Early Prone Positioning Combined With High-Flow Nasal Cannula Versus High-Flow Nasal Cannula in COVID-19 Induced Moderate to Severe ARDS
Phase: NA
Conditions: Prone Positioning, High Flow Nasal Cannula, Acute Respiratory Distress Syndrome, Corona Virus Infection
Sponsor: Rush University Medical Center

A Multi-Center Randomized Controlled Trial of Early Use of Prone Positioning Combined 
with HFNC in COVID-19 Induced Moderate to Severe Acute Respiratory Distress 
Syndrome
Jie Li,1 Sara Mirza, 1 Tyler Weiss, 1 Ahmad A Elshafei, 1 Andrew Klein, 1 Amanda Miller, 1 
Ramandeep Kaur,1 Jonathan B Scott, 1 Lauren J Harnois,1 Kathleen Posa-Kearney, 2 Flor Cerda, 2 
Jacob R Burd, 1  David Vines. 1
1 Department of Cardiopulmonary Sciences, Division of Respiratory Care, Rush University 
Medical Center, Chicago, IL. 
2 Nursing, ICU, Rush University Medical Center, Chicago, IL.
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

1. STUDY PURPOSE:
1.1. Introduction
Acute respiratory distress syndrome (ARDS) has a high mortality of 25~40%, even with the 
improvement of therapies. Previous studies suggest that prone positioning (PP) can increase the 
average ratio of arterial oxygen tension to the fraction of inspired oxygen (PaO2/FiO2) by +35 
mmHg, and reduce mortality in moderate to severe ARDS, especially when combined with 
neuromuscular blocker (NMB) and low tidal volume ventilation, which decrease the risk of 
ventilator induced lung injury (VILI)1-5. However, PP is only recommended in intubated severe 
ARDS with PaO2/FiO2<150mmHg, and the use of PP is still limited in less than 33% of severe 
ARDS patients6.
From a theoretical and physiological point of view, HFNC may be beneficial in patients with 
ARDS. This techniques work via several mechanisms. Firstly, HFNC generates a small positive 
expiratory pressure. The amount of pressure generated depends on the nasal gas flow and 
whether the mouth is open or closed. HFNC works mainly by flushing the nasal airspaces, 
reducing anatomical dead space and providing a high FiO2. Secondly, HFNC is extremely well 
tolerated by delivering warm and well-humidified gas through the nostrils and avoiding the 
discomfort associated with wearing non-invasive ventilation (NIV) masks.7 Lastly, HFNC can 
provide constant FIO2 by avoiding air entrainment since the gas flow can be set to exceed most 
patient’s inspiratory flow. The major goal of HFNC in treating ARDS is to achieve a sufficient 
level of oxygenation. However, HFNC may be viewed as a partial support therapy, but it is not 
totally addressing the underlying pathology of ARDS sufficiently, such as the ventilation–
perfusion mismatching caused by alveolar collapse and consolidation in the dependent areas of 
the lung as this disease process worsens.8 In this regard, combination therapy such as PP with 
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

HFNC may be considered to get better physiological effects by improving ventilation-perfusion 
mismatch in ARDS and a better homogeneity of lung mechanics.
The early application of PP with HFNC, especially in patients with moderate ARDS and 
baseline SpO2>95%, may help avoid intubation. In a preliminary study, PP was well tolerated 
with noninvasive respiratory supports, and the efficacy in terms of PaO2/FiO2 with HFNC + PP 
was higher than HFNC alone. Severe ARDS patients were not appropriate candidates for 
HFNC/NIV+PP, and a risk for delayed intubation should be noticed. A prospective RCT is 
warranted in the future in non-intubated moderate ARDS patients on the true benefits of PP 
before intubation.9
Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first 
reported in Wuhan, China, and had subsequently spread worldwide, including in United States. 
Twenty-nine percent of COVID-19 patients may develop ARDS, 30% of these ARDS patients 
could be successfully supported with HFNC or NIV, and 60% of the ARDS patients needed 
intubation and invasive mechanical ventilation, or even ECMO support10.
Based on the potential beneficial mechanisms of HFNC and PP mentioned above, early use 
of PP combined with HFNC to avoid the need for intubation in COVID-19 patients with 
moderate to severe ARDS needs to be further investigated. 
1.2. Hypothesis / Key Questions
We hypothesize that early use of PP combined with HFNC can avoid the need for intubation 
in moderate to severe ARDS patients. The purpose of this RCT will be to evaluate the effects of 
PP combined with HFNC for improving oxygenation and reducing the need for intubation 
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

