Early Neurological Prognostication of Outcome After Out-of-hospital Cardiac arrest-a STEPCARE Prospective Substudy
Conditions: Cardiac Arrest, Neurological Outcome, EEG, CT, Brain Injuries, Biomarkers
Sponsor: Lund University

 
1 
 
EARLY-NEURO substudy manual  
 
Only for sites participating in the early neuroprognostication 
substudy (other sites please use the “Neurological prognostication 
manual”) 
 
Version 1.0 
5th January 2023 

 
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1. The prospective substudy on early neurological prognostication 
 
The STEPCARE trial will perform a substudy on early neurological prognostication aiming to examine 
whether brain injury markers in blood, electroencephalogram (EEG) and head computed tomography 
(CT) can be used for prediction of outcome already at 24 hours post-arrest.  
 
The hypotheses of this substudy are: 
1) The combination of clinical examinations, blood levels of the brain injury marker NFL, EEG and 
CT predict poor outcome already at 24 h post-arrest without false positive predictions. 
2) Any guideline recommended method (clinical examination/EEG/CT/SSEP) fulfilling criteria for 
a poor outcome according to ERC/ESICM, will have highly elevated blood levels of NFL, 
indicating the presence of severe brain injury. 
3) Extensive sedation will not affect the prognostic accuracy of the prognostic methods EEG, CT, 
SSEP and NFL. 
 
 
Which centers will be eligible for participation? 
The EARLY-NEURO substudy will only include selected centers committed to: 
1) Perform mandatory EEG and CT in all unconscious patients as early as possible after 24 h post-
arrest. 
2) Participate in the STEPCARE biomarker substudy. 
3) Export rawdata for central blinded evaluation for EEG (European Data Transfer, EDT), SSEP 
and CT/MRI (DICOM format).  
 
Please note that prediction of patient outcome and decisions on WLST will strictly 
adhere to the ERC/ESICM guidelines and the STEPCARE protocol, regardless of whether 
sites participate in the early neuroprognostication substudy or not. 
 
 
 
Site investigators interested in recruiting their site to the biomarker and/or early prognostication 
substudies please contact Marion Moseby-Knappe (marion.moseby_knappe@med.lu.se) for more 
information. 

 
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2. Introduction 
 
Evaluating interventions that cannot be blinded to the treating clinicians, the STEPCARE trial will 
employ a conservative and strict protocol for neurological prognostication based on the ERC and 
European Society of Intensive Care Medicine recommendations.1, 2  
Regardless of whether sites participate in the EARLY-NEURO substudy; the clinical prediction of 
functional outcome will not be performed prior to 72 hours post-arrest. However, prognostic 
examinations should be performed according to the protocol below to allow for calculation of 
prognostic accuracies at this earlier timepoint.  
Prognostication will be performed on all participants who are not awake and obeying verbal 
commands, and who are still in the ICU at 72 hours after randomization. The clinical examination used 
for prognostication should not be performed earlier than 72h after cardiac arrest but may be delayed 
due to practical reasons (such as weekends or national holiday). Results from additional examinations 
performed <72 h may be included in the assessment if performed according to ERC/ESICM 
recommendations.  
The physician performing the prognostication will be a neurologist, intensivist or other specialist 
experienced in neuroprognostication after cardiac arrest and who has not been involved in patient care 
of this patient. The prognosticator should be blinded for group allocations, but not for relevant clinical 
data. Prognostication will be based on results of clinical examinations, neurophysiology, biomarkers 
of brain injury and imaging (Fig. 1). 
 
 
Fig. 1. Schematic overview of timepoint for prognostic examinations, neurological prognostication and withdrawal 
of life supporting therapies for neurological reasons (WLST-Neuro) in hours after randomization (R) for the 
EARLY-NEURO substudy.  
 
