High-flow Air Via Nasal Cannula Versus Non-invasive Continuous Positive Airway Pressure Ventilation Support for Hypercapnic Respiratory Failure The HIGH-for-HYPER Study
Phase: NA
Conditions: Hypercapnic Respiratory Failure
Sponsor: Medical University of Vienna

 
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Study protocol 
High-flow Nasal Oxygen versus  
Non-invasive CPAP Ventilation Support 
for Hypercapnic Respiratory Failure 
(The HIGH-for-HYPER study) 
 
Study group 
Dominik Roth 
Verena Fuhrmann 
Michael Schwameis 
Nina Buchtele 
Calvin Kienbacher 
Roberta Laggner 
Harald Herkner 
Anton N. Laggner 
 
Contact 
Priv. Doz. Dr. med. univ. et. scient. med. 
Dominik Roth 
Universitätsklinik für Notfallmedizin 
Medizinische Universität Wien 
Spitalgasse 23 
A-1090 Vienna, Austria 
Tel: 
+ 43 1 / 40400-19640 
Fax: + 43 1 / 40400-19650 
Email: dominik.roth@meduniwien.ac.at 
 
 
 
 

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Background 
Hypercapnic respiratory failure 
Respiratory failure is a leading cause of morbidity and mortality, and one of 
the most frequently encountered problems at the emergency department1,2,3. 
Hypercapnic or hypercarbic respiratory failure, also dubbed respiratory 
failure type II, is characterized by failure of the respiratory system in one of 
its two gas exchange functions: carbon monoxide (CO2) elimination. It is thus 
usually defined via partial pressure of CO2 in the arterial blood gas (PaCO2), a 
value of higher than 50mmHg being a commonly used cut-off4,5. 
Hypercapnic respiratory failure is often associated with severe airway 
disorders, such as asthma and chronic obstructive pulmonary disease 
(COPD), but might also be found in other situations, where respiratory drive 
is restricted, such as intoxications, neuromuscular diseases or chest wall 
abnormities4,5. 
Hypercapnic respiratory failure, i.e. respiratory failure type II, is often 
associated with hypoxemic respiratory failure, i.e. respiratory failure type I, 
failure of oxygenation, however type I failure is also often observed without 
hypercapnia4,5.  
Respiratory failure, both type I and II, may be further classified into either 
acute or chronic. Distinction between both forms is often not easy, and, in 
addition to arterial blood gas analysis, might require additional tests to 
identify clinical markers such as polycythemia or cor pulmonale. For practical 
reasons, acute respiratory failure is often defined as a situation, in which 
respiratory failure develops too fast to allow for renal compensation and an 
increase in bicarbonate (HCO3
-) levels, and thus leading to acidosis (pH less 
than 7.3) 4,5.  
Therapy strategies for hypercapnic respiratory failure include non-invasive 
CPAP ventilation support, intubation and mechanical ventilation (both 
assisted and controlled forms)4,5, and, in very severe cases, extracorporal 
methods, such as extracorporal life support systems6,7. 
 
 
 

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Non-invasive CPAP Ventilation Support 
Non-invasive CPAP ventilation support via either helmets, or different kinds 
of tight masks, is the current method of choice for the treatment of patients 
with acute respiratory failure in the intensive care setting. Eligible patients 
include those with an intact airway, airway-protective reflexes, who are alert 
enough to follow commands, whereas patients who lack those criteria require 
immediate intubation4,5. 
Non-invasive CPAP ventilation support improves both oxygenation (by 
providing an inspired fraction of oygen (FiO2) of 100%, which is not possible 
via a simple venturi-mask, and the possibility of positive end-expiratory 
pressure (PEEP), preventing collapsing of the alveoli), and decarboxygenation 
(by increasing tidal volume). It has been shown to decrease both need for 
intubation and in-hospital mortality8.  
Non-invasive CPAP ventilation support however requires a high grade of skill 
from providers, and intensive communication with the patient to explain to 
him the usefulness of a tight-sitting device in his face in a situation of 
perceived massive dyspnea. Although severe adverse effects of non-invasive 
CPAP ventilation support are very rare, pain and pressure marks may occur. 
Despite all efforts of care providers, there is a relevant faction of patients 
who do not tolerate ventilation support via a tight mask at all. Brochard et al. 
report 15% of patients not tolerating the therapy, with an additional 25% of 
patients presenting with contraindications. These might include general 
contraindications against non-invasive techniques, such as aforementioned 
lack of airway-protective reflexes, but also such specific for tight masks, such 
as anatomical abnormities of the face8,9. 
 
