% despite FIO2 1.0 and 
optimization of flow and/or PEEP settings. 
2. Progressive increase > 10 mmHg in PCO2 and concomitant drop in pH despite maximal attempts to 
enhance ventilation. 
3. Inability to cooperate with therapy in the face of persisting evidence of respiratory failure.  
4. Unremitting agitation interfering with ability to cooperate and with persisting evidence of 
respiratory failure. 
5. Deteriorating mental status despite maximal therapy with HVNI and/or NIPPV. 
6. Worsening hemodynamic status (systemic SBP <90 mmHg or MAP < 60 mmHg despite fluid 
resuscitation and use of low dose pressors), unremitting life-threatening arrhythmias, cardiac or 
respiratory arrest or any other condition which, in the judgment of the clinical care team, warrants 
intubation.  
 
 
Phase 3 – Therapy Evaluation Interval #1  
The Therapy Evaluation Interval 1 at 30-minutes will be used to perform a VBG draw for all patients to 
determine if patients need emergent intubation or if Flow/FiO2 or IPAP/EPAP/FiO2 settings should be 
adjusted. 
 
At the 30-minutes post-initiation of randomized therapy (HVNI or NIPPV), the patient will be evaluated. 
Patient Stability Index evaluation will be evaluated by clinicians and recorded at this time. At 30-minutes 
post initiation of randomized therapy, a venous blood gas sample will be drawn to establish the patient 
status. Patient status for physiologic parameters (RR, HR, SpO2, BP, RPD) and venous blood gas parameters 
(PO2, PCO2, pH, bicarbonate, base excess ) will also be collected at this time. For the RPD, the clinician will 
record patient scores. For VAS, at this time, only patient assessment scores will take place. 
 
Any changes in the assigned therapy settings will be recorded at this interval. Record any relevant treatment 
intolerance and failure, need for endotracheal intubation, time spent under positive-pressure ventilation , 
patient mortality, elevation of patient status, and transfer to other inpatient ward/units. Should the patient 
be placed on intubation prior to this therapy evaluation interval, the physiologic parameters and venous 
blood gas parameters will be subsequently collected at intubation time. Should the patient be designated by 
attending clinician for discharge from the ED prior to this therapy evaluation interval, the physiologic 
parameters, venous blood gas parameters, and final assessment scores (per Phase 6) will be subsequently 
collected at this time. 
 
Phase 4 – Therapy Evaluation Interval #2  
At the 1-hour post-initiation of randomized therapy (HVNI or NIPPV), the patient will be evaluated. Patient 
Stability Index evaluation will be evaluated by clinicians and recorded at this time. At 1-hour post initiation 
of randomized therapy, a venous blood gas sample will be drawn to establish the patient status. Patient 
status for physiologic parameters (RR, HR, SpO2, BP, RPD) and venous blood gas parameters (PO2, PCO2, pH, 

            
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bicarbonate, base excess ) will also be collected at this time. For the RPD, the clinician will record patient 
scores. For VAS, at this time, only patient assessment scores will take place. 
 
Any changes in the assigned therapy settings will be recorded at this interval. Record any relevant treatment 
intolerance and failure, need for endotracheal intubation, time spent under positive-pressure ventilation, 
patient mortality, elevation of patient status, and transfer to other inpatient ward/units. Should the patient 
be placed on intubation prior to this therapy evaluation interval, the physiologic parameters and venous 
blood gas parameters will be subsequently collected at intubation time. Should the patient be designated by 
attending clinician for discharge from the ED prior to this therapy evaluation interval, the physiologic 
parameters, venous blood gas parameters, and final assessment scores (per Phase 6) will be subsequently 
collected at this time. 
 
Phase 5 – Therapy Evaluation Interval #3 
At the 4-hour post-initiation of randomized therapy (HVNI or NIPPV), the patient will be evaluated. Patient 
Stability Index evaluation will be evaluated by clinicians and recorded at this time. At 4-hour post initiation 
of randomized therapy, a venous blood gas sample will be drawn to establish the patient status. Patient 
status for physiologic parameters (RR, HR, SpO2, BP, RPD) and venous blood gas parameters (PO2, PCO2, pH, 
bicarbonate, base excess) will also be collected at this time. For the RPD, the clinician will record patient 
scores. For VAS, at this time, patient assessment scores will take place. Clinician VAS scores may take place 
either at this Phase, or at Study End (Phase 6). 
 
