Awake Prone Positioning and Oxygen Therapy in Patients With COVID-19 (APRONOX)
Conditions: COVID, ARDS, Pneumonia
Sponsor: Hospital General San Juan del Rio

Awake prone positioning and oxygen therapy in patients with COVID-19 (APRONOX) 
Prospective, observational, multicenter study. 
 
APRONOX trial is a retrospective, observational, multicenter study that consists 
of the main objective, which is to observe the impact of the awake prone, and to 
see how many patients required intubation, with the additional objectives 
described in this research 
By the APRONOX group 
Identifiers: NCT04407468  Unique Protocol ID: 1178/SESEQ-HSGJR/08-05- 20/UTI 
Date: 10/05/2020 
      
 
 
 

Awake prone positioning and oxygen therapy in patients with COVID-19 
(APRONOX) 
Prospective, observational, multicenter study. 
Identifiers: NCT04407468  Unique Protocol ID: 1178/SESEQ-HSGJR/08-05- 20/UTI 
 
Theoretical framework 
The prone position strategy for patients with acute respiratory distress syndrome (ARDS) is simple 
and cost-effective since the first description on its use in patients with acute respiratory failure to 
improve hypoxemia. Different studies have looked for its safety and efficacy in various clinical 
scenarios, demonstrating that its early use in combination with non-invasive mechanical 
ventilation (NIV) or high-flow oxygen therapy can reduce intubation rate and mortality in ARDS. 
In the COVID-19 pandemic, high-value medicine and resource optimization are critical. 
Scaravilli et al (1) carried out an analysis of 15 patients admitted presenting acute hypoxemic 
respiratory failure with spontaneous breathing undergoing a prone position, finding that the 
strategy had no deleterious effects on PaCO2, pH, respiratory rate, or hemodynamics. For their 
part, Valter et al (2) reported four cases of patients with respiratory failure where a prone position 
strategy was used, showing an improvement in oxygenation and good tolerance while awake, 
avoiding the need for intubation in these patients without significant complications (2). 
Ding et al (3) recently published a prospective cohort study of patients with moderate to severe 
grade ARDS using the prone position combined with non-invasive mechanical ventilation (NIV) 
or high flow nasal cannula (HFNC), demonstrating the safety and efficiency of the maneuver, 
finding an improvement in oxygenation and a decrease in the need for intubation. Pérez et al (4) 
reported a case series of patients with severe non-infectious ARDS where the strategy of early 
prone and HFNC or NIV, for 2 to 3 hours, improved oxygenation and intubation was avoided in 5 
of the 6 cases studied. 
Sun et al (5), perform an early intervention strategy in patients with coronavirus-2019 disease 
(COVID-19) and respiratory failure, supported by NIV or HFNC using the awake prone 
positioning, reporting a low intubation rate and mortality compared to other regions of China 
affected by the SARS-CoV-2. Caputo et al (6) evaluated an early awake prone positioning in 
patients with COVID-19 in an emergency service; describing 50 cases with an oxygen saturation 
on admission <90%, after the early awake prone strategy for 30-120 minutes, oxygenation 
improved and intubation was avoided in 64% of patients. Slessarev et al (7), analyzed a patient 
with COVID-19-associated pneumonia, who was treated with high-flow nasal cannula and awake 
prone positioning, allowing him to interact with family members and participate in active 
physiotherapy, the primary result showed an improvement in oxygenation.  
There are currently studies in progress to evaluate the benefit of the prone position in patients with 
COVID-19. The APPROVE-CARE-2020 study is an open, randomized, multicenter controlled 
study of acute hypoxemic respiratory failure or COVID-19-induced respiratory distress syndrome 

