Re-Evaluation of the Effects of High PEEP During General Anesthesia For Surgery - An Individual Patient Data Meta-Analysis of PROVHILO, iPROVE and PROBESE
Conditions: Surgery, Mechanical Ventilation Complication, Pulmonary Complication
Sponsor: Hospital Israelita Albert Einstein

 
 
 
 
   
  
 
 
Study Protocol 
 
Contribution of chemical and mechanical power to 
postoperative 
pulmonary 
complications: 
post 
hoc 
analysis 
of 
three 
randomized 
clinical 
trials 
of 
intraoperative ventilation 
 
Principal Investigator: 
Lukas Müller-Wirtz, MD  
Department of Outcomes Research 
Anesthesiology Institute, Cleveland Clinic 
9500 Euclid Ave — L10, Cleveland, OH 44195. 
Email: muellel2@ccf.org; lukas@muellerwirtz.de; 
Web: www.OR.org 
Co-Investigators: 
Marcus J. Schultz, MD, PhD 
Marcelo Gama de Abreu, MD, PhD 
Daniel I Sessler, MD 
Thijs A. Lilien, MD 
David M.P. van Meenen, MD 
Sascha Ott, MD 
Will Patterson, BSc 
and the REPEAT investigators 
Protocol Version and Date: 
Short title: 
Version 7 (September/11/2023) 
ClinHILI (Clinical Hyperoxia-Induced Lung Injury) 
 
 
 
 
 
A collaborative research project of the Department of Outcomes Research, 
Cleveland Clinic and the Departments of Anesthesiology and Intensive Care, 
Amsterdam University Medical Center. 
 
 

 
 
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1. BACKGROUND 
Supplemental oxygen exposes lung tissue to increased oxidative stress which may provoke hyperoxia-
induced lung injury (HILI).1 Intraoperative exposure to high inspiratory oxygen concentrations is 
associated with postoperative pulmonary complications, multiorgan injury, and mortality.2,3 While some 
trials did not detect substantial pulmonary harm,4–6 others showed higher severities of postoperative 
pulmonary concentrations and an increase in postoperative atelectasis after exposure to high inspiratory 
oxygen concentrations.7,8 Despite potential risks, high intraoperative inspiratory oxygen fractions are 
frequently applied,9 most often justified by increased safety margins for airway complications and low-
grade evidence for a reduction in postoperative wound infections.10,11 Although best practice for the use 
of intraoperative oxygen remains controversial, guidelines recommend rather high inspiratory oxygen 
fractions to reduce the risk of postoperative surgical complications.12–15 
Stretching lung tissue is the major mechanism by which mechanical ventilation injures the lung.16 The 
relatively new concept of mechanical power summarizes the mechanical energy transferred from the 
ventilator to the respiratory system which is associated with lung injury.17–22 However, mechanical power 
disregards potential oxygen-related harm. Therefore, an equivalent concept for the exposure to oxygen 
– chemical power – was recently proposed.23 Chemical power estimates the exposure of lung tissue to 
the amount of energy produced by reactive oxygen species resulting from supplemental inspiratory 
oxygen.23 Given the controversial discussion on the intraoperative use of oxygen and the limited number 
of studies on its relationship with lung injury, an evaluation of how harm is balanced between chemical 
and mechanical power is of considerable interest. 
Preclinical experiments suggest that lung tissue exposed to high mechanical power may be especially 
susceptive to oxidative injury, whereas lung tissue might be resilient to high oxygen concentrations when 
mechanical power is low.24–31 An evaluation of harm from chemical and mechanical power should thus 
include the extent to which hyperoxia-induced lung injury depends on the concomitant exposure to 
mechanical power. 
We therefore aim to evaluate the effects of the chemical and mechanical power on postoperative 
pulmonary complications in combined data from three randomized trials that were designed to assess 
relationships between intraoperative ventilator settings, especially positive end-expiratory pressure 
(PEEP), and postoperative pulmonary complications. Additionally, we will test for harm thresholds and 
evaluate the interaction between chemical and mechanical power. Specifically, we seek to identify harm 
thresholds for chemical and mechanical power and will test the hypothesis that there is a synergistic 
interaction between chemical and mechanical power, such that lung injury is most apparent when the 
two are combined. 
1.1 Significance 
More than 300 million surgeries are performed world-wide each year, mostly with general anesthesia 
and mechanical ventilation.32 Despite frequent use of supplemental intraoperative oxygen, best practice 
remains unclear. Previous research largely focused on the effect of intraoperative supplemental oxygen 
on postoperative wound infections, while leaving potentially detrimental effects on the lung aside. 
Results of this analysis will provide indispensable evidence for clinicians about the effects of 