High-flow Nasal Oxygen 
High-flow nasal oxygen (HFNO2) therapy is usually applied via a wide-bore 
nasal cannula. It provides up to 60L/min of a heated and humified gas 
mixtures (at an adjustable mix medical of oxygen and room air). This therapy 
is much less invasive for the patient, and thus often better tolerated.  
HFNO2 has been increasingly used in the last years for hypoxic respiratory 
failure (i.e. type I failure), and numerous studies have shown its efficiency in 
this indication both at the intensive care unit and at the emergency 

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department10-15. A recent systematic review and meta-analysis has concluded 
in improved patient comfort and reduced dyspnea scores16.  
Despite this good evidence for HFNO2 in hypoxic respiratory failure, it has 
only reluctantly been used for hypercapnic respiratory failure. This might in a 
large part be explained by the fact that patients with chronic hypercapnia are 
known to diminish their their respiratory drive when exposed to hyperoxia17. 
However, evidence has begun to change on this indication in recent time. 
HFNO2 has been shown to generate PEEP, despite not being a closed system18, 
and to improve CO2 clearance by flushing anatomical dead space19. It might 
also help to reduce inspiratory resistance and facilitate secretion clearance 
from humidified gas20. A study on COPD patients showed an increase in 
breathing pressure amplitude and mean pressure, as well as tidal volume, 
with a trend towards reduction of pCO221. 
Based on these findings, the use of HFNO2 has increased in clinical practice, 
and a number of case reports and –series indicate successful use22-24. Fraser 
et al. successfully investigated the use of HFNO2 in patients with chronic 
COPD25, and Jeong et al. retrospectively analyzed changes in arterial blood 
gases during use of HFNO2 in the ED for both hypercapnic and non-
hypercapnic patients, and found a significant reduction of pCO226. 
There is, however, to date no randomized controlled trial investigating the 
effect of HFNO2 in acute hypercapnic respiratory failure. 
Objectives 
To assess the efficacy and safety of HFNO2 versus non-invasive CPAP 
ventilation support in acute hypercapnic respiratory failure. 
 
 

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Study 
Setting 
The study will be performed as a randomized controlled on-inferiority trial. 
The study site is the Department of Emergency Medicine (ED) of the Vienna 
General Hospital, a leading academic research center for emergency medicine 
at a large, tertiary care hospital. 
Around 90,000 patients are being treated at the department each year, 
approximately 150-200 of them suffering from hypercapnic respiratory 
failure, and requiring non-invasive ventilation support. 
The department features its own ICU and intermediate-care unit, with 7 
positions each, for a total of 14 positions capable of providing CPAP therapy. 
The Airvo II HFNO2-device is also at regular use at the department. 
 
Sponsoring 
Sponsor of this study will be the Department of Emergency Medicine at the 
Medical University Vienna. There is no industry sponsoring or industrial 
financial support, but we will apply for financial support from research 
grants. 
 
Registration and Regulation 
This project is considered as a study investigating differences of two 
standard medical methods. This study will be submitted for review and 
approval to the ethical committee of the Medical University Vienna and the 
Vienna General Hospital. The office of the medical Director will be 
announced, and the study will be registered at http://www.controlled-
trials.com/. 
 