seeking to determine whether the prone position awake reduces the need for mechanical ventilation 
(8). The OPTIPRONE clinical trial is recruiting patients with the objective of monitoring the PaO2 
/ FiO2 ratio with a strategy based on prone position and high-flow oxygen therapy over a period 
of 2 hours, the current status is awaiting for reporting results (9). 
The awake prone position can be combined with a variety of non-invasive oxygenation strategies. 
The evidence documented so far has shown that it is a safe and effective strategy, and it has been 
observed that performing it early has been associated with benefit in survival and reduction of the 
intubation rate in patients with moderate and severe respiratory failure. Another advantage of this 
technique is that the awake prone position can be performed even in atmospheric air in emergency 
situations, or in contexts of limited resources. This strategy aims to be a safe, dynamic, practical 
and free strategy at any level of health care (3). For the diagnosis of COVID-19, reverse 
transcriptase polymerase chain reaction (RT-PCR) is considered the standard test. However, there 
are limitations such as the shortage of kits, limitations in sampling and transportation that can give 
us cases of false negatives in the early stages of the disease. For this reason, imaging studies such 
as chest tomography (CT) can be a valuable diagnostic method in patients with suspected covid-
19 disease, a sensitivity of up to 97% has been observed (10-12). 
Shang Wan (11) performed a meta-analysis where 1115 patients were included, where chest 
tomography images were observed, in which the following characteristics and image patterns were 
observed: 
1. Ground glass opacities and pleural thickening (69%) 
2. Peripheral distribution (70%) 
3. Consolidation (47%) 
4. Air bronchogram (46%) 
5. Involvement of the right lower lobe (70%) 
6. Involvement of more than 3 lobes (70%) 
7. Crazy paving pattern (15%) 
In particular, a full understanding of the patterns on tomography as well as the clinical features 
may be beneficial for an effective diagnosis and treatment in patients with COVID-19 infection 
(11). 
 
 
 
 
 

Problem statement 
The first case of COVID-19 in Mexico was reported on February 27, 2020, currently our country 
has 27.2 cases per 100,000 habitants. According to the Ministry of Health, there are currently 
36,327 confirmed cases of COVID-19 in the country with a total of 3,573 deaths. The WHO reports 
in the month of May, Mexico presented a case fatality rate (CFR) of 12%, being one of the highest 
reported during the SARS-COV 2 pandemic. COVID-19 has a wide range of clinical 
manifestations, ranging from asymptomatic to severe ARDS that requires invasive mechanical 
ventilation. According to Chinese reports, not all severe cases of COVID-19 required admission 
to the ICU, in Italy 12% of positive patients required admission to the critical care unit. In Mexico 
it has been observed that 56% of the patients who required intubation for severe management of 
the disease die, on the other hand, in China, 49% of the patients with a severe picture of COVID-
19 died. In a multicenter study during the early outbreak in Wuhan 97% of the patients who 
required invasive mechanical ventilation died, although mortality could be affected by medical 
practice in each region. It seems important to highlight that several patients who require intubation 
are in a high risk of dying. There are some comorbidities related to an increased mortality such as 
hypertension, diabetes, vascular diseases, COPD and cancer, highly prevalent diseases in the 
Mexican environment. Mortality in patients with mechanical ventilation is striking, it makes us 
wonder if the ventilatory management per se generates complications that lead the patient to death, 
such as Ventilator-Induced Lung Injury (VILI), hemodynamic repercussion due to positive 
pressure or  the fact that intubated patients are simply more critically ill patients. Another current 
issue that has been observed internationally is the lack of medical equipment due to the high 
demand for patients. One of the strategies that have been reproduced internationally is the 
placement of prone patients early in awake patients without mechanical ventilation, with 
encouraging preliminary results. 
 
 
 
 
 
 
 
 
 
 
 

Research question 
In patients diagnosed with COVID-19 infection. What is the relationship between the awaken 
prone position and the need for orotracheal intubation? 
Justification 
COVID-19 is a pandemic that has significantly challenged health systems worldwide. Due to the 
large number of infections around the world, the implementation of strategies to reduce the number 
of intubations and the need for invasive mechanical ventilation becomes important. In addition to 
the inability of the Mexican health system to respond, patients under invasive ventilation have not 
had a favorable survival outcome. Up to 97% mortality has been reported in patients requiring 
intubation. The exact cause of this poor prognosis is not yet known. Early recognition of 
hypoxemic patients could help with the results. It seems reasonable in these patients to perform 
procedures to improve the clinical respiratory picture before intubation in less severe cases due to 
the quoted above. Prone patient placement during invasive mechanical ventilation is a widespread 
practice in the management of severe ARDS of other etiologies. Currently, few attempts have been 
made to implement the prone position in patients who spontaneously ventilate with supplemental 
oxygen, high-flow nasal cannulas, or noninvasive mechanical ventilation. Taking into account that 
it is a procedure that does not require additional infrastructure within the services and does not 
represent an additional cost for its implementation, it becomes a valuable tool in the context of 
COVID-19 where intubation is associated with high mortality, additionally there are mechanical 
ventilator deficits in most hospitals. This work has feasibility to be carried out because it will be 
carried out in critical areas that have equipment and trained personnel for it in the different shifts, 
in addition to having patients diagnosed with COVID-19. 
 