 
 
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intraoperative supplemental oxygen on postoperative lung injury, its balance and interaction with 
mechanical forces dissipated to the lung, and thresholds of harm. 
2. STUDY OBJECTIVES  
2.1 Primary Aim & Hypothesis 
Primary Aim: To evaluate the relative contributions of intraoperative chemical and mechanical power 
on postoperative pulmonary complications within seven days after surgery. 
Primary Hypothesis: Compared to intraoperative mechanical power, chemical power contributes less 
to postoperative postoperative pulmonary complications within seven days after surgery. 
 
2.2 Secondary Aims & Hypotheses 
Secondary Aim 1: To identify the thresholds of harm for the associations of intraoperative chemical 
and mechanical power with postoperative pulmonary complications within seven days after surgery. 
Secondary Hypothesis 1: The exposures to intraoperative chemical and mechanical power have 
thresholds of harm (inflection points) from which on the risk for postoperative pulmonary complications 
within seven days after surgery increases substantially. 
 
Secondary Aim 2: To evaluate the interaction between the intraoperatively applied chemical and 
mechanical power on postoperative pulmonary complications within seven days after surgery. 
Secondary Hypothesis 2: Chemical power-related harm largely depends on the concomitantly applied 
mechanical power, meaning that chemical power causes significantly more postoperative pulmonary 
complications within seven days after surgery when exposed to high intraoperative mechanical power. 
3. METHODS 
3.1 Study Design and Population 
We will perform a post hoc analysis of the previously combined dataset named ‘Re–evaluation of the 
Effects of High PEEP with Recruitment Manoeuvres versus Low PEEP without Recruitment Manoeuvres 
During General Anaesthesia for Surgery’ (REPEAT), registered at ClinicalTrials.gov: NCT03937375 on 
3rd May 2019. This dataset merged the individual patient data from three RCTs, the ‘High versus low 
positive end–expiratory pressure during general anesthesia for open abdominal surgery’ (PROVHILO) 
study (registered with Controlled-Trials.com: ISRCTN70332574), the ‘Individualized perioperative 
open–lung approach versus standard protective ventilation in abdominal surgery’ (iPROVE) study 
(registered with ClinicalTrials.gov: NCT02158923) and the ‘Effect of intraoperative high positive end–
expiratory pressure with recruitment manoeuvres vs low PEEP on postoperative pulmonary 
complications in obese patients’ (PROBESE) study (registered with ClinicalTrials.gov: NCT02148692). 

 
 
