P25/30 Somatosensory Evoked Potentials Are Associated With Neurological Prognosis of Comatose Survivors After Out of Hospital Cardiac Arrest
Conditions: Out-Of-Hospital Cardiac Arrest
Sponsor: University Hospital Plymouth NHS Trust

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P25/30 somatosensory evoked potentials are 
associated with neurological prognosis of comatose 
survivors after out of hospital cardiac arrest 
 
 
 
 
 
 
 
Version 1.5 
04/01/2021 
 
 
 
 
 
 
 
 
SPONSOR: University Hospitals Plymouth NHS Trust (UHPNT) 
FUNDERS: University Hospitals Plymouth NHS Trust Charitable Funds 
 
RD&I reference: 18/P/088 
REC reference: 18/NW/0623 
 
 
 
 
 
 
 
 
 
 

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Protocol authorised by: 
 
Name & Role 
Date 
Signature 
Dr Nikitas Nikitas: Chief Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Study Management Group 
 
Chief Investigator: Dr Nikitas Nikitas, Consultant in Intensive Care Medicine  
 
Co-investigators [members of the study team, all at Derriford Hospital]:  
Dr Colin Bigham, Consultant in Intensive Care Medicine,  
Mrs Nicola Broomfield, Clinical Scientist, Neurophysiology,  
  
Ms Lucy Nye, Healthcare Scientist, Neurophysiology,  
Ms Rosalyn Squire, ICU Research Nurse  
Dr Andrew Mac Cormick, FY1 doctor  
 
Statistician:  
Dr Doyo Gragn Enki (PhD), Research Fellow in Medical Statistics, Medical Statistics Group, Faculty of 
Medicine and Dentistry, University of Plymouth 
 
Study Management: The Departments of Intensive Care Medicine and Neurophysiology at Derriford 
Hospital, University Hospitals Plymouth NHS Trust.  
Dr Nikitas Nikitas and Mrs Nicola Broomfield as representatives of the department of Intensive Care 
Medicine and Neurophysiology respectively 
 
 
Study Coordination 
For general queries, supply of study documentation, and collection of data, please contact: 
Study Coordinator: Dr Nikitas Nikitas 
 
 
Registration: GMC Fully registered 
Address: Penrose and Pencarrow ICU, Level 4,  
Terence Lewis Building, 
 
 
e-mail: nikitas.nikitas@nhs.net  
Derriford Hospital,  
University Hospitals Plymouth NHS Trust 
Plymouth, PL6 8DH 
Tel: 01752(4)30240, Mobile 07741665616,  
Pager: 81203 
 
 
Clinical Queries 
Clinical queries should be directed to Dr Nikitas Nikitas who will direct the query to the appropriate 
person 

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Sponsor 
University Hospitals Plymouth NHS Trust (UHPNT) is the main research sponsor for this study.  For 
further information regarding the sponsorship conditions, please contact the Research Manager at: 
Research Development & Innovation Office 
University Hospitals Plymouth NHS Trust  
Level 2, MSCP  
Bircham Park Offices 
1 Roscoff Rise 
Plymouth  
PL6 5FP 
+44 (0) 1752 432842 / 32842 
 
 
 
This protocol describes the “Early recorded P25/30 somatosensory evoked potentials are associated 
with neurologic prognosis of comatose survivors after out of hospital cardiac arrest” study and 
provides information about procedures for entering participants.  Every care was taken in its drafting, 
but corrections or amendments may be necessary.  These will be circulated to investigators in the 
study.  Problems relating to this study should be referred, in the first instance, to the Chief 
Investigator.  
This study will adhere to the principles outlined in the UK Policy Framework for Health and Social Care 
Research (2017). It will be conducted in compliance with the protocol, the Data Protection Act (2018) 
and other regulatory requirements as appropriate.  

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Table of Contents 
1.1 
BACKGROUND 
10 
1.2 
RATIONALE FOR CURRENT STUDY 
14 
1.3 
PATIENT AND PUBLIC INVOLVEMENT 
14 
2.  STUDY OBJECTIVES 
18 
3.  STUDY DESIGN 
18 
3.1 
STUDY OUTCOME MEASURES 
19 
4. 
PARTICIPANT ENTRY 
19 
4.1 
RECRUITMENT AND CONDUCTION OF THE STUDY 
19 
4.2 
PRE-REGISTRATION EVALUATIONS 
29 
4.3 
INCLUSION CRITERIA 
29 
4.4 
EXCLUSION CRITERIA 
30 
4.5 
WITHDRAWAL CRITERIA 
30 
5. 
ADVERSE EVENTS 
30 
6. 
ASSESSMENT AND FOLLOW-UP 
31 
7. 
STATISTICS AND DATA ANALYSIS 
32 
7.1 
DESCRIPTION OF STATISTICAL METHODS 
32 
A. 
THE NUMBER OF PARTICIPANTS 
32 
7.3 
THE LEVEL OF STATISTICAL SIGNIFICANCE 
33 
7.4 
CRITERIA FOR THE TERMINATION OF THE TRIAL. 
33 
7.5 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, AND SPURIOUS DATA. 
33 
7.6 
PROCEDURES FOR REPORTING ANY DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN 
33 
7.7 
INCLUSION IN ANALYSIS 
33 
8. 
ARCHIVING 
33 
9. 
REGULATORY ISSUES 
33 
9.1 
ETHICS APPROVAL 
33 
9.2 
CONSENT 
34 
9.3 
CONFIDENTIALITY 
35 
9.4 
INDEMNITY 
35 
9.5 
SPONSOR 
35 
9.6 
FUNDING 
35 
9.7 
AUDITS 
36 
10. 
STUDY MANAGEMENT 
36 
11. 
PUBLICATION POLICY 
36 

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12. 
REFERENCES 
37 
APPENDIX 
38 
TABLE 1. 
SUMMARY OF INVESTIGATIONS, TREATMENT AND ASSESSMENTS 
38 
FIGURE 1. THE CEREBRAL PERFORMANCE CATEGORY SCALE [CPC] 
39 
FIGURE 2. THE ECOG/WHO PERFORMANCE STATUS SCORE 
39 
FIGURE 3. THE CHARLSON COMORBIDITY INDEX SCORING SYSTEM 
40 
 

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GLOSSARY OF ABBREVIATIONS 
BP 
Blood Pressure 
CI 
Chief Investigator 
CPC 
Cerebral Performance Category 
CPR 
Cardiopulmonary Resuscitation 
CT scan 
Computerised Tomography scan 
CT 
Clinical Trials 
CXR 
Chest X-ray 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
FBC 
Full Blood Count 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GP 
General Practitioner 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
ICU 
Intensive Care Unit 
IHCA 
In Hospital Cardiac Arrest 
INR 
International Normalised Ratio 
LFT  
Liver Function Test 
MRI 
Magnetic Resonance Imaging 
N20  
Short latency [20 msec] Somatosensory Evoked Potential  
NHS 
National Health Service 
NPV  
Negative Predictive Value 
NRES 
National Research Ethics Service 
NSE 
Neuron Specific Enolase 
OHCA 
Out of Hospital Cardiac Arrest 

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P25/30 
Short Latency [25-30msec] Somatosensory Evoked Potentials 
PaCO2 
Partial Pressure of Carbon Dioxide of an arterial blood sample 
PaO2 
Partial Pressure of Oxygen of an arterial blood sample 
PI 
Principal Investigator 
PIS 
Participant/ Patient Information Sheet 
PEA  
Pulseless Electrical Activity 
PPV  
Positive Predictive Value 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
ROSC 
Return of Spontaneous Circulation  
SaO2 
Saturation of arterial Blood in Oxygen  
SAP  
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
SPSS 
Statistical Package for Social Sciences 
TSG 
Trials Steering Group 
TTM 
Targeted Temperature Management 
U&Es 
Urea and Electrolytes 
 

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KEYWORDS 
Somatosensory Evoked Potential, P25, P30, N20, cardiac arrest, prognosis 
 
 
STUDY SUMMARY 
 
TITLE Early recorded P25/30 somatosensory evoked potentials are associated with 
neurologic prognosis of comatose survivors after out of hospital cardiac arrest. 
DESIGN Prospective, observational, non-interventional, study – prospective collection of 
data and interpretation. 
Analysis of the data and assessment of prognostic value of the P25/30 in 
critically ill patients post cardiac arrest.  
AIMS To be the first attempt to validate the prognostic potential of early recording 
[between 24-36 hours post Return Of Spontaneous Circulation (ROSC)] of 
P25/30 potentials in comatose survivors who are admitted to a British ICU after 
out of hospital cardiac arrest and who are not treated by hypothermic targeted 
temperature management.  
[Validation of the prognostication significance of P25/30 Somatosensory Evoked 
Potentials in predicting neurologic outcome in comatose survivors post out of 
hospital cardiac arrest who are treated in ICU].  
OUTCOME MEASURES Primary Endpoint: Neurologic outcome assessed by CPC score at hospital 
discharge. 
Secondary endpoints: Mortality at hospital discharge and 28 days [which occurs 
first], comparison of prognostic benefit of N20 and P25/30 based multimodal 
prognostic models. 
POPULATION Comatose survivors, after out of hospital cardiac arrest, treated in Derriford 
Hospital ICU, Penrose and Pencarrow wards. 
ELIGIBILITY Adults [>18 years old], out of hospital cardiac arrest, comatose after ROSC, ICU 
admission 
DURATION 
ESTIMATED COST 
24-36 months 
Cost for statistical analysis and full statistical support.  With all University on 
costs the estimated cost is £4500 and with direct costs only £2300. 
 