 
 

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Population 
Inclusion criteria 
- 
Adult patients (e.g. at least 18 years old) treated at the Emergency 
Department 
- 
Acute hypercapnic respiratory failure defined as a pCO2>50mmHg and a 
pH<7.3 on admission 
Exclusion criteria 
- 
Patients being comatose on admission, with no intact airway, lac of 
airway-protective reflexes, or those who are not alert enough to follow 
commands  
- 
Patients intubated by Emergency Medical Service 
- 
Patients requiring intubation on admission 
- 
Pregnant women 
 
Outcome 
Primary outcome 
- 
Reduction of pCO2 per hour 
Secondary outcomes 
Clinical and safety Parameters 
- 
Frequency of therapy failure (switch to other therapy; intubation) 
- 
Patient’s perception of the therapy (10-point Likert-Scale from very 
uncomfortable to very comfortable) 
- 
Adverse events 
Efficacy Parameters: 
- 
Time until pCO2 reaches 50mmHg or less 
Economic Parameters: 
- 
Length of Stay at the Emergency Department 

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- 
Frequency of admission to ICU 
- 
Frequency of admission to regular ward 
- 
Length of Stay at the ICU 
- 
Length of Stay at the Hospital 
- 
Hospital readmission within 1 month 
 
Methods 
Randomisation 
A random sequence will be generated by a person not involved in the 
enrolment of patients using standard software. Randomisation will be 
performed in variable blocks of 4 to 6, to yield an unpredictable allocation 
yet warranting balanced group sizes.  
Sequentially numbered sealed opaque envelopes (SNOSE), containing 
allocation either to the intervention or the control group, will be pre-
produced. The envelopes will be opened after consent immediately before 
the start of the intervention to allow for allocation concealment and reduce 
the risk of immediate post-random exclusion. 
 
Intervention 
Control consists of HFNO2 using the Airvo II, Fisher & Paykel, New Zealand. A 
gas flow 60L/min and and a FiO2 as clinically feasibile will be used. Therapy 
will be continued until a COHb-level of 50mmHg or less is reached, or 
therapy has to be aborted because of lack of tolerance by the patient or 
indication for intubation. 
Control 
Control consists of non-invasive CPAP ventilation support using a tight mask 
and standard respirator equipment of the Department of Emergency Medicine 
(Servo Ventilator 300, Siemens-Elema AB, Life Support Systems Division, 
Solina, Sweden). A positive airway pressure of 5cm H2O and a FiO2 as 
clinically feasibile will be used. Therapy will be continued until a COHb-level 

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of 50mmHg or less is reached, or therapy has to be aborted because of lack 
of tolerance by the patient or indication for intubation. 
 
Based on treating physician’s judgement, both intervention and control 
treatments might be aborted at any time, and any other therapy (simple 
Venturi-Mask, HFNO2, non-invasive CPAP-ventilation support, intubation, 
extracorporal methods) might be initiated. 
 
Measurement 
Baseline characteristics and demographic variables will include age, sex, 
smoking status, prior diseases, especially any history of COPD or Asthma, 
and duration of treatment of those, medication, body size, pre-hospital 
treatment. pCO2 levels will be measured using blood gas analysis at 0 – 15 – 
30 – 45 – 60 – 90 – 120 (and every 30 minutes thereafter) minutes after the 
beginning of the therapy, and at the end of the therapy. 
Patient’s perception of the therapy will be assessed after the end of the 
therapy using a 10-point Likert-Scale from very uncomfortable to very 
comfortable. 
In case of abortion of assigned therapy, we will follow a carry-on-latest 
principle, by calculating pCO2 reduction per hour by dividing actual reduction 
of pCO2 during assigned therapy by total treatment time (including follow-on 
therapy after abortion), to achieve a maximally conservative interpretation of 
therapy effect. 
 
