Multimodality Monitoring Directed Management of Patients Suffering From Traumatic Brain Injury
Conditions: Traumatic Brain INjury, Microdialysis
Sponsor: University of Cambridge

 
Consultation in use Version 1.0 June 2015 
 
 
Multimodality Monitoring Directed Management of Patients 
Suffering from Traumatic Brain Injury 
 
 
 
 
 
 
 
 
Directed management in brain injury 
 
 
 
 
 
• 
This protocol has regard for the HRA guidance and order of content 
 
 
 
 

 
 
 
Directed management in brain injury. 
 
   
 
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RESEARCH REFERENCE NUMBERS  
R&D: A094233 
 
PROTOCOL VERSION NUMBER AND DATE 
V1.0 31/10/2016 
 
OTHER RESEARCH REFERENCE NUMBERS  
IRAS: 214040 
 
SPONSOR / CO-SPONSORS / JOINT-SPONSORS 
Stephen Kelleher, R&D Manager, Cambridge University Hospitals NHS Foundation Trust, Hills Road, 
Cambridge, CB2 0QQ,  Tel: 01223 217418, Fax: 01223 34849 E-mail: 
research@addenbrookes.nhs.uk  
University of Cambridge 
 

 
 
 
Directed management in brain injury. 
 
   
 
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FULL TITLE: 
Multimodality Monitoring Directed Management of Patients Suffering from Traumatic Brain 
Injury 
 
SHORT TITLE: 
Directed management in brain injury 
 
PROTOCOL VERSION NUMBER AND DATE: 
V1.0 31/10/2016 
 
 

 
 
 
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4 
 
RESEARCH REFERENCE NUMBERS 
 
IRAS Number: 
214040 
SPONSORS Number: 
A094233 
FUNDERS Number: 
N/A 
 
 
 

 
 
 
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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the study in compliance with the approved protocol and will adhere to 
the principles outlined in the Declaration of Helsinki, the Sponsor’s SOPs, and other regulatory 
requirement. 
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the investigation without the prior written 
consent of the Sponsor 
I also confirm that I will make the findings of the study publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained. 
 
For and on behalf of the Study Sponsor: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
 
 
Position: 
...................................................................................................... 
 
 
 
Chief Investigator: 
Signature: 
...................................................................................................... 
 
Date: 
....../....../...... 
Name: (please print): 
...................................................................................................... 
 
 
 
 
 

 
 
 
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KEY STUDY CONTACTS 
 
Chief Investigator 
Mr Adel Helmy, MA MB BChir FRCS PhD 
Mail: Division of Neurosurgery, Box 167 Level 4 Cambridge 
University Hospital, Hills Road, Cambridge CB2 0QQ 
Phone: +44 1223 336946 
E-mail: adelhelmy@doctors.org.uk 
Fax: +44 1223 216926  
Study Co-ordinator 
Dr Eric P Thelin, MD, PhD.  
Mail: Division of Neurosurgery, Box 167 Level 4 Cambridge 
University Hospital, Hills Road, Cambridge CB2 0QQ 
Phone: +44 756 3922425 
E-mail: et417@cam.ac.uk 
Fax: +44 1223 216926  
Sponsor 
Stephen Kelleher, R&D Manager  
Mail: Cambridge University Hospitals NHS Foundation Trust, 
Hills Road, Cambridge, CB2 0QQ 
Phone: 01223 217418 
E-mail: research@addenbrookes.nhs.uk 
Fax: 01223 34849 
Joint-sponsor(s)/co-sponsor(s)  
University of Cambridge, Cambridge, United Kingdom 
Funder(s) 
Swedish Society of Medicine 
Key Protocol Contributors 
N/A 
Committees 
N/A  
 
 
 
 

 
 
 
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STUDY SUMMARY 
 
Study Title 
Multimodality Monitoring Directed Management of Patients 
Suffering from Traumatic Brain Injury 
Internal ref. no. (or short title) 
Directed management in brain injury 
Study Design 
Controlled trial without randomisation 
Study Participants 
Patients with traumatic brain injury and need for intracranial 
monitoring. 
Planned Size of Sample (if applicable) 100 
Follow up duration (if applicable) 
6 months 
Planned Study Period 
5 years 
Research Question/Aim(s) 
 
Primary aim: 
 
Establish and validate a clinical protocol for microdialysis 
derived chemistry driven therapy in TBI and see if it improves 
lactate:pyruvate ratio (<25). 
 