compared with HFNC support alone, as well as the safety of the PP therapy in non-intubated 
COVID-19 induced ARDS patients.
1.3. Primary Objectives
The primary outcome for the efficacy of PP combined with HFNC will be the treatment 
failure rate and intubation rate of HFNC or HFNC+PP support and clinical requirement for 
advanced respiratory support including NIV, invasive ventilation or ECMO. 
1.4. Secondary Objectives
The secondary outcomes for the efficacy of PP combined with HFNC will be the improvement 
of SpO2/FIO2 or PaO2/FiO2 from HFNC alone to HFNC+PP. SpO2/FIO2 will be utilized to 
substitute PaO2/FiO2 as a means for evaluating oxygenation.11-14 As a practical substitute to 
PaO2/ FIO2, SpO2/FIO2 has been shown to have a strong linear relationship in moderate to severe 
ARDS14 and was recommended as a diagnostic tool for early enrollment in clinical trial.13 FIO2 
will be titrated to maintain SpO2 at 90-95%. Other secondary outcomes including the time 
duration for PP therapy, patients’ comfort with PP, PP complications including skin break down, 
tube/I.V. dislodgement, and the threshold of SpO2/FIO2 for successful PP in COVID-19 induced 
ARDS cases, HFNC duration, ICU length of stay and ICU mortality rate.
2. STUDY METHODS
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

This is a multi-center randomized controlled trial, which will be approved by the Ethic 
Committees of all the participant hospitals. This trial is registered with ClinicalTrials.gov 
(NCT04325906).  
2.1. Inclusion criteria
The diagnostic criteria for COVID-19 pneumonia will be based on the CDC guidelines. .The 
diagnosis of ARDS will be assigned to patients who meet the Berlin definition criteria 15: 
1) Presence of acute hypoxemic respiratory failure; 
2) Acute onset within 7 days of insult, or new (within 7 days) or worsening respiratory 
symptoms; 
3) Bilateral opacities on chest x-ray or CT not fully explained by effusions, lobar or lung 
collapse, or nodules; 
4) Cardiac failure not the primary cause of acute respiratory failure. 
Patients are categorized into 2 mutually exclusive classes of ARDS severity using previous 
definitions based on degree of hypoxemia: 
1) Moderate: 100mmHg ≤ PaO2/FIO2 < 200mmHg, or 140 ≤ SpO2/FIO2 < 240; 
2) Severe: PaO2/FIO2 ≤ 100mmHg, or SpO2/FIO2 < 140.
COVID-19 induced adult ARDS patients admitted to the medical ICU will be enrolled when 
their PaO2/FiO2 is less than 200mmHg or FIO2 ≥ 0.4 is required to maintain SpO2 at 88‒93% on 
HFNC treatment.  
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

2.2. Exclusion criteria
The exclusion criterion are 
1) If the patients have a consistent SpO2<80% when on evaluation with a FiO2 of 0.6, or 
signs of respiratory fatigue (RR > 40/min, PaCO2> 50mmHg / pH<7.30, and obvious accessory 
respiratory muscle use); 
2) Immediate need for intubation (PaO2/FiO2< 50mmHg or SpO2/FiO2 <90, unable to protect 
airway or mental status change); 
3) Hemodynamic instability (sustained SBP<90mmHg, sustained MBP below 65 mmHg or 
requirement for vasopressor); 
4) Unable to collaborate with HFNC/PP with agitation or refuse HFNC/PP.
5) Chest trauma or any contraindication for PP
6) Pneumothorax
7) Age < 18 years
8) Pregnant 
9) Unable to communicate
10) Severe obese (BMI ≥ 40)
11) Patient self-proned for more than an hour
3. PROCEDURES INVOLVED
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

3.1. Recruiting and consent 
All patients admitted with COVID-19 will be screened and patients with ARDS who will be 
selected by the inclusion and exclusion criteria are included. 
All participating subjects provide electronic informed consent or telephone consent before 
randomization.
3.2. Randomization and masking
Randomization will be stratified on ARDS severity (moderate and severe)  performed by 
permuted block methods using Fisher and Yates tables of random permutations using a 
centralized interactive contact system is used for randomization. The random block length is 4, 
and random numbers are generated by computer. All of the centers participating in this study are 
immediately put in contact with the central unit (Rush University Medical Center) to obtain a 
randomization number if a patient fulfills the inclusion criteria. Within 6 hr of fulfilling inclusion 
criteria, a patient will be randomly allocated either to the prone positioning group or the control 
group (HFNC alone with no prone positioning therapy).
3.3. Blinding and Quality Control
The trial will be overseen by a steering committee, and data quality control will be 
completed by independent data monitoring board. Clinicians and epidemiologists of above 
organization are not members of participating in our research group. Research coordinator will 
timely verify database and regularly monitored all the centers on site to ensure the accuracy of 
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

