Heartrate Variability During Conventional and Variable Pressure Support Mechanical Ventilation: a Cross-over Study
Phase: NA
Conditions: Mechanical Ventilation Complication
Sponsor: Medical University of Vienna

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CLINICAL INVESTIGATION PLAN (CIP) 
EN ISO 14155 
Klinischer Prüfplan (MPG §40.3) 
 
Heartrate variability during mechanical pressure support 
ventilation – comparing conventional and variable pressure 
support ventilation: a cross-over trial 
 
 
 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of the 
sponsor of this clinical investigation, the Department of Anaesthesia, General Intensive Care and Pain 
Management. It is therefore provided to you in confidence as an investigator, potential investigator, 
or consultant, for review by you, your staff, and an Independent Ethics Committee or Institutional 
Review Board. It is understood that this information will not be disclosed to others without written 
authorization from the Department of Anaesthesia, General Intensive Care and Pain Management, 
except to the extent necessary to obtain informed consent from those persons to whom the 
interventional devices may be administered. 
 
 

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Device Name and 
Manufacturer 
Infinity Delta Monitor, Dräger, Lübeck, Germany 
Evita Infinity V500, Dräger, Lübeck, Germany 
CIP Authors 
Assoc. Prof. PD Dr. Klaus Ulrich Klein 
Cand. med. Maximilian Schnetzinger, BSc 
Academic Investigators 
Assoc. Prof. PD Dr. Klaus Ulrich Klein 
Cand. med. Maximilian Schnetzinger, BSc 
Ao. Univ. Prof. DI Dr. techn. Eugenius Kaniusas 
Projektass. DI Stefan Kampusch 
Projektass. DI Florian Thürk 
Document Type 
Interventional clinical cross-over trial 
Document Status 
Version 2 
Date 
21.11.2017 
Number of Pages 
26 
 
 

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1. 
SPONSORS, INVESTIGATORS, MONITOR AND SIGNATURE 
 
Clinical Investigator 
(MPG §40.3) 
Assoc. Prof. PD Dr. Klaus Ulrich Klein, Department of Anaesthesia, 
General Intensive Care and Pain Management, Medical University of 
Vienna, Austria 
 
 
 
_________________ 
 
___________ 
Signature 
 
Date 
 
 
Applicant 
(MPG §40.3) 
Cand. med. Maximilian Schnetzinger, BSc 
 
 
 
_________________ 
 
___________ 
Signature 
 
Date 
 
 
 
Statistician 
Assoc.Prof. Dr. Alexandra Graf, Section for Medical Statistics, 
Medical University of Vienna 
Sponsor  
(MPG §40.3) 
Univ.-Prof. Dr. Klaus Markstaller 
 
Monitor 
Ass.-Prof. Dr. med. Stefan Böhme 
 
 
 

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2. 
SYNOPSIS OF THE CLINICAL INVESTIGATION 
 
TITLE 
Heartrate variability during mechanical pressure support ventilation – 
comparing conventional and variable pressure support ventilation:  a 
cross-over trial 
ACRONYM 
Heartrate variability during variable pressure support mechanical 
ventilation 
NAME OF DEVICE 
Infinity Delta Monitor, Dräger, Lübeck, Germany 
Evita Infinity V500, Dräger, Lübeck, Germany 
DESCRIPTION 
OF 
THE 
PROCEDURES 
Retrospectively determine heart rate variability from a standard 
electrocardiogram (Infinity Delta Monitor) recorded during 
conventional and variable pressure support mechanical ventilation 
(Evita Infinity V500). We hypothesize that heartrate variability 
(median of high frequency components over one hour) will increase 
during variable pressure support mechanical ventilation as compared 
to the conventional mode of mechanical ventilation. 
OBJECTIVES 
Primary study objective: 
To compare the High frequency components (HF) of Heart Rate 
Variability (median over one hour measurement per patient) between 
conventional and variable pressure support ventilation. 
Secondary study objectives: 
Comparison of applicated tidal volumes and in heart rate variability 
parameters (median of standard deviation of R to R intervals (SDNN), 
median of high frequency to low frequency ratio over one hour 
measurement per patient) between conventional and variable 
pressure support ventilation. 
Exploratory objectives: 
Comparison of change in physiological parameters (e.g. systolic and 
diastolic arterial blood pressure, arterial partial pressure of oxygen, 
arterial partial pressure of carbon dioxide) between conventional and 
variable pressure support ventilation. 
TYPE OF THE INVESTIGATION Interventional MPG § 40.3 cross-over trial 
PERIOD OF ENROLMENT 
First patient 
First visit 
1Q 
 
Last patient 
First visit 
3Q 
 
Last patient 
Last visit 
3Q 
 
CENTER(S) 
/ COUNTRY(IES)  
1 center (Medical University of Vienna), Austria 
PATIENTS / GROUPS 
60 patients  
 

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INCLUSION CRITERIA 
patients undergoing therapy at an ICU  
patients aged between 18 and 80 years 
patients intubated and ventilated using SPN-CPAP/PS ventilator mode 
patients with sinus rhythm in electrocardiogram 
EXCLUSION CRITERIA 
patients aged < 18 or > 80 years 
patients with active heart pace maker / defibrillator 
patients with absent sinus rhythm in electrocardiogram 
patients with known severe disease of autonomous nervous system 
women, who are already known to be pregnant before taking part in 
this study 
COMPARATIVE DEVICE  
  
