Relation Between Lung Protective Mechanical Ventilation, Intracranial Pressure, Autoregulation and Brain Oxygenation in Neurointensive Care Patients
Phase: NA
Conditions: Acute Brain Injury, Ventilator-Induced Lung Injury, Cerebrovascular Circulation
Sponsor: University Hospital of North Norway

Brain-Vent 
    Ventilator Settings on Patients With Acute Brain Injury 
    
NCT03278769 
 
May 2019 
 
 
 

 
 
  
Study protocol 
 
BRAIN VENT- Relation between lung protective ventilation, intracranial pressure, 
autoregulation and brain oxygenation in neurointensive care patients 
 
Research team: 
Chief investigator: Dr. Shirin Frisvold (Tromsø) 
Other study members: Prof Lars Bjertnæs (Tromsø), Associate Prof Peter Smielewski (Cambridge), 
Prof Marek Czosnyka  (Cambridge), Dr Erta Bequiri (Cambridge), Dr Chiara Robba (Cambridge), 
Prof Claude Guérin (Lyon)  
 
 

 
List of Abbreviations 
ABI  
acute brain injuries  
 
 
 
NIRS  
near infrared spectroscopy 
ARDS  acute respiratory distress syndrome 
 
 
PBW 
Predicted body weight 
BMI  
Body mass index   
 
 
 
PaCO2 
partial pressure of carbon dioxide  
PbtO2 
brain tissue oxygen tension   
 
 
PaO2 
partial pressure of oxygen 
RAP 
Compensatory Reserve Index  
 
 
PawEndexpend-expiratory airway pressure   
CPP 
cerebral perfusion pressure  
 
 
Pplateau  
end-inspiratory plateau pressure 
CT  
Computer tomography  
 
 
 
Peso  
esophageal pressure 
etCO2 
end-tidal CO2  
 
 
 
 
Ppeak  
peak airway pressure 
VTexp  
expiratory tidal volume  
 
 
 
PEEP 
positive end-expiratory pressure 
EVLWI  Extravascular lung water index  
 
 
PTP  
transpulmonary pressure 
NEM 
Health research Ethics  
 
 
 
PrX 
pressure reactivity index 
ICM 
intensive care monitoring 
 
 
 
PICCO Pulse Contour Continuous Cardiac Output 
ICU 
Intensive Care Unit 
 
 
 
SpO2 
oxygen saturation measured by pulsoximetry 
I:E 
inspiratory: expiratory  
 
 
 
TCD  
transcranial Doppler 
FiO2 
inspiratory oxygen fraction  
 
 
TV 
tidal volumes 
VTinsp  
inspiratory tidal volume  
 
 
 
UNN 
University hospital of North Norway 
ICP 
intracranial pressure  
 
 
 
VC 
Volume Control 
AMP 
Pulse Wave Amplitude  
 
 
 
Vf 
ventilatory frequency 
MV 
mechanical ventilation 
 
 
 
VILI 
ventilator-induced lung injury 
 
 

 
1. Background 
 
Background, status of knowledge and expected benefit 
Acute brain injury (ABI) including traumatic brain injury and stroke, are important causes of 
disability and death1,2. It is of outmost importance to prevent secondary brain injury after the first 
hit. Respiratory failure frequently occurs in neurocritical care patients both in the prehospital phase 
and in-hospital3. In the context of ABI and respiratory failure, mechanical ventilation (MV) is 
crucial. Firstly, ABI with a poor Glasgow coma scale is an important indication for tracheal 
intubation and MV. Secondly, hypoxia and hypoventilation evolving from respiratory failure and 
inadequate MV are among the main causes of secondary brain injury4. Thirdly, MV, if wrongly 
used, can result in lung injury on its own right, defined as ventilator-induced lung injury5. 
Consequently, it is important to manage MV optimally in order to prevent the emergence of or 
worsening of respiratory failure and secondary brain injury6–8.  
Many recent studies have focused on ventilator settings in intensive care patients in order to prevent 
ventilator-induced lung injury and reduce mortality9,11. One of the main challenges is to apply so-
called protective lung ventilation (PLV), which is sufficiently high positive end-expiratory pressure 
(PEEP), to avoid airway collapse (atelectotrauma) and/or low tidal volumes (TV) to prevent 
volutrauma. In acute respiratory distress syndrome (ARDS), PLV has evolved to become the « gold 
standard » of MV after year 200011. Recently, researchers have shown increased interest in 
measuring transpulmonary pressure (PTP), as a guide for more optimal PEEP settings in PLV12. PTP 
can be determined by measuring the pressure difference between airway pressure and intrapleural 
pressure, as represented by the pressure changes during MV determined by means of an inflated 
balloon in the esophagus.  
 