Secondary aims: 
 
Determine the optimal strategies for correcting abnormalities 
in microdialysis derived parameters. 
 
Determine the inflammatory, tissue and functional outcome 
for patients suffering from different defined pathological 
conditions  
 
 
 
 
 
 

 
 
 
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FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
(Names and contact details of ALL organisations 
providing funding and/or support in kind for this 
study) 
FINANCIAL AND NON FINANCIALSUPPORT 
GIVEN 
Swedish Society of Medicine 
214.000 SEK (Swedish Krona ~ 20.000£) 
 
 
 
 
 
 
 
 

 
 
 
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ROLE OF STUDY SPONSOR AND FUNDER 
The study sponsor will guarantee that the study will be performed according to rules and regulations, 
and will assume overall responsibility for the initiation and management of the study. 
The Funder will guarantee salary for Eric P Thelin. The funder will have no role in study design, 
conduct, data analysis and interpretation, manuscript writing, and dissemination of results.  
Neither sponsors nor funder will have control over the final decision regarding any of these aspects of 
the study.  
 
 
 
 

 
 
 
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ROLES AND RESPONSIBILITIES OF STUDY MANAGEMENT COMMITEES/GROUPS & 
INDIVIDUALS 
Study Steering Groups 
The study has been drafted solely by the research team. No other committee or  group has been 
involved. 
Patient & Public Involvement Group 
We have a longstanding interest in traumatic brain injury research and patients. As well as dealing 
with patients and their families in their acute stay, we have a multi-disciplinary neurotrauma clinic that 
combines healthcare professionals from neurosurgery, neurorehabilitation, neuropsychology as well 
as the Headway Brain Injury Charity.  
 
The details of a project such as this require specialist knowledge to fully appreciate the clinical need 
and scientific design of the study, however, our commitment to head injury extends to improving every 
aspect of patient care as demonstrated by our long track record in this field. 
 
 
 
 

 
 
 
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Protocol contributors 
Mr. Adel Helmy 
Dr. Eric P Thelin 
Dr. Tamara Tajsic 
Dr. Keri LH Carpenter 
Dr Susan van der Heide 
Dr Ari Ercole 
Prof David K Menon 
Mr. Ivan Timofeev 
Prof Peter JA Hutchinson 
 
Neither sponsors nor funder will have control over the final decision regarding any of these aspects of 
the study.  
 
KEY WORDS: 
Microdialysis; Traumatic Brain Injury; Multimodal 
Monitoring; Metabolism; Oxygenation; Intracranial 
pressure;  
 

 
 
 
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LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
TITLE PAGE  
1 
RESEARCH REFERENCE NUMBERS 
 
2 
SIGNATURE PAGE 
5 
STUDY SUMMARY  
7 
FUNDING 
 
8 
ROLE OF SPONSOR AND FUNDER 
9 
ROLES & RESPONSIBILITIES OF STUDY STEERING GROUPS AND INDIVIDUALS   
10 
KEY STUDY CONTACTS 
 
11 
LIST of CONTENTS  
12 
STUDY FLOW CHART 
 
13 
SECTION  
1. BACKGROUND 
 
14 
2. RATIONALE 
 
15 
3. THEORETICAL FRAMEWORK 
15 
4. RESEARCH QUESTION/AIM(S)  
16 
5. STUDY DESIGN/METHODS 
16 
6. STUDY SETTING 
17 
7. SAMPLE AND RECRUITMENT 
17 
8. ETHICAL AND REGULATORY COMPLIANCE 
 
9. DISSEMINATION  POLICY 
 
10. REFERENCES 
 
11. APPENDICIES 
 
 
 
 

 
 
 
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STUDY FLOW CHART 
 
 
 
If a patient presents with a L/P ratio >25 we will include the patient in the study. As the different 
monitoring thresholds are reached, it will trigger different treatment strategies in order to treat a 
specific pathological substrate. 
 
Excess serum, CSF and microdialysis samples will be stored for analyses of inflammatory markers 
and tissue damage markers.  
 
Follow-up at 6 months following trauma will be done through outpatient clinic. 
 