None. 
CONCOMITANT 
MEDICATION/CON-
COMITANT DEVICE 
Every therapy / medication / monitoring is allowed as indicated per 
routine. 
EFFICACY ENDPOINTS 
Primary study endpoint: 
High frequency components (HF) of Heart Rate Variability (median 
over one hour measurement per patient)  
Secondary study endpoints: 
Applicated tidal volumes and other heart rate variability parameters 
(standard deviation of R to R intervals (SDNN), high frequency to low 
frequency ratio), 
Exploratory endpoints: 
physiological parameters (systolic and diastolic arterial blood pressure, 
arterial partial pressure of oxygen, arterial partial pressure of carbon 
dioxide). 
TOLERABILITY 
/ 
SAFETY 
ENDPOINTS 
 The occurrence of adverse events will be documented. 
QUALITY OF LIFE  
No quality of life parameters will be measured. 
STATISTICAL METHODOLOGY  Primary Endpoint 
High frequency components (HF) of Heart Rate Variability (median 
over one hour measurement per patient)  
 
 

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Secondary Endpoints 
Applicated tidal volumes and other heart rate variability parameters 
(median of standard deviation of R to R intervals (SDNN) or high 
frequency to low frequency ratio over one hour measurement per 
patient) 
Exploratory Endpoints 
Physiological parameters (systolic and diastolic arterial blood pressure, 
arterial partial pressure of oxygen, arterial partial pressure of carbon 
dioxide). 
Null and alternative hypotheses: 
Null hypothesis of primary endpoint: there is no difference in the mean 
heartrate variability (measured as median high frequency components 
HF over one hour measurement per patient) between variable/noisy 
pressure support mechanical ventilation compared to conventional 
pressure support mechanical ventilation. 
 
Alternative hypothesis of primary endpoint: there is a difference in the 
mean heartrate variability (measured as median high frequency 
components HF over a one hour measurement per patient) between 
variable/noisy pressure support mechanical ventilation compared to 
conventional pressure support mechanical ventilation. 
 
Type-I and -II errors – power 
The significance level was set to 0.05. The study was planned to achieve 
80% power. 
Interim analysis 
No interim analysis. 
 
Statistical methodology: 
The primary endpoint will be analysed using ANOVA for repeated 
measurements accounting for group of pressure support mechanical 
ventilation as well as randomization order, the interaction between 
group and randomization order as well as gender and age.  
Sample size calculation: 
The study was planned based on preliminary data. When the sample 
size is 52, a single group t-test with a 0.05 two-sided significance level 
will have 80% power to detect the difference between a mean 
heartrate variability of 49 ms2 in the conventional group and an mean 

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of 59 ms2 with variable pressure support mechanical ventilation 
assuming that the standard deviation of the difference is 25 ms2. 
Due to possible Drop-outs the sample size was set to 60 patients. 
 
STUDY EXTENSION 
If collection of data cannot be done in the given time. 
 
 

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3. 
LIST OF ABBREVIATIONS 
EOS 
End of study 
HF 
High frequency components of heart rate variability 
HRV 
Heart rate variability 
ICT 
Interventional clinical trial 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
LF 
Low frequency components of heart rate variability 
PaCO2 
Arterial partial pressure of carbon dioxide 
PaO2 
Arterial partial pressure of oxygen 
Pmax 
Maximum pressure support 
Psupp 
Mean support pressure 
PSV 
Pressure support ventilation 
SOP 
standard operation procedures 
SDNN 
standard deviation of R to R intervals of heart rate variability 
SPN-CPAP/PS 
Spontaneous continuous positive airway pressure/ pressure support 
VPSMV 
Variable pressure support mechanical ventilation 
 
 
 

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4. 
TABLE OF CONTENTS 
 
1. 
SPONSORS, INVESTIGATORS, MONITOR AND SIGNATURE ............................................................. 3 
2. 
SYNOPSIS OF THE CLINICAL INVESTIGATION ................................................................................... 4 
3. 
LIST OF ABBREVIATIONS .................................................................................................................. 8 
4. 
TABLE OF CONTENTS ....................................................................................................................... 9 
TABLE 1. VISIT AND ASSESSMENT SCHEDULE ....................................................................................... 12 
5. 
INTRODUCTION ............................................................................................................................. 13 
5.1 
Background information........................................................................................................ 13 
5.2 
Rationale of clinical investigation .......................................................................................... 13 
6. 
OBJECTIVES OF THE CLINICAL INVESTIGATION (HYPOTHESIS) ...................................................... 14 
6.1 
Primary Objective (Hypothesis) ............................................................................................. 14 
6.2 
Secondary Objectives (Hypothesis) ....................................................................................... 14 
7. 
DESIGN OF THE CLINICAL INVESTIGATION .................................................................................... 14 
7.1 
Population ............................................................................................................................. 14 
7.1.1 
Subject population ............................................................................................................ 14 
7.1.2 
Inclusion criteria ................................................................................................................ 15 
7.1.3 
Exclusion criteria ............................................................................................................... 15 
7.2 
POINT OF ENROLMENT .......................................................................................................... 15 
7.2.1 
Females of childbearing age .............................................................................................. 15 
7.2.2 
Duration of the clinical investigation ................................................................................ 15 
7.3 
Withdrawal and replacement of subjects ............................................................................. 15 
7.3.1 
Criteria for withdrawal ...................................................................................................... 15 
7.3.2 
Follow-up of patients withdrawn from the clinical investigation ..................................... 16 
7.4 
Premature termination of the clinical investigation ............................................................. 16 
8. 
METHODOLOGY ............................................................................................................................. 16 
8.1 
Treatment duration and modification ................................................................................... 16 
8.2 
Medical Devices ..................................................................................................................... 16 
8.2.1 
Manufacturer (Model or Type Number including software and accessories): Storage 
Instructions: ....................................................................................................................................... 16 
8.2.2 
Installation and handling instructions ............................................................................... 16 
8.2.3 
Intended use ...................................................................................................................... 16 
8.2.4 
In-/Decrease of the treatment frequency ......................................................................... 16 
8.2.5 
Interruption of the treatment ........................................................................................... 16 
8.2.6 
Premature permanent discontinuation of the treatment ................................................. 16 

