The Effect of Closed-Loop Versus Conventional Ventilation on Mechanical Power - a Multicenter Crossover Randomized Clinical Trial
Phase: NA
Conditions: Mechanical Ventilation, Mechanical Power
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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RESEARCH PROTOCOL 
 
 
The Effect of Closed–loop versus Conventional 
Ventilation on Mechanical Power 
(INTELLiPOWER) – study protocol for a 
multicenter crossover randomized clinical trial 
 
 
NCT number 04827927    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correspondence: 
Laura A. Buiteman-Kruizinga 
Reinier de Graaf Hospital 
Reinier de Graafweg 5 
2625 AD Delft 
Email: l.kruizinga@rdgg.nl 
 

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PROTOCOL TITLE: The Effect of Closed–loop versus Conventional Ventilation on 
Mechanical Power (INTELLiPOWER) – study protocol for a multicenter crossover 
randomized clinical trial 
Protocol ID 
INTELLiPOWER 
Short title 
The effect of Closed–loop Ventilation on 
Mechanical Power 
Version 
3.0 
Date 
June 16, 2021 
Coordinating 
investigator/project leader 
Laura A. Buiteman-Kruizinga 
Reinier de Graaf Hospital 
Reinier de Graafweg 5 
2625 AD Delft 
Telephone: +31 15 2604040 
Email: l.kruizinga@rdgg.nl 
& 
Frederique Paulus, PhD 
Department of Intensive Care 
Amsterdam University Medical Centers, location 
‘AMC’ 
Meibergdreef 9 
1105 AZ Amsterdam, The Netherlands 
Telephone: +31 20 5669111 
E-mail: f.paulus@amsterdamumc.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Prof. M.J. Schultz, MD PhD 
Department of Intensive Care 
Amsterdam University Medical Centers, location 
‘AMC’ 
Meibergdreef 9 
1105 AZ Amsterdam, The Netherlands 
Telephone: +31 20 5662509 
E-mail: marcus.j.schultz@gmail.com 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Amsterdam University Medical Centers, location 
‘AMC’ 
Meibergdreef 9 
1105 AZ Amsterdam, The Netherlands 
Independent expert(s) 
J. Horn, MD PhD 
Department of Intensive Care 
Amsterdam University Medical Centers, location 
‘AMC’ 
Meibergdreef 9 
1105 AZ Amsterdam, The Netherlands 
Telephone: +31 20 5669111 
E-mail: j.horn@amsterdamumc.nl 
 
 

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PROTOCOL SIGNATURE SHEET 
Name 
Signature 
Date 
Head of Department: 
Prof. M.B. Vroom, MD PhD 
 
 
Principal Investigator: 
Prof. M.J. Schultz, MD PhD 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1. INTRODUCTION AND RATIONALE .................................................................... 8 
1.1 
Invasive ventilation ........................................................................................ 8 
1.2 
Mechanical Power of ventilation .................................................................... 8 
1.3 Fully–automated or closed–loop ventilation ...................................................... 8 
1.4 
Need for this study ......................................................................................... 9 
2. OBJECTIVE AND HYPOTHESIS....................................................................... 10 
2.1 Objective ......................................................................................................... 10 
2.2 Hypothesis....................................................................................................... 10 
3. STUDY DESIGN ................................................................................................ 11 
4. STUDY POPULATION ....................................................................................... 12 
4.1 Population ....................................................................................................... 12 
4.2 Inclusion criteria .............................................................................................. 12 
4.3 Exclusion criteria ............................................................................................. 12 
4.4 Sample size calculation ................................................................................... 12 
5. METHODS ......................................................................................................... 13 
5.1 Primary endpoint ............................................................................................. 13 
5.2 Secondary endpoints ....................................................................................... 13 
5.3 Randomization, blinding and treatment allocation ........................................... 13 
5.4 Study procedures ............................................................................................ 13 
5.5 Data collection ................................................................................................. 14 
5.5.1 Demographic and general data ................................................................. 14 
5.5.2 Baseline ventilator settings, variables and parameters ............................. 14 
5.5.3 Study parameters ...................................................................................... 15 
5.5.4 Blood gas data .......................................................................................... 16 
5.5.5 Follow–up data at day 7 and day 28 ......................................................... 16 
5.6 Automatic data collection ................................................................................ 16 
5.7 Withdrawal of individual subjects ..................................................................... 16 
5.8Replacement of individual subjects after withdrawal ........................................ 16 
5.9 Follow-up of subjects withdrawn from treatment ............................................. 16 
5.10 Premature termination of the study ............................................................... 16 
6. SAFETY REPORTING ......................................................................................... 17 
6.1 Temporary halt for reasons of subject safety................................................... 17 