 
 
 

 
 
 
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STUDY PROTOCOL 
Multimodality Monitoring Directed Management of Patients Suffering from Traumatic Brain Injury 
 
1 
BACKGROUND 
Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide especially in 
population under 40 years of age and has a significant socioeconomic impact. TBI results from the 
head impacting with an object or from acceleration/deceleration forces that produce vigorous 
movement of the brain within the skull, with the resultant mechanical forces potentially damaging glia, 
neurones, axons and blood vessels. The nature of the initiating force, as well as its site, direction and 
magnitude, determine the type and the severity of the injury1.  Contact trauma usually results in focal 
injuries such as skull fractures, extradural or subdural haemorrhages and contusions. Unrestrained 
head movement which generates acceleration/deceleration forces usually results in diffuse axonal 
injury1,2.  
The major determinant of outcome from TBI is the severity of the primary injury, which is 
irreversible. However, all neurological damage does not occur at the moment of initial injury, but 
evolves over the ensuing hours and days. Primary injury invariably leads to the activation of cellular 
and molecular responses which mediate secondary injury. These include an increase in extracellular 
levels of glutamate leading to excitotoxicity, the onset of oxidative stress, inflammation, disruption to 
the blood-brain barrier (BBB) and cerebral oedema formation, all of which exacerbate injury and tissue 
damage3-11. Ultimately, all this leads to brain swelling within the confines of a fixed intracranial 
compartment, leading to increased intracranial pressure (ICP) and compromising cerebral perfusion 
pressure (CPP). Current ICU protocols for the treatment of TBI focus on the treatment of secondary 
injury and ensuring optimal cerebral perfusion12-18. 
Most specialized neurocritical care units now use multimodality monitoring which involves 
placing intraparenchymal probes/catheters to measure the ICP (thus enabling the calculation of 
cerebral perfusion pressure), brain tissue oxygen tension (PbO2) and microdialysis, in order to 
minimize secondary injury.  However, all current clinical protocols are ICP based, i.e. a certain ICP 
threshold triggers a step wise treatment approach. At present, although there is evidence base to 
suggest their usefulness and potential for early detection of secondary, information that microdialysis 
or PbO2 monitors provide has not been implemented in clinical protocols yet.   
Microdialysis is invasive monitoring which uses a semi-permeable membrane inserted into 
brain parenchyma to monitor the biochemistry and metabolic status of the surrounding brain tissue20. 
The use of this technique increased our understanding of the pathophysiology of several neurological 
conditions. Microdialysis provides information about the energy and metabolic status of the focal area 
examined measuring lactate, pyruvate (and the lactate/pyruvate ratio LPR), glucose, glycerol and 
glutamate.  After traumatic brain injury, due to ischemic/hypoxic conditions, energy production will 
decrease while lactate levels, and the LPR, will increase as a sign of tissue ischemia38. In contrast, if 
pyruvate levels remain normal and lactate levels increase, ongoing mitochondrial dysfunction has 
been suggested39. A growing body of evidence shows that microdialysis parameters (principally the 
lactate/pyruvate ratio) correlate with outcomes after TBI24,25,26, and can be used for: early detection of 
secondary insults30,31, monitoring and treatment of low cerebral glucose guiding systemic glucose and 
insulin management32,33,34, monitoring during CPP augmentation/reduction and derivation of optimal 
CPP (CPP opt)35,36,37, evaluating the effect on body temperature on cerebral chemistry24. The recent 
International Consensus Statement from the 2014 International Microdialysis Forum 23summarises 

 
 
 
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data on the utility and prognostic power of microdialysis derived parameters and strongly supports its 
use in TBI treatment, but no microdialysis parameter guided clinical protocols exist to date.  
 
2 
RATIONALE  
 
Microdialysis parameters are recognized to correlate with outcome in population studies, however they 
have not yet been rationalised into treatment strategies for individual patients. Further research is 
needed to determine which interventions may be used to modify or improve microdialysis parameters 
towards a goal directed target. 
Given the failure to demonstrate the benefits of ICP monitoring in a large randomised trial (Chestnut et 
al, 2012) and given the number of possible neuromonitoring technique, how can an evidence base be 
developed for second line monitoring techniques for early detection and minimization of secondary 
brain injury.  
 
3 
THEORETICAL FRAMEWORK 
We aim to include all traumatic brain injured patients admitted to the neuro-critical care unit that are 
being monitored and have multi-modality monitoring already in place. As all patients will follow the 
same protocol, we will minimize the risk of selection and researcher bias. As the patient will be 
unconscious during this process, next of kin will be asked for consent. As mentioned, this is a 
structured form of the standard treatments already provided in intensive care.  
 