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8.2.7 
Premature permanent discontinuation due to an adverse event .................................... 17 
8.2.8 
Premature permanent discontinuation due to another reason than adverse event ....... 17 
8.2.9 
Procedures for subjects’ compliance ................................................................................ 17 
8.2.10 
Concomitant medication ................................................................................................... 17 
8.2.11 
Interactions, reverse reactions and side effect of the medical device: ............................ 17 
8.3 
Randomization and stratification: ......................................................................................... 17 
8.4 
Blinding .................................................................................................................................. 17 
8.4.1 
Emergency procedure for unblinding ................................................................................ 17 
8.4.2 
Unblinding-procedure at the end of the clinical investigation.......................................... 17 
8.5 
Benefit and risk assessment .................................................................................................. 17 
8.6 
Clinical investigation procedures .......................................................................................... 17 
8.6.1 
General rules for clinical investigation procedures ........................................................... 17 
8.6.2 
Screening investigation ..................................................................................................... 18 
8.6.3 
Treatment .......................................................................................................................... 18 
8.6.4 
Laboratory Tests ................................................................................................................ 18 
8.6.5 
End-of-clinical investigation (EOI) examination ................................................................ 18 
9. 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .............................................................. 18 
9.1 
Adverse events (AEs)/Adverse device effects (ADEs) ............................................................ 18 
9.1.1 
Summary of known and potential risks of the medical device ......................................... 18 
9.1.2 
Definition of adverse event and adverse device effect ..................................................... 18 
9.2 
Serious adverse events (SAE)/Serious adverse device effects (SADEs) ................................. 18 
9.2.1 
Hospitalization – Prolongation of existing hospitalization ................................................ 18 
9.2.2 
SAEs /sADE related to study-mandated procedures ......................................................... 19 
9.2.3 
Pregnancy .......................................................................................................................... 19 
9.3 
Severity of adverse events/adverse device effects ............................................................... 19 
9.4 
Relationship to medical device.............................................................................................. 19 
9.5 
Reporting procedures ............................................................................................................ 19 
9.5.1 
Reporting procedures for SAEs/SADEs .............................................................................. 19 
10. 
FOLLOW-UP ............................................................................................................................... 19 
10.1 
Follow-up of clinical investigation participants including follow-up of adverse events ....... 19 
10.2 
Treatment after end of clinical investigation ........................................................................ 19 
11. 
STATISTICAL METHODOLOGY AND ANALYSIS ....................................................................... 19 
11.1 
Analysis sets........................................................................................................................... 19 
11.2 
Sample size considerations ................................................................................................... 19 
11.3 
Relevant CIP deviations ......................................................................................................... 20 
11.4 
Statistical analysis plan .......................................................................................................... 20 

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11.5 
Missing, unused and spurious data ....................................................................................... 20 
11.6 
Endpoints analysis ................................................................................................................. 20 
11.6.1 
Primary endpoint analysis ................................................................................................. 20 
11.6.2 
Secondary endpoint analysis ............................................................................................. 20 
11.6.3 
Safety and tolerability endpoints ...................................................................................... 21 
11.6.4 
Exploratory analyses .......................................................................................................... 21 
11.7 
Interim analysis ..................................................................................................................... 21 
Criteria for the termination of the clinical investigation:.................................................................. 21 
11.8 
Software program(s) ............................................................................................................. 21 
12. 
DOCUMENTATION AND DATA MANAGEMENT ......................................................................... 21 
12.1 
Documentation of study results ............................................................................................ 21 
12.1.1 
Case Report Form (CRF) ..................................................................................................... 21 
12.1.2 
Data Collection .................................................................................................................. 21 
12.1.3 
Identification data to be considered as source data ......................................................... 21 
12.2 
Safekeeping ........................................................................................................................... 21 
12.3 
Quality Control and Quality Assurance ................................................................................. 22 
12.3.1 
Periodic Monitoring ........................................................................................................... 22 
12.3.2 
Audits and Inspections ...................................................................................................... 22 
12.4 
Reporting and Publication ..................................................................................................... 22 
12.4.1 
Final Report ....................................................................................................................... 22 
12.4.2 
Publication of Study Results .............................................................................................. 22 
13. 
ETHICAL AND LEGAL ASPECTS ................................................................................................... 23 
13.1 
Informed Consent of Subjects ............................................................................................... 23 
13.2 
Acknowledgement/approval of the Clinical Investigation .................................................... 23 
13.2.1 
Changes in the Conduct of the Clinical Investigation Plan ................................................ 23 
13.3 
Insurance ............................................................................................................................... 23 
13.4 
Confidentiality ....................................................................................................................... 24 
13.5 
Ethics and Legal Requirements ............................................................................................. 24 
13.5.1 
Declaration of Helsinki ...................................................................................................... 24 
13.5.2 
Good Clinical Practice (EN ISO 14155) ............................................................................... 24 
14. 
ACKNOWLEDGEMENTS ............................................................................................................. 25 
REFERENCES .......................................................................................................................................... 26 
 
 
 

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TABLE 1. VISIT AND ASSESSMENT SCHEDULE 
 
Day 1  
 
 
1. Inclusion 
2. Randomisation 
3. Intervention A-B or B-A1 
 
 
 
 
 
