The Effect of Asymmetrical vs. Symmetrical High Flow Nasal Cannula on the Work of Breathing: A Randomised Cross-over Study
Phase: NA
Conditions: Respiratory Disease (Clinically Stable Individuals - Patients Recovered From Respiratory Disease)
Sponsor: Larissa University Hospital

Study Protocol  
 
 
Title:  
“The Effect of Asymmetrical vs. Symmetrical High Flow Nasal Cannula on the Work of 
Breathing: A randomised cross-over study.” 
 
 
 
NCT number: not yet assigned  
 
Unique Protocol ID: 16171/09.04.2024 
 
 
 
Date: 09.04.2024 
 
 
 
 
 
 
 
 
 
 

INTRODUCTION - CURRENT KNOWLEDGE 
Nasal High Flow (NHF) therapy has become increasingly popular as a non-invasive method 
of respiratory support, used alongside conventional oxygen therapy (COT) and noninvasive 
ventilation (NIV) in the management of acute respiratory failure. In 2020, the European 
Society of Intensive Care Medicine issued a strong recommendation for NHF over COT in 
patients with respiratory failure type I (RFI). Further, in 2022, the European Respiratory 
Society (ERS) recommended NHF over NIV for patients with RF-I. NHF also received a 
conditional recommendation for use in COPD patients with acute hypercapnic respiratory 
failure (RF-II) after a short trial of NIV, particularly for those who cannot tolerate NIV. 
 
The traditional NHF interface design is symmetrical, intended to distribute airflow evenly 
between both nostrils. This design has been effective in providing respiratory support by 
generating dynamic Positive End-Expiratory Pressure (PEEP), decreasing the anatomical 
dead space, improving oxygenation by providing high and stable inspiratory oxygen fraction, 
enhancing secretion clearance through the provision of reliable humidification and reducing 
airway resistance. These benefits are well-documented in various studies, highlighting NHF's 
role in decreasing the work of breathing and improving overall respiratory mechanics. Work 
of breathing is a major contributor to respiratory distress in acute respiratory failure, and 
elevated work of breathing can lead to respiratory muscle fatigue, increased metabolic 
demand, and worsened oxygenation.  
Recent developments have introduced a novel asymmetrical NHF interface, designed to 
optimize key mechanisms of NHF. Simulation studies of this new interface have shown 
promising results, indicating that the asymmetrical design increases PEEP and offers 
improved clearance of dead space compared to its symmetrical counterpart. These findings 
suggest that the asymmetrical interface may further enhance the efficiency of NHF therapy, 
potentially leading to greater reductions in the work of breathing and more effective 
respiratory support. 
Pressure-Time Product (PTP) is widely regarded as one of the most accurate surrogates for 
quantifying the metabolic and mechanical work of breathing. Unlike traditional markers such 
as respiratory rate or tidal volume, which may not fully capture the respiratory load, PTP 
integrates pressure, volume, and timing, providing a comprehensive assessment of the total 
effort exerted by respiratory muscles. By using PTP in this study, we aim to capture subtle 
differences in the work of breathing between the two NHF interfaces. 
Sassoon et al. have previously shown that the metabolic work and the oxygen consumption of 
the respiratory muscles can be estimated by the pressure-time product per minute, which is 
calculated as follows: PTP = ∫Pes + Vt / Ccw * dt * RR, where PTP represents the pressure-
time product, quantifying the total pressure generated by the respiratory muscles over time. Pes 
(esophageal pressure) reflects the pressure drop within the pleura from the respiratory muscles’ 
contraction. Vt (tidal volume) is the amount of air moved in the lungs during a normal breath. 
Ccw (compliance of the chest wall) measures the elasticity of the chest wall, and in  

this context, is defined as 5% of the predicted vital capacity per cmH2O. RR (respiratory rate) 
is the number of breaths per minute, and dt refers to the inspiratory time. 
 
AIM 
Despite the aforementioned encouraging simulation results, there is a lack of empirical data 
comparing the physiological effects of symmetrical versus asymmetrical NHF interfaces in 
real-world settings. This study using precise measurements of esophageal pressure, tidal 
volume, and respiratory flow to quantify the work of breathing, aims to fill this gap by 
directly assessing the impact of these two interface designs on the work of breathing in 
patients recovered from acute respiratory disease.  
 