A few years ago, a leading investigator suggested the application of PLV for all ICU patients13. 
However, unfortunately, randomized trials of MV in acute lung injury/ARDS have excluded 
patients suffering from ABI, and specific data regarding PLV in these patients are limited. The 
ventilator settings in patients with ABI are often different to those applied in patients at risk of,–or 
suffering from ARDS3,15. The main concern is that PLV with high PEEP and low TV might cause 
high intrathoracic pressures, which might give rise to reduced venous return, hypercapnia and 
increased ICP which might be deleterious. Therefore, a tradition has evolved in neurocritical care to 
apply conventional ventilation with, in particular, low PEEP and high tidal volumes14,15. So far, 
studies dealing with the influence of various types of MV and associated PEEP levels on ICP 
remain inconclusive 16–18. In addition, measurements of Ptp to individualize PEEP settings in this 
group of patients are lacking.  
It is generally accepted that monitoring and treatment of ICP as the single cerebral parameter is of 
limited use 19. Therefore, multimodal monitoring of autoregulation, brain metabolism and 
oxygenation is rapidly emerging as part of treatment protocols for ABI20,21. Over more than two 
decades, co-workers at the University of Cambridge have developed a neuro-intensive care 
monitoring (ICM+) software22. The system continuously registers arterial blood pressure and 
intracranial pressure, and the difference between them, the cerebral perfusion pressure (CPP). The 
system also, has options to include hemodynamic variables. By means of ICP waveform analysis, 
the system estimates blood pressure reactivity index (PrX), which might be used therapeutically as a 
guide to optimize CPP. PrX is described as an indirect measurement of cerebrovascular 
autoregulation and correlates positively with patient outcome23. Negative mean arterial pressure-
ICP correlation indicates pressure reactive vessels (negative PrX) and preserved autoregulation. In 
contrast, positive correlation indicates pressure- passive vessels and impaired autoregulation. ICM+ 
also provides the opportunity to study other clinically relevant ICP indices, as well which might be 
used to guide clinical management24. The relationships between ventilator changes and intracranial 
waveform analysis/autoregulation have not been explored. Since recent data suggest benefits from 

individualizing ICP/CPP treatment with the use of ICP indices such as autoregulation and PrX, the 
relationship between this parameter and variables of ventilator mechanics needs elucidation20,25. 
In addition, the associations between MV and brain oxygenation and cerebral blood flow, all need 
further investigation.  
 
Expected benefit  
Better understanding of the influence of MV on multimodal neuromonitoring parameters might 
provide evidence for the best MV strategy to guide the clinical management of brain injury, while 
avoiding respiratory complications that may delay recovery and start of rehabilitation. The data 
gained by this project might lead to new treatment recommendations for patients with ABI focusing 
on outcome measures such as safety and effectiveness of care. The project will also identify 
respiratory and cerebral variables that should be included in a national or international multicenter 
study where the main outcome measures would relate to mortality and number of ICU days.  
The ICM+ software is a research tool that is used in more than 50 neurosurgery centers worldwide 
and the ICP curve analysis has gained international recognition. Nevertheless, there is a lack of 
research on ventilator settings and ICP waveform analysis and this project will be the first to 
integrate the ventilator parameters in ICM+ and study its clinical use. All centers using ICM+ will 
be able to use the new integration that will be developed and tested in this project, should it prove to 
be effective. 
Measurement of Ptp is a well-recognized research and clinical tool to better manage respiratory 
failure. But, there is little competence in the use of this method in Norway. We will develop a high 
level of experience with this methodology, which can then be applied for other patients with 
respiratory failure and the knowledge can also easily be transferred to other hospitals in Norway.  
 
Study objectives 
The proposed study is an exploratory analysis of the relationship between cerebral blood perfusion 
and oxygenation and lung mechanical variables at different ventilator settings. The primary 
approach will be to carry out baseline measurements to enable conclusions concerning the safety of 
PLV on normal ICP before extending the study to patients with more severe brain or lung injury in 
future studies.   
The primary objective of Brain Vent is to investigate if PLV (higher PEEP and lower TV) as 
compared with conventional settings (lower PEEP and higher TV) 
a. increase ICP.  
b. diminish cerebral vasoreactive autoregulation as assessed by PrX, ie PrX will turn positive, 
which  means that it will change the state from intact to impaired autoregulation. 
The secondary objective is an exploratory analysis of the relationship between ventilator settings 
and other well defined respiratory, cerebral, and cardiovascular variables. The endpoints are 
described below.  
There is also a third objective, which is described in the sub-project at the end of this document, 
which is to investigate the role of next of kin in research with ICU patients. 
 