 
 

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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
Suffering an Out of Hospital Cardiac Arrest (OHCA) is a global health problem with a yearly incidence 
of approximately 1:1000 people worldwide (1). In-hospital-cardiac-arrests (IHCA) affect 1-1.5 per 1000 
in-patients (2). Internationally, recent survival figures for such events are 26% and 22% respectively 
(3,4). Much of this mortality is due to patients suffer devastating neurological damage, and so go on 
to receive palliative care. Locally, 200 patients were admitted to the Derriford General Intensive care 
in the last 3 years following an OHCA. Of those, patients who reach the intensive care, 70% died (2). 
Many patients who do not die will suffer varying degrees of neurological damage. Neurological 
outcome is most commonly measured using the Cerebral Performance Categories [CPC] [appendix 
figure 1] either at ICU or hospital discharge or at 3-6 months post cardiac arrest. 
Up to 20% of patients suffering a cardiac arrest will still be in a coma at one week post Return Of 
Spontaneous Circulation [ROSC]. Some of these patients will make a good recovery (5). Predicting 
devastating irreversible neurological damage often takes time and requires a multimodal approach 
using clinical testing, electrophysiological tests, blood biomarkers, and radiological imaging. In the 
most recent guidelines issued by the Resuscitation Council UK in 2015 a specific prognostication 
algorithm is provided to facilitate the integration of these clinical signs and investigations in available 
in order to achieve the best possible prognostic accuracy [Figure 1].  
Importantly, early and accurate detection of patients with severe cerebral damage prevents 
unnecessary patient suffering and assists with clear communication with relatives, reducing their 
distress. There are a number of known factors that are associated with a poor outcome: Age, non-
witnessed arrest, lack of bystander cardiopulmonary resuscitation [CPR], presence of a non-shockable 
rhythm [Asystole or Pulseless Electrical Activity (PEA)], Anoxia time [time lapsed from cardiac arrest 
until ROSC], requirement for adrenaline, a low pH and PaCO2 on admission (6). None of these 
prognostic markers have sufficient sensitivity or specificity to make accurate prognostic decisions. 
Many of the clinical signs [pupils’ reactivity to light, Glasgow Coma Scale (GCS), reflexes, presence of 
myoclonus] and laboratory / radiological tests [Computerised Tomography (CT) scans, 
Electroencephalogram (EEG), Neuron Specific Enolase (NSE), Magnetic Resonance Imaging (MRI) scan] 
also suffer similar uncertainty – either when used alone or in combination in the context of a 
multimodal approach – especially early in an admission. One exception is the Short-latency 
Somatosensory Evoked Potentials (SSEPs). During this test, specific electrical signals are recorded in 
specific area of the brain [cortex]. These electrical signals are produced after stimulation of a nerve on 
the hand. This test establishes presence or absence of intact brain electrical activity. At 20 
milliseconds after median nerve stimulation, a response, an electrical signal, should be recorded in 
the corresponding area of the brain which is called sensory cortex. This electrical signal is called N20. 
Total absence of N20s is strongly correlated with a poor outcome. 
 

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Figure 1: Resuscitation Council UK Post cardiac arrest prognostication algorithm 
 

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However, the presence of N20s does not equate with a good outcome. Many patients with 
unilaterally or bilaterally present N20s may still have devastating neurological damage.  
Kim et al (8) tested the prognostic use of SSEPs in comatose survivors after OHCA, highlighting an 
alternative electrical signal [formally called evoked potential], the P25/30. This is a similar electrical 
signal recorded during the same SSEP test after wrist nerve stimulation. This electrical signal is 
recorded on the same recording sheet with the N20 during the SSEP and follows the N20 
approximately 5msec later [Figure 2]. This electrical signal although recorded during the same test 
with the N20 has been ignored for many years, regarding its potential prognostic significance for the 
neurological outcome of the comatose patients after cardiac arrest.  The authors of this study 
retrospectively examined bilateral P25/30 in 116 consecutive patients 3-4 days after ROSC. 
Neurological outcome was recorded at hospital discharge. Their results suggest bilaterally absent 
P25/30 had a superior prognostic value to N20.  All patients with absent P25/30 had a poor 
neurological outcome. Fewer patients with devastating brain injuries had present P25/30 compared 
to the presence of N20.  
During a retrospective review of 43 cases with cardiac arrest admitted to Derriford ICU between 2015 
and 2018 and in whom N20 testing was performed, the results were similar to the Kim et al study.  
 
Therefore a study that would attempt to validate the proposals below is justified. 
1. 
The prognostic value of P25/30 SSEP when recorded early [between 24-36 hours post ROSC] in 
comatose survivors after OHCA who are admitted to ICU 
2. 
Test the superiority of early [between 24-36 hours post ROSC] P25/30 SSEP recording in 
predicting poor neurologic outcome against the early N20 SSEP recording. 
 
This study would be the first to test this hypothesis in British ICU patients.  
 
To summarise, the Short-latency Somatosensory Evoked Potentials (SSEPs) is one of the most 
promising ways available in predicting the neurological outcome in comatose patients after OHCA. 
This is a bedside test whereby a nerve in the wrist is stimulated and electrodes on the scalp detect the 
brains response to this stimulus. This response is presented as electrical signals recorded on a 
recording sheet. These electrical signals are called SSEPs and can be interpreted by specialist 
scientists, the neurophysiologists. If these electrical signals in the brain are not present (SSEP absent), 
it is well recognised to be a very reliable sign that the brain has suffered irreversible, devastating 
damage (7). Unfortunately, if the scalp electrodes do detect brain electrical signals, it does not equate 
with a good outcome. Many patients with present SSEP may still have devastating brain damage. 
Published data to date has focused on the brain electrical signals 20 milliseconds following the wrist 
stimulus (N20). However, recent data looked at electrical signals 25-30 miliseconds following the wrist 
stimulation (P25/30) recorded on the same recording sheet. The new electrical signals showed the 
potential for more consistent association with the prediction of the neurological outcome not only 
when they are absent but also when they are present.   

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Based on preliminary, retrospectively reviewed data in our intensive care unit; The results concur with 
the findings of the aforementioned results of the international medical literature.   
Therefore, we would propose to analyse: 
1. 
The prognostic value of P25/30 SSEP when recorded early [between 24-36 hours post ROSC] in 
comatose survivors after cardiac arrest who are admitted to ICU 
2. 
Test the superiority of early [between 24-36 hours post ROSC] P25/30 SSEP recording in 
predicting poor neurologic outcome against the early N20 SSEP recording. 
This study would be the first to test this hypothesis in British ICU patients. 
 
 
Figure 2.  Example of recording sheet where N20 and P25/30 electrical signals are present and 
recorded [Kim et al. Crit Care Med 2018;] 
 
  
 
 
 
 
 
 
 
 

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1.2 
RATIONALE FOR CURRENT STUDY 
Research Question: Could the early [between 24-36 hours post ROSC] recorded P25/30 
Somatosensory Evoked Potentials be used to predict the neurologic outcome in comatose survivors 
post out of hospital cardiac arrest who are admitted to ICU and who are not treated by hypothermic 
targeted temperature management? Could the early recording of P25/30 SSEPs be of superior 
prognostic value compared to the early recording of N20 SSEP? 
Study Hypothesis: The early [between 24-36 hours post ROSC] recorded P25/30 SSEPs predicts the 
neurologic outcome in comatose survivors post out of hospital cardiac arrest who are admitted to ICU 
and who are not treated by hypothermic targeted temperature management. Early P25/30 SSEPs 
recording is of superior prognostic value compared to early N20 SSEP recording in the same patients.  
Primary Endpoint: Neurologic outcome assessed by Cerebral Performance Category [CPC] score at 
hospital discharge. 
Secondary endpoints: Mortality at hospital discharge and at 28 days [which occurs first], comparison 
of prognostic benefit of N20 and P25/30 based multimodal prognostic models. 
 