 
 

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Statistics 
Sample size 
Sample size considerations are based on the primary outcome pCO2 
reduction per hour. Based on the published literature, we assume that the 
outcome in the control group is 4±3mmHg/hour8. Based on a clinically 
assumed non-inferiority of 2mmHg we would need 28 experimental subjects 
and 28 control subjects to be able to reject the null hypothesis, that the 
lower limit of a two-sided 90% confidence interval of the true difference 
between two groups is above the non-inferiority limit, at a power of 80%. 
Formally we will have to enrol 56 patients. To allow for potential loss to 
follow up, missing data, measurement issues, or other design factors we will 
increase actual sample size to 62.  
In terms of feasibility, we expect approximately 150 to 200 eligible patients 
within one year, resulting in an expected study-duration of approximately 6 
months. 
Data Analysis 
Baseline data and demographics will be tabulated for the intervention- and 
control-group to assess success of randomisation. Reduction of pCO2 per 
hour will be calculated by dividing delta pCO2 at start of therapy to end of 
therapy by duration of therapy in hours. In case of abortion of assigned 
therapy, we will follow a carry-on-latest principle, by calculating pCO2 
reduction per hour by dividing actual reduction of pCO2 during assigned 
therapy by total treatment time. Reduction of pCO2 per hour will be 
compared between individuals in the intervention and individuals in the 
control group. Primary analysis will follow the intention-to-treat principle. The 
unit of analysis will be single persons. We will calculate effects as differences 
with 95% confidence intervals. For hypothesis tests we will use the t-test or 
Mann-Whitney-U-test, as appropriate. In case of relevant clustering we will 
use regression-based approaches. 
Categorical secondary outcomes will be analysed by calculating relative risks 
with exact standard error based 95% confidence intervals, and the Fisher’s 
exact test will be used for comparison. Continuous secondary outcomes will 
be analyzed like the primary outcome. Length of stay data are expectedly 
lognormally distributed, therefore we plan to use log-transformed values for 
further calculations. 

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For data analysis we will use Stata 11. A two-sided p-value less 0.05 is 
generally considered statistically significant. 
 
1.1.1.1  Privacy and Data safety 
Directly and indirectly patient-related data will be stored physically and 
logically separated. In addition, only members of the study-group will have 
access to study data. Data will be stored on a secured computer of the 
department of emergency medicine and will be accessible only via restricted 
access for members of the study-group. 
 
 
 
 
 
 
 

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Literature 
1. Khan NA, Palepu A, Norena M, et al. Differences in hospital mortality 
among critically ill patients of Asian, Native Indian, and European 
descent. Chest. 2008 Dec. 134(6):1217-22. 
2. Moss M, Mannino DM. Race and gender differences in acute respiratory 
distress syndrome deaths in the United States: an analysis of multiple-
cause mortality data (1979- 1996). Crit Care Med. 2002 Aug. 
30(8):1679-85. 
3. Phua J, Badia JR, Adhikari NK, et al. Has mortality from acute 
respiratory distress syndrome decreased over time?: A systematic 
review. Am J Respir Crit Care Med. 2009 Feb 1. 179(3):220-7. 
4. Kallstrom TJ, American Association for Respiratory Care. AARC Clinical 
Practice Guideline: oxygen therapy for adults in the acute care facility: 
2002 revision & update. Respir Care 2002;47(6):717720. 
5. O’Driscoll BR, Howard LS, Davison AG. Emergency oxygen use in adult 
patients: concise guidance. Clin Med 2011;11(4):372-375. 
6. Lewandowski K. Extracorporeal membrane oxygenation for severe 
acute respiratory failure. Crit Care 2000; 4: 156. 
7. Schellongowski P, Riss K, Staudinger T, et al. Extracorporeal CO2 
removal 
as 
bridge 
to 
lung 
transplantation 
in 
life-threatening 
hypercapnia. Transpl Int. 2015 Mar;28(3):297-304. 
8. Brochard, L., Mancebo, J., Wysocki, M., et al. Noninvasive ventilation for 
acute exacerbations of chronic obstructive pulmonary disease. N Engl J 
Med 1995 Sep 28; 333(13): 817–822. 
9. Tsolaki V, Pastaka C, Kostikas K, Karetsi E, Dimoulis A, Zikiri A, 
Koutsokera A, Gourgoulianis KI: Noninvasive ventilation in chronic 
respiratory failure: effects on quality of life. Respiration 2011;  8 1:  4 
02–410.   
10. Rittayamai N, Tscheikuna J, Praphruetkit N, et al. Use of High-Flow 
Nasal Cannula for Acute Dyspnea and Hypoxemia in the Emergency 
Department. Respir Care 2015;60(10):1377–1382. 
11. Sztrymf B, Messika J, Mayot T, et al: Impact of high-flow nasal cannula 
oxygen therapy on intensive care unit patients with acute respiratory 
failure: A prospective observational study. J Crit Care 2012; 
324:324.e9–e13 