HYPOTHESIS 
We hypothesize that the asymmetrical nasal cannula for high flow oxygen therapy will reduce 
the metabolic work of the respiratory muscles more effectively than the symmetrical interface 
in the individuals.  
 
SUBJECTS 
We will enroll 30 individuals who will be discharged from the Department of Respiratory 
Medicine of the General University Hospital of Larissa after hospitalization for acute 
respiratory disease, who meet the inclusion criteria outlined in the "Methods" section below. 
This sample size has been chosen arbitrarily due to the absence of prior studies that would 
support a formal sample size calculation. 
 
 
METHODS 
Study Design: Randomized, crossover design.  
Inclusion and Exclusion Criteria: 
Inclusion: age ≥18 years old and clinical stability (absence of symptoms and signs of 
respiratory failure, SpO295% at FiΟ2 0.21). 
Exclusion: pregnancy, SpO2<94% at FiΟ2 0.21, neuromuscular disease and contraindications 
to esophageal pressure monitoring (e.g., uncontrolled coagulopathy, esophageal disease, nasal 
trauma, allergy to local lidocaine). 
 
 

Interventions 
Esophageal Balloon Catheter: A lubricated 10 French catheter will be inserted through the 
nostril, advanced to 40-45 cm into the esophagus, and inflated with 1 ml of air. Proper 
placement will be confirmed by performing an occlusion test. During a brief inspiratory hold, 
the patient will be instructed to perform an occlusion maneuver (i.e., a gentle effort against a 
closed airway). The esophageal and airway pressure signals should move in parallel during 
the occlusion. This confirms that the balloon is properly positioned and accurately reflects 
pleural pressure. Additionally, cardiac oscillations and negative deflections on the esophageal 
pressure waveform during inspiration will be observed for further confirmation.  
NHF Oxygen: Administered at 50 L/min and 37°C. The fraction of inspired oxygen will be 
21% for healthy individuals and adjusted for a target oxygen saturation of at least 92. 
Interface Comparison: Participants will receive both the asymmetrical interface (Optiflow 
Duet) and the conventional symmetrical interface. Each interface will be applied for 15 
minutes with a 3-minute washout period between sessions to prevent residual effects. 
Data Collection 
Pre-Randomization: Collect demographic data (age, sex) and baseline clinical information 
(body mass index, comorbidities, smoking status). 
 
During Intervention: 
Measurements: Esophageal pressure (Pes) with an esophageal balloon catheter, tidal volume 
(VT) with an impedance device (ExSpiron, Respiratory Motion Inc., Waltham,MA) device, 
and flow with a pneumotachograph. Collect five repeat measurements at baseline and 
throughout both interventions. 
Parameters: Esophageal pressure, flow, tidal volume, inspiratory and expiratory time, 
respiratory rate, arterial blood gases, end-expiratory pCO2. 
Vital Signs: Monitor throughout both interventions. 
Analysis 
Flow-Time and Pressure-Time Graphs: 
Flow-Time Graphs: Record air flow during inspiration and expiration using the 
pneumotachograph. Identify the onset and end of inspiration and measure the duration of 
inspiration. 
Pressure-Time Graphs: Record esophageal pressure (Pes). Integrate the area under the 
pressure-time curve during inspiration to quantify the work done by respiratory muscles. 
 
 

Static Recoil Pressure Calculation: 
Compliance of the Chest Wall (Ccw): Estimated as 5% of the predicted vital capacity (VC). 
The elastance (Ecw) is the reciprocal of Ccw. 
Static Recoil Pressure (Pcw): Calculated as: Pcw = Ecw × VT  
Example Calculation: VC = 5000 mL, Ccw = 5% of VC = 250 mL/cmH2O, Ecw = 1 / Ccw = 
0.004 cmH2O/mL, VT = 500 mL. Thus, Pcw = 0.005 cmH2O/mL × 500 mL = 2 cmH2O 
Pressure-Time Product (PTP) Calculation: Formula: PTP=(∫(Pes−PEEPi) dt) × RR  
Procedure: Subtract static recoil pressure (Pcw) from Pes. Adjust for intrinsic PEEP (PEEPi) 
determined from end-expiration esophageal pressure recordings. Multiply the area under the 
pressure-time curve by the respiratory rate (RR). 
Statistical Analysis: Software: GraphPad Prism, SPSS. Descriptive Statistics: Means, 
standard deviations, medians, interquartile ranges. Comparisons: Paired t-tests, Wilcoxon 
signed-rank tests, repeated-measures ANOVA. Adjustments: Bonferroni correction for 
multiple comparisons. Significance: p < 0.05. 
Interobserver Reliability: Graph Analysis: Two independent investigators will use Image J 
to digitize and analyze flow-time and pressure-time graphs. Disagreements will be resolved 
by a third senior investigator. 
 
