PRactice of VENTilation in COVID-19 Patients (PRoVENT-COVID) - an Observational Study of Invasively Ventilated Patients in the Netherlands
Conditions: COVID, Mechanical Ventilation, Acute Respiratory Failure
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

 
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NCT04346342 – Protocol with updated analysis plan – June 1, 2020 
 
 
 
PRactice of VENTilation in 
COVID–19 patients (PRoVENT-
COVID) – an observational study 
of invasively ventilated patients 
in the Netherlands 
 
 
Noor Boers1, Michela Botta1, Anissa Tsonas1, Anna Geke Algera1, Janesh Pillay1, 
Dave Dongelmans1, Janneke Horn1, Alexander Vlaar1, Markus Hollmann2, Lieuwe 
Bos1, Frederique Paulus1,3,Ary Serpa Neto4, Marcus J. Schultz1,5,6 for the PRoVENT–
COVID collaborators 
 
 
Amsterdam University Medical Centers, location ‘Academic Medical Center’, 
Amsterdam, The Netherlands: 
1Department of Intensive Care 
2Department of Anesthesiology 
 
Amsterdam University of Applied Sciences, Faculty of Health, Amsterdam, The 
Netherlands: 
3ACHIEVE, Centre of Applied Research 
 
Hospital Israelita Albert Einstein; São Paulo, Brazil: 
4Department of Critical Care Medicine 
 
Mahidol University, Bangkok, Thailand: 
5Mahidol–Oxford Tropical Medicine Research Unit (MORU) 
 
University of Oxford, Oxford, United Kingdom: 
6Nuffield Department of Medicine 
 
 
Correspondence: 
Prof. M.J. Schultz, MD PhD 
Department of Intensive Care 
C3-423 
Meibergdreef 9 
1105 AZ Amsterdam 
The Netherlands 

 
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Email: m.j.schultz@amsterdamumc.nl 

 
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TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 7 
1.1 
The coronavirus disease 2019 ............................................................................... 7 
1.2 
Lung protective ventilation ..................................................................................... 7 
1.3 Need for an observational study on ventilator settings ................................................. 7 
2. 
OBJECTIVES AND HYPOTHESIS ................................................................................. 9 
2.1 
Objectives .............................................................................................................. 9 
2.1.1 
Primary objective ................................................................................................ 9 
2.1.2 
Secondary objective ........................................................................................... 9 
2.2 
Hypothesis ............................................................................................................. 9 
2.2.1 
Primary hypothesis ............................................................................................. 9 
2.2.2 
Secondary hypothesis ........................................................................................ 9 
3. 
STUDY DESIGN ...........................................................................................................10 
4. 
STUDY POPULATION ..................................................................................................11 
4.1 
Population (base) ..................................................................................................11 
4.2 
Inclusion criteria ....................................................................................................11 
4.3 
Exclusion criteria ...................................................................................................11 
4.4 
Sample size calculation .........................................................................................11 
5. 
METHODS ....................................................................................................................12 
5.1 
Study parameters/endpoints .................................................................................12 
5.1.1 
Main study parameters ......................................................................................12 
5.1.2 
Secondary study parameters.............................................................................12 
5.2 
Randomisation, blinding and treatment allocation .................................................12 
5.3 
Study procedures ..................................................................................................12 
5.4 
Data collection ......................................................................................................13 
5.4.1 
Demographic data .............................................................................................13 
5.4.2 
Data on day of intubation OR admission to ICU if transferred from another 
hospital with mechanical ventilation ...............................................................................13 
5.4.3 
Repeated measures ..........................................................................................13 
5.5 
Withdrawal of individual subjects...........................................................................15 
5.6 
Replacement of individual subjects after withdrawal .............................................15 
5.7 
Follow-up of subjects withdrawn from treatment ....................................................15 
5.8 
Premature termination of the study .......................................................................15 
6. 
SAFETY REPORTING ..................................................................................................16 
6.1 
Temporary halt for reasons of subject safety .........................................................16 
6.2 
Serious adverse events (SAEs) ............................................................................16 
6.3 
Follow-up of adverse events .................................................................................16 
6.4 
Data Safety Monitoring Board (DSMB) ..................................................................16 
7. 
STATISTICAL ANALYSIS .............................................................................................17 
8. 
ETHICAL CONSIDERATIONS ......................................................................................19 
8.1 
Regulation statement ............................................................................................19 
8.2 
Recruitment and consent ......................................................................................19 
8.3 
Benefits and risks assessment, group relatedness ................................................19 