The result of the prognostication will be categorized as “YES” or “NO”, based on the answer to the 
question “Does this patient fulfil the STEPCARE criteria for a likely poor neurological outcome?” 
using the trial checklist provided. This assessment will be documented in the case report form and 
will be communicated to the treating clinician. Results of neurological prognostication and the 
potential decision to withdraw active intensive care are closely related but will be considered separate 
entities. 
R
24h
48h
72h
96h
120h
144h
168h
Daily FOUR-M day 0-7 in unconscious patients
Status myoclonus
*EEG
SSEP
*CT
Neurological prognostication
WLST-Neuro?
Pupillary/corneal reflexes
Mandatory substudy
Optional
*Biobank sample collection
MRI
NSE

 
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Any decision to withdraw active life support will be made by the treating physicians, together with 
the patient’s relatives or legal surrogates, as required by local legislation. In making this decision 
the treating physician may use the information from the prognostication. The blinded external 
physician will not make any recommendation on WLST. Efforts will be made to sufficiently delay 
prognostication to ensure that any lingering effects of sedative agents will not affect the assessment. 

 
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3. 
Clinical neurological examinations 
 
A clinical neurological exam is mandatory and should include: 
• 
Daily assessment of the best motor response according to the Full Outline of 
UnResponsiveness (FOUR)-M-score3 recorded daily until day 7 in the ICU (Fig. 2).  
• 
Daily assessment of status myoclonus (continuous and generalized myoclonus persisting for 
at least 30 min) until day 7 in the ICU.  
• 
The presence or absence of pupillary AND corneal reflexes at hospital admission, at 24 h and 
if applicable, at the time-point of neurological prognostication. 
 
Absent, extensor or flexion motor response to pain (FOUR- score motor response 0-2) at 72 h or later 
in a patient who is considered unaffected by sedative agents, will be a prerequisite to consider the 
neurologic prognosis poor. Bilateral absence of pupillary and corneal reflexes at 72h after 
randomization or later and or the presence of an early status myoclonus (within 72 h) are criteria 
indicative of a poor prognosis. 
 
 
 
Fig. 2. Instructions for clinical examination of the FOUR Motor response. Grade the best possible response of the 
arms. A score of M4 indicates that the patient demonstrated at least 1 of 3 hand positions (thumbs-up, fist or peace 
sign) with either hand. A score of M3 indicates that the patient touched the examiner´s hand after a painful 
stimulus compressing the temporomandibular joint or supraorbital nerve (localization). A score of M2 indicates 
any flexion movement of the upper limbs. A score of M1 indicates extensor posturing. A score of M0 indicated no 
motor response or myoclonus status epilepticus.3 
 
 
 
 
 
Wijdicks E. et al. Validation of a new Coma Scale: the FOUR 
score, Annals of Neurology 2005, 58:585-593. 
Motor Response
4 Thumbs up, fist, or peace 
sign to command
3 Localizing to pain
2 Flexion response to pain
1 Extensor posturing
0 No response to pain or 
generalized myoclonus status 
epilepticus

 
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4. 
Additional prognostic examinations 
 
 
Prognostication should always be multimodal and include ≥2 prognostic methods as recommended 
by the ERC/ESICM guidelines.1, 2  
• 
For sites within the EARLY-NEURO substudy, a CT and an EEG from 24 h post-
randomization is mandatory in patients still unconscious (not awake and obeying verbal 
commands). 
• 
Blood samples for the biomarker substudy are mandatory and are collected at 12, 24, 48 and 
72 h after randomization. Samples will be stored in a central biobank and since analyses are 
performed after trial completion, these biomarker results will not be available during 
neurological prognostication.   
• 
The choice of additional prognostic examinations are at the discretion of the treating 
physicians.  
 
4.1 EEG  
 
An EEG as early as possible ≥24 h after randomization is mandatory for substudy patients. Either 
a full-montage and/or simplified continuous EEG-monitoring may be used for this purpose. Results of 
EEG examinations will be reported in the eCRF.   
 