1.3 
PATIENT AND PUBLIC INVOLVEMENT  
During the study design and the design of the patient/relative information sheet it was considered 
necessary to actively listen to patients’ and patients’ families’ comments about the study after 
discussion with them and to collaborate with the patients and their families for the development of 
the Patient Information Sheet. 
Patients and families in Derriford ICU were asked by us to read carefully the Patient Information Sheet 
that we had prepared based on the template provided to us by the local R&D. After having read that, 
we kindly invited the patients and families to provide their written constructive feedback about the 
information sheet and the study and to suggest areas that needed further modification or further 
explanation and/or to make specific suggestions or to express their possible concerns freely and 
honestly about particular parts of the information sheet or the study.  
The feedback that was provided to us was generally positive. Patients and families felt that the study 
will be beneficial for the patients and it will help actively to improve the knowledge about patients’ 
outcomes and the care of the patients.  
There were suggestions to limit the number of words in the “description of the study” part and to 
avoid some unnecessary repetitions. All reviewers have understood the study methods, the analysis, 
the aim of the study and the potential benefit for the patients as they were described in the text. 
They have said in details: 
• “This section is too long, needs to be kept shorter if possible. Maybe adding another section 
which is more detailed and on the brief description section it could just be about the aim of 
the study” [comment about the brief introduction to the study section]. 
• “Take out what would I have to do section as this can be covered in the “Do I have to take part 
section” [Obviously this could not be done because it was part of the template]. 

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• “Other than the points above, this is a very informative sheet and easy to understand.” 
• “As I was reading this information I found in some areas it was a bit long.” 
• “The new study will benefit patient and family members.” 
• “A more quicker and accurate outcome for patient.”      
The team actively listened to their feedback and proceeded to the improvement of the specific part of 
the text. The feedback was positive for all other parts of the information sheet.  
The personal details of the patients and their family members that provided their feedback and were 
involved in this process are available by the study team but for confidentiality reasons they are not 
mentioned in this text.  
Predicting the neurological outcome of comatose patients after out of hospital cardiac arrest that are 
admitted to ICU is one of the major clinical uncertainties and one of the major challenges for the 
modern intensive care medicine. Despite the use of many clinical markers to predict the neurological 
outcome after OHCA, none of these clinical markers alone or in combination have been effective, 
reliable, and reproducible enough, in order to provide a definitive answer to the simple but complex 
and challenging questions of the clinicians and the families: Will the patient be able to recover fully 
neurologically? Would the patient be able to achieve the level of functional independence and the 
quality of life they had before the cardiac arrest? Will the patient be disabled and if yes, at what 
degree?  
These questions, although vital for the patients and their families, as well as for their physicians, 
cannot be definitely answered at an early stage of patient’s care after cardiac arrest. Therefore, 
inevitably, only the prolonged period of time, which will be of variable duration, in ICU, in the hospital 
and in rehabilitation care homes, is required in order to reach a reliable conclusion about the final 
neurological outcome of the patients.  
For those who will achieve a satisfactory neurological recovery, this period of time is associated with 
uncertainty, concerns, stress and frustration for the patients and their families as they cannot have 
the definite answers they seek since the very early stages of their treatment.  
For those patients that they will never achieve a satisfactory neurological recovery and they will 
remain comatose or in vegetative state, the lack of a reliable prediction of the neurological outcome, 
early at the course of their illness, is associated with the provision of unnecessarily prolonged period 
of intensive support and futile treatment that does not result in their recovery but to the prolongation 
of survival in a very poor functional status which is distressing for their families and not beneficial for 
them.  
All of the above make the need for an early and reliable prediction of patients’ neurological outcome 
after OHCA, urgent and challenging. This definitive answer would help patients avoid prolonged futile 
treatments, would minimise families’ uncertainties about the future outcomes and would help 

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clinicians reach more confident and definite decisions for their patients’ complex clinical condition at 
the earliest possible stage of their treatment.  
Derriford ICU team consists of clinicians intensivists with extensive and prolonged experience in 
Intensive care medicine and in the management of comatose patients after OHCA.  
The Derriford ICU team, for many years, have interacted continuously with the families of the patients 
and have listened actively to their thoughts, their wishes, their concerns, their fears, and most 
importantly their need for definite answers about the one and most important question for the 
families: “Will our loved one be able to be functionally independent again and will their brain function 
be as before.” And most of the time, despite the advances in modern intensive care medicine support 
and diagnostic tests, the answer to this question was impossible to be provided, especially during the 
early stages of the patients’ treatment in Derriford ICU.  
Thus, inevitably, both families and clinicians have gone through the same path of stepwise approach 
to the prognosis, which has been long and uncertain, with regards to the final outcome.  
After admission to ICU post cardiac arrest, the ICU team members, including the members of this 
study team, have discussed extensively, repeatedly and consistently, with the patients’ families and 
with the patients themselves [if possible], approaching and addressing their questions about 
neurological prognosis. Those discussions have taken place in the context of the patient/family 
communication meetings, bereavement meetings and bedside updates. All these hours of discussions 
had made absolutely clear that the main concern for the families and the patients is the lack of the 
definite answer about the final outcome of the brain damage that the patients suffer during cardiac 
arrest.  
Taking into consideration all the above, the Derriford ICU team decided to proceed to the design and 
conduction of this research study, aiming to provide more reliable and more definite answers 
regarding the patients’ final outcome after cardiac arrest at the earliest possible stage of their 
treatment in ICU.  
The reason for the selection of this specific research topic and this specific research project was not 
only the need to provide an answer about a challenging and complex clinical uncertainty but also the 
need to address the uncertainties and provide answers to the families of all these patients that suffer 
from the consequences of cardiac arrest.  
The concept of this study is not only the product of a strictly scientific approach to a challenging 
clinical question. The concept of this study is the product of the long and active interaction with 
families of all the patients that had made completely clear that their major concern and uncertainty 
and fear lies around the definite answer about the final outcome of the brain damage of their loved 
ones.  

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That interaction with families was a continuous source of inspiration for the Derriford ICU team in 
order to identify and focus on the critical questions that are associated with the outcome of the 
comatose patients after OHCA and to try to address those questions through a high quality research 
project.  
Therefore, the families of the patients that are treated in comatose state on ICU after a OHCA and the 
patients that regain brain function during recovery, actively guided our research interest to the 
specific area of the neurological outcome and they made us understand what are the crucial 
questions that intensive care medicine research must answer about the patients after OHCA.   
The longstanding interaction with the families and the patients and the continuous discussions with 
them, not only during the period of ICU admission but also after the ICU discharge, regardless of the 
outcome of the ICU care, helped our team to achieve an enormous level of experience regarding the 
understanding of families’ and patients’ needs, concerns, thoughts, wishes and fears and the ways to 
effectively approach all of them.  
In order to address that in the maximum efficiency, during the conduction of this study, the members 
of the study group will actively listen to the thoughts of the next of kin and other family members if 
available and they will try to provide the maximum information to them not only about the study but 
also about the general potential benefit for the patients by research, the importance of the research 
in modern medicine and specifically in the specialty of Intensive Care Medicine where many clinical 
and prognostic uncertainties still exist.  
Also, with the help of their next of kin for each one of the potential participants – before their 
enrolment in the study – we will explore the potential participants’ likely previously expressed wishes 
or thoughts or opinions about the importance of medical research and the participation in medical 
research for the benefit of the patients.  
The study group would be responsible to keep each one of the next of kin and/or the patients aware 
about the results of the study and the relevant publications [abstracts in conferences and scientific 
manuscripts in journals]. At that point the study group will invite the next of kin and/or the 
participants to provide their constructive feedback about the results of the study and their feelings 
with regards to their participation in this study. This could be an effective way to maximise the 
participation and involvement of the participants to the research process, from the initial discussion 
and consent to the results of the research study and their feedback.  
Also, that kind of interaction with the next of kin and/or the patients would give the opportunity to 
the members of the study group to actively explore the perspectives of the participants in their study, 
to maximise their experience and ultimately to help them developing their research performance by 
integrating useful learning points from the participants’ constructive feedback to the design and 
practical application of their future research projects.  

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The aforementioned process would potentially involve the participants of this study to the dynamic 
development of the research process in general. 
 
2.  STUDY OBJECTIVES 
Primary objectives  
1. To be the first attempt to validate the prognostic potential of early recording [between 24-36 
hours post ROSC] of P25/30 potentials in comatose survivors who are admitted to a British ICU 
after out of hospital cardiac arrest and who are not treated hypothermic targeted temperature 
management.  
2. To assess the Specificity, the Sensitivity, the Positive and Negative Predictive Value of the early 
[between 24-36 hours post ROSC] P25/30 SSEPs recording in predicting poor neurological 
outcome after out of hospital cardiac arrest.  
 
Secondary Objectives 
1. To test the potential prognostic superiority of early P25/30 SSEPs recording against the early 
N20 SSEP recording in predicting poor neurologic outcome in the same cohort of patients.  
2. To test if P25/30 SSEPs are associated with higher sensitivity and negative predictive value 
than N20 and subsequently to test if that superiority of P25/30 is consistently  associated with 
greater accuracy in the early detection of poor neurologic outcome [especially among those 
patients with unilaterally or bilaterally present N20 SSEPs].  
3. Add further knowledge regarding the prognostication significance of SSEP and specifically of 
P25/30 potentials in comatose survivors post out of hospital cardiac arrest who are treated in 
ICU. Provide reliable prospective evidence of the accuracy and reproducibility of the P25/30 
signal recording.  
 