 
 
 
 
 
 
 
 
 
 
Hypothesis 

Null hypothesis (H0): In patients diagnosed with COVID-19 infection, there is no relationship 
between the awaken prone positioning and orotracheal intubation. 
Alternate hypothesis (H1): In patients diagnosed with COVID-19 infection, there is a relationship 
between the awaken prone positioning and the need for orotracheal intubation. 
Objective 
Main objective 
To analyze the relationship between the awaken prone positioning and the need for orotracheal 
intubation. 
Specific objectives 
To explore the impact of the awaken prone positioning on the partial oxygen saturation / inspired 
oxygen fraction index (SaO2 / FiO2). 
Determine the free hours without the need for orotracheal intubation of patients in the awaken 
prone positioning. 
To describe the characteristics of the patients in need of orotracheal intubation who were in the 
awaken prone positioning and those who were not. 
 
 
 
 
 
 
 
 
 
 
 
 
Methodology 
Study type: Observational, retrospective cohort study. 

Study characteristics 
• Based on an intervention or not for research purposes: Observational. 
• For follow up or not of patients over time: Longitudinal 
• For directionality in obtaining information: Retrospective 
• By the search or not of associations between two variables: Comparative 
• By type of population: Homodemic, multicenter. 
 
Inclusion criteria 
Patient’s records with the following characteristics: 
• Patients over 18 years of age 
• Patients of both genders 
• Patients diagnosed with COVID-19 infection 
• Patients admitted to hospital 
• Complete file 
 
Exclution criteria 
• Files not found. 
• Patients who do not decide to participate in the study. 
 
Elimination criteria 
• Files with incomplete data 
• File with a voluntary discharge form or transfer note. 
 
Study population 
Patients diagnosed with COVID-19 
Variables categorization 
The source of collection of the variables will be the clinical file. 
 
Dependent 

Variable 
Conceptual 
definition 
Operational 
definition 
Type 
Measurement 
scale 
Orotracheal 
intubation 
Placing a probe into the 
trachea 
through 
the 
mouth 
or 
nose 
to 
connect to a mechanical 
ventilator. 
Performing intubation 
for any cause or non-
intubation during your 
hospitalization. 
Qualitative 
Nominal 
(dichotomous): 
Yes 
No 
 
Independent variable 
Variable 
Conceptual 
definition 
Operational 
definition 
Type 
Measurement scale 
(years) 
Age 
Time elapsed from 
the 
birth 
of 
a 
person to a certain 
moment. 
The age recorded in 
the clinical record at 
the 
patient's 
admission 
to 
the 
hospital 
will 
be 
considered. 
Discrete 
quantitative 
1. 18 a 27  
2. 28 a 37  
3. 38 a 47  
4. 48 a 57  
5. 58 a 67  
6. 68 a 77  
7. 78 a 87  
8. 88 a 97  
9. >97  
Gender 
Social concepts of 
functions, 
behaviors, 
activities 
and 
attributes for men 
and women. 
Gender 
that 
is 
registered 
in 
the 
clinical record 
Qualitative 
nominal 
Male  
Female 
Prone position 
What is called the 
prone position 
Record in the record 
of the placement of 
the patient in the 
prone position for a 
minimum of 2 hours. 
Qualitative 
Nominal 
(dichotomous): 
Yes 
No 
Type of oxygen 
support 
supplied 
Device used for 
supplemental 
oxygen 
administration. 
Record in the clinical 
record of the type of 
oxygen supplied. 
Qualitative 
nominal 
1. Nasal cannulas 
2. High flow nasal 
cannulas 
3. Face mask 
4. Other 
Partial 
oxygen 
saturation index 
(SpO2) 
/ 
inspired oxygen 
fraction (FiO2) 
Resulting index for 
SpO2 / FiO2 ratio 
2 index records will 
be 
taken 
at 
admission and the 
second 
after 
the 
patient's 
prone 
position, recorded in 
the clinical record. 
Discrete 
quantitative 
1. 100 a 150 
2. 151 a 200 
3. 201 a 250 
4. 251 a 300 
5. 301 a 350 
 

 
Confusing variables 
Variable 
Conceptual 
definition 
Operational 
definition 
Type 
Measurement scale 
Comorbidities 
Presence of 
one or more 
disorders 
in 
addition 
to 
the 
primary 
disease 
or 
disorder 
Registration in the 
clinical record of any 
of the comorbidities 
described. 
Qualitative 
nominal 
1.- Diabetes mellitus 
2.- 
Systemic 
arterial 
hypertension 
3.- 
Chronic 
obstructive 
pulmonary disease 
4.- Obesity 
5.- Chronic kidney disease 
6.- Ischemic heart disease 
7.- Other heart diseases 
8.- Other diseases 
Pharmacotherapy 
Drugs given 
to treat the 
disease 
Registration in the 
clinical record of the 
described 
management. 
Qualitative 
nominal 
1. Antivirals 
2. Hydroxychloroquine 
3. Antibiotics 
4. Corticosteroids 
5. Immunomodulators 
6. Others 
 