                                                          
1 A-B = conventional PSV – variable PSV, B-A = variable PSV – conventional PSV 

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5. 
INTRODUCTION 
5.1 
Background information 
Spontaneous-continuous positive airway pressure support (SPN-CPAP/PS) is the routine ventilator 
mode used in critically ill patients submitted to an intensive care unit (ICU). It guarantees a positive 
end expiratory pressure, which prevents atelectasis and minimizes weaning time, by supporting the 
patient’s respiratory drive. 
A few years ago, this very established ventilation technique was modified by simply altering the rhythm 
and volume of gas application: instead of administering same tidal volumes in equal time intervals a 
variation of applied volume as well as altering frequency in ventilation is introduced. This ventilation 
method is termed noisy pressure support ventilation (noisy PSV) or variable pressure support 
ventilation (variable PSV). The variation of pressure support will be within a range around a mean 
support-pressure (Psupp) and won’t exceed a maximum pressure (Pmax), which are both adjusted before 
starting noisy PSV. 
Any variation of breathing is physiological and may occur during speaking, moving and many other 
factors. As novel concept, we propose that such variation of ventilation rhythm and volume may have 
an important impact on heart rate variability (HRV), which is known as to be an indicator of a healthy 
heart (Wenckebach, 1914). Since Wolff et al. observed that HRV is an important predictor of mortality 
in coronary care units, investigation of HRV became more important (Wolf et al., 1978). Thayer and 
Lane recently found that low HRV is associated with an increasing mortality and proposed low HRV to 
be a marker for critical illness (Thayer et al., 2010, Thayer and Lane, 2007). 
The analysis and further investigation of HRV has therefore become an important issue in modern 
medicine. Mechanical ventilation plays a pivotal role in ICUs and should be further improved. 
Mechanical ventilation per se is stressful for the cardiovascular system. Cardiovascular homeostasis is 
of major importance and we hypothesise that noisy PSV will decrease the stress applied to the human 
heart measured via heart rate variability (Zipes, 2004, Kleiger et al., 1987, Fozzard).  
 
5.2 
Rationale of clinical investigation 
In this interventional clinical study, we will apply, in a randomized fashion, conventional PSV and 
variable PSV each for a duration of one hour. During ventilation we will record all data of the patients 
monitor, including the electrocardiogram (ECG), which is routinely monitored in our patients, and 
respiratory data, to determine HRV parameters retrospectively. All other ventilatory, hemodynamic 
and pharmacological treatment will be part of the clinical routine. As two modes of ventilation will be 
compared, this study is an interventional clinical cross-over trial.  
Primary study objective: 
To compare the high frequency components (HF) of Heart Rate Variability (median over one hour 
measurement per patient) from ECG data between conventional and variable pressure support 
ventilation. 
The following parameters will be measured and calculated: 
• 
ECG waveform at 200 Hz 
• 
Pulse pressure waveform as part of the clinical routine 
• 
Arterial blood gas analysis at the beginning and end of each ventilation mode 
o Arterial partial pressure of oxygen (PaO2) 

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o Arterial partial pressure of carbon dioxide (PaCO2) 
• 
Arterial pressure waveform if part of the clinical routine 
• 
All respirator data 
6. 
OBJECTIVES OF THE CLINICAL INVESTIGATION (HYPOTHESIS) 
6.1 
Primary Objective (Hypothesis) 
 
Primary endpoint is the High frequency component (HF) of the heart rate variability. For each patient 
a median of the HF-curve over one hour treatment will be calculated. This value is chosen, since the 
median of high frequency components is stable to measurement related artefacts. 
 
Null hypothesis of primary endpoint:  
There is no difference in the mean heartrate variability (median high frequency components HF over a 
one hour measurement per patient) between variable/noisy pressure support mechanical ventilation 
compared to conventional pressure support mechanical ventilation. 
 
6.2 
Secondary Objectives (Hypothesis) 
 
Comparison of applicated tidal volumes and other heart rate variability parameters (median standard 
deviation of R to R intervals (SDNN) and median high frequency to low frequency ratio over one hour 
measurement per patients) between conventional and variable pressure support ventilation. Note that 
also for the secondary parameters, the median over a one hour continuous measurement per patient 
will be used for statistical analyses. 
 
6.3 
Exploratory Objectives 
 
Comparison of change in Physiological parameters (systolic and diastolic arterial blood pressure, 
arterial partial pressure of oxygen, arterial partial pressure of carbon dioxide) between conventional 
and variable pressure support ventilation. In contrast to the primary and secondary parameters, the 
exploratory parameters are not measured during the whole study duration (one hour per treatment) 
but at the beginning and end of each treatment. 
7. 
DESIGN OF THE CLINICAL INVESTIGATION 
7.1 
Population 
This study is an interventional cross-over trial in N=60 patients. 
 
7.1.1 Subject population 
The study will include subjects between 18-80 years undergoing therapy at an anesthesiological ICU 
(ICUs: 9D, 13B1, 13C2). No absent sinus rhythm and no active implanted pacemaker or defibrillator is 
allowed. Participants will be informed and sign the written informed consent form after extubation 
and improvement of clinical condition.  

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7.1.2 Inclusion criteria 
• 
patients undergoing therapy at an ICU 
• 
patients aged between 18 and 80 years 
• 
patients intubated and ventilated on SPN-CPAP/PS mode 
• 
patients with sinus rhythm in electrocardiogram 
7.1.3 Exclusion criteria 
• 
patients aged under 18 or over 80 years 
• 
patients with active heart pacemaker/defibrillator 
• 
patients with absent sinus rhythm in ECG 
• 
patients with severe autonomous nervous system disease 
• 
women, who are already known to be pregnant before taking part in this study 
 
7.2 
POINT OF ENROLMENT 
The subjects will be recruited on ICUs from the Department of Anaesthesia, General Intensive Care 
and Pain Management. The study will be performed in accordance with the Declaration of Helsinki 
(1964), including current revisions and the study protocol will be submitted to the Ethics Committee 
of the Medical University of Vienna for approval. The subject's consent will be collected after 
extubation and clinical improvement, as far as possible regarding the patient’s state of health. All 
subject names will be kept confidential in the investigators files. Subjects will be identified throughout 
documentation and evaluation by the number allotted to them during the study. The subjects will be 
informed that all study findings will be stored and handled in strictest confidence. A data protocol in 
case report form will be used. 
7.2.1 Females of childbearing age 
Females of childbearing age will be included.  
7.2.2 Duration of the clinical investigation 
The duration of the clinical cross-over trial is one year. First, subjects will be included in the clinical 
study according to inclusion and exclusion criteria. The order of the two interventions will be 
randomized. According to the randomization, subjects will be allocated first to conventional PSV 
(duration one hour) then to variable PSV (one hour) or vice versa. Thereafter, the study observation 
period will be over. Subjects will not have to come to follow up visits or investigations.  
 