 
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8.4 
Compensation for injury ........................................................................................19 
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................20 
9.1 
Handling and storage of data and documents .......................................................20 
9.2 
Monitoring and Quality Assurance.........................................................................20 
9.3 
Amendments .........................................................................................................20 
9.4 
Annual progress report ..........................................................................................20 
9.5 
Temporary halt and (prematurely) end of study report ...........................................20 
9.6 
Public disclosure and publication policy ................................................................20 
10. 
REFERENCES .........................................................................................................21 

 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
AKI 
Acute Kidney Injury 
APACHE 
Acute Physiology And Chronic Health Evaluation 
ARDS 
Acute Respiratory Distress Syndrome 
COVID-19 
Coronavirus disease 2019  
DP 
Driving Pressure 
EtCO2 
End-tidal Carbon Dioxide 
FiO2 
Fraction of inspired Oxygen 
HCO3- 
Bicarbonate 
IBW 
Ideal Body Weight 
ICU 
Intensive Care Unit 
I:E ratio 
Inspiratory : Expiratory ratio 
NIV 
Non-invasive ventilation  
Pmax 
Maximum airway pressure  
Ppeak 
Peak pressure 
Pplateau 
Plateau pressure 
PaO2 
Partial Arterial Pressure of Oxygen 
PaCO2 
Partial Arterial Pressure of Carbon Dioxide 
PBW 
Predicted Body Weight 
PEEP 
Positive End–Expiratory Pressure 
RR 
Respiratory Rate 
RRSET 
Set Respiratory Rate 
SaO2 
Saturation of Arterial Oxygen 
SAPS 
Simplified Acute Physiology Score 
SARS–CoV–2 
Severe acute respiratory coronavirus–2 
SD 
Standard Deviation 
SOFA 
Sequential Organ Failure Assessment Score 
SpO2 
Saturation of peripheral Oxygen 
VT 
Tidal Volume 
VILI 
Ventilator induced lung injury 
VTE 
Expiratory tidal volume  
 

 
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SUMMARY 
Rationale 
The novel coronavirus disease (COVID–19) pandemic is rapidly expanding across the 
world, with over 60.000 new cases each day as of late March 2020. Healthcare workers 
are struggling to provide the best care for patients with proven or suspected COVID–
19. Approaches for clinical care vary widely between and within countries and new 
insights are acquired rapidly. This includes the way invasive ventilation is applied. 
Objective 
To determine and compare invasive ventilation settings and parameters in COVID–19 
patients in the Netherlands, and to determine associations with clinical outcomes. 
Hypotheses 
Invasive ventilation settings and parameters vary between intensive care units (ICUs) 
in hospitals in the Netherlands; certain ventilator settings have an independent 
association with duration of ventilation in COVID–19 patients. 
Study design 
National, multicenter, service review. 
Study population 
Invasively ventilated patients with proven or suspected COVID–19. 
Methods 
In every patient, granular ventilator settings and parameters are collected from start of 
invasive ventilation for up to 72 hours. Patients will be followed up until ICU and 
hospital discharge, and until day 90. 
Study endpoints 
Main ventilator settings (including tidal volume, airway pressures, oxygen fraction and 
respiratory rate) (primary) and parameters (blood gas results); use of rescue therapies 
(including prone positioning); use of sedatives, vasopressors and inotropes; daily 
cumulative fluid balances; development of kidney injury; ventilator–free days and alive 
at day 28 (VFD–28), duration of ICU and hospital stay, and ICU, hospital and 90–day 
mortality. 
Nature and extent of the burden and risks associated with participation, benefit 
and group relatedness 
Retrospective collection of data regarding ventilation management and major clinical 
endpoints is without risk for the individual patient. 
 