 
Sample size calculation 
For the calculation of the sample size, the case of previous studies that explored this same 
relationship will be taken as the basis, using the following formula: 
n = (N) (Zα/2)2 (p)(q) / (N-1) (E)2 + (Zα/2)2 (p)(q) 
Where 
• N = total infected population in Mexico (8463) Source: SISVER, SINAVE, DGE, SSA, 
May 12, 2020. 
• Z α/2 = 95% bilateral confidence level (1.96) 
• p = 50% success rate (0.5) 

• q = 50% failure rate (0.5) 
• E = 5% error range (0.05) 
 
Substituting the values 
n = (8463) (1.96)2 (0.5) (0.5) / (8463 – 1) (0.05)2 + (1.96)2 (0.5) (0.5) 
n = 368 patients. 
Statistical analysis 
Descriptive statistics, measures of central tendency, measures of dispersion and standard deviation 
will be used. 
While for the qualitative variable’s frequency measures (relative, absolute and percentage) were 
used. Relative risk will be performed with a 95% confidence interval of significance (95% CI) and 
contingency tables. 
For inferential statistics, the difference in proportions between the dependent (orotracheal 
intubation) and independent (prone position) variables will first be verified based on the number 
of expected observations (<5) Fisher's exact test or (> 5) Chi square test, contrasting H0: ɸ = 1, 
taking p <0.05 as a statistically significant value. 
A multivariate analysis will be used to generate linear regression models with the different 
variables: prone time, age, gender and orotracheal intubation, SpO2 / FiO2 index in order to 
explain their interactions (if the time in prone, age or gender affects the main objective) as well as 
adopting the best model that matches the observations (best R2, AIC) as a predictive model. 
The results will be presented in graphs and / or tables as appropriate. 
 
 
 
Ethical considerations 
This research project will be carried out under the ethical precepts indicated in the General 
Health Law, Regulation on Health Research, Official Mexican Standard 012. It is an 
investigation without risk for the research subjects, data will be obtained from the clinical record 
of patients diagnosed with COVID-19. The group of researchers commits to the confidentiality 
of the data of the files, as well as to safeguard the identities of the patients and for academic and 
scientific purposes. Within the scope of this study, it is to favor the implementation of the 
awaking prone position of the patients with COVID-19 that contributes to improving 
oxygenation. 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bibliography 
 
1. Valter C, Christensen A, Tollund C, Schønemann N. Response totheprone position 
in spontaneously breathing patients with hypoxemic respiratory failure; Act 
AnaesthesiolScand. 2003; 47: 416 - 418. 
https://doi.org/10.1034/j.1399-6576.2003.00088.x 
 
2. Scaravilli V, Grasselli G, Castagna L, et al. Prone positioning improves oxygenation 
in spontaneously breathing non intubated patients with hypoxemic acute respiratory 

failure: A retrospective study. J Crit Care. 2015; 30 (6): 1390-1394. https://doi: 
10.1016/j.jcrc.2015.07.008. 
 
3. 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. 
https://doi: 10.1186/s13054-020-2738-5. 
 
4. Pérez-Nieto OR, Guerrero-Gutiérrez MA, Deloya-Tomas E, et al. Prone positioning 
combined with high-flow nasal cannula in severe noninfectious ARDS. Crit Care. 
2020; 24: 114. https://doi.org/10.1186/s13054-020-2821-y 
 
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and intervention: experience from Jiangsu Province Ann. Intensive Care. 2020; 
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https://doi.org/10.1111/acem.13994 
 
7. Slessarev M, Cheng J, Ondrejicka M, Arntfield R. Patientself-proningwithhigh-flow 
nasal cannulaimprovesoxygenation in COVID-19 pneumonia. Can J Anaesth. 2020 
[Apr 20]. https://doi: 10.1007/s12630-020-01661-0. 
 
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Information gathering instrument 
 
Case 
Gender 
Age 
Comorbidities 
Type of 
oxygen 
support 
supplied 
Pharmacotherapy 
Awake 
prone 
position 
(Yes/no) 
Time 
of 
Awake 
prone 
position 
(hours) 
 
Initial 
SaO2/FiO2  
SaO2/FiO2 
before to the 
prone 
position 
Prone 
position 
(hours) 
 
Intubation 
Yes/No