The study will also lead to increased knowledge in this area, which will serve to: 
2. Improve ventilator settings for the lungs that at the same time are safe for the perfusion of the 
brain. 
3. Identify important ventilator variables that affect the ICP curve analysis and evaluation of brain 
compliance and autoregulation, going from basic science to clinical integration.  
4. Individualize mechanical ventilation based on airway pressure, transpulmonary pressure and 
severity of brain injury. 
5. Develop the ICM+ monitoring software with incorporation of relevant ventilator signals.  
 
Methodology 
 

 
Study design 
Brain Vent is a single center, blinded, randomized, cross-over clinical trial in a tertiary trauma, 
neurosurgery center, which will be conducted at the ICU, UNN Tromsø.  
 
Study population 
All consecutive admitted tracheally intubated adult patients with ICP monitoring (independent of 
the study) will be considered for inclusion within 12 hours by the principal investigator through the 
duration of the study, which is expected to require approximately 18 months to achieve the 
necessary sample size (see below).  
A screening log will be used for participation or non-participation. Reason for non-participation 
will be recorded.   
 
Inclusion criteria 
• Any tracheally intubated or tracheotomized adult patient with ABI with GCS< 10 or Hunt-
Hess grade>3 on controlled ventilation requiring continuous ICP measurement.  
• Admission within 24 h after ABI.  
• Proxy informed consent from relatives.   
 
Exclusion criteria 
• ICP > 22 mmHg before treatment of high ICP 
• Acute respiratory failure defined as partial pressure of oxygen/ inspiratory oxygen fraction 
(PaO2/FiO2) ratio < 40 kPa and X ray pathology 
• History of pulmonary disese: Chronic respiratory failure diagnosis stage III and IV in the 
GOLD classification, pulmectomy, lobectomy or restrictive lung disease.  
• Body mass index (BMI) > 35.  
• Known right or biventricular cardiac failure with cardiac index < 2,5 L/min/m2 
or ejection fracture < 40 %.  
• Refractory hypovolemia as diagnosed with pulse pressure variation > 12 % with tidal 
volume 8 ml/predicted bodyweight (intubated on controlled ventilation) or passive leg rise 
test with > 10 % increase in stroke volume measured by VTI echocardiography or PICCO. 
• Medulla lesion that affect the autonomic nervous system. 
• Patients who has undergone decompressive craniectomy.  
 
Planned number of participants and statistical analysis  
 
In this study setting, we aim to show that LPV is non-inferior to conventional ventilator setting,  
with regards to ICP increase or change of PrX> 0.3 (diminished autoregulation). 
Sample size calculation is based on the primary outcome and the cross-over study design. Assuming 
a difference of zero, a standard deviation of 4 mmHg and a non-inferiority margin of 3mmHg, 
power of 80% and a significance level of 0.025, a total of 28 patients will be included 16. We will 
recruit 30 patients to Brain Vent to take account of technical issues or dropouts. The non-inferiority 
margin is chosen to be lower than the minimal clinical important difference of 5 mmHg. It is 
assumed that there will be no missing data in the period 2 measurements due to the short time 
interval between the two different interventions. The sample size calculation is done with STATA 
15.1 and the main analysis will be done in SPSS. 
 
Descriptive statistics will be presented with mean and standard deviations or median and 
interquartile range as appropriate for continuous variables. Categorical variables will be presented 
as proportion of patients in the different categories. Subject level profiles for each group (AB, BA) 
will be plotted to visualize the results. The hypothesis of non-inferiority will be tested based on the 

lower confidence limits of the difference. Period effect, sequence effect and secondary outcomes 
will be analysed with linear mixed models. 
 
Procedure 
Patients will be ventilated with Servo Uventilators (Maquet, Rastatt, Germany). Treatment will 
follow local procedures.  
 