Any changes in the assigned therapy settings will be recorded at this interval. Record any relevant treatment 
intolerance and failure, need for endotracheal intubation, time spent under positive-pressure ventilation, 
patient mortality, elevation of patient status, and transfer to other inpatient ward/units. Should the patient 
be placed on intubation prior to this therapy evaluation interval, the physiologic parameters and venous 
blood gas parameters will be subsequently collected at intubation time. Should the patient be designated by 
attending clinician for discharge from the ED prior to this therapy evaluation interval, the physiologic 
parameters, venous blood gas parameters, and final assessment scores (per Phase 6) will be subsequently 
collected at this time. 
 
Phase 6 – Study End & Assessment Scores  
Following the Therapy Evaluation Interval at 4 hours, Phase 6 will be implemented, which concludes with 
Study End. Patients will be actively screened for adverse events. Any information regarding patient 
intubation and rationale, if it pertains, will be recorded, if not previously recorded. The therapy settings at 
time of study end will be recorded. Any patient disposition information during the time course of these study 
procedures will be recorded, in addition to the patient transfer/discharge information (e.g. home, outpatient, 
hospital ward, etc.). A patient severity assessment score, BAP-65, will be calculated (or data needed for the 
calculation will be collected) before the study is completed.  
 
At the end of the study, Phase 6 will include VAS for patient assessment score, and clinician assessment score 
(if not completed during Phase 5).  
 
Upon completion of this last Phase, the study testing procedures will be deemed completed, and any final 
study data will be completed at this time.  
 
 
Other Medical Care 

            
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All other medical treatment will remain the purview of the attending physician and will be administered per 
institution standards.  This head-to-head randomized control trial, performed as a prospective, unblinded, 
multicenter, 1:1 randomized trial is designed to evaluate the efficacy of HVNI compared to NIPPV in the 
stabilization and relief of moderate-to-severe hypercapnic respiratory distress upon presentation. It is 
assumed that the ancillary interventions will follow common clinical practice guidelines and conventions.  
All treatments given to the subjects will be noted on their CRFs.  
 

            
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VII. Data Collection 
 
Table 1. Key study data and collection points for each Phase of the Study. 
  
Study 
Start 
Baseline 
Characterization 
Therapy 
@ 30 
minutes 
Therapy 
@ 1hr 
Therapy 
@ 4hr 
 @ Study 
End 
Patient History & Health Profile 
X 
 
 
 
 
X 
Treatment: Flow & O2 
X 
X 
X 
X 
X 
X 
Patient Stability Index 
 
X 
X 
X 
X 
 
Physiologic Parameters 
X 
X 
X 
X 
X 
 
Blood Gas Parameters 
 
X 
X 
X 
X 
 
Clinician Perception Scores 
 
X 
 
 
X 
X 
Patient Perception Scores 
 
X 
X 
X 
X 
X 
 
Patient enrollment data collection will include patient history, health, demographics, and current respiratory 
therapies. Patient data will also include COVID-19 status. Only Phase 1, study start, will record the patient 
history and background information.  All data collection will be noted with date/time as possible by the 
clinicians and per the SOC or available medical records. Blood samples (VBG) will be drawn within +15/-15 
min of the indicated time from therapy initiation.  Vital signs and indices will be recorded within +5/-5 of the 
indicated time from therapy initiation.  Vital signs, including heart rate (HR), respiratory rate (RR) and blood 
oxygen saturation by pulse oximetry (SpO2), will be reported from the patient monitoring systems in use. If 
patient is intubated this date and time, blood gases, and physiologic parameters will be recorded in addition 
to the reason for intubation, as deemed by the clinician(s).  
 