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6.2 Serious adverse events (SAE) ........................................................................ 17 
6.3 Follow-up of adverse events ............................................................................ 17 
6.4 Data Safety Monitoring Board (DSMB) ............................................................ 17 
7. STATISTICAL ANALYSIS .................................................................................. 18 
8. ETHICAL CONSIDERATIONS ........................................................................... 19 
8.1 Regulation statement ...................................................................................... 19 
8.2 Recruitment and consent................................................................................. 19 
8.3 Benefits and risks assessment, group relatedness ......................................... 19 
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 
APPENDIX I ............................................................................................................. 23 
APPENDIX II ............................................................................................................ 24 
 
 

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ABBREVATIONS AND DEFINITIONS 
APACHE 
Acute Physiology and Chronic Health Evaluation 
EtCO2 
End-tidal Carbon Dioxide 
FiO2 
Fraction of inspired Oxygen 
ICU 
Intensive Care Unit 
I:E ratio 
Inspiratory to Expiratory ratio 
MP 
Mechanical Power 
PEEP 
Positive End–Expiratory Pressure 
Pplateau 
Plateau pressure 
Pmax 
Maximum airway pressure 
Ppeak 
Peak pressure 
RR 
Respiratory Rate 
RRset 
Set Respiratory Rate 
SaO2 
Saturation of Arterial Oxygen 
SpO2 
Saturation of peripheral Oxygen 
VT 
Tidal Volume 
VILI 
Ventilator induced lung injury 
ΔP 
Driving pressure 
 
 

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SUMMARY 
Rationale 
Mechanical ventilation can cause ventilator–induced lung injury (VILI). Lung protective 
ventilation, consisting of a low tidal volume (VT), a low plateau pressure (Pplateau) and 
a low driving pressure (ΔP) improves survival and shortens duration of ventilation in 
patients with acute respiratory distress syndrome (ARDS). Lung protective ventilation 
may also benefit critically ill patients with respiratory failure not caused by ARDS. 
‘Mechanical Power of ventilation’ (MP), the amount of energy per time transferred from 
the ventilator to the respiratory system, is a summary variable that includes all the 
components that play a role in VILI. With fully–automated closed–loop ventilation, 
these components are no longer set by the operator, but under control of the algorithms 
in the ventilator. 
Objective 
To compare MP under INTELLiVENT–adaptive support ventilation (ASV), a fully–
automated closed–loop ventilation, with MP under conventional ventilation. 
Hypothesis 
INTELLiVENT–ASV compared to conventional ventilation results in a lower MP. 
Study design 
National, multicenter, crossover, randomized clinical trial. 
Study population 
Invasively ventilated critically ill patients. 
Methods 
The ventilator will be randomly switched between INTELLiVENT–ASV for 3 hours and 
conventional ventilation for 3 hours. The amount of MP is calculated using various 
equations proposed in the literature. 
Study endpoints 
The primary endpoint is the amount of MP with each form of invasive ventilation. 
Nature and extent of the burden and risks associated with participation, benefit 
and group relatedness 
Differences in burden and risks of the two ventilation strategies compared in the current 
study are not expected. Both modes of ventilation are interchangeably used as part of 
standard care in the participating centers. No other interventions are performed. 
Neither the collection of demographic and outcome data, nor the capturing of 
ventilation characteristics causes harm to patients. 