Intervention 
PLV include change in two parameters, PEEP and TV. In order to analyse whether a change in TV 
affects the patient, we will test TV and PEEP changes in two different ventilation protocols, called 
intervention 1 and intervention 2 (Table 1). One of these will have lower TV, and the other will 
have lower TV and higher PEEP.  We are not testing higher PEEP without lower TV to minimize 
risk of overdistending the lungs. Baseline is standard ventilator settings as described in Table 1. 
Each patient will receive the two interventions using a cross-over design, in which they will be 
randomly allocated to either have intervention 1 first followed by intervention 2, or vice versa. This 
will boost the power of the analysis because each patient's outcomes on intervention 1 will be 
compared with her/his outcomes on intervention 2. The basic model, as described in Table 2, is 
chosen because being a complex ICU patient, within-patient variability in respiration and brain 
damage is less than between patient variability. Because the patient’s study time is short, all patients 
should reach the second period of their randomization and receive both interventions. Therefore, 
this is a powerful design in this study setting. 
The randomization will be done with dedicated software at the research department of the study 
hospital and her/his randomized order will be concealed until the patient has entered the study. 
Subsequently, the analysis will be blinded for which intervention is which. The treatment 
responsible physician (not the researcher who makes the recordings) will change the ventilator 
settings in accordance with the randomised order and will interrupt the intervention if ICP rises 
above 22 over 5 minutes, for safety reasons. 
 
Table 1. Study procedure (for those patients randomly allocated to the intervention 1 followed by intervention 2 
sequence. Group A). Group B will have the reverse order with Intervention 2 first.  
  
Procedure 
Observation time 
Baseline (run-in period) 
2 h 
Intervention 1 
1.5 h 
Baseline (wash-out) 
1,5 h 
Intervention 2 
1,5 h 
PEEP (mmHg) 
5 
5 
5 
12 
TV (ml/kg PBW) 
9 
6 
9 
6 
 
Table 2. The basic design model26. Each patient is treated for 2 periods of time. Patients are randomly allocated to 
receive treatments in this order (intervention 1 first, followed by intervention 2) or the reverse order (intervention 2 
first, followed by intervention 1) 
 
 
 
 
 
 
Ventilatory settings in detail: 
a. Conventional settings- Volume control (VC), inspiratory: expiratory (I:E) ratio 1:2, Tinsp 10 %, 
PEEP 5 cm H2O, VT 9 ml/predicted bodyweight, ventilator frequency (Vf) needed to give partial 
pressure of carbon dioxide (PaCO2) 4.5-5 kPa, oxygen saturation (SpO2) > 96. Plateau pressure< 
30 cm H2O  
b. Intervention 1- VC, I:E ratio 1:2, Tinsp 10 %, PEEP 5, TV 6 ml/predicted bodyweight, Vf 
(<30/min) will be increased to the same minute ventilation as in a. Plateau pressure< 30 cm H2O  
c. Intervention 2- VC, I:E ratio 1:2, Tinsp 10 %, PEEP 12, TV 6 ml/PBW, Vf (<30/min) will be 
increased to the same minute ventilation as in a., SpO2> 96. Plateau pressure< 30 cm H2O  
  
 
Group A 
 
Group B 
Period 1 
Intervention 1   
Intervention 2 
Period 2
Intervention 2
Intervention 1

 
Age (>= 70, < 70) and type of damage (TBI or SAB) will be stratified in the two groups in the 
randomisation. 
 
Observations and outcome measurements during the study: 
All primary and secondary outcome measurements will be recorded from minimum 2 hours before 
to 1 hours after intervention. ICM + will record monitoring signals for 3 h during the start setting 
for calibration of the PrX signal.   
 
Respiratory component 
Respiratory settings and changes will be measured by 
• Blood gases: PaO2/FiO2 ratio. 
• Pressure transducer in esophagus: Esophageal pressure (Peso). Continously and end- 
insp/end-exp just.   
• Ventilator: Oxygenation index, end-tidal CO2 (etCO2), inspiratory oxygen fraction (FiO2), 
Peak airway pressure (Ppeak), Pplateau, PEEP, End-expiratory airway pressure (PawEndexp), Vf, 
tidal volume inspiratory (VTinsp), tidal volume expiratory (VTexp) at each breath, Total PEEP 
(end expiratory occlusion), from Paw and Peso and hence from Ptp. 
• Pulse Contour Continuous Cardiac Output (PICCO) thermodilution: Extravascular lung 
water index (EVLWI) as a determinant of fluids in the lungs.  
 