For each phase, the following data will be recorded for comparison: 
Physiologic Parameters  
o Rated Perceived Dyspnea (RPD), SpO2, HR, RR, BP 
Blood Gas Parameters 
o Venous PCO2, PO2, pH, bicarbonate, base excess Patient Stability Index 
o continuous VAS score on a scale from unable to speak, due to severe respiratory distress, up 
to speaks in full sentences without severe respiratory distress. 
Primary Endpoint 
• 
Primary Parameter – Change in modified Borg (RPD) over 4-hours 
 
Secondary Endpoints 
• 
Physiologic parameters –SpO2, HR, RR, BP,  
• 
Secondary Blood Gas parameters – Changes in venous PCO2, venous PO2, venous pH, venous 
bicarbonate, venous base excess  
• 
Patient Stability Index – continuous VAS score on a scale from unable to speak, due to severe 
respiratory distress, up to speaks in full sentences without severe respiratory distress. 
 
Tertiary Endpoints – Patient & Clinician Assessment 

            
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• 
Patient Assessment 
o Patient assessment of respiratory response to therapy, ranging from Insufficient to Excellent 
Response, as continuous VAS. 
o Patient assessment of comfort and tolerance of the therapy, ranging from Insufficient to 
Excellent, as continuous VAS. 
• 
Clinician Assessment 
o Clinician assessment of patient respiratory response to therapy, ranging from Insufficient to 
Excellent Response, as continuous VAS.  
▪ 
“How satisfied were you with the degree of respiratory support that this patient 
received since presenting and enrolling in the study?” 
o Clinician assessment of patient comfort and tolerance of therapy, ranging from Insufficient to 
Excellent as continuous VAS.  
▪ 
“How satisfied were you with the degree of comfort and tolerance exhibited by this 
patient on the received therapy since presenting and enrolling in the study?” 
o Clinician assessment of simplicity of set-up and use, ranging from Complex to Simple, as 
continuous VAS.  
▪ 
“During the study procedures, what degree of challenge did you find in setting up and 
using/adjusting the device providing therapy for this patient?” 
 
VIII. Statistical Analysis 
The data analysis will be “per protocol,” and per the “intention-to-treat” model. Baseline patient 
demographics and characteristics will be summarized, compared, and appropriate statistical testing will be 
performed for the continuous and categorical variables. Primary outcomes will be analyzed for statistical 
significance to test the null hypothesis. Assuming a non-normal data distribution for this randomized study 
design, the non-parametric Wilcoxon Signed Rank Sum test will be performed with significance interval of 
0.05 on all applicable variables. Parametric analytical analogues (e.g. t-test) will be used if the measurements 
present a normal distribution. Otherwise, for the categorical variables, the Fisher’s Exact test will be 
performed and shown by category. Data for patient parameters will be compared across treatment arms and 
time-period using Repeated Measures analysis ANOVAs to assess dependence on treatment and interactions 
with time. Data will be compared and graphed accordingly for a visual comparison with accompanied 
statistical notations. Significance will be accepted where p < 0.05. Analyses will be performed using SAS 
version 9.2 or higher or comparable statistical software. 
IX. Risks and Discomforts 
Vapotherm HVNI therapy has been deemed non-inferior to NIPPV.5 This study in this patient population of 
acute hypercapnic respiratory failure does not present significant risk to patients, as supplemental oxygen 
and flushing of anatomic dead space is routinely provided to patients as a standard/routine practice in the 
study hospitals. 3,4,17,18 Use of the high flow nasal cannula therapy has no known risks and has been used in 
the clinical setting for approximately seventeen years without known reports of adverse events related to 
the administration of high nasal flows when appropriately conditioned to near body temperature and fully 
humidified.  The literature indicates that approximately only 4 cmH2O of distending pressure may be 
generated in the upper airway, which is well below any known threshold for injury. 19,20  In addition, it has 

            
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been demonstrated that delivery of high flows of conditioned gas from a nasal cannula has a positive effect 
on airway mucosal function. 21,22 The patients will be closely monitored as part of standard medical practice.  
 
For these reasons, we have determined that this study represents non-significant risk to the subjects. The 
high flow nasal cannula system used has no known risk and has been used in hospitals for approximately 
seventeen years. During either study arm, patients will be closely monitored as part of the normal care. 
Patients may experience mild discomfort from a cannula in contact with their nose, face or around their ears 
and possibly a runny nose from the humidity contained in the gas flow.  
 