3.  STUDY DESIGN 
Prospective Observational, Non-interventional, Study: Analysis of the recordings of Somatosensory 
Evoked Potentials test which is performed for prognostication in Derriford intensive Care Unit, in 
comatose survivors after Out of Hospital Cardiac Arrest. The interpretation of the recordings will 
include the presence or absence of P25/30 SSEPs, of N20 SSEP and possible other short or long 
latency evoked potentials on these recordings. After the interpretation of the recordings then a test 
for possible correlations of the recorded P25/30 SSEPs with the neurologic prognosis of the survivors 
will be performed. 
Estimated Study Duration:  24-36 months 
Estimated Number of patients:  One hundred and twenty adult Intensive Care Unit patients. In order 
to be included in the study, all patients must be adults, comatose survivors after out of hospital 
cardiac arrest who are admitted to Derriford Intensive Care Unit. 

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3.1 
STUDY OUTCOME MEASURES 
Primary Endpoint: Neurologic outcome assessed by Cerebral Performance Category [CPC] score at 
hospital discharge. 
Secondary endpoints: Mortality at hospital discharge and at 28 days [which occurs first], comparison 
of prognostic benefit of N20 and P25/30 SSEPs-based multimodal prognostic models. 
 
 
4. 
PARTICIPANT ENTRY 
4.1 
RECRUITMENT AND CONDUCTION OF THE STUDY 
The general management of adult comatose survivors after OHCA, who are admitted to the Derriford 
ICU, consists of provision of organ support as required [mechanical ventilation, cardiovascular 
support, renal replacement therapy], targeted temperature management aiming to maintain patients 
in normothermic condition for the first 72 hours, continuous invasive and non-invasive multimodal 
monitoring  [vital signs, respiratory and haemodynamic monitoring, neurologic monitoring] and 
treatment of the underlying cause of cardiac arrest [if known-diagnosed]. The patients remain 
sedated for the first 36 hours to facilitate brain protection, optimisation of patient’s organ function 
parameters and achievement of targeted temperature within very strict temperature limits [For the 
first 24 hours temperature target is 36⁰C and for the next 48 hours the temperature target is 36-
37⁰C]. The targeted temperature management is achieved with the use of external cooling devices. 
The neurologic prognostication of the post cardiac arrest patients is mainly based on a multimodal 
approach guided by the clinical picture of the patient [Level of consciousness, Glasgow Coma Scale, 
presence or absence of reflexes and focal neurologic signs], the results of the CT imaging studies [CT 
or MRI of the Head], the results of the Electroencephalogram and SomatoSensory Evoked Potentials 
[SSEPs] recording which usually are performed after the first 24 hours post ROSC. The SSEPs recording 
are performed in all comatose survivors after OHCA who are admitted to Derriford ICU as an integral 
part of their normal care. The recording and the analysis of the recording are conducted by the 
members of the neurophysiology team in Derriford Hospital. The main aim of that routine, 
established and used for the last 3 years, prognostication test is to assess the presence or absence of 
the N20 SSEP in comatose survivors after out of hospital cardiac arrest. According to the international 
medical literature and the national guidelines, N20 presence is associated with unknown [ranging 
from full neurological recovery to severely disabled status] neurological prognosis, whereas N20 
absence is always reliably associated with poor neurologic prognosis.  
During our study, we will interpret further the results of the SSEP recordings not only for N20 but also 
for the presence or absence of the P25/30 SSEPs and we will test if they are related with patients’ 
neurological prognosis. No consent is required for the SSEP recording as this is a part of the normal 
clinical care of the patients in Derriford ICU and has been already used for years in daily clinical 
practice of our unit, as a useful tool for the neurologic prognostication of post cardiac arrest patients. 

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During the study, consent will be required only for the additional interpretation of the SSEP recording 
sheet, regarding the presence or absence of P25/30 SSEPs and their potential prognostic significance. 
Nothing in the post cardiac arrest ICU management changes because of the study as no additional 
intervention and no additional tests will be introduced further to the normal care of the ICU patients 
that is established currently [figure 3].  
Explaining that in further details: On the admission to Derriford ICU [Penrose and Pencarrow wards], 
all adult comatose survivors after OHCA will be managed according to the already established routine 
Derriford ICU protocol for the management of all patients after out of hospital cardiac arrest.  
According to the current ICU routine care protocol: the patients will remain sedated for the first 36 
hours as per ICU policy. As per normal ICU care, the sedatives that will be administered as a 
continuous infusion will be propofol [at a rate of 1-4mg/kg/h] and fentanyl [at a rate of 50-200mcg/h]. 
Midazolam infusion would be used only if the use of propofol is could not be tolerated due to severe 
haemodynamic instability or adverse effects to propofol developed. Neuromuscular Blocking agents 
[Atracurium or Rocuronium] may intermittently or continuously be administered to the patients, if 
required, for the management of their ventilation and / or for the control of severe rigor during the 
targeted temperature management and / or for the control of myoclonus or convulsions.  
The reasons that the patients remain sedated for the first 36 hours are to facilitate brain protection, 
to optimise patient’s organ function parameters and to achieve targeted temperature management 
within very strict temperature limits.  
According to the Targeted Temperature Management protocol of the Derriford ICU, the body 
temperature will be maintained at 36⁰C for the first 24 hours and between 36-37⁰C for the next 48 
hours up to a total of 72 hours. As per ICU management practice, organ support as required 
[mechanical ventilation, cardiovascular support, renal replacement therapy], continuous invasive and 
non-invasive multimodal monitoring [vital signs, respiratory and haemodynamic monitoring, 
neurologic monitoring] and treatment of the underlying cause of cardiac arrest [if known-diagnosed] 
will be provided. The targeted temperature management is achieved with the use of external cooling 
devices.  
Between the 24 hours and the 36 hours after ROSC, the usual SSEP recording will take place in ICU by 
members of the neurophysiology team. The recording will be performed, as usual and normal ICU 
care without any modification for the study, while patients are on sedation [as described above]. The 
use of neuromuscular blocking agents will be applicable if indicated for any of the aforementioned 
clinical reasons or in order to achieve the best recording quality [clear recording of SSEP baseline in 
patients to facilitate the optimal interpretation of the recording mainly in patients with tremor or 
myoclonus] if that is not possible to be achieved while patients are on sedation. A single dose of 
Atracurium or Rocuronium will be administered for this purpose only if this is absolutely necessary. 
The Neurophysiology team members may request the use of neuromuscular blocking agent if they 

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think that the quality of their recording is poor. It will be the decision of the ICU consultant in charge if 
the neuromuscular blocking agent could be administered. 
Within the first 24 hours in the ICU the patients will be assessed by the members of the research 
study team regarding their eligibility to be enrolled in the study. If the patients meet the specific 
inclusion and exclusion criteria for the study, their next of kin [NOK] will be approached by a member 
of the research team [who is also a member of the ICU clinical team] at ICU. All NOK will be spoken to 
in person. A full explanation of the study design, of the study protocol and of the study objectives, as 
well as a specific relative information leaflet containing all the information for the study, will be 
provided. The provision of informed consent by the NOK will be requested if patients meet the 
eligibility criteria for study enrolment. The meeting with the NOK may be done ideally before the SSEP 
recording or, in case of non-availability of the NOK, after the SSEP recording.  
During the informed consent process, the members of the study group will actively listen to the 
thoughts of the next of kin, and they will try to provide the maximum information to them not only 
about the study but also about the general potential benefit for the patients by research, the 
importance of the research in modern medicine and specifically in the specialty of Intensive Care 
Medicine where many clinical and prognostic uncertainties still exist.  
The next of kin for each potential participant will be asked to consent for the participation of the 
patients in the study, after being fully informed both verbally and by the provision of the relevant Trial 
Participant Information Sheet and a copy of the Trial Informed consent form that can be found in the 
appendix of this document. The patient will also be given the contact details of the ICU Research 
Nurse, should they wish to seek further information about the study. In most cases, the next of kin of 
potential participants will have at least 24 hours to decide whether or not to participate in the study.  
Method of SSEP recording – Neurophysiology Data Acquisition and Interpretation 
The following protocol of N20 SSEP recordings, currently used in Derriford ICU, will be applied for the 
purpose of the study. N20 and P25/30 SSEPs are expected to be recorded and then during the study 
interpretation of the results the presence or absence of either or both and the correlation between 
them will be assessed   
Neurophysiology protocol of Somatosensory Evoked Potentials [upper limb Median/ Ulnar] in 
Derriford ICU following Out Of Hospital Cardiac Arrest. 
This protocol has been used successfully for SSEP recording in Derriford ICU since 2015. This is part of 
the usual, established Derriford ICU policy for the management of the comatose survivors after out of 
hospital cardiac arrest and is not added or at any way modified, because of the study. The study 
purpose is the interpretation of the recording sheet of the SSEP test in order to answer the question 
whether the P25/30 potential that is recorded along with the N20 may have prognostic significance 
for the patients’ neurological outcome.  