Cerebral component: 
ICP will be measured by:  
• Invasive- ICP probe placed intraparenchymal or in the ventricular space  
• Non-invasive ICP with transcranial Doppler (TCD) measurement of optic nerve sheath 
diameter and straight systolic flow velocity or flow velocity of MCA bilaterally.  
Intracranial pressure indices, as a measure of compensatory reserve and autoregulation will be 
assessed by 
• Intracranial and arterial pressure waveform analysis with ICM+® - PrX. Compensatory 
reserve index (RAP) index and mean pulse amplitude (AMP). Slow AMP. See further down 
for references.  
Brain blood perfusion and oxygenation;  
• Brain tissue oxygen tension (PbtO2). Only for patients having a clinical indication for CT 
caput. 
•  if clinically indicated.  
• TCD measurement of flow velocity in arteria cerebri media.   
• Computer tomography (CT) of brain perfusion for assessment of global and local cerebral 
perfusion during the first 24 h. Only for patients having a clinical indication for CT caput. 
• Protein S100B is a new outcome prediction tool in brain injury, which is not thoroughly 
explored27. It will be analysed on admission as part of a description of the severity of ABI.   
 
Cardiovascular component: 
Positive pressure ventilation may hamper venous return, which might decrease cardiac index and 
cerebral blood flow. Therefore, data from the cardiovascular system also will be included. 
A PICCO arterial catheter and a central venous catheter will be inserted for continuous 
measurement of the following intravascular pressures and cardiac index and derived variables by 
thermodilution once/hour: 
• Cardiac output  
• Stroke volume  
• Arterial blood pressure  
• Central venous pressure 

• Intrathoracic blood volume index (ITBVI) as determinants of preload.  
• The following treatment will be documented: 
• Vasopressor dose 
o Inotropic support 
• Any fluid transfusion, amount and constitution 
 
Other patient data that will be registered  
Background and baseline demographic data of the study population: Sex, Glasgow coma scale 
before intubation, diagnosis, age, PBW, BMI, type of ICP monitoring, CT Marshall score, 
extracranial injuries.  
In hospital treatment data: Daily fluid administration, duration of invasive and non invasive 
ventilation, duration and dose of sedation, ICU days, duration of the hospital stay in days from 
admission to hospital to discharge to home or rehabilitation. 
 
Rationale for choice of monitoring   
Cerebral monitoring:  
ICP will be measured continously as part of routine monitoring by invasive ICP probe in the brain. 
It will also be assessed noninvasively with transcranial Doppler (TCD)28. . In the future, non- 
invasive ICP measurements will most likely be the gold standard. Therefore, it is important to find 
out if TCD changes reflect changes in ventilator settings as accurate as the invasively measured ICP 
changes. 
Neurointensive treatment is guided by multimodal monitoring. Brain perfusion and oxygenation is 
crucial for cerebral metabolism. The latter will be monitored locally with with a probe measuring 
partial pressure of oxygen in brain and regionally with near infrared spectroscopy. 
Protein S100B is a new outcome prediction tool in brain injury, which is not thoroughly explored27. 
It will be analysed on admission as part of a description of the severity of ABI. The analysis of 
S100B is part of the Scandinavian guidelines for traumatic brain injury. 
 
ICM+® software for brain monitoring (University of Cambridge Enterprise, Cambridge, UK) is 
downloaded on a computer that is connected to a Philips monitor. The software monitors signals 
and performs waveform analysis and correlation analysis. ICP waveform analysis provides 
individualized information about the patient’s intracranial compliance and pressure reactivity 
including calculation of PrX, AMP, RAP29. This helps the clinician to be alert on patients at risk of 
cerebral hypoperfusion. The pressure reactivity index (PrX), is the moving correlation analysis 
between mean arterial pressure (MAP) and mean ICP. When autoregulation is intact, the cerebral 
vasculature dilates or constricts dependent on the arterial blood pressure. This can be trended by the 
ICP monitoring online: Negative MAP-ICP correlation indicates pressure reactive vessels (negative 
PrX) and preserved autoregulation and positive correlation indicates pressure- passive vessels and 
impaired autoregulation. This correlation can be used to individualize CPP treatment to hold CPP in 
the negative PrX area.  
For this study, in addition to waveform analysis, the ICM+ continuously monitors the ventilator 
signals: etCO2, FiO2, Ppeak, Pplateau, PEEP, PawEndexp, Vf, VTinsp, VTexp and Peso of each breath. 
Respiratory monitoring 
Esophagus manometer (FluxMed):  
This is a gastric tube equipped with an esophagus balloon connected to a manometer for Peso 
monitoring. Proper placement of the balloon is assessed from Baydur test and optimal volume 
filling the balloon assessed from the balloon PV curve in vivo30. 
 Peso measurement enable calculation of tidal PTP, which is the pressure needed to insufflate the 
lung12. It can be determined by measuring the pressure difference in end inspiration and end 
expiration between airway pressure and intrapleural pressure, represented indirectly by the pressure 
changes determined in the esophagus. By calculating Ptp  we will document if there is any 
relationship between the tidal Ptp and monitored cerebral parameters in the different procedures. 