 
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1. INTRODUCTION AND RATIONALE 
1.1  The coronavirus disease 2019 
Coronavirus disease 2019 (COVID–19) is a lower respiratory tract infection caused by 
the severe acute respiratory coronavirus–2 (SARS–CoV–2), of which the first outbreak 
was reported in Wuhan, China in the beginning of December, 2019. Since then, it has 
rapidly spread across the globe, with over 60.000 new cases each day as of late March 
2020. 
Although most people who are infected by SARS–CoV–2 only develop mild 
symptoms, an estimated 5% of reported cases are admitted to the intensive care unit 
(ICU) because of severe hypoxemia and dyspnoea [1]. The majority of these patients 
have shown to require invasive ventilation, and in this group, the mortality is 
considerable [2]. 
1.2 Lung protective ventilation 
Although invasive ventilation can be a necessary supportive strategy in patients with 
respiratory failure, it also has the potential to worsen pre-existing lung injury or even 
initiate it [3]. ‘Ventilator-induced lung injury’ (VILI) is mainly due to overdistension of 
the lungs, and is associated with a longer duration of ventilation and a higher mortality 
[4]. Lung protective ventilation, featuring low tidal volume (VT), reduced inspiratory 
plateau pressure (Pplateau) [5] and low driving pressure (DP) [6] has been suggested to 
reduce the risk of mortality and is considered the standard of care ([7-10]. The benefit 
of high positive end–expiratory pressure (PEEP) remains uncertain, as does the use 
of recruitment maneuvers. There is evidence that high PEEP with recruitment 
maneuvers harms patients with ARDS [11]. It is highly uncertain whether high PEEP 
with recruitment maneuvers benefits COVID–19 patients. 
1.3 Need for an observational study on ventilator settings 
Due to the rapid spread of COVID–19, ICUs worldwide are being overloaded with 
patients requiring invasive ventilation and healthcare workers are struggling to provide 
the best care. Approaches in clinical care are already known to vary widely between 
countries and regions, including the way invasive ventilation is applied [12-15]. It is 
probable that these variances are amplified by a lack of consensus in treatment due to 
the novelty of COVID–19. Because invasive ventilation of itself has a strong potential 
to cause lung damage, these variances could be associated with a difference in 
patient–centered outcomes, like duration of ventilation and mortality. 

 
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Therefore, it is of the utmost importance to observe ventilation strategies that 
are currently being applied in the treatment of COVID–19 patients. To make haste in 
this time of crisis, we propose a national, observational, retrospective study that is 
focused on the inventory of ventilation parameters. This study will form an important 
first step in creating standard guidelines for invasive ventilation of COVID–19 patients. 
Implementation of standard guidelines could reduce mortality worldwide. 
 
 

 
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2. OBJECTIVES AND HYPOTHESIS 
2.1 Objectives 
2.1.1 
Primary objective 
To determine and compare invasive ventilation settings and parameters in COVID–19 
patients in intensive care units (ICU) of hospitals in the Netherlands. 
2.1.2 
Secondary objective 
To determine whether certain ventilation settings have an independent association with 
duration of ventilation. 
2.2 Hypothesis 
2.2.1 
Primary hypothesis 
There is substantial variation in ventilation practices in COVID–19 patients admitted to 
the ICU’s of hospitals in the Netherlands. 
2.2.2 
Secondary hypothesis 
Certain ventilation settings impact duration of ventilation. 

 
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3. STUDY DESIGN 
Multicenter, national, retrospective, observational study in COVID–19 patients with 
respiratory failure, requiring invasive ventilation in intensive care unit (ICU) settings in 
hospitals in the Netherlands. 

 
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4. STUDY POPULATION 
4.1 Population (base) 
The data of at least 1,000 consecutively invasively ventilated COVID–19 patients 
admitted to intensive care units (ICUs) of hospitals in the Netherlands. This study will 
not be restricted to the ‘formal’ ICUs, as patients may also receive invasive ventilation 
at other locations within the hospital during the COVID–19 pandemic. 
4.2 Inclusion criteria 
• COVID–19, confirmed with PCR and/or presence of typical abnormalities on 
chest computer tomography (CT) 
• Suspected COVID–19 infection, with no exclusion of diagnosis 
• Having received invasive ventilation 
4.3 Exclusion criteria 
• Age <18 years 
• Already included in the same study in another hospital 
• Having had received invasive ventilation > 24 hours in a non–participating 
hospital 
4.4 Sample size calculation 
No formal sample size calculation is needed. We expect to capture at least 1,000 
patients, but will continue collecting data of new patients for at least 8 weeks. 