We will specifically identify patients in whom the microdialysis lactate:pyruvate ratio (LPR) increase 
above 25. This threshold has been proven to relate to a worse outcome after head injury. This will 
trigger our protocol which will consist of the following steps: 
 
 
1. If ICP >20 mmHg, we will aim to escalate intracranial pressure decreasing measures by 
administering hypertonic saline (5%) 100 ml and if necessary continue on with further ICP decreasing 
measures. 
 
2. If the brain oxygen pressure falls <15 mmHg, and the pressure reactivity index is >0.3 (an indication 
that the normal auto-regulation of the brain blood flow is not functioning properly), will increase the 
cerebral perfusion pressure by 10-20 mmHg. 
 
3. If this still does not improve the brain oxygen pressure, we will increase the flow of inspired oxygen 
up to a maximum of 60-80%. 
 
4. These steps do not adjust the LPR and if there is a decrease in glucose in the affected brain tissue 
(<1 mmol/l), we will increase the plasma glucose levels to a maximum 10 mmol/l in order to ensure 
that the correct amount of nutrients is being delivered, using 50% dextrose (sugar) solution. 
 
5. If all the above steps fail to improve the LPR, it could be due to mitochondrial failure, the 
powerhouse of the cell. There are currently no approved therapies for this condition. However, at the 
treating physicians discretion, energy supplementation (e.g. succinate) or neuro-protective drugs (e.g. 
cyclosporine A) could be provided. 
 

 
 
 
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Following a 6 month period, we will see the patients in our outpatient clinic to assess functional 
outcome. This is part of the patient’s standard clinical care as all our patients are offered clinical follow 
up in this way. 
 
We will collect any biological samples that are available as part of the standard clinical care of the 
patient and will not subject the patients to any additional procedures. This would consist of: 
 
-left over microdialysate samples that are not used for the standard clinical care of the patient  
-blood samples if the patient has an arterial line 
-cerebrospinal fluid samples if the patient has an external ventricular drain inserted into the ventricles. 
 
4 
RESEARCH QUESTION/AIM(S) 
 
Primary aim: 
 
Establish and validate a clinical protocol for microdialysis derived chemistry driven therapy in TBI and 
see if it improves lactate:pyruvate ratio (<25). 
 
Secondary aims: 
 
Determine the optimal strategies for correcting abnormalities in microdialysis derived parameters. 
 
Determine the inflammatory, tissue and functional outcome for patients suffering from different defined 
pathological conditions  
 
4.1 
Objectives 
 
1. We wish to determine which of the provided therapies that was superior to others in improving the 
deranged brain metabolism. 
 
2. We also wish to determine the inter-relationships between parameters detected using the 
microdialysis and other monitoring techniques, such as brain oxygen saturation and perfusion 
pressure in the damaged brain, and how microdialysis may complement these techniques. 
 
3. How the protocol will alter cytokine, chemokine and markers of brain damage markers (S100B) in 
serum and microdialysate for patients suffering from different pathological states? 
 
4. How will the functional outcome distribution be for patients suffering from different pathological 
states? 
 
4.2 
Outcome 
Improvement of lactate/pyruvate ratio <25 (by different treatment strategies). 
 
5 
STUDY DESIGN and METHODS of DATA COLLECTION AND DATA ANALYIS 
Multimodality monitoring parameters that will be included: 
 

 
 
 
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a) Standard monitoring 
 
Intracranial pressure 
 
Cerebral perfusion pressure (mean arterial pressure – intracranial pressure)  
Brain tissue oxygen tension 
Pressure reactivity index (PRx) 
Therapy intensity levels 
 
b) Microdialysis parameters  
Metabolic intermediaries (lactate, pyruvate, glucose, glutamate, glycerol) 
 
Cytokine analysis 
 
Nitric oxide  
 
 
c) CSF parameters 
Cytokines and chemokines 
 
 
d) Serum 
Circulating cytokines, chemokines, tissue damage markers (S100B) 
 
The monitoring data will be stored automatically. The chemokine, cytokine and tissue damage marker 
samples will be analysed using commercially available LUMINEX kits by members of the research 
team. 
Standardized questionnaires to assess extended Glasgow Outcome Score (eGOS) as well and Short 
Form 36 (SF-36) will be used during the follow-up appointment in the outpatient clinic by members of 
the research team. 
Data will be analysed by members of the research team using comparative statistics between patients 
with different pathological targets. The statistical program R will be used. 
 