Even if we use the same TV and PEEP in lung protective ventilator settings in different patients, 
there might be a different change in tidal Ptp that need to be addressed in future studies.  
 
PICCO monitoring system (Pulsion Medical Systems, Munich, Germany):  
A thermistor catheter will be placed in a femoral or brachial artery. PICCO measurement will be 
used to monitor both preload, cardiac output and changes in EVLW. All these parameters might be 
affected by the lung protective settings and can be related to cerebral parameters, such as ICP, CPP, 
ICP  indices and cerebral oxygenation and metabolism variables. Increased EVLW has been 
noticed, on the average, more than two days before the patients meet ARDS criteria 31. Therefore, 
we suggest that measurement of EVLW and pulmonary vascular permeability index (PVPI) in ABI 
patients at risk might enhance our possibilities of diagnosing the condition at the stage of emerging 
or “mild ARDS”. In addition, determining pre-load by means of changes in intra-thoracic blood 
volume index (ITBVI), might provide valuable information about fluid load 32.  
 
Detailed conduct of the study 
Pre- intervention phase: 
1. 
A member of the research team will recruit the patient within the first 24 hours after the ABI 
after rigorous consideration of the exclusion criteria 
2. 
The patient will receive standard care with deep sedation, fentanyl/propofol and elevated 
upper body by 20 degrees.  
3. 
Pleural effusion > 2 cm will be excluded with ultrasound.  
4. 
The ventilator settings will be conventional as described above and in Table 1.  
Intervention phase with randomized order of intervention 1 and 2:   
a. 
Intervention 1: Reduce tidal volume to 6 ml/kg predicted bodyweight, as a first step towards 
protective lungventilation. Maintain PEEP 5.  
b. 
Monitor 1,5 h.  
c. 
Go back to conventional ventilator settings for 1,5 hours.  
d. 
Decrease TV to 6 ml/kg predicted bodyweight and increase PEEP to 12 cm H2O as in LPV.  
e. 
Monitor 1,5 h.  
f. 
Go back to conventional settings or other settings on the discretion of the treating clinician. 
For safety reasons, the intervention will be interrupted if ICP increases to over 22 over 5 minutes, or 
CPP decreases to below 50 mmHg.  
 
 
 
Questionnaire to the next of kin and the patient 
A questionnaire will be given to the patient´s next of kin at the start of the study and 6 months after 
the ICU stay. It will contain questions about: 
• What does the next of kin feel about the request/inclusion of their relative in a research 
project?  
o Did the relative understand the information given about the study? 
o In what setting was the relative given information about the study? 
o Who was providing the information given to the relative? (ansvarlig lege, sykepleier, 
andre, prosjektleder?) 
o Did you as a relative feel confident that the study would not impact on the patients 
outcome in a negative way if you agreed/disagreed to participate on behalf of the 
patient? 
• Is it necessary to consent on behalf of the relative before he or she regains the mental 
capacity to consent on his/her own behalf? 
o Did you as a relative think it was positive or negative to be asked to participate on 
behalf of the patient? 
o Did the relative have any difficulties taking decisions on behalf of the patient? 

o  
 
Cooperation 
The methodology presupposes cooperation with leading European scientific communities. The 
methodology learnt from these communities will be introduced in our hospital, not only for research 
purposes but also as a valuable tool for daily clinical work. The research team consists of 
neurophysiologists, anaesthesiologists, nurses and neurosurgeons from tertiary hospitals with 
several publications and PhD projects on the relevant methodologies.  Professor Guerin at Hospital 
de la Croix Rousse in Lyon is a prominent researcher in lung mechanics and the treatment of 
patients with ARDS. The knowledge obtained through cooperation with the colleagues in Lyon will 
also be of use for other categories of patients. It is also a part of our ICU department´s strategic plan 
to incorporate Ptp. 
The Department of Clinical Neurosciences in Cambridge, where the applicant will be working is a 
leading institution in neurointensive research, which hosts many visiting doctors and researchers. 
Apart from learning ICP wave analysis, the stay at the University hospital in Cambridge will 
contribute increased cooperation and knowledge transfer in monitoring and treatment of traumatic 
brain injury and cerebrovascular and neurological diseases. The technique with non-invasive ICP 
measurement will be useful for clinicians in other hospitals in North Norway as well. This will 
make it more easy for colleagues at remote local hospitals to discuss the status of the patient with 
the neurosurgeon via telephone or video conference equipment over distances corresponding to 
more than 2 ½ hours with an ambulance plane. 
A multicenter study is already under discussion and will be further planned during the time course 
of the present study. 
  