 
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5. METHODS 
5.1 Study parameters/endpoints 
5.1.1 
Main study parameters 
• Ventilation mode; 
• Tidal volume set (VT) (mL); 
• Expiratory tidal volume (VTE) 
• Positive end–expiratory pressure (PEEP) (cm H2O); 
• Maximum airway pressure (Pmax) (cm H2O) or plateau pressure 
(Pplateau) or peak pressure (Ppeak) (cm H2O); 
• Level of pressure support above PEEP (cm H2O); 
• Inspired fraction of oxygen (FiO2) (%); 
• Set and measured respiratory rate (RR) (min-1); and 
• Inspiration to expiration ratio (I:E) (ratio). 
5.1.2 
Secondary study parameters 
• Number of ventilation–free days and alive at day 28 (VFD–28); 
• Duration of ventilation in survivors; 
• Use of prone positioning; 
• Use of recruitment maneuvers; 
• Incidence of acute kidney injury (AKI); 
• Duration of ICU stay; 
• Duration of hospital stay; 
• ICU mortality; 
• Hospital mortality; 
• 28-day mortality; and 
• 90-day mortality. 
5.2 Randomisation, blinding and treatment allocation 
Not applicable. 
5.3 Study procedures 
Patients will be included by the attending clinician. Participating centers will be visited 
by researchers to collect data of included patients. 

 
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5.4 Data collection 
5.4.1 
Demographic data 
• Age (age categories); 
• Gender (male or female); 
• Height (cm); 
• Weight (kg); 
• Medication (categories); and 
• Comorbidities (categories). 
5.4.2 
Data on day of intubation OR admission to ICU if transferred from 
another hospital with mechanical ventilation  
• Date of hospital admission; 
• Date of ICU admission; 
• Date and time of intubation (if possible, also in transferred patients); 
• Transferred under ventilation (if applicable) (yes or no); 
• Duration of ventilation in previous hospital (if applicable) (days); 
• Use of non-invasive ventilation (NIV) before intubation (yes or no) and 
if so, duration (hours); 
• Acute Physiology and Chronic Health (APACHE) II score or APACHE 
IV score, or Simplified Acute Physiology Score (SAPS) II;  
• Sequential Organ Failure Scores (SOFA); and 
• Plasma creatinine in 24 hours before admission/intubation (mmol/L) 
5.4.3 
Repeated measures 
o Within one hour after initiation of ventilation OR within first hour of arrival 
when the patient has been intubated in another hospital, AND 3 times a 
day at fixed time points (8:00 AM, and 4:00 PM and 8:00 PM) for a following 
3-day period: 
• Ventilation data 
o Ventilation mode; 
o Tidal volume set (VT) (mL); 
o Expiratory tidal volume (VTE); 
o Positive end–expiratory pressure (PEEP) (cm H2O); 

 
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o Maximum airway pressure (Pmax) (cm H2O) or plateau pressure 
(Pplateau) or peak pressure (Ppeak) (cm H2O); 
o Level of pressure support above PEEP (cm H2O); 
o Inspired fraction of oxygen (FiO2) (%); 
o Set an measured respiratory rate (RR) (min-1); 
o Inspiration to expiration ratio (I:E) (ratio); 
o Saturation of peripheral oxygen (SpO2) (%); and 
o End-tidal carbondioxide (ETCO2) (kPa). 
• Arterial blood gas (ABG) analysis 
o pH; 
o Partial pressure of oxygen (PaO2) (kPa or mmHg); 
o Partial pressure of carbon dioxide (PaCO2) (kPa or mm Hg); 
o Bicarbonate (HCO3-) (mmol/L); 
o Arterial saturation of oxygen (SaO2) (%); 
o Arterial lactate levels (mmol/L);  
o FiO2 (%) at time point of ABG; and 
o Position of patient in which ABG was taken. 
• Hemodynamics 
o Mean arterial pressure (mmHg); 
o Heart rate (bpm);  
o 3 times a day at fixed time points (8:00 AM, and 4:00 PM and 8:00 PM) for 
a following 3-day period: 
• Received paralytic drugs within the previous 8 hours (yes or no). 
o Every day at 8:00 AM for 72–hour period after admission 
• Life status (alive or deceased); 
• Location (in ICU, hospital or other facility); 
• Intubation status; 
• Sequential Organ Failure Scores (SOFA);  
• Cumulative dose of sedatives (mg); 
• Cumulative dose of vasopressors (mg); 
• Cumulative fluid balance during last 24 hours (ml); 
• Amount of fluid administered during last 24 hours (ml); 
• Urine output (ml/hour); and 