6 
STUDY SETTING 
This will be a single-center (Addenbrooke’s Hospital) prospective study utilising a new treatment 
algorithm using lactate/pyruvate ratio to direct management following traumatic brain injury. We will 
assess patients admitted to the neuro-critical care unit to see if they are eligible for inclusion. 
 
7 
SAMPLE AND RECRUITMENT 
7.1  
Eligibility Criteria 
We will include patients with traumatic brain injury in need of intracranial monitoring admitted to the in 
the neuro-critical care unit, fulfilling the inclusion criteria. 
 
7.1.1 Inclusion criteria  
a) Patients with head injury requiring ICP monitoring 
b) Age 18-65 years 

 
 
 
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c) Abnormal CT scan 
 
7.1.2 Exclusion criteria  
a) Bilateral fixed and dilated pupils 
b) Bleeding diathesis 
c) Thrombocytopenia (platelets < 100) 
d) Devastating injuries; patient not expected to survive > 24 hours 
e) Brainstem damage 
f) Pregnancy 
g) Involvement in other studies non-observational studies 
h) MD catheter located in haemorrhagic lesion 
 
7.2  
Sampling 
 
All patients will have a full medical history taken and a clinical examination.  
The following are to be recorded: 
 
a) Weight and BMI 
b) Sex 
c) Age and date of birth 
d) Any significant past medical history 
e) Full blood count (including platelets and differential white cell count) 
f) Biochemical series (including urea, creatinine, uric acid, electrolytes, calcium, alkaline phosphatase, 
AST, CRP and serum glucose) 
g) Initial Glasgow Coma Scale score  
h) Focal neurological deficit  
h) CT diagnosis, Marshall and Rotterdam score  
i) Drug dosages of paralysing and sedating agents 
j) Drug doses of vasoactive agents 
k) Fraction of inspired oxygen (FiO2), partial pressure of oxygen in arterial bloods (PaO2) partial 
pressure of carbon-dioxide in arterial blood (PaCO2)  
 
 
Study Assessments 
 
Dynamic 
 
 
Multi-modality monitoring (ICP, CPP, PbtO2), MAP, FiO2 
Every 30 minutes 
 
Microdialysis Parameters 
Hourly 
 
 
GCS, Clinical examination,  
PaO2, PaCO2, serum sodium, serum glucose 
2xDaily 
 
 
Serum and if possible CSF sampling. 
 
Brain imaging will be performed when clinically indicated.  
 
All monitored parameters will be extracted automatically and stored on hospital computers as part of 
conventional care. Microdialysis sampling, as part of the standard routine, will be done twice hourly where 
20 µl will be extracted. If the patient has an extra-ventricular drain, it will be used to sample cerebrospinal 
fluid as part of standard routine in the department (200 µl per sample, if available). Blood samples will be 
drawn twice daily, and we will use discarded samples for analysis (200µlx2 per day).   

 
 
 
Directed management in brain injury. 
 
   
 
19 
 
 
7.2.1  Size of sample 
The aim is to reach a sample size where there is a statistical difference between patients with different 
pathological targets. It is difficult to assess what this sample size is considering this has never been done 
before, but we estimate that a n=100 will suffice. 
 
7.2.2  Sampling technique 
All monitored samples will be digitally stored automatically. All bodily fluids will be sampled at 
convenience, as these samples would have been otherwise discarded. 
 
7.3 
 Recruitment 
Members of the research team will daily approach the staff in the neuro-critical care unit to determine 
if any of the newly admitted patients are eligible for inclusion in the study. 
 
7.3.1 Sample identification 
Members of the research team, together with the staff in the NCCU at Addenbrooke’s Hospital, will 
identify patients eligible for inclusion. 
 
7.2.2 Consent 
The next-of-kin, or consultee, will be informed about the study and will have to provide written assent as 
patients who require multimodality monitoring are unconscious and not able to give consent. Patients will, 
after regaining consciousness, be given the option to consent into the study, or withdraw if they choose, 
without prejudice for future care. 
 
8 
ETHICAL AND REGULATORY CONSIDERATIONS 
The main ethical issue is that the eligible patients will be unconscious at admission to the hospital and 
the neuro-critical care unit and therefore not be able to provide an informed consent. In these cases, 
family and next of kin will be asked if the will allow the patient to take part in the study. The study will 
not specifically withhold treatments from any patient, we will be delivering treatments that would be 
considered anyway, but in a structured fashion. 
Data collection and storage will be done in password protected computers, and blood/CSF samples 
will be stored in locked freezers, at the University of Cambridge. 
The protocol is in line with relevant legislation and regulation.  