7.3 
Withdrawal and replacement of subjects 
7.3.1 Criteria for withdrawal 
Discontinuation from the study is to be understood when the subject did not undergo the end of study 
(EOS) examination and/or all pivotal assessments during the clinical investigation. 
Subjects must be withdrawn under the following circumstances: 
• 
at their own request 
• 
if the investigator feels it would not be in the best interest of the subject to continue 
• 
if the subject violates conditions laid out in the consent form / information sheet or disregards 
instructions by the clinical investigation personal 

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• 
in case of severe medical emergency (e.g. cardiac arrest, reanimation) 
 
In all cases, the reason why subjects are withdrawn must be recorded in detail in the case record file 
(CRF) and in the subject’s medical records. Should the clinical investigation be discontinued 
prematurely, all clinical investigation materials (complete, partially completed and empty CRFs) will be 
retained. 
7.3.2 Follow-up of patients withdrawn from the clinical investigation 
In case of premature discontinuation, no follow-up will be performed. Replacement policy  
Patients excluded from the study for any of the reasons above will be replaced. 
7.4 
Premature termination of the clinical investigation 
The sponsor has the right to close this clinical investigation at any time. The internal ethical committee 
(IEC) and the competent regulatory authority must be informed. 
8. 
METHODOLOGY 
The study will be performed for the time of HRV measurement (one hour conventional PSV followed 
by one hour variable PSV, in total two hours without interruption, randomized fashion). 
8.1 
Treatment duration and modification 
Patients will be screened for eligibility before ventilation-mode switch according to inclusion and 
exclusion criteria. 
8.2 
Medical Devices 
All devices used in the present cross-over trial are part of the clinical routine (Evita Infinity V500 and 
Infinity Delta). No extra medical device will be used. Both ECG recording and classical as well as variable 
PSV ventilator modes are used in routine clinical ICU therapy. 
8.2.1 Manufacturer (Model or Type Number including software and accessories): 
Storage Instructions: 
Manufacturer: Dräger, Model: Evita Infinity V500, Serial Number: Clinical routine ventilation on ICU 
Manufacturer: Dräger, Model: Infinity Delta, Serial Number: Clinical routine monitoring on ICU 
8.2.2 Installation and handling instructions 
According to clinical routine instructions. 
8.2.3 Intended use 
According to clinical routine instructions. 
8.2.4 In-/Decrease of the treatment frequency 
Not applicable. 
8.2.5 Interruption of the treatment 
The treatment will be interrupted in case of technological failure, emergency situation, unstable 
cardiovascular or pulmonary conditions, cardiac arrest and cardiopulmonary reanimation. 
8.2.6 Premature permanent discontinuation of the treatment 
Premature discontinuation of the cross-over trial is not planned. There are no interim analyses. 

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8.2.7 Premature permanent discontinuation due to an adverse event 
Not applicable. 
8.2.8 Premature permanent discontinuation due to another reason than adverse event 
Not applicable. 
8.2.9 Procedures for subjects’ compliance 
All recordings will be performed by the investigators.  
8.2.10 Concomitant medication 
All concomitant medications are allowed. 
8.2.11 Interactions, reverse reactions and side effect of the medical device:   
Not applicable. All devices used are part of the clinical routine ICU therapy. Both the conventional and 
variable PSV modes are part of the clinical routine ICU therapy. The arterial blood gas analyses are not 
part of the clinical routine ICU therapy. Potential risks and side effects of taking arterial blood gas 
analyses include infection and bleeding only in case of inappropriate usage. 
8.3 
Randomization and stratification:  
Subjects will be randomized to the order of conventional and variable PSV treatment (first 
conventional PSV and then variable PSV or first variable PSV and then conventional PSV). The 
randomization will be performed by block-randomization using the online randomization program of 
the Medical University of Vienna (https://www.meduniwien.ac.at/randomizer/web/login.php). There 
will be no stratification of subjects studied. Only the statistician (Dr. Graf) and the responsible person 
performing measurements (Mr. Schnetzinger) will have access to the online randomization program. 
 
8.4 
Blinding 
No blinding procedure will be performed. The patient will be blinded, with respect to the respiratory-
treatment, due his medical status. 
8.4.1 Emergency procedure for unblinding 
Not applicable. 
8.4.2 Unblinding-procedure at the end of the clinical investigation. 
Not applicable. 
8.5 
Benefit and risk assessment 
Both the Infinity Delta Monitor and the Evita Infinity V500 are part of the clinical routine ICU therapy. 
Also, the ventilator mode conventional PSV and variable PSV are part of the clinical routine ICU 
therapy. The only procedures performed in the present cross-over trial is that the ventilator mode will 
be changed from conventional PSV to variable PSV or vice versa. Therefore, there are no actual risks 
for the patients during the present study or clinical ICU routine therapy. The only additional procedures 
attributed to this study is that extra arterial blood gas measurements will be performed during the 
study. These risks are low, as the person performing the study will be trained in taking arterial blood 
gas analysis and such procedures are taken also routinely during ICU stay. 
8.6 
Clinical investigation procedures 
8.6.1 General rules for clinical investigation procedures 
• 
All investigation measures have to be documented with date (dd.mm.yyyy).  

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• 
The dates of all procedures should be according to the clinical investigation plan (CIP). The 
time margins mentioned in the clinical investigation flow chart are admissible. If, for any 
reason, a clinical investigation procedure is not performed within scheduled margins a CIP 
deviation should be noted, and the procedure should be performed as soon as possible or as 
adequate. 
 