 
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• Plasma creatinine (mmol/L). 
• Prone position (yes or no), and if yes, time and duration (hours); 
• ABG in supine position;  
• Use of recruitment maneuver (yes or no); 
• Undergoing 
veno–venous, 
veno–arterial 
or 
arterio–venous 
extracorporeal membrane oxygenation (ECMO) (yes or no); 
• Pneumothorax (yes or no) 
o  Follow-up 
• Life status at day 7, day 28 and day 90; 
• Alive (yes or no), and if not, the date of passing; 
• Location (ICU, hospital, home); 
• Intubated (yes or no), and if not, extubation date; 
• Acute Kidney Injury (yes or no); 
• Date of discharge from ICU; and 
• Date of discharge from hospital. 
5.5 Withdrawal of individual subjects 
Not applicable. 
5.6 Replacement of individual subjects after withdrawal 
Not applicable. 
5.7 Follow-up of subjects withdrawn from treatment 
Not applicable. 
5.8 Premature termination of the study 
Not applicable. 

 
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6. SAFETY REPORTING 
6.1 Temporary halt for reasons of subject safety 
Not applicable. 
6.2 Serious adverse events (SAEs) 
Not applicable. 
6.3 Follow-up of adverse events 
Not applicable. 
6.4 Data Safety Monitoring Board (DSMB) 
 Not applicable. 
 

 
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7. STATISTICAL ANALYSIS 
Descriptive statistics will be used to describe the study population, and data are 
expressed in number and relative proportions for categorical variables and median 
(quartile 25% – quartile 75%) for continuous variables. 
As the outcome of this study is urgently needed, data analysis will be done in 
two sequential steps. The first step includes an analysis of all patients admitted for 
invasive ventilation in one of the participating ICUs in the first four weeks after 
admission of the first COVID–19 patients, which was in all centers within the first weeks 
of March 2020. This part of the analysis focusses on ventilation practices in the first 
weeks of the pandemic in the Netherlands. This analysis may underestimate the effect 
of ventilation variables and parameters on outcomes, as many patients will not yet be 
weaned from the ventilator and remain admitted in the ICU. The second step includes 
an analysis of all COVID–19 patients admitted during the total 10 weeks PRoVENT 
COVID will enroll patients, with a complete follow up till day 90. This analysis will 
provide an answer to the question whether certain ventilator settings, variables and 
parameters are associated with patient–centered and other important outcomes. 
All analyses will be performed using multilevel (patients nested in hospitals), 
mixed modelling with hospitals as random effect. Ventilatory variables and parameters 
will be compared among the groups, and absolute differences with the respective 
95%–confidence interval (CI) will be calculated as the absolute difference from a 
mixed–effect linear model considering the hospitals as random effect to account for 
within–center clustering. Categorical variables will be compared as the risk difference 
from the same model. 
Cumulative distribution plots will be used to demonstrate the cumulative 
distribution frequency of ventilation variables. Vertical dotted lines will represent the 
cut–off for each variable and the horizontal dotted lines the respective proportion of 
patients reaching each cut–off. Cut–offs to form matrices may use widely accepted 
values for each variable, specifically 8 mL/kg PBW for tidal volume, 10 cm H2O for 
PEEP, 30 cm H2O for plateau pressure, and 15 cm H2O for ΔP. 
Mixed–effect multivariable logistic or linear regression model will used to identify 
factors independently associated with major outcomes, like death and VFD–28. 
Subanalyses are planned to investigate differences in ventilation practice and 
outcomes in the following prespecified subgroups: women versus men, and patients 
categorized by the body mass index. 