the data recorded. An investigator at each center is responsible for enrolling patients in the study, 
ensuring adherence to the protocol, and completing the electronic case-report form. Although the 
individual study assignments of the patients could not be blinded, the coordinating center and all 
the investigators will remain unaware of the study group outcomes until the data are unlocked. 
All the analyses are performed by the study statistician not involved in study recruitment, and 
blind of randomization group until database lock.
3.4. Prone positioning implementation
PP will be performed before or 1 hour after meal. Before PP, all the I.V. lines and nasal 
cannula will be checked by clinicians. PP will be performed by patient under the supervision of 
clinicians. Assistance will be offered if needed. If tolerated, PP will be maintained for at least 30 
minutes, until the patients feel tired to keep that position. PP will be performed minimum twice a 
day for the first 3 days after the patient’s enrollment. Patients will be informed to maintain prone 
position as long as they can. FIO2 will be adjusted to maintain SpO2 at 92-95%. 
Protocol for sedation and comfort evaluation during PP: No sedation will be used during the 
PP. The patients are monitored by bedside respiratory therapist and nurses for their comfort and 
tolerance for the PP at 5mins, 30 minutes after PP for the first PP in each day. 
3.5. HFNC treatment
HFNC will be initiated at 50 L/min (AIRVO2 or Optiflow, Fisher &Paykel Health care 
Limited., Auckland, New Zealand) with temperature set at 37 oC. Nasal cannula size should be ≤ 
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

50% of the patient’s nostril size. FIO2 will be adjusted to maintain SpO2 at 90% to 95%. Flow 
and temperature will be adjusted based on patient’s comfort and clinical response. Patients’ vital 
signs, SpO2, oxygen device and FIO2 before HFNC will be recorded, Patients’ vital signs, SpO2, 
HFNC flow and FIO2 at 30 mins, and 2 hour of HFNC will also be recorded for both groups. 
HFNC will be continuously delivered after enrollment in the study for ≥16 hours a day in the 
first 3 days. Patient comfort to HFNC, will be assessed by means of a scale used and validated in 
previous studies that is defined as follows: 1, bad; 2, poor; 3, sufficient; 4, good; 5, very good. 
Patients’ vital signs, SpO2, HFNC flow and FIO2, as well as patient comfort will be documented 
every 4-6 hours. In order to prevent virus transmission, all the patients with HFNC treatments 
will wear a surgical mask over the face. 16
3.6. Withdraw criteria
1) Patients cannot tolerate HFNC or prone position for 30 mins 
2) Patients experience any side effects during prone position, including vomit, dizzy, 
hypotension, etc.
3.7 Weaning criteria
1) Patients’ PaO2/FIO2 > 300mmHg, or SpO2/FIO2 > 340
 
3.8 Treatment Failure Criteria 
Failure criteria: treatment failure is defined as one of the following criteria 17: 
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

(1) Signs of persisting or worsening respiratory failure, defined by at least two of the 
following criteria: 
- Respiratory rate above 40 cycles/min
-Lack of improvement of signs of respiratory-muscle fatigue
-Development of copious tracheal secretions
-Respiratory acidosis with a pH below 7.35
-SpO2 below 90% at FIO2 ≥ 0.8 for more than 5 min without technical dysfunction
(2) Hemodynamic instability defined by a SBP below 90 mmHg, MBP below 65 mmHg or 
requirement for vasopressor;
(3) Deterioration of neurologic status (with a Glasgow coma scale below 12 points).
For patients who meet the failure criteria in the HFNC and HFNC+PP groups, a trial of NIV 
might be allowed according to the physician’s preference in patients with signs of persisting or 
worsening respiratory failure and no other organ dysfunction before performing endotracheal 
intubation and invasive ventilation. Reasons for intubation will be recorded as well. 
3.8 Primary endpoint 
28 days after randomization.
3.9 Comprehensive therapy
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