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1. INTRODUCTION AND RATIONALE 
1.1 Invasive ventilation 
Invasive ventilation is an often needed and at times even life–saving intervention, but 
has the potential to cause so–called ‘ventilator–induced lung injury’ (VILI). VILI is at 
least in part due to overdistension of the lungs, and is associated with a higher mortality 
and longer duration of mechanical ventilation [1]. ‘Lung–protective’ ventilation 
consisting of a low tidal volume (VT), a low plateau (Pplateau) [2] and a low driving 
pressure (ΔP) [3] improves survival and is leads to a faster liberation from the ventilator 
in patients with acute respiratory distress syndrome (ARDS) [4]. Lung–protective 
ventilation may also benefit critically ill invasively ventilated patients not having ARDS. 
1.2 Mechanical Power of ventilation 
The ‘Mechanical Power of ventilation’ (MP) is the amount of energy per time transferred 
from the ventilator to the respiratory system. While this energy is mainly used to 
overcome airway resistance (Raw) and respiratory system compliance (CRS), part of it 
can act directly on lung tissue, causing VILI [5,6]. MP has been shown to be associated 
with important patient–centered outcomes in critically ill patients in need of invasive 
ventilation [7]. MP is a summary variable that includes all components that play a role 
in VILI [8], including VT and pressures, and also the respiratory rate (RR). Several 
equations have been proposed for calculating MP (see Appendix I) [8-12]. 
1.3 Fully–automated or closed–loop ventilation 
INTELLiVENT–ASV is a fully–automated closed–loop mode that automatically controls 
minute ventilation and oxygenation to reach targets set by the user. It provides either 
pressure–controlled (i.e., assist) or pressure–support (i.e., assisted) ventilation, 
depending on patient’s activity. Minute ventilation is adjusted to reach a chosen target 
for end–tidal CO2 (etCO2), in which VT and RR are adjusted according to respiratory 
mechanics, including respiratory system compliance (Crs), airway resistance (Raw) and 
the expiratory time constant (RCexp), and based on the minimal work of breathing 
principle as described by Otis [13], and the minimal force of breathing as described by 
Meade [14]. Positive end–expiratory pressure (PEEP) and the oxygen level in inspired 
air (FiO2) are adjusted to reach a chosen target for pulse oximetry (SpO2). In addition, 
with INTELLiVENT–ASV PEEP is adjusted to reach the lowest ΔP. Thus, with 
INTELLiVENT–ASV, all components that play a role in VILI are under full control of the 
ventilator. 

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1.4  Need for this study 
Several studies suggest fully–automated ventilation to ventilate with a lower amount of 
MP in unselected ICU patients [15], patients after cardiac surgery [16], and patients 
with and without ARDS [17]. The current study will directly compare the amount of MP 
in invasively ventilated critically ill patients by calculating MP breath–by–breath, using 
the various equations proposed in the literature. 
 
 

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2. OBJECTIVE AND HYPOTHESIS 
2.1 Objective 
To compare INTELLiVENT–adaptive support ventilation (ASV) with conventional 
ventilation with respect to the ‘Mechanical Power of ventilation’ (MP). 
2.2 Hypothesis 
INTELLiVENT–ASV compared to conventional ventilation results in a lower MP. 
 
 

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3. STUDY DESIGN 
National, multicenter, crossover, randomized clinical trial in invasively ventilated 
critically ill patients. 
 
 