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3.2 Ethics 
The Amsterdam UMC institutional review board (IRB) is the IRB of reference. According to local 
standards at Amsterdam UMC, no additional IRB approval and no additional individual consent aside 
those previously obtained for the underlying prospective trials are necessary. 
3.3 Data Management 
Data will be made available in an Amsterdam UMC remote working environment equipped with the 
applicable statistical software to perform the statistical analysis (R, Rstudio, etc.). Investigators of the 
Cleveland Clinic that are involved in the statistical analysis will get an Amsterdam UMC guest account 
enabling access to the remote working environment. No individual patient data will be transferred 
between the involved institutions during this project. 
3.4 Exposures 
Chemical and mechanical power will be calculated in hourly intervals during intraoperative ventilation. 
Time−weighted average chemical and mechanical power will be calculated as the area under the driving 
pressure and mechanical power time curve divided by the number of hours of exposure for quantifying 
cumulative exposure. 
3.4.1 
Primary Exposure 
Chemical power calculated according to Lilien et al. [Lilien et al. 2023]: 
Step 1: Estimation of local superoxide (O2-) production (PulmROS) from lung oxygen consumption as a 
function of FIO2 
𝑃𝑢𝑙𝑚𝑅𝑂𝑆 =  1.7 ∗10−5 + ( (𝐹𝑖𝑂2 −0.21) × 1.63 ∗10−4) (mol/min) 
Step 2: Calculate chemical power (CP) from step 1 based on the first electron affinity of oxygen (141 
kJ/mol). 
CP = 141000 × 𝑃𝑢𝑙𝑚𝑅𝑂𝑆 (J/min) 
3.4.2 
Secondary Exposure 
Since plateau pressure was not recorded in every patient, dynamic driving pressure will be calculated 
as peak pressure – PEEP and dynamic mechanical power will be calculated according to the following 
formula: 
𝑀𝑃= 0.098 ∗𝑉𝑡∗𝑅𝑅∗(𝑃𝑝𝑒𝑎𝑘−0.5 ∗𝛥𝑃𝑖𝑛𝑠𝑝) 
3.5 Outcome 
3.5.1 
Primary Outcome 
Collapsed composite outcome of postoperative pulmonary complications (PPCs) during the first seven 
postoperative days according to the definitions of the underlying studies presented in table 1. 

 
 
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Table 1. Definitions of postoperative pulmonary complications. 
 
PROVHILO 
iPROVE 
PROBESE 
Mild respiratory failure 
PaO2 < 60 mmHg or SpO2 
< 90% breathing at least 10 
minutes of room air but 
responding to supplemental 
oxygen of 2 L/minute 
SpO2 < 92% with FiO2 of 
0.21 or SpO2 < 95% with 
FiO2 of 0.50 
PaO2 < 60 mmHg or SpO2 
< 90% breathing at least 10 
minutes of room air but 
responding to supplemental 
oxygen of 2 L/minute 
Severe respiratory failure 
PaO2 < 60 mmHg or SpO2 
< 90% breathing ≥ 10 
minutes of room air but 
responding only to 
supplemental oxygen > 2 
L/minute or need for 
noninvasive or invasive 
mechanical ventilation 
Increased FiO2, increased 
requirement for CPAP, or 
the need for noninvasive or 
invasive ventilation 
PaO2< 60 mmHg or SpO2 < 
90% breathing ≥ 10 minutes 
of room air but responding 
only to supplemental oxygen 
> 2 L/minute or need for 
noninvasive or invasive 
mechanical ventilation 
ARDS 
AECC criteria* 
Berlin criteria** 
Berlin criteria** 
Pulmonary infection 
Need of antibiotics and at 
least one of the following 
criteria: new or changed 
sputum, new or changed 
lung opacities on chest X-
ray when clinically indicated, 
tympanic temperature 
>38.3°C, WBC count 
>12,000/μl in the absence of 
other infectious focus 
Presence of a new 
pulmonary infiltrate and/or 
progression of previous 
pulmonary infiltrates on a 
chest radiograph plus at 
least two of the following 
criteria: (a) leukocytosis with 
> 12,000 WBC/mm3 or 
leukopenia with < 4000 
WBC/mm3, (b) fever > 
38.5°C or hypothermia < 
36°C, and (c) increased 
secretions with purulent 
sputum and a positive 
bronchial aspirate 
Presence of a new 
pulmonary infiltrate and/or 
progression of previous 
pulmonary infiltrates on a 
chest radiograph plus at 
least two of the following 
criteria: (a) leukocytosis with 
> 12,000 WBC/mm3 or 
leukopenia with < 4000 
WBC/mm3, (b) fever > 
38.5°C or hypothermia < 
36°C, and (c) increased 
secretions with purulent 
sputum and a positive 
bronchial aspirate 
Pleural effusion 
Chest radiography with the 
presence of costophrenic 
angle blunting, displacement 
of adjacent anatomical 
structures, and blunting of 
the hemidiaphragmatic 
silhouette in the supine 
position 
Chest radiography with the 
presence of costophrenic 
angle blunting, displacement 
of adjacent anatomical 
structures, and blunting of 
the hemidiaphragmatic 
silhouette in the supine 
position 
Chest radiography with the 
presence of costophrenic 
angle blunting, displacement 
of adjacent anatomical 
structures, and blunting of 
the hemidiaphragmatic 
silhouette in the supine 
position 
Atelectasis 
Chest radiography with lung 
opacification with shift of the 
mediastinum, hilum, or 
hemidiaphragm towards the 
affected area, and 
compensatory overinflation 
in the adjacent non-
atelectatic lung 
Combination of SpO2 ≤ 96% 
during the air test and chest 
radiography with lung 
opacification with shift of the 
mediastinum, hilum, or 
hemidiaphragm towards the 
affected area, and 
compensatory overinflation 
in the adjacent non-
atelectatic lung 
Chest radiography with lung 
opacification with shift of the 
mediastinum, hilum, or 
hemidiaphragm towards the 
affected area, and 
compensatory overinflation 
in the adjacent non-
atelectatic lung 
Pneumothorax 
Chest radiography with air in 
the pleural space with no 
vascular bed surrounding 
the visceral pleura 
Chest radiography with air in 
the pleural space with no 
vascular bed surrounding 
the visceral pleura 
Chest radiography with air in 
the pleural space with no 
vascular bed surrounding 
the visceral pleura 
Bronchospasm 
Presence of expiratory 
wheezing treated with 
bronchodilator 
Presence of expiratory 
wheezing treated with 
bronchodilator 
Presence of expiratory 
wheezing 
ARDS: Acute Respiratory Distress Syndrome; SIRS: systemic inflammatory response syndrome; AECC: American–European consensus conference; WBC: White blood 
cells; PaO2: Arterial oxygen pressure: SpO2: peripheral oxygen saturation; FiO2: inspired oxygen fraction. 
*Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical 
trial coordination. The Consensus Committee. Intensive Care Med 1994;20:225–232. 
**Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526–2533. 
 
