The Full Closed Loop Ventilation Mode INTELLiVENT-ASV: User-friendly and Effective Mechanical Ventilation in High Risk Postoperative Patient on the Intensive Care Unit
Phase: NA
Conditions: Ventilators, Mechanical, Intensive Care Units, Postoperative Care
Sponsor: Catharina Ziekenhuis Eindhoven

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COVER PAGE 
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Full title: 
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The Full Closed Loop Ventilation Mode INTELLiVENT-ASV: 
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User-friendly and Effective Mechanical Ventilation in High Risk 
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Postoperative Patient on the Intensive Care Unit. 
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Brief title: 
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Postoperative INTELLiVENT-ASV Ventilation (POSITiVE). 
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Unique Protocol ID: 
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NL58975.100.16 
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NCT number: 
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NCT03180203 
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DOCUMENT: 
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Statistical analysis plan and protocol update. 
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VERSION & DATE OF DOCUMENT: 
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Version 1.0 from September 14, 2018. 
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Statistical analysis plan and protocol 
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update of the POSiTIVE study. 
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Ashley J.R. De Bie MD 1,2, Ary Serpa Neto MD MSc PhD 3,4,5 , David.M.P. 
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Meenen MD 3, Arthur R. A. Bouwman MD PhD6, Arnout.N. Roos MD PhD 1, Erik 
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H.M. Korsten MD PhD 2,6, Marcus J Schultz MD PhD,3,7,8, Alexander G.J.H. 
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Bindels MD PhD 1. 
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Catharina Hospital, Eindhoven, The Netherlands 
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1Department of Intensive Care 
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6Department of Anesthesiology 
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Technical University Eindhoven, Eindhoven, The Netherlands 
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2Department of Signal Processing Systems 
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Academic Medical Center, Amsterdam, The Netherlands 
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3Department of Intensive Care 
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7Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A) 
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Hospital Israelita Albert Einstein, São Paulo, Brazil 
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4Department of Critical Care Medicine 
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5Laboratory for Critical Care Research 
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Mahidol University, Bangkok, Thailand 
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8Mahidol Oxford Research Unit (MORU) 
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Version 1.0 from September 14, 2018. 
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Correspondence: 
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Ashley De Bie, MD 
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Department of Intensive Care, Catharina Hospital Eindhoven 
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Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands 
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E–mail: Ashley.d.bie@catharinaziekenhuis.nl 
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ABSTRACT 
BACKGROUND: INTELLiVENT-ASV is a fully closed ventilation mode that can 
automatically adjust ventilation settings in both passive and active ventilated 
patients. Current literature shows that this mode is safe to use in patients 
admitted on the intensive care unit. Compared to conventional modes of 
ventilation, INTELLiVENT-ASV may be even more effective in terms of lung 
protective ventilation compared to conventional mechanical ventilation, while 
being more user-friendly, since the ventilator regulates the ventilation 
automatically. However, randomized trials testing these hypotheses in 
postoperative high-risk patients are scarce. 
METHODS/DESIGN: The POSiTIVE trial was a prospective randomized 
controlled trial that compared conventional ventilation (continuous mandatory or 
pressure controlled ventilation with pressure support) with INTELLiVENT-ASV in 
postoperative high-risk cardiac surgery patients. The primary outcome was to 
compare the percentage of mechanical ventilation time  within the unacceptable 
zone between both groups. Secondary endpoints included comparing the 
percentage of mechanical ventilation time and breathings in the optimal and 
acceptable zones, time until extubation, number of successful extubations 
(without reintubation ≤48hours), the incidence of complications including 
pneumonia, atelectasis and pneumothorax, user-acceptance, number of 
ventilator alarms and interactions, and the course of mechanical ventilation 
parameters like tidal volume based on ideal body weight, driving pressure and 
mechanical power. 
DISCUSSION: Enrollment of patients was complete on April 19, 2018. The 30-
day follow–up for the last included patient was on the end of May, 2018. 

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Thereafter, the database will be cleaned and locked, which is expected on 
October 1, 2018. 
TRIAL REGISTRATION: The trial is registered at www.clinicaltrials.gov under 
reference number NCT03180203 on 08 June 2017. 
KEYWORDS: Mechanical ventilation, protective ventilation, intensive care unit,  
INTELLiVENT-ASV ventilation mode, Fully closed loop ventilation, 
postoperative ventilation.

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INTRODUCTION 
The POSiTIVE trial is a randomized clinical trial comparing two strategies of 
ventilation, the conventional ventilation and the full closed loop mode, in 
postoperative high-risk cardiac surgery patients admitted in the intensive care 
unit (ICU) [1]. The primary objective of this trial is to determine whether the 
percentage of ventilation time within the unacceptable zone is lower when 
patients are ventilated with INTELLiVENT-ASV compared to conventional 
ventilation (the combination of continuous mandatory or pressure controlled 
ventilation with pressure support) in the first three hours of ventilation or until 
extubation. Enrollment of patients started on the May 20, 2017, and completed 
on April 19, 2018. Follow–up of the last patient completed on the end of May, 
2018. Since data was collected in a breath by breath way, data collection and 
cleaning is expected to be complete within 6 months. Thereafter the database will 
be finally closed. 
Based on recommendations of the International Conference on 
Harmonization of Good Clinical Practice (ICH–GCP) a pre–specified detailed 
statistical analysis plan is conceived to prevent outcome reporting bias and data–
driven analysis results [2]. The present study update and statistical analysis plan 
are drafted without knowledge of outcome data. 

