Multicenter Validation of the Scandinavian Guidelines for Management of Minimal, Mild and Moderate Head Injury in Adults: a Study Protocol.
Conditions: Traumatic Brain Injury
Sponsor: Halmstad County Hospital

 
 
 
 
 
 
 
 
 
Multicenter validation of the Scandinavian Guidelines for management of 
minimal, mild and moderate head injury in adults: a study protocol. 
 
 
Principal investigator: 
 
Olga Calcagnile, MD, PhD 
Pediatric department, Halland Hospital Halmstad 
 
Date of protocol: 30th of august 2017 
 
 

Multicenter validation of the Scandinavian Guidelines for management of 
minimal, mild and moderate head injury in adults: a study protocol. 
 
 
 
Introduction 
 
Traumatic brain injuries (TBI) are one of the most common reasons for patients to attend the 
emergency department (ED) with an estimated incidence in Europe of 260 per 100 000 for 
admitted TBI1,2,3. Approximately 90% of patients with TBI are defined as mild TBI (mTBI)4. 
These patients have a normal or minimally altered level of consciousness and Glasgow Coma 
Scale (GCS) 13 to 15 when attending the ED.  
A small minority of patients with mTBI would show pathological results, such as intracranial 
hemorrhages or cerebral contusions on a computed tomography (CT), and even fewer need 
neurosurgical intervention5. Nevertheless, complications would be so severe, if neurosurgical 
intervention is delayed, that it has become common practice to subject all patients with mTBI 
to CT6. The high number of CT scans has an impact on health care resources but may also 
involve risk by subjecting patients through potentially harmful ionizing radiations7.  
 
In the past years, several independent research groups have attempted to optimize CT use in 
mTBI patients by forming guidelines that aim to identify patients at high risk for intracranial 
complications8. Most guidelines have been published in the past 15 years and have been 
validated both prospectively internally and externally; all guidelines have been shown to be 
safe when implemented in clinical use with few missed complications. However the number 
of CT scans has not been reduced dramatically, in some cases it has even increased9. 
 
In 2013, the new Scandinavian guidelines (SNC13) were published. They are the first 
guidelines that use a biomarker, S100B, as a tool for managing patients with mTBI. Although 
S100B has a low specificity for intracranial complications, a high sensitivity makes it suitable 
to be implemented into clinical practice as a tool for CT reduction. 
Previous SNC guidelines have been compared to other prominent guidelines with impressive 
results10. The SNC13 have been externally validated in a retrospective multicenter center 
study from the USA that was underpowered for important outcomes 11. Nevertheless, SNC13 
have already been partially implemented in clinical practice in Scandinavia. However, a strict 

multicenter validation has not been performed yet nor a systematic comparison to other 
available guidelines. 
Aims 
Our primary aim is to validate the performance of the SNC13 in predicting intracranial 
complications in adult patients presenting with traumatic head injury in Swedish hospitals. A 
secondary aim is to compare the performance of SNC 13 with 6 other clinical guidelines, with 
respect to important outcomes. Moreover, we want to explore the performances of different 
biomarkers in predicting intracranial complications in predefined subgroups of TBI. Finally, 
we want to evaluate the possibility of further improvement of the SNC13 guidelines. 
 
Methods 
 
Design 
We will perform a prospective, multicenter, pragmatic, observational study of adults 
presenting with traumatic head injury at the ED.  
All data necessary for analysis including predictor variables and outcome data for all the 
seven guidelines included in the study will be registered (table 1). Patients will be managed 
clinically accordingly to the judgment of the responsible physician and/or local guidelines.  
Study setting and population 
The study will be set in Halmstad, Malmö, Lund, Örebro and Linköping, Sweden. Hallands 
Hospital Halmstad (HS) is a level II trauma centre, Skåne University Hospital in Malmö and 
Lund (SUS), Örebro University Hospital, Linköping University Hospital are level I trauma 
centers. 
The coordinating site for the study will be HS where the statistical and the comparative 
biomarker analysis will be performed. 
Inclusion criteria 
From September 2017 we will prospectively enroll all adult patients with a GCS 9-15 that 
seek the ED within 24h after TBI.  
Exclusion criteria  
We will exclude: 
- patients younger than 18 years of age;  
- patients without a Swedish personal identification number due to difficulties in performing 
the follow up phase;  

- all patients that refuse to participate.  
 