X. Potential Benefits 
Subjects may or may not receive any direct health benefit from participation. The trial may result in 
knowledge that leads to improvements in the quality of care, patient experience and the effect HVNI therapy 
can have on patient dyspnea relief, in addition to providing valuable information on other effective 
modalities shown to provide comparable therapeutic effect to NIPPV.  
 
XI. Monitoring and Quality Assurance 
The clinical trial site will be monitored in accordance with policies at Vapotherm and federal regulations that 
pertain to clinical research, namely 21 CFR Parts 50, 54, 56 and 812 and others as applicable.  Monitoring 
will occur at regular frequency by the PI or designee, such as to allow ongoing review of data collected, site 
qualifications and compliance with the protocol.  All investigators will be appropriately trained to ensure 
compliance with the protocol. Audit of the study CRF’s will be regularly conducted by the Sponsor. The 
clinical trial site will follow all IRB regulations.  
 
XII. Protocol Deviations 
Any deviations from the Data Collection plan identified during monitoring or through other means will be 
documented on case report forms. These include, but are not limited to items such as the following:  
• 
Deviation from the procedural sequencing, per the protocol 
• 
Failure to complete the Baseline characterization  
• 
Failure to complete all sections of the Study Phases 
• 
Failure to capture time and place in trial of any device failure 
• 
Failure to capture/record data included in the protocol 
• 
Subject inability to complete either of the randomized study arms 
If the study site demonstrates a pattern of consistent and frequent deviations, the sponsor will undertake 
appropriate activities (e.g. re-training) to attempt to bring the site into compliance with the protocol. A 
pattern of repeated serious deviations from the protocol may result in site termination from the study. 
 
XIII. Adverse Event Reporting 
During the course of the subject’s participation in the study, the investigator will determine whether any 
adverse events have occurred.  For the purposes of this protocol, an adverse event is any undesirable event 
experienced by a subject, that is or is not attributed to the device or procedure required by this protocol.  If 

            
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any adverse event occurs, either anticipated or unanticipated, the investigators will immediately contact the 
sponsor representative (site monitor) indicated on page 1. The CRFs will have a list of predetermined 
adverse events to be used actively to screen during the study procedures.  
 
XIV. Confidentiality 
Rigorous procedures will be followed to maintain confidentiality of subject identification and test-related 
information and to adhere to government regulations concerning privacy.  Methods to protect the privacy of 
subjects and clinical information are employed and built into the trial.  A unique identification number 
designed to protect the identity of subjects will be used to identify the subject on case report forms, 
recruitment logs, data forms or other reports. 
 
This unique identification number will not be linked to identifiable data; no personal or identifiable patient 
data will be collected.  The Vapotherm clinical research staff member managing the study will be the only 
person to have knowledge pertaining to the link between the unique identifiable number and the subject.  All 
other Vapotherm representatives involved in this study will only have access to the patients’ unique 
identification number.  The linked data will be maintained by the site study staff and stored at the study site 
for two years from the end of the study.  
 
Confidentiality will be protected and maintained to the extent allowed by law. 
                                                                                                                                                                                                                                        
XV. References 
a. 
1. 
Ejiofor SI, Bayliss S, Gassamma A, Turner AM. Ambulatory Oxygen for Exercise-Induced 
Desaturation and Dyspnea in Chronic Obstructive Pulmonary Disease (COPD): Systematic Review and 
Meta-Analysis. Chronic Obstr Pulm Dis. 2016;3(1):419-434. 
b. 
2. 
Osadnik CR, Tee VS, Carson-Chahhoud KV, Picot J, Wedzicha JA, Smith BJ. Non-invasive 
ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of 
chronic obstructive pulmonary disease. The Cochrane database of systematic reviews. 
2017;7:CD004104. 
c. 
3. 
Dysart K, Miller TL, Wolfson MR, Shaffer TH. Research in high flow therapy: mechanisms of 
action. Respiratory medicine. 2009;103(10):1400-1405. 
d. 
4. 
Miller TL, Saberi B, Saberi S. Computational Fluid Dynamics Modeling of Extrathoracic 
Airway Flush: Evaluation of High Flow Nasal Cannula Design Elements. Journal of Pulmonary & 
Respiratory Medicine. 2016;6(5):376. 
e. 
5. 
Doshi P, Whittle JS, Bublewicz M, et al. High-Velocity Nasal Insufflation in the Treatment of 
Respiratory Failure: A Randomized Clinical Trial. Ann Emerg Med. 2018;72(1):73-83 e75. 
f. 
6. 
Hernández G, Roca O, Colinas L. High-flow nasal cannula support therapy: new insights and. 
Critical care. 2017;21(1):1-11. 
g. 
7. 
Lavizzari A, Colnaghi M, Ciuffini F, et al. Heated, Humidified High-Flow Nasal Cannula vs Nasal 
Continuous Positive Airway Pressure for Respiratory Distress Syndrome of Prematurity: A 
Randomized Clinical Noninferiority Trial. JAMA Pediatr. 2016. 
h. 
8. 
Waugh JB, Granger WM. An evaluation of 2 new devices for nasal high-flow gas therapy. 
Respiratory care. 2004;49(8):902-906. 