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The protocol of the SSEP recording is described below in details: 
Deymed evoked potential system is used  
Open Acquisition 
Open EP protocol and select SEP from list 
Select Median 4 Channel Right or Left depending on side being tested  
Press On which brings up live trace to monitor 
Turn up stimulation until a visible thumb twitch is seen, then select average; wait until at least 500 
samples has been performed on each channel. 
Measure wave forms accordingly using the measuring tool, - to print the waveforms press Quick 
report this will bring up document to print and then press the print icon. 
A note of the patient’s height if known should be made in cm. 
Any sedative medication being used must be recorded on the request form. Patient should be 
paralysed with muscle relaxant agent to minimise EMG/movement artefact 
Stimulation is routinely performed of the median or ulnar nerve in the hand; however this can be 
modified where necessary. 
 
Machine Settings: 
Stimulus Settings 
Amplifiers (Default) 
 
Duration 0.1ms 
Rate 2.9Hz 
Sensitivity 20-50uV/division 
Low frequency Filter 20Hz 
High Frequency Filter 2KHz 
Notch Off 
Artefact rejection On 20uV Divisions 
(Channel must be selected individually) 
Impedance Value must be below 5Kohm. 
The machine settings may be altered as the physiologist doing the test sees fit 
 
Electrode Placement 
Position 
Label (headbox) 
Mid clavicle 
Erb’s point 
Channel 4 Ipsilateral/contralateral Erbs 
Nape of neck 
CV2 
Channel 2 
Over prominent 
spinous process 
CV7 
Channel 3 
 
Cortex (2cm posterior to Cz and 
6cm lateral on contralateral 
hemisphere) 
Channel 1 C3/ C4 
 
Fz reference 
Fz + input 
 
Ground strap on limb tested 
Ground (linked) 

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Montage 
Channel 1 
Fz – C3/C4 
 
Channel 2 
Fz/Front neck ref – Cervical C2 
 
Channel 3 
Fz/Front of  neck – Cervical C7 
 
Channel 4 
Fz/Ips/ContErb – Erbs Ips/Cont 
 
Sweep time: 100ms 
 
Recording procedure 
SSEPs must be recorded after at least 24hours following ROSC. Usually to be performed between 24-
36 hours after ROSC. 
Temperature must be recorded; mild to moderate hypothermia ≥36
does not abolish the cortical 
N20 responses.  Cortical responses have been proven to remain until a nasopharyngeal temp of 20’C 
is reached. 
The N20 remains present even at a sedation level sufficient to induce an iso-electric EEG. 
 
Running the test 
The established, used for many years in Derriford ICU, SSEP recording protocol is used. No changes 
in terms of either the method of recording or the length of the test would be done as a result of the 
study. Besides, the study does not have to do anything with the SSEP recording but with the further 
interpretation only of the recording paper for evidence of other potentials that could be used for 
prognosis.  
The patient is positioned to reduce muscle artefact.  If this is not possible and muscle artefact is high 
muscle relaxants may need to be prescribed to improve quality of recording and quality of SEP, 
especially in cases where it is thought to be absent. 
The level of stimulation is subjective and needs to elicit a visible twitch of the appropriate muscle.  
Therefore this should be achieved prior to administration of muscle relaxant 
Averaging begins once adequate stimulation is achieved, a minimum of 500 trials is required, and this 
must be increased where necessary. A minimum of two trials must be recorded to check for 
reproducibility.  
 
Interpretation of the recording regarding N20s at the bedside for clinical purposes. This is part of 
the current established normal ICU care and is not part of the study.  
Cortical N20 response is to be described as bilaterally absent (which is a good predictor of poor 
neurological outcome), or in other cases in may be present on one or both sides. 

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If the cortical N20 response is absent, the presence of the peripheral N9 and N13 response must be 
present to ensure that the response has arrived at the cortex.  Cervical lesions need to be excluded if 
Cortical N20 response is absent. Immediately after SSEP recording, each recording will be interpreted 
for N20 and the result will be disclosed to the ICU clinicians as currently happens in the context of the 
ICU clinical policy and the Resuscitation Council UK Guidelines.  
 
After SSEP recording  
After the SSEP recording the result of the N20 potential will be disclosed to the ICU clinical team as it 
happens currently as per the established Derriford ICU care and that will not be part of the study.  
In the context of the research study: 
For those patients who informed consent is obtained from their next of kins and are enrolled in the 
study, a copy of each recording will be produced for the study purposes by one member of the study 
team who is not participating in the interpretation of the recording. This copy will be anonymised by 
giving a specific number for the study. The date of the recording and the time will be available on the 
copy. The specific study number of each recording will correspond to the specific patient and will be 
kept on a list not accessible by the neurophysiology study team members who will perform the 
interpretation of the recording for the study purposes.  
After each copy has been anonymised and added in the study databank, the anonymised copy will 
become available to the first and to the second interpreter [both members of the study team 
(neurophysiology)] who will interpret the recordings with regards to the presence and absence of the 
N20 and P25/30 SSEPs and they will record the results of their interpretation in the results databank. 
The two interpreters will be blinded for the personal and the clinical details of the patient. Also each 
one of the interpreters will not be aware about the result of the interpretation of the other. The ICU 
clinicians will not be aware about the results of the P25/30 interpretation as this will be part of the 
study and should not be disclosed to them during the conduction of the study. In this way, the P25/30 
interpretation results will be impossible to affect the treatment of the patients and / or any of the 
clinical decisions made about them by the ICU clinicians who will strictly be kept unaware about the 
results of the P25/30 SSEPs.  
In the unlikely event that there was a discrepancy in interpretation of the SSEP recording between the 
two delegated interpreters, then a third member [not a member of the study team] of the 
Neurophysiology team would be asked to review the anonymised recording only in order to decide 
about the result. The data of the patients as well as the date of recording and the results of the 
interpretation of the two study team interpreters would not be disclosed to the third independent 
interpreter.   
 

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Interpretation of the SSEP recording for study purposes in details 
Cortical N20 response is to be described as bilaterally absent (which is a good predictor of poor 
neurological outcome), or in other cases in may be present on one or both sides. 
If the cortical N20 response is absent, the presence of the peripheral N9 and N13 response must be 
present to ensure that the response has arrived at the cortex.  Cervical lesions need to be excluded if 
Cortical N20 response is absent. 
The results of the SSEP from the patients enrolled to the study will be additionally interpreted for the 
presence or absence of the P25/30 waveforms.  The additional interpretation for the study purposes 
will be as follows: 
1. Check that baseline is clear and stable.  
2. Check that all measured components are reproducible (should be possible to superimpose 
waves) 
3. Check that peripheral nerve (N9) potential is present 
4. Check that cervical spinal (N13) potential is present 
5. Check that scalp (N20) potential is present and  higher than 0.5 microvolts.  
6. Check that scalp (P25/30) potential is present and higher than 0.5 microvolts.. 
7. As the P25/30 pottential could be generated in the absence of N20 as they come from two 
distinct areas of the brain cortex, the presence of either the P25/30 or the N20 would be 
confirmed when the amplitude of each one is equal or higher than the amplitude threshold 
[0.5 microvolts] used for the analysis of the SSEPs. The presence and the amplitude of P25/30 
will not be dependent on the presence of N20 in the same recording as each one of them can 
exist in the absence of the other  
8. Measurement of the amplitude of recorded P25/30 and N20 and their combinations. Test if 
there is a correlation of the recorded amplitudes and their ratio [P25/30 to N20] with the 
positive predictive value of N20 for the favourable neurological outcome. 