Study protocol V 1.0 
28-03-2017 
Page 12 / 13 
12. Rello J, Pérez M, Roca O, et al; CRIPS Investigators: High-flow nasal 
therapy in adults with severe acute respiratory infection: A cohort 
study in patients with 2009 influenza A/H1N1v. J Crit Care 2012; 
27:434–439 
13. Roca O, Riera J, Torres F, et al: High-flow oxygen therapy in acute 
respiratory failure. Respir Care 2010; 55:408–413 
14. Atwood C, Miller T, McMillan N et al: Effect of high flow highly 
humidified air via nasal cannula on respiratory effort in patients with 
advanced COPD. Chest 2011; 140:536A 
15. Sztrymf B, Messika J, Bertrand F, Hurel D, Leon R, Dreyfuss D, Ricard 
JD. Beneficial effects of humidified high flow nasal oxygen in critical 
care patients: a prospective pilot study. Intensive Care Med 
2011;37(11):1780-1786. 
16. Monro-Somerville T, Sim M, Ruddy J, Vilas M, Gillies MA. The Effect of 
High-Flow Nasal Cannula Oxygen Therapy on Mortality and Intubation 
Rate in Acute Respiratory Failure: A Systematic Review and Meta-
Analysis. Crit Care Med. 2017 Apr;45(4):e449-e456. 
17. Sassoon CS, Hassell KT, Mahutte CK. Hyperoxic-induced hypercapnia 
in stable chronic obstructive pulmonary disease. Am Rev Respir Dis. 
1987 Apr;135(4):907-11. 
18. Parke, R., McGuinness, S., Eccleston, M. Nasal high-flow therapy 
delivers low level positive airway pressure. Br J Anaesth 2009; 103: 
886–890. 
19. Ricard, J.High flow nasal oxygen in acute respiratory failure. Minerva 
Anesthesiol 2002; 78: 836–841. 
20. Dysart K, Miller TL, Wolfson MR, Shaffer TH. Research in high flow 
therapy: mechanisms of action. Respir Med 2009;103(10):1400-1405. 
21. Bräunlich J, Beyer D, Mai D, Hammerschmidt S, Seyfarth HJ, Wirtz H: 
Effects of nasal high flow on ventilation in volunteers, COPD and 
idiopathic pulmonary fibrosis patients. Respiration 2013;   85:   319–
325.    
22. Pavlov I, Plamondon P, Delisle S. Nasal high-flow therapy for type II 
respiratory failure in COPD: A report of four cases. Respir Med Case 
Rep. 2017 Jan 1;20:87-88. 

Study protocol V 1.0 
28-03-2017 
Page 13 / 13 
23. Lepere V, Messika J, La Combe B, Ricard JD. High-flow nasal cannula 
oxygen supply as treatment in hypercapnic respiratory failure. 
24. Millar J, Lutton S, O'Connor P. The use of high-flow nasal oxygen 
therapy in the management of hypercarbic respiratory failure. Ther 
Adv Respir Dis. 2014 Apr;8(2):63-4. 
25. Fraser JF, Spooner AJ, Dunster KR, Anstey CM, Corley A. Nasal high 
flow oxygen therapy in patients with COPD reduces respiratory rate 
and tissue carbon dioxide while increasing tidal and end-expiratory 
lung 
volumes: 
a 
randomised 
crossover 
trial. 
Thorax. 
2016 
Aug;71(8):759-61. 
26. Jeong JH, Kim DH, Kim SC, et al. Changes in arterial blood gases after 
use of high-flow nasal cannula therapy in the ED. Am J Emerg Med. 
2015 Oct;33(10):1344-9.