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METHODS 
Design 
This is a single center, randomized, controlled, pragmatic trial comparing two 
strategies of ventilation, the conventional ventilation and the full closed loop 
mode, in postoperative high-risk cardiac surgery patients admitted in the 
intensive care unit (ICU). The trial was conducted in the ICU of the Catharina 
hospital in The Netherlands, a tertiary teaching hospital, specialized in cardiac 
surgery. The trial protocol was registered in ClinicalTrials.gov (NCT03180203) 
and was approved by the Medical Research Ethics Committees United (MEC-U), 
Nieuwegein, The Netherlands, under reference number R16.054. 
 
Eligibility of the patients 
Consecutive patients that would be admitted to receive cardiac surgery were 
screened for eligibility. Patients received information of the trial on the day they 
had their preoperative anesthesia assessment and consent was obtained the day 
before surgery if the patient fulfilled the inclusion and exclusion criteria. Informed 
consent was asked from the patient in all cases before surgery. The patient was 
excluded if after randomization the consent was withdrew. 
 
Inclusion and exclusion criteria 
Inclusion criteria were an age >18 years old, elective cardiac surgery which 
included bypass, valve and ascending aortic surgery, a body mass index of < 35 
kg/m2, and postoperative treatment with mechanical ventilation on a high or 
intensive care unit. Exclusion criteria were, postoperative ARDS according to the 
Berlin definition [3], postoperative need for extracorporeal membrane 

7 
 
oxygenation, postoperative admission on the Post Anesthesia Care Unit (which 
was preoperatively determined by the anesthiologist), a medical history 
containing pneumonectomy, lobectomy or chronic obstructive lung disease 
GOLD 3 or 4 classification, and patients participating in another postoperative 
study on the intensive care.  
 
Randomization and blinding. 
A simple randomization method was used to randomly allocate patients in a 1:1 
ratio to the conventional ventilation group or the INTELLiVENT-ASV group. 
Randomization was performed using the list randomizer on the website 
www.random.org. Randomization and allocation was performed immediately 
after the informed consent form was signed and the allocation of the patient was 
known only at the moment of the randomization. A hardcopy of the randomization 
outcome was printed with timestamp, signed and archived.  
The physician and the team caring for the patients were not blinded. The 
researcher performing the data analyses, the radiologist that evaluates the 
postoperative chest X-rays, and the statistician performing the data analyses will 
be blinded.  
 
The ventilation strategies 
Patients randomized to the conventional ventilation group received a continuous 
mandatory volume or pressure controlled ventilation, if they were not breathing 
spontaneously, immediately after the admission in the ICU. Based on physician 
criterion ventilator settings were set by the anesthesiologist in consultation with 
the intensivist and ICU nurse on duty during the postoperative handover. 

8 
 
Pressure support mode was selected if patients were breathing spontaneously 
during handover. After the handover the ICU nurse or ICU physician could adjust 
ventilator settings during mechanical ventilation. If needed the ICU nurse could 
always consult the ICU physicians on duty. It was not possible to extubate the 
patient without consulting the ICU physician on duty, who made the final call to 
extubate. Spontaneous breathing trials (SBT) were not applied during the first 
three hours of mechanical ventilation. The patient was extubated without a SBT 
if the physicians decided that the patient could be extubated within the first three 
hours of mechanical ventilation. Postoperative ventilation and weaning was 
performed based on local hospital protocols that targets lung protective 
ventilations with a target tidal volume of 6ml/kg of PBW. The standard operating 
procedure is described in appendix 1.The predicted body weight (PBW) that is 
used in etable 3 is calculated according to a previously used formula [5]: 
 50 + 0.91 x (centimeters of height – 152.4) for male; and 
 45.5 + 0.91 x (centimeters of height – 152.4) for females. 
 
Patients randomized to the INTELLiVENT-ASV group received this mode 
of ventilation immediately after the admission in the ICU. Quickwean was 
immediately activated at that time, but the SBT mode was switch off for the first 
three hours of mechanical ventilation. It was not possible to extubate the patient 
without consulting the ICU physician on duty, who made the final call to extubate. 
Spontaneous breathing trials (SBT) were not applied during the first three hours 
of mechanical ventilation. The patient was extubated without a SBT if the 
physicians decided that the patient could be extubated within the first three hours 
of mechanical ventilation. After the first three hours of ventilation the SBT function 

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of INTELLiVENT-ASV was initiated and the patient could be extubated if the 
patient had a successful SBT of at least 10 minutes with a consultation of the ICU 
physician on duty. The standard operating procedure is described in appendix 2. 
In both arms it was possible to deviate from protocol if the ICU physician 
deemed it necessary for the safety of the patient. In these cases the patient could 
be switched to the not allocated mode. 
In both arms the same alarm settings were used, which were: 1) pressure 
alarm ≥35 cmH2O; 2) expiratory minute volume alarm ≤3.0 and ≥15.0 L/min; 3) 
respiratory rate alarm ≥35 breaths per min; 4) tidal volume alarm ≥ 900 ml; 5) 
apnea time alarm ≥30 seconds; 6) EtCO2 alarm ≤30 and  ≥60mmHg; and 7) 
SpO2 alarm ≤90%. 
 