6. 
User involvement 
 
1 former ICU patients and 2 next of kin have contributed to the information sheet and consent form. 
These users were contacted directly by the chief investigator. The protocol was also introduced to 
them in their native language (Norwegian) in order to get valuable inputs as regards the study 
design and inclusion criteria. We also consulted them with regard to the potential positive impact of 
the study on the patient group. Their opinion was also sought on identifying factors that could 
hamper or increase patient participation.  
After the analysis, we will also ask the users and the patient’s next of kin for advices on how the 
results can be transferred to patients, their next of kin and other forums.  
 
4. 
Ethical and regulatory considerations  
 
The study will be conducted according to Good Clinical Practice guidelines. The protocol, the 
information and the informed consent forms will undergo approval by the Regional Committee for 
Medical and Health Research Ethics (REC). Informed consent will be obtained from the next of kin 
at admission and later by the patient whenever it is appropriate. The current conventional ventilator 
management of patients with ABI appears to be suboptimal. Although the treatment protocol for 
mechanical ventilation will not automatically be changed during these studies, we believe that this 
research might elucidate the respiratory management of the included patients on individual basis 
The interventions will be performed during a limited time period and within clinically safe tidal 
volume and airway pressure limits. We do not anticipate that the monitoring, or the intervention, 
will impose any risk or burden to the patient. By studying previous studies on ventilator settings, 
care has been taken to choose settings that are within safe range and do not overdistend the lungs. 
Risks with high PEEP include low cardiac output due to reduced venous return caused by 
hypovolemia or right cardiac failure. These patients will be excluded from the study. Another 
consequence might be increased ICP. This is continuously monitored and if above a certain value, it 

will be a trigger to finish the intervention. The risk for violating patient integrity is very low since 
data will be stored in accordance with Norwegian law requirements. 
 
5. 
Publication 
 
We will publish the results in an international peer-reviewed medical journal, and additionally in 
national and international congresses. Moreover, we will present the results in forums of interest 
groups for cerebrovascular diseases including previous patients and relatives.  
 
 
 