8.6.2 Screening investigation  
All patients scheduled for ICU will be screened. Eligible patients will be included in the study. Informed 
patient consent will be taken after the patients have been extubated and transferred to the normal 
ward.  
8.6.3 Treatment 
The treatment includes setting the ventilator to conventional PSV mode for one hour and variable PSV 
mode for one hour (in total 2 hours of treatment per patient, randomized fashion). Arterial blood gases 
taken at the beginning and the end of each ventilator mode (2x per mode, in total 4 arterial blood 
gases per patients) will be taken in addition to the clinical routine therapy. Thereafter, the treatment 
will be terminated and no patient follow up will be performed. 
8.6.4 Laboratory Tests 
Blood gas analysis will be taken at the beginning and the end of each treatment (2 times 2 arterial 
blood gas analyses, in total 4 blood gas analyses per patient). 
8.6.5 End-of-clinical investigation (EOI) examination 
No end-of-clinical-investigation (EOI) examination will be performed. 
 
9. 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 
Adverse events (AEs)/Adverse device effects (ADEs) 
9.1.1 Summary of known and potential risks of the medical device  
Both the Infinity Delta Monitor and the Evita Infinity V500 are part of the clinical routine ICU therapy. 
These devices are licensed for the clinical usage and will be used only for their specific purpose. 
Therefore, there are no extra risks associated with this clinical study. Theoretical risks include failure 
of the device with harm to the patients. In case of technological failure of the devices the subject may 
be harmed as monitoring of vital parameters (Infinity Delta Monitor) or mechanical ventilation (Evita 
Infinity V500) might be inadequate, injurious or in theory lethal. 
9.1.2 Definition of adverse event and adverse device effect 
Adverse events (AEs) are any significant hemodynamic or respiratory impairment (e.g. in- or decrease 
of systolic or diastolic arterial blood pressure or heart rate or parameters of respiration of < or >30% 
baseline). Further, any technological problems are defined adverse device effects (ADEs). Such 
impairments are not expected during the present study. 
9.2 
Serious adverse events (SAE)/Serious adverse device effects (SADEs) 
Serious adverse events (SAEs) are hemodynamic or respiratory impairments (see AEs) that are 
potentially life-threatening to the subject. Serious adverse device effects (ADEs) are technological 
problems that are potentially life-threatening to the subject. 
9.2.1 Hospitalization – Prolongation of existing hospitalization 
Not applicable. 

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9.2.2 SAEs /sADE related to study-mandated procedures 
Not applicable. 
9.2.3 Pregnancy 
Women, who are known to be pregnant before taking part in the study, are excluded.  
9.3 
Severity of adverse events/adverse device effects 
Not applicable. 
9.4 
Relationship to medical device 
There is no financial or other relationship between the authors/investigators and the manufacturer of 
the medical devices used. 
9.5 
Reporting procedures 
AEs or ADEs will be reported within one week to the ethical care committee. 
9.5.1 Reporting procedures for SAEs/SADEs  
SAEs and SADEs will be reported within 24 hours to the ethical care committee and the study will be 
paused until clarity about the SAEs/SADEs reason. 
10. FOLLOW-UP 
10.1 Follow-up of clinical investigation participants including follow-up of adverse 
events 
No follow-up of clinical investigation participants will be performed. 
10.2 Treatment after end of clinical investigation 
The clinical investigation has no effect on the treatment of the patient especially not after its end. 
11. 
STATISTICAL METHODOLOGY AND ANALYSIS 
11.1 Analysis sets 
The study will be analyzed using the per-protocol set. This analysis set comprises all subjects who 
underwent treatment with both pressure support systems and did not violate the protocol in a way 
that might affect the evaluation of the primary study parameter. Drop-outs may occur if the treatment 
will be interrupted in case of technological failure, emergency situation, unstable cardiovascular or 
pulmonary conditions, cardiac arrest and cardiopulmonary reanimation. In case of a drop-out, the 
evaluation of the primary parameter is not meaningful so that drop-outs will be excluded from the 
analysis. All treatment interruptions will be documented and summarized.  
Violations of the protocol due to a wrong randomization ordering (reverse than randomized) are less 
likely because measurements are done by one person (Mr. Schnetzinger) who is also the holder of the 
randomization list. 
11.2 Sample size considerations 
A sample size calculation has been carried out. Basis for this sample size calculation is preliminary data 
for the primary endpoint, the high frequency components of heart rate variability (median over one 
hour measurement per patient, further on denoted as HF). We assume a mean HF of about 49 ms2 for 
the conventional mode of mechanical ventilation. An increase of on average 10 ms2 (to 59 ms2) for the 
variable pressure support mechanical ventilation is assumed. For sample size calculation, the standard 
deviation of the difference was set to 25 ms2. 

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When the sample size is 52, a single group t-test with a 0.05 two-sided significance level will have 80% 
power to detect the assumed effect. 
Empirical knowledge of eventual intervention-related drop-out of patients from the study, leads to a 
sample size of 60 patients. (drop outs due to technological failure, emergency situation, unstable 
cardiovascular or pulmonary conditions, cardiac arrest and cardiopulmonary reanimation). 
 
11.3 Relevant protocol deviations 
Protocol deviations may occur if the treatment will be interrupted in case of technological failure, 
emergency situation, unstable cardiovascular or pulmonary conditions, cardiac arrest and 
cardiopulmonary reanimation. In case of a drop-out, the evaluation of the primary parameter is not 
meaningful, so that drop-outs will be excluded from the statistical analysis.  
11.4 Statistical analysis plan 
see 11.6 
11.5 Missing, unused and spurious data 
Missing, unused or spurious data due technological failure, emergency situation, unstable 
cardiovascular or pulmonary conditions, cardiac arrest and cardiopulmonary reanimation will be 
reported and presented. Records with missing data will be excluded from the analysis. 
11.6 Endpoints analysis 
11.6.1 Primary endpoint analysis 
The median of the high frequency components (HF) measured over one hour per patient will be 
described descriptively separately for the two pressure support mechanical ventilation groups using 
means, standard deviations as well as medians and quantiles. Graphical illustration will be performed 
using boxplots. 
To compare the mean HF between conventional and variable pressure support mechanical ventilation, 
first a paired t-test will be performed. 
Furthermore, an ANOVA for repeated measurements, accounting for group (conventional vs. variable), 
randomization order, the interaction between group and randomization order as well as other 
influence factors (as gender and age) will be performed. 
The significance level for the primary analysis is set to 0.05. 
 