Outcomes 
Primary outcome: 
1. Percentage of time (during at least 30 seconds) in the unacceptable zone 
according to the total postoperative ventilation time on the ICU during the first 
three hours of ventilation or until extubation, if extubated earlier.  
Secondary outcomes:  
1. Percentage of time (during at least 30 seconds) in the optimal and acceptable 
zone according to the total postoperative ventilation time during the first three 
hours of ventilation or until extubation, if extubated earlier. 
2. Percentage of breaths in the optimal, acceptable and unacceptable zone 
according to the total number of recorded breaths during the first three hours 
of ventilation or until extubation, if extubated earlier. 

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3. Percentage of time (during at least 30 seconds) in the optimal, acceptable 
and unacceptable zone according to the total number of recorded time. 
4. Percentage of breaths in the optimal, acceptable and unacceptable zone 
according to the total number of recorded breaths. 
5. Ventilator variables and vital signs will be reported after each half an hour 
from ICU admission until spontaneous breathing (>5 consecutive 
spontaneous breaths) or the first three hours of mechanical controlled 
ventilation. Ventilator variables include the manually measured tidal volume, 
driving pressure and mechanical power. Driving pressure will be calculated 
by extracting the PEEP after >5 seconds of an expiratory hold from the 
plateau pressure level after >5 seconds of an inspiratory hold. Both this 
recorded PEEP and plateau pressure were used with other manually 
recorded 
parameters 
to 
calculate 
the 
mechanical 
power: 
Powerrs=RR⋅{ΔV2*[(0.5*ELrs)+(RR*((1+I:E)/(60*I:E))*Raw))]+ΔV*PEEP}.[6] 
Vital signs include also EtCO2: PaCO2 and PaO2: FIO2 ratio that were 
conducted at admission and after approximately an hour of ventilation. 
6. The number patients extubated in the first six, twelve and twenty-four hours 
after surgery without a reintubation or non-invasive ventilation ≤48 hours after 
extubation for respiratory insufficiency (a successful extubation). 
7. Ventilation time considered as the time from intubation during surgery until 
first and first successful extubation adjusted by the duration of surgery.  
8. Weaning duration considered as the time from stopping intravenous 
sedativesand a rectal temperature of ≥35.5°C since admission on the ICU 
until  successful extubation. 

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9. The time from intubation during surgery until spontaneous breathing (at least 
≥5 consecutive spontaneous breaths) adjusted by the duration of surgery. 
10. The time from stopping intravenous sedatives with a rectal temperature of 
≥35.5°C during admission on the ICU until spontaneous breathing (at least 
≥5 consecutive spontaneous breaths).  
11. The total number of alarms and interventions per hour within the first 3 hours 
or until extubation. 
12. The total number of alarms and interventions per hour according to the total 
registered ventilation time. 
13. ICU mortality 
14. 30 day mortality 
15. The number of ICU readmissions during the first 72 hours after ICU 
discharge. 
16. ICU length of stay.  
17. The number of agitated moment, established by the nurse at the bedside.  
18. The number of bolus administration of sedatives and analgesics.  
19. The number of patients with postoperative pulmonary complications (like 
pneumonia, pneumothorax, atelectasis on the X-ray within the first 72 hours 
after surgery). 
20. The percentage of breaths that the SpO2 measurements were <85% 
according to the total number of recorded breaths (when the measured SpO2 
had a quality index of >50%). 
21. The percentage of breaths that the EtCO2 and SpO2 measurements were 
missing or of a quality of <51%. 

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22. The median acceptance score (1-10) of the nurse. The answers of the whole 
survey will be published as supplementary data. 
23. During this study the pressure, volume, flow and EtCO2 wave patterns were 
recorded to analyze and detect patient-ventilator asynchronies. Currently 
new algorithms are developed to analyze the wave patterns in an objective 
and reliable manner. Based on these algorithms the research group will try 
to compare the number and the type of asynchronies during mechanical 
controlled and supportive ventilation in both groups.  These outcomes will be 
reported in another manuscript than the outcomes described above. 
 
Study organization 
The steering committee was composed of the principal investigator that was also 
the local coordinating investigator and five experts in ventilator support in critically 
ill patients all contribute to the design and revisions of the original study protocol 
and the statistical analysis plan. The local coordinating investigator was 
responsible for administrative management and for collection and management. 
The local coordinating investigator was supported by six local investigators to 
cover in duties when the local coordinating investigator could not record the data. 
All local investigators were registered in the delegation log. The study was 
conducted according to the ICH–GCP guidelines, to guaranty integrity of data 
collection and to ensure timely completion of the case report forms at the bedside 
completed by the ventilator users.  
 