 
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All analyses will be conducted in R v.3.60 and a p value < 0.05 will be 
considered statistically significant. 
 
 

 
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8. ETHICAL CONSIDERATIONS 
8.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki 
(revision Fortaleza, Brazil, October 2013). 
8.2 Recruitment and consent 
Since the proposed study concerns a service review, no research related interventions 
will take place. Therefore, no ethical concerns exist. As pseudo–anonymous data, 
which can no longer be attributed to a specific data subject will be used, there is no 
concern for informed consent. 
8.3 Benefits and risks assessment, group relatedness 
This study does not result in any risk or burdens to patients. 
8.4 Compensation for injury 
Not applicable. 

 
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9. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
9.1 Handling and storage of data and documents 
Subject data will be stored a pseudo–anonymized, which means that relating the 
individual data to identifiable patients would require disproportional effort. Used data 
as written in the case report form will not contain any identifiable or relatable data. All 
handling of personal data will comply with the General Data Protection Regulation and 
the ‘Reuse of care data for the purpose of research’ standard of the AMC. 
9.2 Monitoring and Quality Assurance 
Not applicable. 
9.3 Amendments 
Not applicable. 
9.4 Annual progress report 
Not applicable. 
9.5 Temporary halt and (prematurely) end of study report 
Not applicable. 
9.6 Public disclosure and publication policy 
Not applicable. 

 
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10. REFERENCES 
1.  
Guan, W.J., et al., Clinical Characteristics of Coronavirus Disease 2019 in 
China. N Engl J Med, 2020. 
2.  
Yang, X., 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. 
3.  
Slutsky, A.S. and V.M. Ranieri, Ventilator-induced lung injury. N Engl J Med, 
2014. 370(10): p. 980. 
4.  
Acute Respiratory Distress Syndrome, N., et al., Ventilation with lower tidal 
volumes as compared with traditional tidal volumes for acute lung injury and the 
acute respiratory distress syndrome. N Engl J Med, 2000. 342(18): p. 1301-8. 
5.  
Fan, E., et al., An Official American Thoracic Society/European Society of 
Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice 
Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory 
Distress Syndrome. Am J Respir Crit Care Med, 2017. 195(9): p. 1253-1263. 
6.  
Amato, M.B., et al., Driving pressure and survival in the acute respiratory 
distress syndrome. N Engl J Med, 2015. 372(8): p. 747-55. 
7.  
Esteban, A., et al., Evolution of mechanical ventilation in response to clinical 
research. Am J Respir Crit Care Med, 2008. 177(2): p. 170-7. 
8.  
Esteban, A., et al., Evolution of mortality over time in patients receiving 
mechanical ventilation. Am J Respir Crit Care Med, 2013. 188(2): p. 220-30. 
9.  
Matthay, M.A., L.B. Ware, and G.A. Zimmerman, The acute respiratory distress 
syndrome. J Clin Invest, 2012. 122(8): p. 2731-40. 
10. 
Needham, D.M., et al., Lung protective mechanical ventilation and two year 
survival in patients with acute lung injury: prospective cohort study. BMJ, 2012. 
344: p. e2124. 
11. 
Writing Group for the Alveolar Recruitment for Acute Respiratory Distress 
Syndrome Trial, I., et al., Effect of Lung Recruitment and Titrated Positive End-
Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute 
Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA, 2017. 
318(14): p. 1335-1345. 
12. 
Bellani, G., et al., Epidemiology, Patterns of Care, and Mortality for Patients 
With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 
Countries. JAMA, 2016. 315(8): p. 788-800. 

 
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13. 
Laffey, J.G., et al., Potentially modifiable factors contributing to outcome from 
acute respiratory distress syndrome: the LUNG SAFE study. Intensive Care 
Med, 2016. 42(12): p. 1865-1876. 
14. 
de Graaff, A.E., et al., Clinicians' response to hyperoxia in ventilated patients in 
a Dutch ICU depends on the level of FiO2. Intensive Care Med, 2011. 37(1): p. 
46-51. 
15. 
Simonis, F.D., et al., Potentially modifiable respiratory variables contributing to 
outcome in ICU patients without ARDS: a secondary analysis of PRoVENT. Ann 
Intensive Care, 2018. 8(1): p. 39.