An EEG with a “highly malignant pattern” defined using the terminology of the American Clinical 
Neurophysiology Society, and without reactivity to sound and pain is indicative of a poor prognosis if 
lingering effects of sedation are ruled out.4-6  
 
Highly malignant EEG patterns are: 
• 
burst suppression (amplitudes <10µV constituting >50% of the recording) with or without 
superimposed discharges. 
• 
suppression (amplitudes <10µV during the entirety of the recording) with or without 
discharges. 
 
EEG-reactivity should be tested at least 2 times with an interval of more than 20 seconds in all 
patients and include the following: 
• 
Sound stimulations - Call the patient’s name, clapping hands for a few seconds. Should be 
repeated at least 2 times with an interval of more than 20 seconds. 
• 
Pain stimulations - Recommended to include at least one proximal stimulation (i.e. sternal 
rubbing, jaw compression or squeezing of trapezius/deltoid).  
• 
EEG-reactivity may include a change in amplitude or frequency, including attenuation of 
activity. Appearance of muscle activity or eye blink artefacts or SIRPIDs (Stimuli Induced 
Rhythmic, Periodic or Ictal Discharges) do not qualify as EEG-reactivity.  
 
4.2 Brain CT  
 
A brain computed tomography (CT) is mandatory for unconscious patients ≥24 h after 
randomization within the EARLY-NEURO substudy.  
 
If a brain-CT shows signs of severe hypoxic ischemic injury, such as: generalized oedema with reduced 
grey/white matter differentiation and sulcal effacement, this is indicative of a poor prognosis, 
regardless of the time-point of examination.7, 8  
 
 
4.3 Brain MRI  
 
A brain magnetic resonance imaging (MRI) may be incorporated into prognostication if it has been 
performed. Signs of diffuse and extensive hypoxic injury on MRI is indicative of a poor prognosis at 
2-5 days post-arrest.1, 2  

 
7 
 
4.4 
Neuron specific enolase 
 
High serial blood levels of NSE (> 60 ng/mL at 48 h and/or 72 h) are indicative of a poor prognosis.1, 
2 Hemolysis, malignancies, and other intracranial pathologies are potential confounders and should 
be excluded.  
 
 
4.5 
SSEP  
 
Somatosensory evoked potentials (SSEP) N20-responses may be used for prognostication if the 
technical quality is adequate. Absent SSEP N20-responses bilaterally ≥24 h are indicative of a poor 
prognosis.1, 2 
 
 

 
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5 
Trial criteria for a likely poor neurological outcome 
 
In the trial the prognosis is considered likely poor if criteria A, B and C are all fulfilled (Fig. 3):  
A. Confounding factors such as severe metabolic derangement and lingering sedation has been 
ruled out. The ERC/ESICM recommend awaiting 5 half-lives of the sedative with the longest 
half-life prior to clinical evaluation.1, 2  
B. The patient has no response, a stereotypic extensor response or a stereotypic flexor response 
(FOUR-M ≤2) to bilateral central and peripheral painful stimulation at ≥ 72 h after 
randomization.  
C. At least two of the below mentioned signs of a poor prognosis are present:  
C1. Bilateral absence of pupillary AND corneal reflexes at 72 h after randomization or later 
C2. Bilaterally absent SSEP N20-responses more than 24 h post-randomization.  
C3. A highly malignant EEG-pattern ≥24 h without reactivity to sound and painful 
stimulation without lingering effects of sedation.  
C4. Serial blood-NSE above >60 ng/mL at 48 h and/or 72 h without hemolysis or malignancies 
as potential confounders. 
C5. A documented early generalized status myoclonus within 72 h. 
C6. Neuroimaging (CT at any time or MRI 2-5 days post-arrest) with signs of diffuse and 
extensive hypoxic injury. 
 