Reference list 
1. 
Langlois, J. A., Rutland-Brown, W. & Wald, M. M. The Epidemiology and Impact of Traumatic Brain Injury A Brief 
Overview. J Head Trauma Rehabil 21, 375–378 (2006). 
2. 
Feigin, V. L. et al. Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease 
Study 2010 on behalf of the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) and the GBD 
Stroke Experts Group. 
3. 
Koutsoukou, A. et al. Respiratory mechanics in brain injury: A review. World J. Crit. care Med. 5, 65–73 (2016). 
4. 
Chi, J. H. et al. Prehospital Hypoxia Affects Outcome in Patients With Traumatic Brain Injury: A Prospective Multicenter 
Study. J. Trauma Inj. Infect. Crit. Care 61, 1134–1141 (2006). 
5. 
Gattinoni, L. et al. Ventilator-related causes of lung injury: the mechanical power. Intensive Care Med. 42, 1567–75 (2016). 
6. 
Holland, M. C. et al. The Development of Acute Lung Injury Is Associated with Worse Neurologic Outcome in Patients 
with Severe Traumatic Brain Injury. J. Trauma Inj. Infect. Crit. Care 55, 106–111 (2003). 
7. 
Mascia, L. Acute Lung Injury in Patients with Severe Brain Injury: A Double Hit Model. Neurocrit. Care 11, 417–426 
(2009). 
8. 
Borsellino, B., Schultz, M. J., Gama de Abreu, M., Robba, C. & Bilotta, F. Mechanical ventilation in neurocritical care 
patients: a systematic literature review. Expert Rev. Respir. Med. 10, 1123–1132 (2016). 
9. 
Guerin, C. et al. Efficacy and safety of recruitment maneuvers in acute respiratory distress syndrome. Ann. Intensive Care 1, 
1–6 (2011). 
10. 
Goligher, E. C., Ferguson, N. D. & Brochard, L. J. Clinical challenges in mechanical ventilation. Lancet 387, 1856–1866 
(2016). 
11. 
Fan, E. et al. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care 
Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. 
Am. J. Respir. Crit. Care Med. 195, 1253–1263 (2017). 
12. 
Mauri, T. et al. Esophageal and transpulmonary pressure in the clinical setting: meaning, usefulness and perspectives. 
Intensive Care Medicine (2016). doi:10.1007/s00134-016-4400-x 
13. 
Ferguson, N. D. Low Tidal Volumes for All? Jama 308, 1689 (2012). 
14. 
Swain, A., Bhagat, H., Sahni, N. & Salunke, P. Mechanical ventilation in neurological and neurosurgical patients. Neurol. 
India 64, (2016). 
15. 
Della Torre, V. et al. Acute respiratory distress syndrome in traumatic brain injury: How do we manage it? J. Thorac. Dis. 
9, 5368–5381 (2017). 
16. 
Boone, M. D. et al. The Effect of Positive End-Expiratory Pressure on Intracranial Pressure and Cerebral Hemodynamics. 
Neurocrit. Care 1–8 (2016). doi:10.1007/s12028-016-0328-9 
17. 
McGuire, G., Crossley, D., Richards, J. & Wong, D. Effects of varying levels of positive end-expiratory pressure on 
intracranial pressure and cerebral perfusion pressure. Crit. Care Med. 25, 1059–62 (1997). 
18. 
Zhang, X., Yang, Z., Wang RRT, Q. & Fan, H. Impact of positive end-expiratory pressure on cerebral injury patients with 
hypoxemia. Am. J. Emerg. Med. 29, 699–703 (2011). 
19. 
Kirkman, M. A. & Smith, M. Multimodal Intracranial Monitoring. Anesthesiol. Clin. 30, 269–287 (2012). 
20. 
Donnelly, J., Budohoski, K. P., Smielewski, P. & Czosnyka, M. Regulation of the cerebral circulation: bedside assessment 
and clinical implications. Crit. Care 20, 129 (2016). 
21. 
Ko, S.-B. Multimodality Monitoring in the Neurointensive Care Unit: A Special Perspective for Patients with Stroke. J. 
stroke 15, 99–108 (2013). 
22. 
Smielewski, P. et al. ICM+, a flexible platform for investigations of cerebrospinal dynamics in clinical practice. Acta 
Neurochir. Suppl. 102, 145–51 (2008). 
23. 
Zeiler, F. A. et al. Critical Thresholds of ICP Derived Continuous Cerebrovascular Reactivity Indices for outcome 
prediction in Non-Craniectomized TBI Patients: PRx, PAx and RAC. J. Neurotrauma 35, 1107–1115 (2018). 
24. 
Hall, A. & O’Kane, R. The best marker for guiding the clinical management of patients with raised intracranial pressure—
the RAP index or the mean pulse amplitude? Acta Neurochir. (Wien). 158, 1997–2009 (2016). 
25. 
Petkus, V. et al. Benefit on optimal cerebral perfusion pressure targeted treatment for traumatic brain injury patients. J. Crit. 
Care 41, 49–55 (2017). 
26. 
Hills, M. & Armitage, P. The two???period cross???over clinical trial. Br. J. Clin. Pharmacol. 8, 7–20 (1979). 
27. 
Thelin, E. P., Nelson, D. W. & Bellander, B.-M. A review of the clinical utility of serum S100B protein levels in the 
assessment of traumatic brain injury. Acta Neurochir. (Wien). 159, 209–225 (2017). 
28. 
Robba, C. et al. Ultrasound non-invasive measurement of intracranial pressure in neurointensive care: A prospective 
observational study. PLoS Med. 14, (2017). 
29. 
Czosnyka, M. & Pickard, J. D. Monitoring and interpretation of intracranial pressure. J Neurol Neurosurg Psychiatry 75, 
813–821 (2004). 
30. 
Baydur, A., Behrakis, P. K., Zin, W. A., Jaeger, M. & Milic-Emili, J. A simple method for assessing the validity of the 
esophageal balloon technique. Am. Rev. Respir. Dis. 126, 788–91 (1982). 
31. 
Kuzkov, V. V. et al. Extravascular lung water determined with single transpulmonary thermodilution correlates with the 
severity of sepsis-induced acute lung injury. Crit. Care Med. 34, 1647–1653 (2006). 
32. 
Guerin, L., Monnet, X. & Teboul, J.-L. Monitoring volume and fluid responsiveness: From static to dynamic indicators. 
Best Pract. Res. Clin. Anaesthesiol. 27, 177–185 (2013).