The treatment of COVID-19 is followed by the CDC protocol. Comprehensive therapy is 
provided by the ICU attending physicians based on published ARDS guidelines. Antivirus 
treatment and the use of steroids will be recorded as well. 
4. CHARACTERISTICS OF DATA/SPECIMENS TO BE ANALYZED
4.1. Data collection
The following information of all patients is collected in a data file: patients’ characteristics, 
including age, gender, medical history, diagnosis for COVID-19, the laboratory and 
microbiology findings, treatment and outcome. Complications including skin breakdown, IV line 
or nasal cannula dislodgement or desaturation during position change. The respiratory 
assessments before, during the treatments of HFNC or HFNC with prone position.
4.2. Statistical analysis
Definition of the two groups: The patients who receive the prone positioning are classified 
as prone positioning group. The patients who receive HFNC alone are classified as HFNC group.
Comparisons between the two groups: Quantitative continuous variables are given as either 
means (±SDs) or medians (with inter-quartile ranges) are compared using the unpaired Student’s 
t test or the Mann-Whitney test. Qualitative or categorical variables are compared with the chi-
square test or the Fisher’s exact test. ANOVA for paired tests to compare the same variables 
collected at different time points are used. The cumulative probability of remaining on 
spontaneous breathing are compared with the Kaplan-Meier estimate of survival and the log-rank 
test to compare the two groups. Univariate and multivariate analyses of risk factors for PP failure 
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

are performed with logistic regression. All analyses are in intention to treat, and the level of 
significance is set at 0.05.
4.3. Sample size calculation
Sample size estimation: Base on the intubation rate for COVID-19 induced ARDS patients 
reported in previous studies from 40% to 77% 18-20, we estimate at least a total of 346 subjects 
with an expected intubation rate of 60% in the moderate to severe ARDS patients with HFNC 
support, and of 45% [80% * (1-0.25)=45%, a 25% reduction] in the PP patients in our cases, 
with a confidence level (1-α)=95% and power level(1- β)=80%.
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

References
1.
Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory 
distress syndrome. N Engl J Med. 2013;368(23):2159-2168.
2.
Munshi L, Del Sorbo L, Adhikari NKJ, et al. Prone Position for Acute Respiratory 
Distress Syndrome. A Systematic Review and Meta-Analysis. Ann Am Thorac Soc. 
2017;14(Supplement_4):S280-S288.
3.
Marini JJ, Hurford WE. Should Early Prone Positioning Be a Standard of Care in ARDS 
With Refractory Hypoxemia? Wrong Question-Reply. Respir Care. 2016;61(11):1564-
1565.
4.
Scholten EL, Beitler JR, Prisk GK, Malhotra A. Treatment of ARDS With Prone 
Positioning. Chest. 2017;151(1):215-224.
5.
Kallet RH. A Comprehensive Review of Prone Position in ARDS. Respir Care. 
2015;60(11):1660-1687.
6.
Guerin C, Beuret P, Constantin JM, et al. A prospective international observational 
prevalence study on prone positioning of ARDS patients: the APRONET (ARDS Prone 
Position Network) study. Intensive Care Med. 2018;44(1):22-37.
7.
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.
8.
Demoule A, Hill N, Navalesi P. Can we prevent intubation in patients with ARDS? 
Intensive Care Med. 2016;42(5):768-771.
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

9.
Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined 
with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. 
Crit Care. 2020;24(1):28.
10.
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel 
coronavirus in Wuhan, China. Lancet. 2020.
11.
Pisani L, Roozeman JP, Simonis FD, et al. Risk stratification using SpO2/FiO2 and PEEP 
at initial ARDS diagnosis and after 24 h in patients with moderate or severe ARDS. Ann 
Intensive Care. 2017;7(1):108.
12.
Brown SM, Duggal A, Hou PC, et al. Nonlinear Imputation of PaO2/FIO2 From 
SpO2/FIO2 Among Mechanically Ventilated Patients in the ICU: A Prospective, 
Observational Study. Crit Care Med. 2017;45(8):1317-1324.
13.
Chen W, Janz DR, Shaver CM, Bernard GR, Bastarache JA, Ware LB. Clinical 
Characteristics and Outcomes Are Similar in ARDS Diagnosed by Oxygen 
Saturation/Fio2 Ratio Compared With Pao2/Fio2 Ratio. Chest. 2015;148(6):1477-1483.
14.
Rice TW, Wheeler AP, Bernard GR, et al. Comparison of the SpO2/FIO2 ratio and the 
PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest. 2007;132(2):410-
417.
15.
Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the 
Berlin Definition. JAMA. 2012;307(23):2526-2533.
ORA: 20032604-IRB01   Date IRB Approved: 4/1/2020   Amendment Date: 9/15/2020

16.
Respiratory care committee of Chinese Thoracic Society. Expert consensus on preventing 
nosocomial transmission during respiratory care for critically ill patients infected by 2019 
novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi ZaZhi. 2020;17(0):E020.
17.
Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute 
hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185-2196.
18.
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with 
SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, 
observational study. Lancet Respir Med. 2020.
19.
Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress 
Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, 
China. JAMA Intern Med. 2020.
20.       Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 
2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020.
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