EXPECTED RESULTS: 
We expect that the asymmetrical high flow nasal cannula will result in a greater reduction in 
the PTP, indicating a lower work of breathing compared to the symmetrical interface. 
Additionally, we expect to observe a reduction in respiratory rate and hemodynamics 
parameters with the asymmetrical interface, alongside an increase in expiratory time.  
 
IMPLICATIONS: 
The findings from this study could influence clinical practice by providing evidence for the 
use of the asymmetrical NHF cannula as a more efficient option for reducing the work of 
breathing compared to the conventional symmetrical interface. If the asymmetrical interface 
demonstrates superiority, it could lead to its wider adoption in respiratory care. Clinically, this 
may result in improved patient comfort, reduced respiratory effort, and potentially shorter 
durations of NHF therapy, which could help minimize the need for escalation to more 
invasive respiratory support, such as mechanical ventilation. The implications extend beyond 
patient care, as improved NHF efficiency could also reduce healthcare costs by shortening 
hospital stays and decreasing the resources required for respiratory support. Moreover, this 
study could pave the way for future research exploring the benefits of asymmetrical 
interfaces in other patient populations or conditions. If proven successful, the asymmetrical 
design may set a new standard for NHF therapy, potentially influencing clinical guidelines 

and furthering technological innovation in respiratory support. Finally, should the 
asymmetrical interface prove effective, future studies could explore its potential benefits in 
patients with RF-II, where reducing the work of breathing and enhancing carbon dioxide 
clearance are critical therapeutic goals. 
 
 
REFERENCES: 
1. Mauri T, Turrini C, Eronia N, et al. Physiologic Effects of High-Flow Nasal Cannula 
in Acute Hypoxemic Respiratory Failure. Am J Respir Crit Care Med. 2017 
May1;195(9):1207–15. 
2. Tatkov S, Rees M, Gulley A, et al. Asymmetrical nasal high flow ventilation 
improves clearance of CO2 from the anatomical dead space and increases 
positive airway pressure. J Appl Physiol Bethesda Md 1985. 2023 Feb 
1;134(2):365–77.  
3. Slobod D, Spinelli E, Crotti S, et al. Effects of an asymmetrical high flow nasal 
cannula interface in hypoxemic patients. Crit Care. 2023 Apr 18;27(1):145.  
4. Pantazopoulos I, Daniil Z, Moylan M, et al. Nasal High Flow Use in COPD Patients 
with Hypercapnic Respiratory Failure: Treatment Algorithm & Review of the 
Literature. COPD. 2020 Feb;17(1):101–11.  
5. Ischaki E, Pantazopoulos I, Zakynthinos S. Nasal high flow therapy: a novel 
treatment rather than a more expensive oxygen device. Eur Respir Rev Off J Eur 
Respir Soc. 2017 Sep 30;26(145):170028.  
6. Sassoon CSH, Light RW, Lodia R, et al. Pressure-Time Product during Continuous 
Positive Airway Pressure, Pressure Support Ventilation, and T-Piece during 
Weaning from Mechanical Ventilation. Am Rev Respir Dis. 1991 Mar;143(3):469–
75. 
7. Akoumianaki E, Maggiore SM, Valenza F, et al. The Application of Esophageal 
Pressure Measurement in Patients with Respiratory Failure. Am J Respir Crit Care 
Med. 2014 Mar;189(5):520–31.  
8. Rochwerg B, Einav S, Chaudhuri D, et al. The role for high flow nasal cannula as a 
respiratory support strategy in adults: a clinical practice guideline. Intensive Care 
Med. 2020 Dec;46(12):2226–37.  
9. Ovtcharenko N, Ho E, Alhazzani W, et al. High-flow nasal cannula versus non-
invasive ventilation for acute hypercapnic respiratory failure in adults: a 
systematic review and meta-analysis of randomized trials. Crit Care. 2022 Nov 
9;26(1):348.