 
 
 
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8.1 
Assessment and management of risk 
The study is designed to closely follow the standard clinical management of traumatic brain injury. 
Patients with injuries severe enough to participate in this study are by definition unconscious, and will 
not suffer any discomfort from the study. We will work closely with the treating clinicians and ensure 
that they are happy with every aspect of the protocol in each individual patient and that the opinion of 
the treating clinician is respected. 
As this protocol is a more structured version of the conventional therapy provided on a regular basis, 
we do not believe that there will be are any additional risks with this protocol. 
 
8.2  
Research Ethics Committee (REC) review & reports 
Before the start of the study, approval will be sought from REC and IRAS, this include all protocols, 
informed consent forms and other relevant documents. 
All correspondence with the REC will be retained. 
The chief investigator will produce annual reports as required and will notify the REC at the end of the 
study. 
 
8.3  
Peer review 
The protocol has been reviewed extensively within the research team and with staff from the neuro-
critical care unit during several meetings and has been approved by the head the unit.  
The protocol was discussed at the International Consensus Meeting on Microdialysis 2014 (external 
peer review). The results of this meeting are published as a scientific paper and outline the scientific 
rationale for the study. 
 
8.4  
Patient & Public Involvement  
 
We have a longstanding interest in traumatic brain injury research and patients. As well as dealing with 
patients and their families in their acute stay, we have a multi-disciplinary neurotrauma clinic that 
combines healthcare professionals from neurosurgery, neurorehabilitation, neuropsychology as well as 
the Headway Brain Injury Charity.  
 
The details of a project such as this require specialist knowledge to fully appreciate the clinical need and 
scientific design of the study, however, our commitment to head injury extends to improving every aspect 
of patient care as demonstrated by our long track record in this field. 
 
8.5 
Regulatory Compliance  
Before patients will be enrolled in the current study, necessary regulatory measures will be taken through 
NHS R&D (the Sponsor). We will work in partnership with the study sponsor to ensure the study is 
conducted in a safe fashion and complies with all aspects of GCP. The sponsor has arrangements in 
place to monitor or audit the conduct of this study as part of the sponsor’s obligations under the 
Department of Health’s Research Governance Framework. 
For any amendment that will potentially affect a site’s NHS permission, the Principal Investigator or 
designee will confirm with that site’s R&D department that NHS permission is ongoing 

 
 
 
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8.6  
Protocol compliance  
Any accidental protocol deviation will be adequately documented on the relevant forms and reported to 
the Chief Investigator and Sponsor immediately. Deviations from the protocol which are found to 
frequently recur are not acceptable, will require immediate action and could potentially be classified as a 
serious breach. 
 
8.7 
Data protection and patient confidentiality  
The Principal Investigator will be responsible for access to any source data. Only defined researchers 
will be delegated this responsibility.  
 
It is expected that the data generated from the study will be kept on electronic media in the form of a 
database. This will be kept on computers which are password protected and under the care of the 
research team. Data from the study will be kept on digital media for a period of ten years to assist in 
the design and implementation of future studies. 
 
Any stored tissue (blood and CSF) samples will be kept anonymized in a locked freezer. 
 
8.8 
Indemnity 
As NHS will act as a sponsor, the standard NHS indemnity scheme will apply. 
 
8.9 
Amendments  
Currently no amendments to the protocol 
8.10 
Access to the final study dataset 
Only members of the study team will have access to the final dataset.  
 
9 
DISSEMINIATION POLICY 
9.1  
Dissemination policy 
The authors will own the data following completion of the study. Upon completion of the study, the 
data will be analysed and tabulated and a Final Study Report prepared accessible via the University of 
Cambridge website. We aim to publish the study in an open-access peer-reviewed scientific journal, 
where the public will be able to access it. While the funding bodies will be acknowledged, they have no 
role in the assessment of data or preparation of the study. 
The study participants will be informed by the results of the study, as mentioned in the Patient 
Information Sheet. 
 
9.2  
Authorship eligibility guidelines and any intended use of professional writers 
The research team will be granted authorship in the upcoming publication. We have no plan to use 
any professional writers. 