Data collection 

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During the study paper case report forms and a paper survey for user-acceptance 
were used at the bedside. All paper forms were archived. Patient characteristics 
and follow-up data were extracted from the electronic medical record. All 
collected data were registered in digital databases, Excel (© 2010 Microsoft 
Corporation, Redmond, Washington) and SPSS (© version 25, IBM Corp., 
Armonk, NY, USA). A datalogger (© 2013 HAMILTON MEDICAL AG, 
Switzerland) connected to the mechanical ventilator was used to obtain the 
objective “breath-by-breath” data concerning ventilation parameters. Local 
investigators entered other data on paper which was archived and this data was 
registered in the previous mentioned digital databases by the local coordinating 
investigator. Electronic files were archived in the Catharina Hospital based server 
in a secure and controlled environment to maintain confidentiality. Electronic 
documents were controlled with password protection according to best practices. 
 
Data management 
An independent monitor of the Catharina Hospital evaluated the study. The 
monitoring comprised controlling presence and completeness of the research 
dossier and the informed consent forms, and source data checks were 
performed. The monitor decided that data collection and management was 
according to the ICH–GCP guidelines and that the integrity of data collection and 
management was guaranteed.  
 
Data monitoring board and safety analyses 
The Medical Research Ethics Committees United and local hospital board 
decided that a data monitoring board (DSMB) and safety analyses were not 

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required since all used ventilation modes in the study were already common 
practice on the studied ICU.  
 
Cleaning and locking of the database 
The ventilatory variables will be extracted from the datalogger output files and 
transferred to the databases that will be exported for statistical analysis. After 
that, these study databases will be locked and exported for statistical analysis to 
the Academic Medical Center, Amsterdam, The Netherlands.  The results of this 
analyses will be documented in a comprehensive database. At this stage, this 
last database will be locked as soon as all data are entered and all discrepant or 
missing data are resolved – or if all efforts are employed and remaining issues 
cannot be fixed. At this step, the data will be reviewed before database locking. 
At this stage, permission for access to the database will be removed for all 
investigators, and the database will be archived. 
 
Missing data 
No or minimal missing for the primary and secondary outcomes are anticipated, 
except for the quality and number of SpO2 measurement in the datalogger. These 
measurement are assessed with fingertip pulse oximeter that sometimes cannot 
assess a value or the quality of the assessment is not sufficient. Breaths with 
missing SpO2 or a quality of the assessment of < 51% will be excluded from the 
analyses of the primary and secondary outcomes where this measurements are 
necessary.  
 
Sample size 

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A power analysis was performed using G*Power (version 3.1.9.2.; Franz Faul, 
Universitiet Kiel, Duitsland). Based on this analysis the trial was designed to enroll 
at least 196 patients in total. This number of patients was expected to be sufficient 
to detect a reduced ventilation time of 14.0 minutes in the unacceptable zone in 
the INTELLiVENT-ASV group considering a common standard deviation of 10.0 
minutes [4], a type I error of 5%, 95% of power, similar allocation of subjects to 
each group and corrected for dropouts. 
 
Predefined statistical analysis plan 
There were no major adjustments from the preliminary analysis plan, as reported 
previously in the online accessible protocol [1]. In accordance, all statistical 
analyses will be conducted according to an intention–to–treat principle, 
considering all patients in the treatment groups to which they were randomly 
assigned.  
Visual inspection of histograms and D’Agostino–Pearson’s normality tests 
will be used to assess continuous distribution of the data. For the conventional 
ventilation and INTELLiVENT-ASV arms, the baseline characteristics will be 
expressed as counts and percentages, means and standard deviations (SD), or 
medians and interquartile ranges (IQR) whenever appropriate. Hypothesis tests 
will be two–sided with a significance level of 5%. We will not adjust P–values for 
multiple comparisons. Analyses will be performed using the R (R Core Team, 
2016, Vienna, Austria) program. 
Trial profile: Patient flows will be presented in a CONSORT flowchart (Figure 1). 
Baseline comparisons: Patient’s baseline characteristics will be presented by 
study arm (eTable 2). 

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Adherence to study interventions and, ventilator variables and vital signs: 
Ventilatory variables and vital signs will be reported from ICU admission until 
extubation or up to the first 72hours of recorded mechanical ventilation time  
(eTable 3). These variables, including driving pressure and mechanical power, 
will be compared among the groups using Student’s t test. Also, the trend of the 
ventilator variables every 30 minutes for the first three hours will be compared 
between the groups using mixed-effect linear models, considering an interaction 
term between time and group and the patients as random effects. 
 
Outcomes: 
Percentage of time in the optimal, acceptable and unacceptable zone for at 
least 30 seconds during the first three hours of ventilation or until 
extubation, if extubated earlier, and according to the postoperative total 
recorded ventilation time (eTable 4). 
The number of episodes where the ventilation stays in one of the three zone for 
at least 30 consecutive seconds will be calculated. Then, this number will be 
corrected by the total duration of ventilation as: 
%UZ = (TUZ / DV) x 100 
Where %UZ is the percentage of time in a zone, TUZ is the time in seconds where 
the ventilation stays in the specific zone for at least 30 consecutive seconds, and 
DV is the total duration of ventilation in seconds. This number will be reported as 
mean ± standard deviation and median (interquartile range). The effect of the 
intervention will be estimated with a Student’s t–test and reported as the mean 
difference between the two groups. The consistency of the findings of the 
Student’s t-test will be tested using a bootstrapped Student’s t-test with 1,000 

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replications. If a very nonsymmetrical distribution is found, we will use the best 
distribution that fits the data. 
 