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4. STUDY POPULATION 
4.1 Population 
This crossover randomized clinical trial, named ‘INTELLiPOWER’ will recruit 
consecutive intubated and invasively ventilated critically ill ICU patients who are 
expected to be ventilated beyond the following calendar day. Patients are included in 
the ICUs of academic and non–academic centers in the Netherlands. Patients are 
screened for eligibility and randomized after initial stabilization at INTELLiVENT–ASV, 
one of the standard modes of ventilation in the participating ICUs. 
4.2 Inclusion criteria 
 Admitted to one of the participating ICUs; 
 Receiving invasive ventilation through a standard endotracheal (i.e., oral) tube; 
 Expected to be ventilated > 24 hours; and 
 Ventilation is applied by a ventilator that can provide INTELLiVENT–ASV and 
conventional ventilation. 
4.3 Exclusion criteria 
 Age under 18 years; 
 No written informed consent; 
 Morbidly obese; and 
 Any contra–indication for use of INTELLiVENT–ASV 
4.4 Sample size calculation 
Considering a standard deviation of 10.5 J/min (conventional), 90% power, 5% of 
alpha, a reduction of 3.5 J/min (15% of 24.2 J/min, conventional) and a crossover 
design, 48 patients in each arm (sequence) is needed (96 in total), ~ 32 at each center. 
This calculation is based on the results of a non–randomized parallel group study that 
showed a reduction in MP from 24.2 (± 9.2) to 18.0 (± 11.4) J/min [17]. The report of 
this study is under review; data are presented in Appendix II. 
 
 

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5. METHODS 
5.1 Primary endpoint 
The primary endpoint is the amount of MP delivered with each form of invasive 
ventilation, calculated every 30 minutes using the needed variables for all proposed 
equations (see Appendix I). Between each ventilation mode, there will be a 30–minutes 
wash out time. 
5.2 Secondary endpoints 
Secondary endpoints include: 
 Several ventilation parameters (including tidal volume, pressures and 
respiratory rate) 
 Duration of ventilation 
 Hospital length of stay (LOS) 
 7- and 28 day-mortality 
5.3 Randomization, blinding and treatment allocation 
Randomization will be performed using a password protected, SSL–encrypted 
program (Castor EDC). Randomization sequence is generated by a dedicated 
computer randomization software program, using random block sizes and is stratified 
per center. Due to the nature of the treatment, blinding is not possible. Patients are 
randomly assigned to start with a 3–hour block of conventional ventilation or 
INTELLiVENT–ASV. 
5.4 Study procedures 
Patients in participating ICUs are screened and randomized after initial stabilization at 
INTELLiVENT–ASV. On the following calendar day, but always within 24 hours after 
start of ventilation in the ICU, patients are then placed in random order for 3 hours at 
INTELLiVENT–ASV, or at pressure–controlled (called: PCV) or pressure support 
ventilation (called: SPONT) depending on patient’s activity.  
With 
INTELLiVENT–ASV, 
the 
patient’s 
conditions, 
‘ARDS’, 
‘Chronic 
Hypercapnia’ or ‘Traumatic Brain Injury’ can be chosen, if applicable. The controllers 
for minute volume, PEEP and FiO2 are all activated, and the target shifts for etCO2 and 
SpO2 are adjusted, if necessary. 
With conventional ventilation, the same etCO2 and SpO2 levels are targeted as 
with INTELLiVENT–ASV, but here the caregiver is fully responsible for choosing the 
settings. 

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5.5 Data collection 
The data will be collected in Castor Electronic Data Capture (EDC), which meets the 
criteria of Good Clinical Practice (GCP).  
5.5.1 Demographic and general data 
 Age (years); 
 Gender (male/female); 
 Height (cm); 
 Weight (kg); 
 Comorbidities; 
 Date of hospital admission; 
 Date of ICU admission; 
 Time of ICU admission; 
 Time of intubation; 
 Reason for ICU admission; 
 Cause of respiratory failure; 
 Date and time of intubation (if possible, also in transferred patients); and 
 Acute Physiology and Chronic Health (APACHE) IV score;  
5.5.2 Baseline ventilator settings, variables and parameters to be collected 
before randomization 
 Ventilation mode; 
 Tidal volume, inspired (VTi) (mL); 
 Tidal volume, expired (VTe) (mL); 
 respiratory rate measured (RRmeasured); 
 Maximum airway pressure (Pmax) (cmH2O); 
 Peak pressure (Ppeak) (cmH2O); 
 Plateau pressure (Pplateau) (cmH2O) (performed with an inspiratory hold); 
 Positive end–expiratory pressure (PEEP) (cmH2O) (performed with an 
expiratory hold); 
 Inspiratory pressure or level of pressure support above PEEP (cmH2O); 
 Tinsp (sec) or set and measured inspiration to expiration ratio (I:E) (ratio); 
 Minute volume (MV) (L/min); 
 Inspiratory flow (L/min); 
 Tslope (sec); 