Primary endpoint 
The primary endpoint for this study will be the sensitivity, specificity, predictive values and 
likelihood ratios for the SNC13 for identifying traumatic intracranial complications.  
Definition 
Traumatic intracranial complications are defined as a composite variable of death as 
consequence of the TBI, need for neurosurgical intervention or marked abnormality on CT. 
CT abnormalities are defined as any new, acute, traumatic intracranial pathology including 
intracranial hematomas of any size, cerebral contusions and depressed skull fractures.  
Secondary endpoints 
- 
Measure the sensitivity, specificity, predictive values and likelihood ratios for the 
SNC13 for identifying patients needing neurosurgery or neurointensive care for the 
TBI within the first week following trauma.   
- 
Measure the sensitivity, specificity, predictive values and likelihood ratios for the 
SNC13 for identifying patients with new, acute, traumatic intracranial pathology on 
CT including intracranial hematomas of any size, cerebral contusions and depressed 
skull fractures. 
- 
Measure the sensitivity, specificity, predictive values and likelihood ratios for the 
SNC13 for identifying patients with clinically relevant CT findings (according to the 
CCHR) 12, defined as contusions larger than 5mm in diameter, subarachnoid bleeding 
thicker than 1mm, subdural hematoma thicker than 4mm, pneumocephaly that will 
need intervention, depressed skull fracture through the inner table. 
- 
We will calculate sensitivity, specificity, predictive values and likelihood ratios of 
each guideline in identifying traumatic intracranial CT finding when applied to the 
same TBI population. We will also measure frequency of CT scans. We will 
investigate the performance of the SNC13 in comparison to other guidelines in 
reducing CT frequency without missing complications. We hypothesize that the 
implementation of a biomarker as S100B into clinical guidelines will achieve a further 
reduction in CT scans. Accuracy variables will be statistically compared with Chi-
squared test. 
- 
Measure performances of novel biomarkers such as GFAP, SBP-50 and TAU. S100B 
is the most studied brain biomarker and is the only one that is clinically used as a 
screening tool. However, S100B is not the perfect brain biomarker for TBI and new 

biomarkers appear promising. In a explorative analysis we will compare S100B with 
GFAP, SBP-50 and TAU on the same selected mTBI population in order to determine 
the potential value of a panel of biomarkers for identifying high and low risk patients. 
We will calculate sensitivity, specificity, predictive values and likelihood ratios of 
each biomarker in identifying traumatic intracranial CT finding when applied to the 
same TBI population. ROC curves will be calculated in order to compare cut off 
values. We will also use the net reclassification index to see if each biomarker 
improves the accuracy of the classification. 
- 
The final aspect that we would like to study is the derivation of a new improved 
guideline: binary logistic regressions analysis of all the variables taken into account 
and registered during the study will be performed. We will a priori divide the 
population into a derivation cohort, obtain ROC curves, and use these cutoffs after the 
bootstrapping process and other clinical and biochemical variables to construct a mode 
losing multivariable analysis. 
 
Guidelines 
A secondary goal of the study is to compare how the same mTBI population would be 
managed according to 7 guidelines that are clinically used in this particular patient group; we 
included the Canadian CT Head Rule13 (CCHR), the New Orleans criteria14 (NOC), the 
National Institute of Clinical Excellence15 (NICE), the CT in head injury patients Prediction 
Rule16 (CHIP) , the Neurotraumatology Committee of the World Federation of Neurosurgical 
Society17 (NCWFNS), the National Emergency X-Radiography Utilization Study II18 
(NEXUS-II) and the SNC 201319. 
Each guideline has specific inclusion and exclusion criteria, and outcome measures, see table 
2.  
For each guideline patients will be divided into different groups: those who should be 
dismissed without a CT, those who should do a CT and those who do not fit the inclusion 
criteria for the guideline. A comparison of the 7 guidelines is shown in table 3.  
The CCHR includes only patients with GCS 13-15 that have suffered LOC, have amnesia for 
trauma or are disoriented. Patients are divided into a high risk group, where CT is mandatory 
because of elevated risk for neurosurgical intervention, and medium risk for CT 
complications, in which case CT is only recommended. Both groups are analyzed 
independently but reported together for the group where CT scan should be performed. The 
CCHR primary outcome measure is the need for neurological intervention and the secondary 