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Figure 3.  Explanation-clarification of the usual Derriford ICU post cardiac arrest care and what 
additionally will be done for the research study purposes 
 
During the conduction of the study the patient’s confidentiality and the unbiased analysis / 
interpretation of the SSEP recordings of the patients will be continuously ensured by the fact that 
once enrolled in the study their personal data will be replaced by a study number that will be 
representative of them.  Only the members of the team that collect the data and do not take part in 
any interpretation of the results of the SSEPs and are not involved as clinicians in the clinical care of 
the patient will be aware about the correspondence between the study number and the personal and 
clinical details of each patient.  The members of the study team that will be SSEP interpreters will be 
blinded for any clinical and personal data of the patients and the clinical ICU team will be not aware 
about the result of the P25/30 study interpretation.  
After the SSEP recording has been conducted, between 24 and 36 hours post ROSC, the patients will 
be followed up by members of the study team.  Those members of the team will assess the patients, 
by CPC and by performing full neurologic clinical examination, on the day of ICU discharge and on the 

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day of their discharge from Derriford Hospital.  The online system SALUS of Derriford hospital will be 
used to follow up the patients after their discharge from ICU and before their discharge from the 
hospital.  
The study team has already worked collaboratively with the IT and SALUS teams members and they 
have developed an effective way of patients follow up for the study purposes. 
Through SALUS system, the members of the study team responsible for the patients follow up will be 
notified for the planned patients’ discharge date in order the patients to be assessed by a study team 
member before they leave the hospital.  The neurologic outcome, assessed with the Cerebral 
Performance Category [see figure 1 on the Appendix], will be recorded on the day of Hospital 
discharge [within the last 24 hours before discharge].  
If a study participant died on ICU as a result of severe brain dysfunction or after the decision of ICU 
Consultant to be withdrawn from invasive organ support due to extremely poor prognosis and futility 
of further continuation of treatment, then, the discharge CPC would be the most recently recorded, 
after the patient have remained consistently off sedation [for a period of time varied for different 
sedatives or combination of sedatives].  
Specifically, in a case that the ICU Consultant in charge considered withdrawing the invasive organ 
support in one of the study participants due to extremely poor prognosis, then the ICU consultant 
should notify the ICU research nurse in order one member of the team to perform the CPC score 
recording.  The assessment by CPC must always take place before the decision for withdrawal of 
treatment is implemented and strictly before the palliative pathway is initiated. If the study team 
members failed to be notified by the ICU consultant about the withdrawal of treatment and the 
Palliative pathway is initiated before patient’s CPC and neurologic examination recorded then the 
patient will be excluded from the study. 
If a participant died unexpectedly from another cause rather than severe brain dysfunction and / or 
withdrawal of invasive organ support, then the most recent CPC before death [if possible to be 
recorded] will be based on the last available clinical assessment off sedation and will be considered as 
indicative of neurologic outcome for the patients.  In case the CPC could not be assessed, the patient 
would be excluded from the study analysis. 
If patients die on ICU while still on sedation and before being possible to assess their CPC then they 
will be excluded from the study analysis as the assessment of their outcome based on CPC will not be 
possible.  
The Results of the CPC assessment and the outcome of the patients will be stored in the general study 
databank for further analysis. 
The members of the study team with the help of the Derriford Hospital IT team have already created 
a study team folder on the hospital computer system.  Rights to access the study folder have been 

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provided by Derriford hospital IT only and strictly to the study team members. The access to the 
folder is password protected.  Each member of the study team must protect the patients’ 
confidentiality and treat the data safely as per Good Clinical Practice and Research Governance 
Principles.  
The study folder will contain four separate databanks: The first databank will contain the personal 
data of the patients [Name, Age, Hospital number, next of kin, and contact details] and their 
corresponding study numbers by which the patients will be known to all the members of the study 
team.  During the conduction of the study, specific members of the study team will be responsible for 
the creation and management of this databank and only they will have access to this during the 
conduction of the study.  
The second databank will contain all the clinical data that will be recorded for each patient 
[represented by a study number on this databank] on the day of ICU admission, the day of ICU 
discharge and the day of hospital discharge [see below for further information regarding clinical data 
expected to be collected for each patient].  
The third databank will contain the results of the interpretation of the SSEP recordings with regards to 
P25/30 and N20 SSEPs.  This databank will be accessible during the study conduction only by the study 
team members who will be the interpreters of the SSEP recording.  
The fourth databank will contain the results of the neurologic outcome of the patients, in the form of 
Cerebral Performance Category recorded on ICU discharge day and on hospital discharge day. 
At the End of the study, all data will be merged and statistically analysed and from the result of this 
analysis one or more relevant manuscripts must be submitted to a peer-review journal within the first 
4 months after the completion of the study. 
For each one of the patients-participants, the following clinical data must be collected prospectively, 
during the conduction of the study [at different stages i.e. at the time of enrolment and follow up] 
and must be kept safely in an anonymised form in a suitable database [see above for explanation].  
The principles of patients’ confidentiality and privacy must be applied at all times. 
1. Age 
2. Gender 
3. Comorbidities [Scored by Charlson Comorbidity Index (see figure 3 on the Appendix)] 
4. Pre-admission performance status [Assessed by the ECOG/WHO performance status score (see 
figure 2 on Appendix)] 
5. Cardiac Arrest Rhythm [Rhythm that was initially recorded after cardiac arrest, usually at 
scene] 
6. Bystander – witness of cardiac arrest and Cardiopulmonary resuscitation  

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7. Anoxic time [total time between cardiac arrest was noted and ROSC]. If multiple episodes of 
cardiac arrest then the sum of all anoxic times to be considered.   
8. GCS before intubation [total or with components if available] 
9. Aetiology of cardiac arrest [cardiac or non-cardiac or unknown] 
10. CT scan report if performed because it was clinically indicated  
11. Cerebral performance category at ICU discharge and Hospital discharge. 
12. Date of death, number of days post ROSC that death occurred  
13. ICU length of stay, hospital length of stay 
14. Time of SSEP performed [hours post ROSC] 
15. Time between ROSC and ICU admission,  
16. First 24 hours post ROSC: mean SpO2, mean PaO2, mean PaCO2, mean HR, mean BP, mean 
Glucose levels, mean Lactate levels, mean pH, mean BE, Urea and Creatinine levels, liver 
function tests: ALT, INR, Bil and ammonia in patients with pre-admission acute or chronic 
hepatic dysfunction], Plasma Na levels, Temperature, SOFA Score, APACHE II score.  
No particulars tests needed for the study purposes. The aforementioned tests are performed and the 
aforementioned clinical data are recorded for all patients admitted to Derriford ICU after out of 
hospital cardiac arrest as part of daily clinical practice.  
 
4.2 
PRE-REGISTRATION EVALUATIONS  
No specific laboratory tests or imaging tests results are required in order to guide the decision to 
enrol a patient in the study. The inclusion and exclusion criteria [as described below] are solely based 
on clinical assessment and history taking that would be available at the time of ICU admission. 
 
4.3 
INCLUSION CRITERIA 
1. All adult comatose survivors after out of hospital cardiac arrest who are admitted to Derriford 
Hospital Intensive Care Unit [Penrose and Pencarrow wards]. The cause of cardiac arrest may 
be cardiac and/or non-cardiac or unknown at the time of enrolment.  
2. All patients must be comatose before intubation [GCS equal or lower than 8]. 
3. All patients must be on one or more invasive organ support [e.g. Endotracheal intubation and 
mechanical ventilation, vasopressor and/or inotropic support, Continuous Renal Replacement 
Therapy Sedated and/or on neuromuscular blocking agents].  
4. All patients must be sedated before and during the time of SSEP recording. If clinically 
indicated, neuromuscular blocking agents may also be used. 
5. All patients must be on targeted temperature management as per Derriford ICU policy and 
protocol: For the first 24 hours after ICU admission, the target-temperature is 36°C with 
temperature control commencing within the first hour after critical care admission. For the 

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next 48 hours the temperature of the patients will be maintained between 36-37°C. The 
aforementioned temperature targets are achieved with external cooling devices. 
6. Patients must have a CT scan of the head if severe cerebral pathology which is part of the 
exclusion criteria is clinically suspected. 
7. Absence of all exclusion criteria 
 
4.4 
EXCLUSION CRITERIA 
1. Non-comatose patients after ROSC  
2. Coma secondary to Intracranial and Intracerebral haemorrhage  
3. Patients with haemorrhagic shock 
4. Patients with severe neurologic disability [CPC level higher than 2] during the pre-cardiac 
arrest period  
5. Presence of active Demyelinating disease or past medical history of Demyelinating disease 
6. Trauma-induced Cardiac arrest 
7. Previously or during the current admission diagnosed Spinal Cord and /or brain stem lesions   
8. Patients with Implantable defibrillator device [incompatibility with SSEP recordings device] 
 
4.5 
WITHDRAWAL CRITERIA 
1. If during the analysis of the results will become evident that any of the exclusion criteria was 
present but not diagnosed during the time of enrolment  
2. Decision of the patient-participant or their next of kin [who have initially consented] to 
withdraw from the study. All participants should be considered free to withdraw at any time 
from the study without giving reasons and without prejudicing further treatment 
3. Patients that were lost during the follow up period 
4. Patients that died within the first 24 hours 
5. Patients that were transferred to other hospitals within the first 24 hours 
6. Technical Error during recording of N20 and P25/30 SSEPs  
7. Recordings of poor quality that it is not possible to be reliably interpreted  
 
5. 
ADVERSE EVENTS 
There are no active interventions to the patients during the conduction of this study  
Therefore there is no potential for any adverse events to the patients associated with the conduction 
of the study 
The conduction of the study will not have any effect on the clinical decision-making by the responsible 
clinicians for the participants and it will not have any effect on the treatment of the participants.   