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 FiO2 (%) 
 P0.1 (cmH2O)  
 Compliance of the respiratory system (Crs) (L/cmH2O); 
 Resistance of the respiratory system (Raw) (cmH2O/L/sec); 
 End–tidal carbon dioxide (EtCO2 (kPa); 
 Saturation of peripheral oxygen (SpO2) (%) 
5.5.3 Study parameters, also to be collected through an automated data 
capturing tool  
 Ventilation mode; 
 Tidal volume set (VT-set) (mL) (only with conventional ventilation); 
 Tidal volume, inspired (VTi) (mL); 
 Tidal volume, expired (VTe) (mL); 
 respiratory rate set (RRset) (only with conventional ventilation); 
 respiratory rate measured (RRmeasured); 
 Maximum airway pressure (Pmax) (cmH2O); 
 Peak pressure (Ppeak) (cmH2O); 
 Plateau pressure (Pplateau) (cmH2O) (performed every 30 minutes with an 
inspiratory hold); 
 Positive end–expiratory pressure (PEEP) (cmH2O) (performed every 30 
minutes with an expiratory hold); 
 Inspiratory pressure or level of pressure support above PEEP (cmH2O); 
 Tinsp (sec) or set and measured inspiration to expiration ratio (I:E) (ratio); 
 Minute volume (MV) (L/min); 
 Inspiratory flow (L/min); 
 Tslope (sec); 
 FiO2 (%) 
 P0.1 (cmH2O)  
 Compliance of the respiratory system (Crs) (L/cmH2O); 
 Resistance of the respiratory system (Raw) (cmH2O/L/sec); 
 End–tidal carbon dioxide (EtCO2 (kPa); and 
 Saturation of peripheral oxygen (SpO2) (%) 

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5.5.4 Blood gas analyses results, if blood gas analyses are performed as part 
of daily care, within each randomization block 
 pH; 
 pCO2 (kPa); 
 Bicarbonate (mmol/l); 
 pO2 (kPa); and 
 SaO2 (%) 
5.5.5 Follow–up data at day 7 and day 28 
 Life status, and if not alive, date of death; 
 Location (ICU, hospital, home); and 
 Intubation status, if no longer intubated extubation date 
5.6 Automatic data collection 
The breath–by–breath ventilation data will also be collected using so–called ‘memory 
boxes’, connected to a free communication port at the ventilator. 
5.7 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 
5.8Replacement of individual subjects after withdrawal 
The calculated number of subjects is intended to be included, i.e., patients who 
withdraw from the study will be replaced. 
5.9 Follow-up of subjects withdrawn from treatment 
There will be no follow-up beyond day 28. 
5.10 Premature termination of the study 
Not applicable. 
 
 
 
 
 
 
 
 