 
Fig. 3. STEPCARE criteria for a “poor outcome likely” adapted from the ERC/ESICM guideline algorithm.1, 2 
 
Note: Participants with suspected ongoing status myoclonus at the time of assessment should still be 
assessed for a response to pain. An increase in the frequency or amplitude of myoclonic jerks when a 
painful stimulus is applied should not be considered as a motor response. If the participant localizes to 
pain or EEG-background is continuous, the prognosis should not be stated as "poor outcome likely", as 
this state may be compatible with a diagnosis of Lance-Adams syndrome. 
A
B
C
Level of consciousness?
Confounding factors?
Poor outcome criteria
Unconscious patient, 
FOUR-M≤2 at ≥72h without confounders

 
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6 
Withdrawal of life supporting therapies (WLST) 
 
All participants in the trial will be actively treated until 72 hours after randomization. There will 
be two exceptions from this rule. 
1. 
Participants in whom further treatment is considered unethical due to irreversible organ 
failure; or, following inclusion in the trial, information becomes available such as an 
advanced medical comorbidity (e.g., generalized malignant disease) or a pre-existing 
Advance Care Directive that prohibits treatment. 
2. Participants in whom brain death is established according to local legislation, however 
this will be defined as death and not WLST. We recommend that the clinical diagnosis of 
brain death should be avoided during the first 24 hours after ROSC and be supported by 
radiological evidence of herniation and loss of intracerebral blood-flow when there is any 
doubt about the diagnosis. 
 
The assumption of a poor neurological prognosis alone will not be considered sufficient to employ 
withdrawal of active intensive care prior to 72 hours after randomization. After prognostication has 
been performed, WLST due to a presumed poor prognosis will be allowed as per the treating clinician 
if the STEPCARE criteria for a likely poor neurological outcome are fulfilled. 
 
Participants who have an unclear prognosis at 72 h after randomization should be reexamined daily 
and WLST may be considered if neurological function does not improve and, metabolic and 
pharmacological reasons for prolonged unconsciousness are ruled out. If a decision of WLST is made, 
the time point and the main reasons for withdrawing life-supporting therapies will be documented. 
However, supporting therapy may also be continued regardless of the neurological assessment of 
prognosis, at the discretion of the treating physician. 
 
 
 
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Brain death 
 
Participants in whom brain death is established will be registered as dead when a conclusive 
assessment, based on national criteria, has been made. If death is due to brain death this will be 
registered. 
 
 
 

 
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References 
1. 
Nolan JP, Sandroni C, Bottiger BW, et al. European Resuscitation Council and European 
Society of Intensive Care Medicine Guidelines 2021: Post-resuscitation care. Resuscitation 
2021;161:220-269. 
2. 
Nolan JP, Sandroni C, Bottiger BW, et al. European Resuscitation Council and European 
Society of Intensive Care Medicine guidelines 2021: post-resuscitation care. Intensive Care Med 
2021;47:369-421. 
3. 
Wijdicks EF, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new 
coma scale: The FOUR score. Annals of neurology 2005;58:585-593. 
4. 
Backman S, Cronberg T, Friberg H, et al. Highly malignant routine EEG predicts poor 
prognosis after cardiac arrest in the Target Temperature Management trial. Resuscitation 
2018;131:24-28. 
5. 
Westhall E, Rossetti AO, van Rootselaar AF, et al. Standardized EEG interpretation accurately 
predicts prognosis after cardiac arrest. Neurology 2016;86:1482-1490. 
6. 
Hirsch LJ, Fong MWK, Leitinger M, et al. American Clinical Neurophysiology Society's 
Standardized Critical Care EEG Terminology: 2021 Version. J Clin Neurophysiol 2021;38:1-29. 
7. 
Lang M, Nielsen N, Ullen S, et al. A pilot study of methods for prediction of poor outcome by 
head computed tomography after cardiac arrest. Resuscitation 2022;179:61-70. 
8. 
Streitberger KJ, Endisch C, Ploner CJ, et al. Timing of brain computed tomography and 
accuracy of outcome prediction after cardiac arrest. Resuscitation 2019;145:8-14.