Percentage of breaths in the optimal, acceptable and unacceptable zone 
according to the total number of breaths during the first three hours of 
ventilation or until extubation, if extubated earlier, and according to the 
postoperative total recorded ventilation time. (eTable 4). 
The percentage of breaths in the three zones will be reported as number and 
percentages (according to the total number of breaths and not according to the 
number of patients) and the effects of the intervention will be estimated with risk 
ratio and 95% confidence intervals calculated with Wald’s likelihood ratio 
approximation test and with χ2 tests for hypothesis testing. 
 
Number of successful extubations within the first 6, 12 and 24hours after 
surgery (eTable 5). 
The effects of the intervention on the number of successful extubation within the 
first  6, 12 and 24 hours of mechanical ventilation after admission on the ICU will 
be reported as number and percentages and estimated with risk ratio and 95% 
confidence intervals calculated with Wald’s likelihood ratio approximation test and 
with χ2 tests for hypothesis testing. These findings will be confirmed using logistic 
models adjusted by the duration of surgery, total intravenous sedatives dosage 
and the time from ICU admission until a rectal temperature >35.5°C. 
 
Total Time until extubation (considering the time from ICU admission until 
extubation) (eTable 5). 

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The time until extubation will be assessed using Kaplan–Meier curves, and 
hazard ratios with a 95% confidence interval will be calculated with Cox 
proportional hazard models without adjustment for covariates. The proportional 
hazard assumptions will be tested and alternative parametric survival models will 
be used if the proportionality assumption is not sustained. These findings will be 
confirmed using Cox proportional hazard models adjusted by the duration of 
surgery, total intravenous sedatives dosage and the time from ICU admission 
until a rectal temperature >35.5°C. 
 
Time until first spontaneous breathing (considering the time from ICU 
admission until first spontaneous breathing) (eTable 5). 
The time until first spontaneous breathing will be assessed using Kaplan–Meier 
curves, and hazard ratios with a 95% confidence interval will be calculated with 
Cox proportional hazard models without adjustment for covariates. The 
proportional hazard assumptions will be tested and alternative parametric 
survival models will be used if the proportionality assumption is not sustained. 
These findings will be confirmed using Cox proportional hazard models adjusted 
by the duration of surgery the duration of surgery, total intravenous sedatives 
dosage and the time from ICU admission until a rectal temperature >35.5°C. 
 
The total number of alarms and intervention within the first 3 hours or until 
extubation (eTable 5). 
The total number of alarms and intervention within the first 3 hours or until 
extubation will be reported as mean ± standard deviation and median 
(interquartile range). The effect of the intervention will be estimated with a 

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Student’s t–test and reported as the mean difference between the two groups. 
The consistency of the findings of the Student’s t-test will be tested using a 
bootstrapped Student’s t-test with 1,000 replications. If a very nonsymmetrical 
distribution is found, we will use the best distribution that fits the data. 
 
ICUmortality (eTable 5). 
The effects of the intervention on ICU mortality rate will be reported as number 
and percentages and estimated with risk ratio and 95% confidence intervals 
calculated with Wald’s likelihood ratio approximation test and with χ2 tests for 
hypothesis testing. 
 
ICU readmission (eTable 5). 
The effects of the intervention on ICU readmission rate will be reported as number 
and percentages and estimated with risk ratio and 95% confidence intervals 
calculated with Wald’s likelihood ratio approximation test and with χ2 tests for 
hypothesis testing. 
 
30-Day mortality (eTable 5). 
Survival within 30 days will be assessed using Kaplan–Meier curves, and hazard 
ratios with a 95% confidence interval will be calculated with Cox proportional 
hazard models without adjustment for covariates. The proportional hazard 
assumptions will be tested and alternative parametric survival models will be used 
if the proportionality assumption is not sustained. 
 
ICU length of stay (eTable 5). 

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The effects of the intervention on ICU length of stay will be estimated with 
generalized linear models considering distributions that will fit a possible heavy 
right–tailed distribution without zero (such as truncated Poisson, gamma 
distribution or inverse Gaussian), choosing the best fit according to model’s 
deviance. 
 
Postoperative pulmonary complications (eTable 5). 
The effects of the intervention on the incidence of postoperative pulmonary 
complications will be reported as number and percentages and estimated with 
risk ratio and 95% confidence intervals calculated with Wald’s likelihood ratio 
approximation test and with χ2 tests for hypothesis testing. 
 
Percentage of breaths that the EtCO2 and/or SpO2 measurements were 
missing or of a quality of < 51% (eTable 5). 
The percentage of breaths that the EtCO2 or SpO2 measurements were missing 
or of a quality of < 51% will be reported as number and percentages (according 
to the total number of breaths and not according to the number of patients) and 
the effects of the intervention will be estimated with risk ratio and 95% confidence 
intervals calculated with Wald’s likelihood ratio approximation test and with χ2 
tests for hypothesis testing. 
 
The median acceptance score (1-10) of the nurse (eTable 5). 
The median acceptance score of the nurse will be reported as mean ± standard 
deviation and median (interquartile range). The effect of the intervention will be 
estimated with a Student’s t–test and reported as the mean difference between 

21 
 
the two groups. The consistency of the findings of the Student’s t-test will be 
tested using a bootstrapped Student’s t-test with 1,000 replications. If a very 
nonsymmetrical distribution is found, we will use the best distribution that fits the 
data. 
 