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6. SAFETY REPORTING 
6.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardize subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of 
a temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed. 
6.2 Serious adverse events (SAE) 
This study compares two ventilation modes with which the teams have extensive 
experience––both ventilatory modes are seen and used as standard care in the 
participating intensive care units. Therefore, related serious adverse events (SAEs) or 
adverse events (AEs) are not expected. 
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 
The statistical analysis will be based on an intention–to–treat principle and a per 
protocol analysis. 
Descriptive statistics are first used to study patient characteristics, ventilation 
parameters and outcomes. Proportions are compared using the chi–squared test or 
Fisher exact test as required by variable distribution and continuous variables are 
compared using the Wilcoxon Rank–Sum Test or the Wilcoxon signed–rank test as 
appropriate. Effects are shown as the average odds ratio (OR) with its 95% confidence 
interval (95% CI). 
To compare the two ventilation strategies, distribution plots showing cumulative 
rates for VT, PEEP, Pplat, RR, and mechanical power are constructed. All ventilatory 
parameters, including VT, PEEP, Pplat and RR, are presented as medians with their 
interquartile ranges.  
A P value < 0.05 was considered 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) and in accordance with the Medical 
Research Involving Human Subjects Act (WMO). 
8.2 Recruitment and consent 
Informed consent will be obtained before any study–related action is taken. Critically ill 
patients admitted for invasive ventilation to an intensive care unit are, without 
exception, incompetent to give informed consent, and so a legal representative will be 
asked for the informed consent. Re–consent is asked when the patient is adequately 
awake. 
8.3 Benefits and risks assessment, group relatedness 
Not applicable. 
8.4 Compensation for injury 
The sponsor/investigator and the studysites have a liability insurance which is in 
accordance with article 7 of the WMO. As this study compares two ventilation 
strategies used for standard care, an exception form the requirement for insurance to 
cover for damage to research objects through injury or death caused by the study is 
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 in a pseudonymized form, which means only local 
investigators will have access to the key to the code that relates the individual data to 
identifiable patients. 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 
Queries on the database will be done and analyzed by the monitor to signalize early 
aberrant patterns, trends, issues with consistency of credibility and other anomalies. 
On site monitoring will compromise controlling presence and completeness of the 
research dossier and the informed consent forms, source data checks will be 
performed as described in the monitoring plan. A monitoring plan is being developed. 
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 
The study protocol will be registered before inclusion of the first patient at 
clinicaltrials.gov. The results of the study will find their way into (inter–)national 
scientific journals and guidelines. We will submit analyses to scientific journals in the 
field of intensive care medicine. 
 
 

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10. REFERENCES 
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M.J. (2020). Effect of a closed–loop versus conventional ventilation strategy on 
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17. Buiteman-Kruizinga, L.A., Mkadmi, H.E., Schultz, M.J., Tangkau, P.L., van der 
Heiden, P.L.J. (2021). The effect of closed–loop ventilation on mechanical power 
– results from a pilot study of adaptive support ventilation. In press; Critical Care 
Explorations  
 
 

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23 
 
APPENDIX I 
Equations for MP to be used: 
 
MP = 0.098 * RR * {ΔV2 x [½ * ELrs + RR * 
(1+I:E)
60 x I∶E  * Raw] + ΔV * PEEP} [Eq. 1] 9 
 
MP = 0.098 * VT * RR * (Ppeak – ½ * ΔP) [Eq. 2] 9 
 
MP = 
minute volume ∗ (peak pressure (Ppeak) + PEEP +F
6)
20
  [Eq. 3] 8 
 
MP = 0.098 ∗RR ∗Vt ∙(PEEP + Pinsp ∙(1 −e
−Tinsp
τ
)) [Eq. 4] 11 
 
MP = 0.098 ∗𝑅𝑅(𝑃𝐸𝐸𝑃+ ∆𝑃𝑖𝑛𝑠𝑝) ∗𝑉𝑡−∆𝑃𝑖𝑛𝑠𝑝² 𝐶∗(0.5 − 
𝜏
𝑇𝑠𝑙𝑜𝑝𝑒+
𝜏²
𝑇𝑠𝑙𝑜𝑝𝑒² (1 −𝑒
𝑇𝑠𝑙𝑜𝑝𝑒
𝜏
) ) [Eq. 5] 10 
 
MP = 0.098 * RR * VT *(∆Pinsp + PEEP) [Eq. 6] 11 
 
MP = VT * ∆PRS * RR [Eq. 7] 12 
 
 
 
 
 
 
 

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APPENDIX II 
 
Pilot study data: 
N=24 
Conventional ventilation N=12 
 
Mean 
Median 
Standard 
Deviation 
Percentile 
25 
Percentile 
75 
MP 
24.28 
22.94 
9.23 
16.36 
30.63 
 
 
Closed-loop ventilation N=12 
 
Mean 
Median 
Standard 
Deviation 
Percentile 
25 
Percentile 
75 
MP 
18.00 
15.08 
11.42 
11.73 
19.82