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What is analysed during the study is the recorded Somatosensory Evoked Potentials. Apart from the 
N20 Somatosensory Evoked Potential that is analysed during that clinical test we will further analyse 
the recordings with regards to the presence or absence of P25/30 Somatosensory Evoked Potentials. 
The Physicians responsible for the treatment of the patient will not become aware about the 
presence or absence of P25/30 SSEPs at any point of patient’s care. The care physicians will continue 
to become aware about the results of N20 SSEP as currently.  
The neurophysiology scientists who will interpret the recordings will not become aware about the 
patients’ clinical data at any point of the study. 
 
6. 
ASSESSMENT AND FOLLOW-UP  
After the SSEP recording has been conducted, between 24 and 36 hours post ROSC, the patients will 
be followed up by members of the study team. Those members of the team will assess the patients, 
by CPC and by performing full neurologic clinical examination, on the day of ICU discharge and on the 
day of their discharge from Derriford Hospital.  The online system SALUS of Derriford hospital will be 
used to follow up the patients after their discharge from ICU and before their discharge from the 
hospital. Through SALUS system, the members of the study team responsible for the patients follow 
up will be notified for the planned patients’ discharge date in order the patients to be assessed by a 
study team member before they leave the hospital. The neurologic outcome, assessed with the 
Cerebral Performance Category [see figure 1 on the Appendix], will be recorded on the day of Hospital 
discharge [within the last 24 hours before discharge].  
If a study participant died on ICU as a result of severe brain dysfunction or after the decision of ICU 
Consultant to be withdrawn from invasive organ support due to extremely poor prognosis and futility 
of further continuation of treatment, then, the discharge CPC would be the most recently recorded, 
after the patient have remained consistently off sedation [for a period of time varied for different 
sedatives or combination of sedatives].  
Specifically, in a case that the ICU Consultant in charge considered withdrawing the invasive organ 
support in one of the study participants due to extremely poor prognosis, then the ICU consultant 
should notify the ICU research nurse in order one member of the team to perform the CPC score 
recording. The assessment by CPC must always take place before the decision for withdrawal of 
treatment is implemented and strictly before the palliative pathway is initiated. If the study team 
members failed to be notified by the ICU consultant about the withdrawal of treatment and the 
Palliative pathway is initiated before patient’s CPC and neurologic examination recorded then the 
patient will be excluded from the study.     
If a participant died unexpectedly from another cause rather than severe brain dysfunction and / or 
withdrawal of invasive organ support, then the most recent CPC before death [if possible to be 
recorded] will be based on the last available clinical assessment off sedation and will be considered as 

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indicative of neurologic outcome for the patients. In case the CPC could not be assessed, the patient 
would be excluded from the study analysis. 
If patients die on ICU while still on sedation and before being possible to assess their CPC then they 
will be excluded from the study analysis as the assessment of their outcome based on CPC will not be 
possible.  
The end of the study for each of the patients-participants will be either the discharge from hospital or 
their death at any time after the SSEP recording. 
 
 
7. 
STATISTICS AND DATA ANALYSIS  
7.1 
DESCRIPTION OF STATISTICAL METHODS 
Demographic information of participants will be summarized using descriptive statistics and 
presented in tables to provide an exploratory overview of the study population.  
Continuous measures will be summarised as means, standard deviations and ranges where the 
distribution appears normal, and as medians, inter-quartile ranges and ranges otherwise.  
Categorical data will be summarised by frequencies and percentages.  
The primary outcome measure is the CPC score at hospital discharge with discrete values ranging 
from 1 to 5. The score will be dichotomised as 1-2 (positive or good outcome) and 3-5 (negative or 
poor outcome).  
Sensitivity, specificity and predictive values of P25/30 in predicting poor outcome will be computed 
and the results compared to that of N20. Where appropriate, parameter estimates will be presented 
with 95% confidence intervals. Significant demographic and clinical predictors of poor neurological 
outcomes will be assessed and identified using regression models.  
Statistical data analysis will be undertaken once data collection from the required number of 
participants is completed. No interim analysis is scheduled for this study.  
Analyses will be performed in SPSS version 24 (or later), supplemented where required by Stata SE 
version 14.2 (or later) and R. 
 
a. THE NUMBER OF PARTICIPANTS 
Sample size calculation was based on diagnostic test accuracy (adequate sensitivity) of P25/30. A 
previous study (Kim et al. 2018) on patients treated by hypothermic targeted temperature 
management showed that the sensitivity of P25/30 in predicting poor outcome is 90.12% (95% CI, 
81.5–95.6%). Though the proposed study will be based on those who are not treated by hypothermic 
targeted temperature management, the result (90%) is the ‘best’ available information regarding pre-
determined sensitivity of P25/30. From experience of the team and analysis of the past three-years 

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pilot data, the prevalence of poor outcome was assumed to be 75%. In order the maximum marginal 
error of estimate does not exceed from 5% with 95% confidence level, and adjusting for drop-out/lack 
of consent at 3%, the minimum required sample size will be 115. No power was assumed in the 
calculation of the sample size as there is no testing of hypothesis.  
7.3 
THE LEVEL OF STATISTICAL SIGNIFICANCE 
Whenever applicable, a 5% level of significance will be used.  
7.4 
CRITERIA FOR THE TERMINATION OF THE TRIAL. 
As this is not an interventional study, the chance to terminate the trial is minimal. 
7.5 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, AND SPURIOUS DATA. 
Spurious and/or missing data will be summarised and reasons for missingness given where possible.  
All data analyses will be based on the complete data only. 
7.6 
PROCEDURES FOR REPORTING ANY DEVIATION(S) FROM THE ORIGINAL STATISTICAL PLAN 
Statistical analysis of the data will be performed at the end of the study as per Section 7.1 above. If 
deemed necessary, a separate statistical analysis plan (SAP) can be prepared prior to the completion 
of the study and approved by the oversight committee. The study team will discuss any deviation 
from the analysis plan and report it to the oversight committee.  Any revisions to the SAP will be 
documented, including a brief justification and timing of revision.   
7.7 
INCLUSION IN ANALYSIS 
All eligible participants will be included in the analyses.  
8. 
ARCHIVING 
Data and all appropriate documentation will be stored on safe databanks as described [on section 4.1] 
and will be kept for a minimum of 5 years after the completion of the study. After that period of time 
all data will be deleted. Similarly the data will be immediately deleted if any of the study participants 
or their NOK who have provided informed consent to participate in the study decides retrospectively 
to withdraw from the study.    
 
9. 
REGULATORY ISSUES 
9.1 
ETHICS APPROVAL 
The Chief Investigator had applied for approval from the Health Research Authority [HRA] and the 
North West – Haydock Research Ethics Committee. The study has been approved by the HRA and the 
North West – Haydock Research Ethics Committee.  The Investigator will ensure that this study is 
conducted in full conformity with relevant regulations and with UK Policy Framework for Health and 
Social Care Research (2017), which have their basis in the Declaration of Helsinki. 

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9.2 
CONSENT  
Consent to enter the study must be sought from each participant only after a full explanation has 
been given, an information leaflet offered and time allowed for consideration.  Signed participant 
consent should be obtained.  The right of the participant to refuse to participate without giving 
reasons must be respected.  All participants are free to withdraw at any time from the protocol 
treatment without giving reasons and without prejudicing further treatment.  In these cases the 
participants remain within the study for the purposes of follow-up and data analysis. 
However, all the patients enrolled in the study are expected to be in coma at the time of enrolment.  
This is a reality about most of the ICU patients.  Therefore, within the first 24 hours after ICU 
admission, the members of the study group will discuss with the next of kin of the patients regarding 
the potential participation in the study and the informed consent process.  
During this process, the members of the study group will actively listen to the thoughts of the next of 
kin and other family members if available and they will try to provide the maximum information to 
them not only about the study but also about the general potential benefit for the patients by 
research, the importance of the research in modern medicine and specifically in the specialty of 
Intensive Care Medicine where many clinical and prognostic uncertainties still exist.  
The next of kin for each potential participant would be asked to consent for the participation of the 
patients to the study after being fully informed, both verbally and by the provision of the relevant 
relatives’ information booklet that can be found in the appendix of this document.  
Also, with the help of their next of kin for each one of the potential participants – before their 
enrolment in the study – we will explore the potential participants’ likely previously expressed wishes 
or thoughts or opinions about the importance of medical research and the participation in medical 
research for the benefit of the patients.  
If the participants in the study regain full mental capacity to provide informed consent and make 
informed decisions after their enrolment in the study, then they will be fully informed about the study 
by a member of the study group and they will be asked if they agree to continue with their 
participation in the study.  If the participants are happy to remain in the study cohort then their data 
will be used for analysis and publication purposes.  If they decide anytime to withdraw from the study 
then their decision will be respected but it will be explained that that their data already collected may 
still be analysed as part of the study. 
The same options will be available for the next of kin that would have consented initially for the 
participation of patients in the study.  Similarly, if the next of kin at any point before the completion 
of the study decided to withdraw their initial consent, then their decision would be respected but it 
will be explained that that the patients data already collected may still be analysed as part of the 
study. 