 
 
 
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Mr. Adel Helmy 
Dr. Eric P Thelin 
Dr. Tamara Tajsic 
Dr. Keri LH Carpenter 
Dr Susan van der Heide 
Dr Ari Ercole 
Prof David K Menon 
Mr. Ivan Timofeev 
Prof Peter JA Hutchinson 
 
10 
REFERENCES 
 
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Nemecek A, Newell DW, Rosenthal G, Schouten J, Shutter L, Timmons SD, Ullman JS, 
Videtta W, Wilberger JE, Wright DW. (2007) Guidelines for the management of severe 
traumatic brain injury. Blood pressure and oxygenation. J Neurotrauma. 24(1):S7-13 

 
 
 
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15. Bratton SL, Chestnut RM, Ghajar J, McConnell Hammond FF, Harris OA, Hartl R, Manley GT, 
Nemecek A, Newell DW, Rosenthal G, Schouten J, Shutter L, Timmons SD, Ullman JS, 
Videtta W, Wilberger JE, Wright DW. (2007) Guidelines for the management of severe 
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Nemecek A, Newell DW, Rosenthal G, Schouten J, Shutter L, Timmons SD, Ullman JS, 
Videtta W, Wilberger JE, Wright DW. (2007) Guidelines for the management of severe 
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25. Stein, N. R., D. L. McArthur, et al. (2012). "Early cerebral metabolic crisis after TBI influences 
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traumatic brain injury: a randomized controlled within-subjects trial." Crit Care Med 40(6): 
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episodes of intracranial hypertension in patients with traumatic brain injury." J Am Coll Surg 
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31. Belli, A., J. Sen, et al. (2008). "Metabolic failure precedes intracranial pressure rises in 
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metabolism after severe brain injury: a microdialysis study." Crit Care Med 36(12): 3233-3238. 

 
 
 
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24 
 
33. Vespa, P., R. Boonyaputthikul, et al. (2006). "Intensive insulin therapy reduces microdialysis 
glucose values without altering glucose utilization or improving the lactate/pyruvate ratio after 
traumatic brain injury." Crit Care Med 34(3): 850-856. 
34. Vespa, P., D. L. McArthur, et al. (2012). "Tight glycemic control increases metabolic distress in 
traumatic brain injury: a randomized controlled within-subjects trial." Crit Care Med 40(6): 
1923-1929. 
35. Johnston, A. J., L. A. Steiner, et al. (2004). "Effect of cerebral perfusion pressure augmentation 
with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain 
injury." Intensive Care Med 30(5): 791-797. 
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on regional oxygenation and metabolism after head injury." Crit Care Med 33(1): 189-195; 
discussion 255-187. 
37. Nordstrom, C. H., P. Reinstrup, et al. (2003). "Assessment of the lower limit for cerebral 
perfusion pressure in severe head injuries by bedside monitoring of regional energy 
metabolism." Anesthesiology 98(4): 809-814. 
38. Persson L, Hillered L. (1992) Chemical monitoring of neurosurgical intensive care patients 
using intracerebral microdialysis. J Neurosurg 76:72–80 
39. Nielsen TH, Bindslev TT, Pedersen SM, Toft P, Olsen NV, Nordstrom CH. Cerebral energy 
metabolism during induced mitochondrial dysfunction. Acta Anaesthesiol Scand (2013) 
57:229–3510 
 
 
 

 
 
 
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25 
 
11.  
APPENDICIES 
 
11.1 
Appendix 1- Required documentation  
- Short CV from Principal Investigator 
- Patient consent form  
Version 1.0, Date 31/10/2016 
- Patent information sheet 
Version 1.0, Date 31/10/2016 
- Consultee declaration form 
Version 1.0, Date 31/10/2016 
- Consultee information sheet 
Version 1.0, Date 31/10/2016 
 
 
11.2  Appendix 2 – Schedule of Procedures  
 
Procedures 
Visits (insert visit numbers as appropriate) 
Screening 
Baseline 
Week 1-2 
6 Months 
Informed consent 
x 
 
 
 
 
Demographics 
 
x 
 
 
 
Medical history 
 
x 
 
 
 
Observation of treatment 
 
x 
x 
 
 
Monitoring 
 
 
x 
 
 
Follow-up interview  
 
 
 
x 
 
 
 
13.3 
Appendix 3 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
 
 
 
 
 
 
Currently no existing amendments.