            
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i. 
9. 
Woodhead DD, Lambert DK, Clark JM, Christensen RD. Comparing two methods of delivering 
high-flow gas therapy by nasal cannula following endotracheal extubation: a prospective, randomized, 
masked, crossover trial. Journal of perinatology : official journal of the California Perinatal 
Association. 2006;26(8):481-485. 
j. 
10. 
Frizzola M, Miller TL, Rodriguez ME, et al. High-flow nasal cannula: impact on oxygenation and 
ventilation in an acute lung injury model. Pediatric pulmonology. 2011;46(1):67-74. 
k. 
11. 
Doshi P, Whittle JS, Bublewicz M, et al. High-Velocity Nasal Insufflation in the Treatment of 
Respiratory Failure: A Randomized Clinical Trial. Ann Emerg Med. 2018. 
l. 
12. 
Weiler T, Kamerkar A, Hotz J, Ross PA, Newth CJL, Khemani RG. The Relationship between 
High Flow Nasal Cannula Flow Rate and Effort of Breathing in Children. The Journal of pediatrics. 
2017;189:66-71. 
m. 
13. 
Yoder BA, Manley B, Collins CL, et al. Consensus approach to nasal high-flow therapy in 
neonates. Journal of Perinatology. 2017;Advanced Online Publication. 
n. 
14. 
Greenspan JS, Wolfson MR, Shaffer TH. Airway responsiveness to low inspired gas 
temperature in preterm neonates. The Journal of pediatrics. 1991;118(3):443-445. 
o. 
15. 
Shepard JW, Jr., Burger CD. Nasal and oral flow-volume loops in normal subjects and patients 
with obstructive sleep apnea. The American review of respiratory disease. 1990;142(6 Pt 1):1288-
1293. 
p. 
16. 
Ries AL. Minimally clinically important difference for the UCSD Shortness of Breath 
Questionnaire, Borg Scale, and Visual Analog Scale. Copd. 2005;2(1):105-110. 
q. 
17. 
Spoletini G, Alotaibi M, Blasi F, Hill NS. Heated Humidified High-Flow Nasal Oxygen in 
Adults: Mechanisms of Action and Clinical Implications. Chest. 2015;148(1):253-261. 
r. 
18. 
Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test. Am J 
Respir Crit Care Med. 2002;166(1):111-117. 
s. 
19. 
McGinley BM, Patil SP, Kirkness JP, Smith PL, Schwartz AR, Schneider H. A nasal cannula can 
be used to treat obstructive sleep apnea. Am J Respir Crit Care Med. 2007;176(2):194-200. 
t. 
20. 
Parke R, McGuinness S, Eccleston M. Nasal high-flow therapy delivers low level positive 
airway pressure. British journal of anaesthesia. 2009;103(6):886-890. 
u. 
21. 
Hasani A, Chapman TH, McCool D, Smith RE, Dilworth JP, Agnew JE. Domiciliary 
humidification improves lung mucociliary clearance in patients with bronchiectasis. Chron Respir Dis. 
2008;5(2):81-86. 
v. 
22. 
Williams R, Rankin N, Smith T, Galler D, Seakins P. Relationship between the humidity and 
temperature of inspired gas and the function of the airway mucosa. Critical care medicine. 
1996;24(11):1920-1929.