Per–protocol analysis: In creating a per–protocol population we will exclude 
patients who had one or more major protocol violations. Patients receiving the 
mode of the group that they were not assigned to will be excluded for the per–
protocol analysis of the primary outcome. The patient will be included for the per 
protocol analysis of the primary outcome during the first three hours, if the change 
in mode occurred after the first three hours of ventilation.  
Patients that died or had a re-sternotomy (for example due to bleeding) 
during the first three hours (for the first three hours per protocol analysis) or during 
the logging of the datalogger (for the overall recorded per protocol analysis) will 
be excluded for the per–protocol analysis of the primary outcome. 
As treated analysis: In creating a as treated analysis we will  analyze the 
recorded ventilation data according to the treatment they actually received. 
Patients receiving the mode of the group that they were not assigned to will be 
excluded for the per–protocol analysis of the primary outcome.  
Subgroup analyses: Treatment effects on the primary outcome will be analyzed 
according to the following subgroups: 1) patient who were successfully extubated 
before or after the median postoperative mechanical ventilation time (eTable 6); 
2) subgroup analysis based on the intraoperative mechanical ventilation time: 
shorter or longer than the median intraoperative mechanical ventilation time 
(eTable 7); 3 ) patients with PaO2 / FiO2 below or above the median PaO2 / FiO2 

22 
 
at admission on the ICU (eTable 8); The effects on subgroups will be evaluated 
according to the interaction effects between each subgroup and the study arms 
by generalized linear models considering zero–inflated distributions and 
presented in a forest plot. 
 
CONCLUSION 
According to best research practice, we reported here the pre–specified detailed 
statistical analysis plan prior to locking the database and starting analyses. This 
document guarantees against reporting bias, selective reporting and data–driven 
results, as such enhancing the utility of the reported results. 
 
 

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TABLES 
eTable 1 
Predefined zones of ventilation 
 
Optimal 
Acceptable* 
Not acceptable*  
Tidal volume 
(ml/kg PBW) 
6-8 (proposed 4-
8) 
>8-12 
>12 
EtCO2 (mmHg) 
30-45 
<30-25 
>45-50 
<25 
≥51 
Peak pressure 
(cmH2O) 
≤30 
31-35 
>35 
SpO2 (%) 
93-98 (≥93 if 
FIO2 <40%) 
93-85 
≥98 
<85 
*for analysis calculated as lasting >30 seconds and per breathing. 
 
 

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eTable 2 – Baseline characteristics of the patients 
 
INTELLiVENT-
ASV 
Conventional 
ventilation 
Age, years 
Mean ± SD 
Mean ± SD 
Male sex 
N / Total (%) 
N / Total (%) 
BMI, kg/m2 
Mean ± SD 
Mean ± SD 
PBW, kg 
Mean ± SD 
Mean ± SD 
SAPS II score 
Mean ± SD 
Mean ± SD 
APACHE IV score 
Mean ± SD 
Mean ± SD 
Euroscore II 
Mean ± SD 
Mean ± SD 
Tobacco use 
N / Total (%) 
N / Total (%) 
History of alcohol abuse 
N / Total (%) 
N / Total (%) 
Edmonton frailty scale 
N / Total (%) 
N / Total (%) 
Medical history 
 
 
   COPD GOLD ≥ 2 
N / Total (%) 
N / Total (%) 
   Asthma 
N / Total (%) 
N / Total (%) 
   OSAS 
N / Total (%) 
N / Total (%) 
   CVA 
N / Total (%) 
N / Total (%) 
   Diabetes Mellitus 
N / Total (%) 
N / Total (%) 
   Hypertension  
N / Total (%) 
N / Total (%) 
   NYHA ≥ 2 
N / Total (%) 
N / Total (%) 
   CKD (MDRD <30ml/min) 
N / Total (%) 
N / Total (%) 
Preoperative left ventricle function 
(%) 
 
 
   Normal (EF = ≥55%) 
N / Total (%) 
N / Total (%) 
   Moderate impaired (EF = 30-54%) 
N / Total (%) 
N / Total (%) 
   Severely impaired (EF = <30%) 
N / Total (%) 
N / Total (%) 
Type of surgery 
   CABG 
   Off-pump coronary artery bypass 
   Valve surgery 
   CABG + valve surgery 
   Aortic ascendens surgery 
   Aortic ascendens + CABG/valve 
 
N / Total (%) 
N / Total (%) 
N / Total (%) 
N / Total (%) 
N / Total (%) 
N / Total (%) 
 
N / Total (%) 
N / Total (%) 
N / Total (%) 
N / Total (%) 
N / Total (%) 
N / Total (%) 
Extracorporeal circulation (minutes) 
Median (IQR) 
Median (IQR) 
Aortic occlusion time (minutes) 
Median (IQR) 
Median (IQR) 
First postoperative CKMB (U/L) 
Median (IQR) 
Median (IQR) 
APACHE: Acute Physiology And Chronic Health Evaluation; ASV: Adaptive Support 
Ventilation; BMI: body mass index; CABG: coronary artery bypass grafting; CKD: chronic 
kideny disease; CKMB: creatine kinase myocardial band; COPD:  Chronic Obstructive 
Pulmonary Disease; CVA: cerebral vascular accident; EF: ejection fraction; SAPS: Simplified 
Acute Physiology Score; PBW: predicted body weight;  IQR: interquartile range; SD: 
standard deviation. 
 