3.6 Statistical Analysis 
3.6.1 
Descriptive statistics 
The following variables will be descriptively presented, and additionally grouped by low, moderate, 
marked, and substantial chemical power (<25%, 25-50%, 50-75%, and 75-100% quantile of mechanical 
power), and considered as potential confounders (*) for the inferential statistics. Mean (standard 
deviation), median (interquartile range), frequency (percentage) will be reported based on variable type 

 
 
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and distribution. 
Demographics 
• 
Age * 
• 
Sex * 
• 
Height (cm) 
• 
Weight (kg) 
• 
BMI (kg/m2) * 
• 
ASA physical status * 
• 
Trial * 
Respiratory risk factors 
• 
ARISCAT score * 
• 
Preoperative SpO2 * 
• 
Respiratory infection within the past month * 
• 
Anemia * 
Coexisting conditions 
• 
Heart failure * 
• 
Chronic obstructive pulmonary disease * 
• 
Cancer * 
Surgery characteristics 
• 
Preoperative hemoglobin (g/dL) * 
• 
Type of surgery (abdominal versus non-abdominal) * 
• 
Specific procedure 
• 
Surgical approach (laparoscopic versus non-laparoscopic) * 
• 
Year of surgery * 
• 
Emergency or elective procedure * 
• 
Duration of surgery * 
Intraoperative mechanical ventilation parameters 
• 
Tidal volume (Vt) 
• 
Respiratory rate (RR) 
• 
Peak pressure (Pinsp) 
• 
Driving pressure (ΔPinsp) 
• 
Inspiratory oxygen fraction (FiO2) 
• 
Positive end-expiratory pressure (PEEP) * 
• 
Exposures: chemical power and mechanical power 
• 
Ventilation mode (VCV vs. PCV) 
3.6.2 
Inferential statistics 
Primary aim:  
We will summarize intraoperative chemical and mechanical power by calculating time-weighted 
averages for each patient. The influence of the intraoperatively applied time-weighted average chemical 
and mechanical power on composite postoperative pulmonary complications will be evaluated by 
multivariable logistic regression – estimating the odds ratios related to the effect of 1 unit increase in 
chemical or mechanical power. The regression model will be calculated with and without the above-
mentioned confounders. We will consider the exclusion of a potential confounder if its inclusion results 
in a change in the regression coefficients (beta) for both exposures of less than 10%. 