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The study group would be responsible to keep each one of the next of kin and/or the patients aware 
about the results of the study and the relevant publications [abstracts in conferences and scientific 
manuscripts in journals].  At that point the study group will invite the next of kin and or the 
participants to provide their constructive feedback about the results of the study and their feelings 
with regards to their participation in this study.  This could be an effective way to maximise the 
participation and involvement of the participants to the research process, from the initial discussion 
and consent to the results of the research study and their feedback.  
Also, that kind of interaction with the next of kin and/or the patients would give the opportunity to 
the members of the study group to actively explore the perspectives of the participants in their study, 
to maximise their experience and ultimately to help them developing their research performance by 
integrating useful learning points from the participants’ constructive feedback to the design and 
practical application of their future research projects.  
The aforementioned process would potentially involve the participants of this study to the dynamic 
development of the research process in general. 
 
9.3 
CONFIDENTIALITY 
The Chief Investigator will preserve the confidentiality of participants taking part in the study and will 
comply with the Data Protection Act (2018). 
 
9.4 
INDEMNITY 
This is an NHS-sponsored research study.  If an individual suffers negligent harm as a result of 
participating in the study, NHS indemnity covers NHS staff and those people responsible for 
conducting the trial who have honorary contracts with the relevant NHS Trust.  In the case of non-
negligent harm, the NHS is unable to agree in advance to pay compensation, but an ex-gratia 
payment may be considered in the event of a claim. 
This study is non-interventional and therefore no risk for potential harm of the participants is 
expected to be associated with this study  
 
9.5 
SPONSOR 
University Hospitals Plymouth NHS Trust will act as the main sponsor for this study.  
 
9.6 
FUNDING 
There is funding from the University Hospitals Plymouth NHS Trust Charitable Funds for £2,300 for the 
cost of statistical analysis. 

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9.7 
AUDITS  
The study may be subject to audit and monitoring by University Hospitals Plymouth NHS Trust under 
their remit as sponsor and other regulatory bodies to ensure adherence to the study protocol and the 
UK Policy Framework for Health and Social Care Research (2017). 
 
10. 
STUDY MANAGEMENT 
The day-to-day management of the study will be co-ordinated through Dr Nikitas Nikitas and Mrs 
Nicola Broomfield, from the departments of Intensive Care Medicine and Neurophysiology, 
respectively. 
 
11. 
PUBLICATION POLICY 
The interim and final results of the study will be disseminated via presentations at appropriate 
scientific meetings and conferences and publication in appropriate peer-reviewed journals. 
The research findings is planned to be disseminated in the following manner: 
a) 
The annual meeting of the Intensive Care Society UK 
b) 
International meetings: European Society of Intensive Care Medicine and International 
Symposium in Intensive Care and Emergency Medicine 
c) 
Publication in a peer reviewed journal. 
d) 
Feeback to study participants 
The study team would be responsible to keep each one of the next of kin and/or the patients aware 
about the results of the study and the relevant publications [abstracts in conferences and scientific 
manuscript in journal].  By submitting a copy of the relevant publication [accompanied by a plain 
English summary/explanation of the results] to each participant and/or their next of kin, the study 
team will invite the next of kin and/or the participants to provide constructive feedback about the 
results of the study and their feelings with regards to their participation in this study.  

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12. 
REFERENCES 
 
(1) Berdowski J, Berg R, Tigjssen J et al. Global incidences of out-of-hospital cardiac arrest and 
survival rates: systematic review of 67prospective studies. Resuscitation 2010; 81:1479-87 
(2) Local Data: Derriford Hospital 01/01/2013- 01/04/2018 
(3) Van Diepen  S, Girotra  S, Abella  B, et al. Multi‐statewide 5‐year initiative to improve care for 
out‐of‐hospital cardiac arrest: primary results from the HeartRescue Project. J Am Heart 
Assoc.2017;6:e005716. DOI: 10.1161/JAHA.117.005716. 
(4) Girotra S, Nallamothu B, Spertus J et al. Trends in Survival after In-Hospital Cardiac Arrest.  N 
Engl J Med 2012; 367:1912-1920.  DOI: 10.1056/NEJMoa1109148 
(5) Paul M, Bougouin W, Geri G et al. Delayed awakening after cardiac arrest: prevalence and risk 
factors in the Parisian registry. Intensive Care 2016; 42:1128-1136 
(6) Martinell L, Nielsen N et al. Early predictors of poor outcome after out-of-hospital cardiac 
arrest. Critical Care 2017 21:96 
(7) Sandori C, Cariou A, Cavallaro F, et al. Prognostication in comatose survivors of cardiac arrest: 
an advisory statement from the European Resuscitation Council and the European Society of 
Intensive Care Medicine. Intensive Care Med 2014; 40: 1816-31 
(8) Kim SW, Oh JS, Park J, Jeong HH et al. Short Latency Positive Peak Following N20 
Somatosensory Evoked potential is Superior to N20 in Predicting neurological outcome after 
out-of 
–hospital 
cardiac 
arrest. 
Crit 
Care 
Medicine 
(Published 
on 
line. 
DOI: 
10.1097/CCM.0000000000003083 

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APPENDIX 
Additional information to the protocol, consisting of: 
• 
Schedule of events table 
• 
Cerebral Performance Category 
• 
Performance status 
• 
Comorbidities score 
• 
Participant/patient information sheet 
 
TABLE 1. 
SUMMARY OF INVESTIGATIONS, TREATMENT AND ASSESSMENTS 
Investigations / Treatments / 
Assessments 
Time performed / recorded 
At enrolment 
[First 24 hours 
post ROSC] 
ICU discharge 
Hospital 
Discharge 
History of Present Complaint and 
Past medical History 
X 
 
 
Neurological examination 
X 
X 
X 
ECG 
X 
 
 
Cardiac arrest Rhythm 
X 
 
 
CXR 
X 
 
 
FBC, Creatinine-U&E, LFT, INR, 
Ammonia [if acute or chronic 
hepatic dysfunction], mean Glucose 
levels, mean Lactate levels 
X 
 
 
Mean SpO2, mean PaO2, mean 
PaCO2 
X 
 
 
Mean HR, mean BP, mean T 
 
 
 
APACHE II score 
X 
 
 
SOFA score 
X 
 
 
Cerebral Performance Category 
 
X 
X 
ECOG / WHO pre-admission 
performance status 
X 
 
 
Charlson Comorbidity Index Scoring 
System 
X 
 
 
Informed consent 
X 
 
 
 

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FIGURE 1. THE CEREBRAL PERFORMANCE CATEGORY SCALE [CPC] 
Cerebral Performance Category [CPC] Scale 
Positive [good] 
Neurologic Outcomes 
CPC 1: Full Recovery or Mild Disability 
CPC 2: Moderate Disability but Independent in Activities of Daily Living 
Negative [poor] 
Neurologic Outcomes 
CPC 3: Severe Disability – Dependent in Activities of Daily Living 
CPC 4: Persistent Vegetative State 
CPC 5: Death 
 
 
 
FIGURE 2. THE ECOG/WHO PERFORMANCE STATUS SCORE 
ECOG/WHO Performance Status score 
Grade 
Performance status 
0 
Fully active, able to carry on all pre-disease 
performance without restriction 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature e.g. light house work, office work 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities. Up and about more than 
50% of waking hours 
3 
Capable of only self-limited care, confined to bed or 
chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self- care. 
Totally confined to bed or chair 
5 
Dead 
 
 
 
 
 
 
 
 

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FIGURE 3. THE CHARLSON COMORBIDITY INDEX SCORING SYSTEM 
Charlson Comorbidity Index Scoring System 
Score 
Condition 
1 
Myocardial infarction [history, not ECG 
changes only] 
Congestive Heart Failure 
Peripheral Vascular Disease [includes aortic 
aneurysm ≥ 6cm] 
Cerebrovascular disease; CVA with mild or no 
residua or TIA 
Dementia 
Chronic Pulmonary Disease 
Connective Tissue Disease 
Peptic Ulcer Disease 
Mild Liver Disease [without portal 
hypertension, includes chronic hepatitis] 
Diabetes without end-organ damage 
[excludes diet-controlled alone] 
2 
Hemiplegia 
Moderate or severe renal disease 
Diabetes with end-organ damage 
[retinopathy, neuropathy, nephropathy, 
brittle diabetes] 
Tumour without metastases [exclude if >5y 
from diagnosis] 
Leukaemia [acute or chronic] 
Lymphoma 
3 
Moderate or severe Liver Disease 
6 
Metastatic Solid Tumour  
AIDS [not just HIV-positive] 
NB. For each decade > 40 years of age, a score of 1 is added to the above score. 
 
Abbreviations: ECG: electrocardiogram, CVA: cerebrovascular accident, TIA: transient ischaemic attack, AIDS: acquired immunodeficiency syndrome, HIV: 
human immunodeficiency virus