25 
 
eTable 3 – Ventilatory variables over time 
 
At ICU admission 
After 30 minutes 
After 60 minutes 
After 90 minutes 
 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
Number of patients 
N 
N 
 
N 
N 
 
N 
N 
 
N 
N 
 
Tidal volume, mL/kg PBW 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
PEEP, cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Plateau pressure, cmH2O* 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Driving pressure, cmH2O* 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mechanical Power (J/min)* 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Respiratory rate, bpm 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Static compliance, mL/cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
FiO2 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
SpO2, % 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
EtCO2, mmHg 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
PaO2 / FiO2 
Mean ± SD 
Mean ± SD 
 
 
 
 
Mean ± SD 
Mean ± SD 
 
 
 
 
EtCO2 / PaCO2 
Mean ± SD 
Mean ± SD 
 
 
 
 
Mean ± SD 
Mean ± SD 
 
 
 
 
Arterial pH 
Mean ± SD 
Mean ± SD 
 
 
 
 
Mean ± SD 
Mean ± SD 
 
 
 
 
 
At ICU admission 
After 120 minutes 
After 150 minutes 
After 180 minutes 
 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
Number of patients 
N 
N 
 
N 
N 
 
N 
N 
 
N 
N 
 
Tidal volume, mL/kg PBW 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
PEEP, cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Plateau pressure, cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Driving pressure, cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mechanical Power (J/min) 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Respiratory rate, bpm 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Static compliance, mL/cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
FiO2 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
SpO2, % 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
EtCO2 mmHg 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
 
At ICU admission 
After 6 hours 
After 12 hours 
After 24 hours 
 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
Number of patients 
N 
N 
 
N 
N 
 
N 
N 
 
N 
N 
 
Tidal volume, mL/kg PBW 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
PEEP, cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Peak pressure, cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Respiratory rate, bpm 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 

26 
 
Static compliance, mL/cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
FiO2 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
SpO2, % 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
EtCO2, mmHg 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
 
At ICU admission 
After 36 minutes 
After 48 minutes 
After 72 hours 
 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
I-ASV 
Conventional 
p 
value 
Number of patients 
N 
N 
 
N 
N 
 
N 
N 
 
N 
N 
 
Tidal volume, mL/kg PBW 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
PEEP, cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Peak pressure, cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Respiratory rate, bpm 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Static compliance, mL/cmH2O 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
FiO2 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
SpO2, % 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
EtCO2 mmHg 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
Mean ± SD 
Mean ± SD 
 
PBW: predicted body weight; bpm: breaths per minute; PEEP: positive end-expiratory pressure; SD: standard deviation 
* based on manually retrieved values during both an inspiratory and expiratory hold of at least 5 seconds 
 
 

27 
 
eTable 4 – Intention-to-treat, as treated and per protocol analysis of the percentage of breaths and time in the optimal, 
acceptable and unacceptable zones during the first 3 hours of postoperative mechanical ventilation or extubation, and for 
all recorded breaths. 
 
 
Intention-to-treat analysis 
As treated analysis 
Per protocol analysis 
First 3 hours of 
mechanical ventilation 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
Percentage of breaths in:   
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
Percentage of time* in: 
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
  All recorded breaths and time 
 
 
 
 
 
 
 
 
 
 
 
Percentage of breaths in:   
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
Percentage of time* in: 
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 

28 
 
eTable 5 – Secondary outcomes 
 
Intention-to-tread 
 
Per-protocol 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
P 
value 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
P 
value 
Ventilation time 
 
 
 
 
 
 
 
 
 Intubation – successful extubation* 
    Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
 ICU admission – successful extubation* 
    Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Weaning time 
 
 
 
 
 
 
 
 
 Stop sedation – successful extubation* 
    Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Time until spontaneous breathing** 
 
 
 
 
 
 
 
 
 Intubation – spontaneous breathing    
   Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
 ICU admission – spontaneous breathing 
   Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
 Stop sedation – spontaneous breathing 
   Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mortality 
 
 
 
 
 
 
 
 
 ICU 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
 30-day 
N / Total (%) 
N / Total (%) 
Hazard 
ratio 
 
N / Total (%) 
N / Total (%) 
Hazard 
ratio 
 
Length of stay 
 
 
 
 
 
 
 
 
  ICU 
    Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
ICU readmissions  
 
 
 
 
 
 
 
 
 Readmission <72 hours after discharge 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
Number of alarms 
 
 
 
 
 
 
 
 
 First 3 hours (n/3 hours) 
   Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 

29 
 
 All recorded time (n/hour) 
       Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Times SpO2 measurement of <85% during mechanical ventilation* 
 First 3 hours (n/3 hours) 
   Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
 All recorded time (n/hour) 
       Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Lowest measured SpO2 over all recorded 
time. 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Missing measurement**: all recorded time 
EtCO2 
 
SpO2  
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
 
Mean 
difference 
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
Mean 
difference 
 
Number of interventions 
 
 
 
 
 
 
 
 
 First 3 hours (n/3 hours) 
    Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
 All recorded time (n/hour) 
    Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Pulmonary complication (first 72 hours) 
 
 
 
 
 
 
 
 Pneumonia 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
 Pneumothorax 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
 Atelectasis 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
 Overall 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
N / Total (%) 
N / Total (%) 
Risk ratio 
 
Acceptance score 
 
 
 
 
 
 
 
 
 Score (1-10) 
   Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR) 
Mean 
difference 
 
*Measurement with a quality index >50% 
** Measurement with a quality index <51% 
 
 

30 
 
eTable 6 – Intention-to treat analysis and per protocol analysis of the percentage of breaths and time in the optimal, 
acceptable and unacceptable zones during the first 3 hours of postoperative mechanical ventilation or extubation, and for 
all recorded breaths for patient who were successfully extubated before or after the median postoperative mechanical 
ventilation time. 
 