 
 
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Secondary aim 1: 
The relationship between varying levels of chemical / mechanical power and postoperative pulmonary 
complications will be analysed via multivariable logistic regression including cubic splines with up to five 
knots of chemical and mechanical power. We will further evaluate whether chemical and mechanical 
power have an upper threshold of harm, whereafter the odds for PPCs increase substantially by means 
of threshold regression. We will consider a 5% change in slope as clinically relevant, although there is 
no established minimal clinically important difference for PPCs, and this definition remains arbitrary. 
Secondary aim 2: 
We will evaluate the interaction between chemical power and mechanical power by implementing an 
interaction term for the intraoperatively applied time-weighted average mechanical power in the 
multivariable regression model performed to evaluate the primary aim. Additionally, we will analyse the 
effect of chemical and mechanical power on PPCs for 5 subsets of the study population stratified by 
chemical or mechanical power for each of the following patterns: 1) increasing chemical power and 
matched mechanical power, 2) matched chemical power and increasing mechanical power, 3) 
increasing chemical power and decreasing mechanical power, and 4) increasing chemical power and 
increasing mechanical power. Data will also be graphically presented with a 3D surface plot showing 
chemical and mechanical power on the x- and z-axes and the percentage of PPCs on the y-axis. 
Therefore, the population will be divided into equally sized groups including an certain fraction of patients 
of the ranges of both exposures. 
3.6.3 
Tables and figures (planned) 
Table 1: Patient characteristics 
Demographics, respiratory risk factors, coexisting conditions, and surgery characteristics will be 
descriptively presented, grouped by low, moderate, marked, and substantial chemical power (<25%, 
25-50%, 50-75%, and 75-100% quantile of mechanical power). 
Table 2: Intraoperative mechanical ventilation parameters (alternatively as figure) 
Intraoperative mechanical ventilation parameters will be descriptively presented, grouped by low, 
moderate, marked, and substantial chemical power (<25%, 25-50%, 50-75%, and 75-100% quantile of 
mechanical power) 
Figure 1: CONSORT diagram 
Figure 2: Ranges of chemical, mechanical, and mechanochemical power quartiles 
Barplots showing the ranges of time-weighted averages of chemical, mechanical, and 
mechanochemical power for patients with low (first quartile: <25%), moderate (second quartile: 25-50%), 
marked (third quartile: 50-75%), and substantial (fourth quartile: 75-100%) power. 
Figure 3 a/b (take-away-figure): Chemical and mechanical versus the risk of PPCs. 
Smoothed spline regression curves with the odds ratios for each spline presenting the risk for PPCs 
over the observed ranges of chemical (a), and mechanical power (b). 

 
 
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Figure 4 a/b/c: Stratified analysis of chemical and mechanical power on PPCs 
Bar plots on top: a) increasing chemical power and matched mechanical power, b) matched chemical 
power and increasing mechanical power, c) increasing chemical power and decreasing mechanical 
power, and d) increasing chemical power and increasing mechanical power. Error bars on bottom: 
corresponding relative risks of PPC, calculated for each subsample; error bars represent the 95% 
confidence interval. 
Figure 5 (alternative take-away-figure): Chemical and mechanical versus the risk of PPCs 
A 3D surface plot with chemical and mechanical power on the x- and z-axes and the percentage of 
PPCs on the y-axis. The population will be divided into equally sized groups including an applicable 
fraction of patients of the ranges of both exposures. 
3.6.4 
Sample size considerations 
We do not perform a formal power calculation; instead, the available number of patients in the pooled 
dataset serves as the sample size. 
3.6.5 
Limitations 
We are aware of several limitations of our analyzes. (1) Although the database was derived from trials, 
our study is observational, meaning we may detect associations but not establish causality. (2) Due to 
a widespread use of lung-protective mechanical ventilation exposure to higher ranges of mechanical 
power is presumably rare. (3) The use of supplemental oxygen (FiO2) is potentially highly confounded 
by underlying pulmonary risk and patients’ intraoperative responses to surgery and mechanical 
ventilation. (4) The underlying trials used slightly different definitions of postoperative pulmonary 
complications, adding further variability and potential bias to the results. 
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