11.6.2 Secondary endpoint analysis 
Similar to the main outcome parameters the median of the standard deviation of normal to normal 
(SDNN) and the median of high-frequency-low-frequency-ratios (HF-LF-ratio) over one hour 
measurements will be described descriptively with boxplots as well as means, standard deviations, 
medians and quantiles. 
Furthermore, mean SDNN and HF-LF-ratio will be compared between treatment groups using paired 
t-tests. In addition, an ANOVA for repeated measurements, accounting for group, randomization 
order, the interaction between group and randomization order as well as other influence factors (as 
gender and age) will be performed. 
The significance level for the secondary analyses is set to 0.05. 
 

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11.6.3 Safety and tolerability endpoints 
The occurrence of adverse events will be described descriptively by frequencies and percentages. 
 
11.6.4 Exploratory analyses 
All exploratory parameters, which are obtained from arterial blood gas analysis (systolic and diastolic 
arterial blood pressure, arterial partial pressure of oxygen, arterial partial pressure of carbon dioxide) 
will be described with descriptive statistics (boxplots, means, standard deviations, medians and 
quartiles) separately for the two groups. 
11.7 Interim analysis 
No interim analysis is planned. 
Criteria for the termination of the clinical investigation: 
Not applicable as no interim analysis planned.  
11.8 Software program(s) 
Statistical evaluation will be performed using SPSS and R. 
12. DOCUMENTATION AND DATA MANAGEMENT 
12.1 Documentation of study results 
A subject screening and enrollment Log will be completed for all eligible or non-eligible subjects with 
the reasons for exclusion. 
12.1.1 Case Report Form (CRF) 
For each subject enrolled, regardless of medical device initiation, a “Paper-CRF” must be completed 
and signed by the principal investigator or co-investigator. This also applies to those subjects who fail 
to complete the study. If a subject withdraws from the study, the reason must be noted on the CRF. 
Case report forms are to be completed on an ongoing basis. CRF entries and corrections will only be 
performed by study site staff and authorized by the investigator. In a “Paper-CRF” all forms should be 
completed using a pen and must be legible. Errors should be crossed out but not obliterated, the 
correction inserted, and the change initialed and dated by the investigator, co-investigator or study 
nurse. The entries will be checked by trained personnel (Monitor) and any errors or inconsistencies 
will be checked immediately. The monitor will collect original completed and signed CRFs at the end 
of the study. A copy of the completed and signed CRFs will remain on site. The original “Paper-CRFs” 
will be passed to Maximilian Schnetzinger. He is the data manager. 
12.1.2 Data Collection 
Data collected at all visits are entered into an interactive form. The CRFs will be source documents 
verified following guidelines established before study onset as detailed in the Monitoring Plan. 
Maintenance of the study database will be performed by Maximilian Schnetzinger. 
12.1.3 Identification data to be considered as source data 
Not applicable. 
12.2 Safekeeping 
The investigator will maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. These documents will be classified 
into two different categories: investigator's file, and subject clinical source documents. The 
investigator's file will contain the CIP/amendments, IB/Manual for Medical Device, CRFs (eCRF 

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printout), standard operation procedures (SOPs), data clarification and query forms, EC/IRB and Health 
Authority approval with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization 
forms, 
screening 
and 
enrollment 
logs, 
and 
other 
appropriate 
documents/correspondence as per EUROPENAN Standard of EN ISO 14155 (incl. GCP) and local 
regulations. 
Subject clinical source documents include, but are not limited to subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, X-ray, pathology 
and special assessment reports, consultant letters, etc. These two categories of documents must be 
kept on file by the investigator for as long as needed to comply with national and international 
regulations (in Austria 15 years after discontinuing clinical development or after the last marketing 
approval). If source documents are not durable as long as needed (e.g. ECG printouts) they must be 
preserved as a copy. No study document should be destroyed without prior written approval. When 
source documents are required for the continued care of the subject, appropriate copies should be 
made for storing outside of the site. 
12.3 Quality Control and Quality Assurance 
Datasets will be controlled weekly by all members of the team. 
12.3.1 Periodic Monitoring 
The monitor will contact and visit the investigator regularly and will be allowed, on request, to have 
access to all source documents needed to verify the entries in the CRFs and other CIP-related 
documents provided that subject confidentiality is maintained in agreement with local regulations. It 
will be the monitor's responsibility to inspect the CRFs at regular intervals throughout the study, to 
verify the adherence to the CIP and the completeness, consistency and accuracy of the data being 
entered on them. The monitoring standards require full verification for the presence of informed 
consent, adherence to the inclusion/exclusion criteria, documentation of SAEs/SADEs and the 
recording of the main efficacy, safety, and tolerability endpoints. To be ISO 14155 compliant at least 3 
monitoring visits are scheduled. An initiation visit, one routine visit and a final visit (3 visits in total) 
after the last patient, had finished the study. The monitor will be working according to SOPs and will 
provide an ISO 14155-compliant monitoring report after each visit for the sponsor and the investigator. 
12.3.2 Audits and Inspections 
Upon request, the investigator will make all study-related source data and records available to a 
qualified quality assurance auditor mandated by the sponsor or to regulatory authority inspectors. The 
main purpose of an audit or inspection is to confirm that the rights and welfare of the subjects have 
been adequately protected, and that all data relevant for assessment of safety and efficacy of the 
investigational product have appropriately been reported to the sponsor. 
12.4 Reporting and Publication 
12.4.1 Final Report 
Within one year after the final completion of the study, a full report will be written. The principal 
Investigator will be asked to review and sign the final report. 
12.4.2 Publication of Study Results 
The findings of this study will be used to design prospective trials using HRV in the perioperative 
setting. 
 