 
Intention-to-treat analysis 
As treated analysis 
Per protocol analysis 
First 3 hours of 
mechanical ventilation 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
Percentage of breaths in:   
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
Percentage of time* in: 
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
  All recorded breaths and time 
 
 
 
 
 
 
 
 
 
 
 
Percentage of breaths in:   
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
Percentage of time* in: 
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
*for at least 30 seconds in a zone 
 

31 
 
eTable 7 – Intention-to treat analysis and per protocol analysis of the percentage of breaths and time in the optimal, 
acceptable and unacceptable zones during the first 3 hours of postoperative mechanical ventilation or extubation, and for 
all recorded breaths for patients with a intraoperative mechanical ventilation time that was shorter or longer than the 
median intraoperative mechanical ventilation time.  
 
 
Intention-to-treat analysis 
As treated analysis 
Per protocol analysis 
First 3 hours of 
mechanical ventilation 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
Percentage of breaths in:   
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
Percentage of time* in: 
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
  All recorded breaths and time 
 
 
 
 
 
 
 
 
 
 
 
Percentage of breaths in:   
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
Percentage of time* in: 
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
*for at least 30 seconds in a zone 
 

32 
 
eTable 8 – Intention-to treat-analysis, as treated analysis and per protocol analysis of the percentage of breaths and time 
in the optimal, acceptable and unacceptable zones during the first 3 hours of postoperative mechanical ventilation or 
extubation, and for all recorded breaths for patients with PaO2 / FiO2 below or above the median PaO2 / FiO2 at admission 
on the ICU. 
 
 
Intention-to-treat analysis 
As treated analysis 
Per protocol analysis 
First 3 hours of 
mechanical ventilation 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
INTELLiVENT-
ASV 
Conventional 
mode 
Effect 
Estimate 
(95% CI) 
p 
value 
Percentage of breaths in:   
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
Percentage of time* in: 
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
  All recorded breaths and time 
 
 
 
 
 
 
 
 
 
 
 
Percentage of breaths in:   
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
Percentage of time* in: 
   Optimal zone 
       Median (IQR) 
   Acceptable zone  
       Median (IQR) 
   Unacceptable zone 
       Median (IQR) 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean ± SD 
Median (IQR) 
Mean ± SD 
Median (IQR 
Mean ± SD 
Median (IQR 
 
Mean 
difference 
Mean 
difference  
Mean 
difference 
 
*for at least 30 seconds in a zone

33 
 
FIGURE LEGENDS 
Figure 1 – Flow of the patients in the POSiTIVE trial 
 
 
 
 
Eligible patients 
Based on inclusion criteria 
Total inclusions 
Exclusions: 
Reasons for exclusion based 
on the exclusion criteria. 
Conventional ventilation 
Inclusions (n) 
Intention-to-tread analysis 
INTELLiVENT-ASV 
Inclusions (n) 
Intention-to-tread analysis 
Inclusions 
Per protocol analysis 
Inclusions 
Per protocol analysis 

34 
 
LIST OF ABBREVIATIONS 
ARDS: acute respiratory distress syndrome  
APACHE: Acute Physiology And Chronic Health Evaluation 
CONSORT: Consolidated Standards of Reporting Trials 
COPD: chronic obstructive pulmonary disease  
DSMB: Data and Safety Monitoring Board  
GOLD: Global Initiative for Chronic Obstructive Lung Disease 
ICH-GCP: International Conference on Harmonization - Good Clinical Practice 
ICU: intensive care unit 
IQR: interquartile range  
LOS: length of stay  
PBW: predicted body weight  
SAP: statistical analysis plan 
SAPS: Simplified Acute Physiology Score 
SBT: Spontaneous breathing trial 
SD: standard deviation 

35 
 
DECLARATIONS 
Ethics approval and consent to participate: The Medical Research Ethics 
Committees United (MEC-U), Nieuwegein, The Netherlands, under reference 
number R16.054. 
Consent for publication: Not applicable. 
Availability of data and material: Not applicable. 
Competing interests: The authors declare that they have no competing 
interests. 
Funding: This study is an investigator–initiated trial. The principal investigator is 
funded by the Catharina Hospital, Eindhoven, The Netherlands. 
Authors’ contributions:  
AJR, ASN, DMP, RA, AN, HHM, MJS, AGJH, designed the study, the statistical 
analysis plan and approved the initially submitted version of this manuscript. All 
authors read and approved the final manuscript. 
Acknowledgments: None. 
 
 

36 
 
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