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13. ETHICAL AND LEGAL ASPECTS 
13.1 Informed Consent of Subjects 
Following comprehensive instruction regarding the nature, significance, impact and risks of this clinical 
investigation, the patient must give written consent to participation in the study. During the 
instruction, the patients are to be made aware of the fact that they can with-draw their consent - 
without giving reasons – at any time without their further medical care being influenced in any way. In 
addition to the comprehensive instructions given to the patients by the investigator, the patients also 
receive a written patient information sheet in comprehensible language, explaining the nature and 
purpose of the study and its progress. The patients must agree to the possibility of study-related data 
being passed on to relevant authorities. The patients must be informed in detail of their obligations in 
relation to the patient insurance in order not to jeopardize insurance cover. 
13.2 Acknowledgement/approval of the Clinical Investigation 
The investigator (or a designated CRO) will submit this CIP and any related document provided to the 
subject (such as subject information used to obtain informed consent) to an Ethics Committee (EC) or 
Institutional Review Board (IRB). Approval from the committee must be obtained before starting the 
clinical investigation, and should be documented in a dated letter to the investigator. Serious Adverse 
Events /Serious Adverse Device Effects have to be reported to the ethics committee and to the Austrian 
Agency for health and Food Safety (AGES). Adverse events / Adverse device effects- whether serious 
and/or unexpected, and possibly endangering the safety of the study participants are likewise to be 
reported to the ethics committee. The clinical investigation shall be performed in full compliance with 
the valid legal regulations according to the Medical Device Law (MPG Medizinproduktegesetz as actual 
amendment) of the Republic of Austria and the ISO 14155 (as actual amended). The study must be 
notified to the Austrian Agency for Health and Food Safety (AGES) and Ethics Committee. 
13.2.1 Changes in the Conduct of the Clinical Investigation Plan 
Amendments of the clinical investigation plan 
Proposed amendments must be submitted to the appropriate CA and ECs. Substantial amendments 
may be implemented only after CA/EC approval has been obtained. Amendments that are intended to 
eliminate an apparent immediate hazard to subjects may be implemented prior to receiving CA/EC 
approval. However, in this case, approval must be obtained as soon as possible after implementation. 
Termination of the clinical investigation 
If the sponsor or the investigator decides to terminate the clinical investigation before it is completed, 
they will notify each other in writing stating the reasons of early termination. In terminating the study, 
the sponsor and the investigator will ensure the adequate consideration is given to the protection of 
the subject interests. The investigator, sponsor or designated CRO will notify the relevant regulatory 
authorities and EC. Documentation will be filed in the Trial Master (Clinical Investigation) clinical 
investigation and Investigator Files. 
13.3 Insurance 
During their participation in the clinical investigation the patients will be insured as defined by legal 
requirements. The principal investigator of the clinical investigation will receive a copy of the insurance 
conditions of the patient’s insurance. The sponsor is providing insurance in order to indemnify (legal 
and financial coverage) the investigator/centre against claims arising from the clinical investigation, 
except for claims that arise from malpractice and/or negligence. The compensation of the subject in 
the event of clinical investigation-related injuries will comply with the applicable regulations. Details 

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on the existing patient’s insurance are given in the patient information sheet and will be filed 
subsequently. 
13.4 Confidentiality 
The information contained in this document, especially unpublished data, is the property of the 
Department of Anaesthesia, General Intensive Care and Pain Management, Medical University Vienna. 
It is therefore provided to you in confidence as an investigator, potential investigator, or consultant, 
for review by you, your staff, and an Ethics Committee or Institutional Review Board. It is understood 
that this information will not be disclosed to others without written authorization from Department of 
Anaesthesia, General Intensive Care and Pain Management, Medical University Vienna, except to the 
extent necessary to obtain informed consent from those persons to whom the medical device may be 
treated with. 
13.5 Ethics and Legal Requirements 
13.5.1 Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformance with the principles of the 
"Declaration of Helsinki" (as amended at the 56th WMA General Assembly, Tokyo, Japan, 2008). 
13.5.2 Good Clinical Practice (EN ISO 14155) 
ISO 14155 addresses good clinical practices for the design, conduct, recording and reporting of clinical 
investigations carried out in human subjects to assess the safety and performance of medical devices 
for regulatory purposes. 
It specifies general requirements intended to: 
• 
protect the rights, safety and well-being of human subjects, 
• 
ensure the scientific conduct of the clinical investigation and the credibility of the clinical 
o investigation results, 
• 
assist sponsors, monitors, investigators, ethics committees, regulatory authorities and other 
o bodies involved in the conformity assessment of medical devices 
The principal investigator of the clinical investigation shall guarantee that only appropriately trained 
personnel will be involved in this. All clinical investigations must follow the EUROPENAN Standard of 
EN ISO 14155 and, if applicable, the Code of Federal Regulations (USA). In other countries in which EN 
ISO Guidelines exist, the investigators will strictly ensure adherence to the stated provisions. 
Therefore, this study follows the EN ISO Guidelines embedded in the Austrian medical device act. 
 
 

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14. ACKNOWLEDGEMENTS 
None. 
 
 

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THAYER, J. F., YAMAMOTO, S. S. & BROSSCHOT, J. F. 2010. The relationship of autonomic imbalance, 
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WOLF, M. M., VARIGOS, G. A., HUNT, D. & SLOMAN, J. G. 1978. Sinus arrhythmia in acute myocardial 
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ZIPES, D. P. 2004. Cardiac electrophysiology : from cell to bedside. Cardiac electrophysiology.