outcome is clinically relevant brain injury on CT. Clinically relevant CT findings are defined 
as contusions larger than 5mm in diameter, subarachnoid bleeding thicker than 1mm, subdural 
hematoma thicker than 4mm, pneumocephaly that will need intervention, depressed skull 
fracture through the inner table. 
The NOC includes only patients with GCS of 15, thus according to these guidelines patients 
with GCS 14 or less were considered to have an indication for CT20. The NOC outcome 
measure is any acute traumatic intracranial lesion on CT. 
The NICE guidelines stratify patients that are eligible for CT into two groups, those who 
should undergo a CT within 1 hour and those within 8 hours. Both groups are analyzed 
independently but reported together for the group where CT scan should be performed.  
The CHIP prediction rule does not have strict inclusion criteria, and recommends CT in the 
presence of one major or at least 2 minor risk factors. Both groups are analyzed independently 
but reported together for the group where CT scan should be performed. The CHIP primary 
outcome measure is any intracranial traumatic finding on CT, secondary outcome is all 
neurosurgical intervention after the initial CT. 
The NCWFNS guidelines identify three levels of risk for intracranial complications. Low risk 
patients can be dismissed without any further investigation while patients with medium and 
high risk should have a CT scan and therefore are analyzed together. 
NEXUS II does not stratify patients or take into account injury mechanism, it focuses mostly 
on symptoms at presentation at ED. The NEXUS II outcome measure is any intracranial 
injury on CT. 
The SNC13 guidelines include all patients with head injury within 24h and a GCS 9-13. 
Patients with mild head injury are divided into high risk, medium risk or low risk for 
intracranial complications. Low risk patients (GCS 14 or GCS 15 and LOC or repeated 
vomiting) with normal S100B can be dismissed directly. The SNC13 primary outcome is the 
need for any neurosurgical intervention. The secondary outcome measures are identification 
of non-neurosurgical intracranial traumatic complications. 
 
Data registration and follow-up 
Details of how patients are managed, including patient characteristics, injury type, patient 
history, clinical examination results, current medications and CT findings will be documented 
in a pre-determined case-report form by the triage nurse and/or physician on call. 
All patients will be asked to answer a questionnaire sent by mail 3 months after the injury. 
The questionnaire will be re-sent if no answer is received. If no answer is received from these 

attempts, patients will be contacted via telephone. The questionnaire includes questions that 
would identify a significant intracranial lesion, data concerning sick-days, new contacts with 
medical professionals and information concerning quality of life. In cases where patients can 
not be reached by mail or telephone, medical records and national mortality databases will be 
consulted for evidence of complications and/or death. The Swedish health care system allows 
full visibility of data for persons with a Swedish personal identification number for medical 
records and mortality database over the whole country. Patients who suffer significant 
(enough to seek medical care) intracranial complications after discharge would therefore be 
identified. 
Details on study period are specified on figure 1 with an algorithm for patient eligibility and 
data analysis. 
Data will be registered in an Excel® file. Descriptive statistics will be analysed using IBM 
SPSS® Statistics Version 20 software.  
S100B analysis 
A 5ml blood sample is drawn from patient's cubital vein in the ED. Samples are analysed with 
the fully automated Elecsys® S100 (Roche AB) at the Clinical Chemistry Department of HS, 
SUS, Örebro University Hospital and Linköping University Hospital, Sweden. Cut-off level 
for normal levels of S100B according to the SNC guidelines is less than 0.10μg/L and a 
window of sampling of within 6 hours from the time of the injury. 
From all patients seeking care within 24h form injury with medium and low risk TBI, 
according to SNC13 (including multitrauma patients), a 5ml blood sample will be drawn, 
centrifuged and frozen at -70 degrees Celsius. Samplings will be coded and registered for 
analysis of GFAP, SBP-50 and TAU. 
CT examinations 
CT scans are always analysed by a board certified radiologist. 
 
Sample size 
We assume that the Scandinavian guidelines will recommend discharge (i.e. neither CT nor 
admission) in approximately 50% of patients and a prevalence of our primary outcome of 5% 
(from our own observations and from data derived from a pre-selected cohort)21. Allowing for 
one missed case, a sensitivity of >99% with a lower 95% confidence interval, a sample size of 
2490 patients is required to detect traumatic intracranial complications according to the 
SNC13. Allowing for a 10% lost to follow-up, our desired sample size is 2767 patients. 
Interim analysis 

After 1000 patients we will measure prevalence for the primary outcome in order to be able to 
reevaluate sample size. 
 
Ethics 
Ethical approval was granted from the Regional Ethical Review Board of Lund (approval 
number 2012/574). 
Informed verbal consent will be obtained and registered by nurses responsible for triage at 
ED.  
Patients’ data and social security number will be stored and handled accordingly to Swedish 
Personal Data Act, (PUL 1998: 204). 
Written consent will be obtained from all patients from whom the extra blood sampling for 
biomarker analysis will be requested. Sampling will be coded and patients will be able at any 
time to refuse to be part of the study. 
 
 
Discussion 
The main purpose of this study is to perform a prospective validation of the new SNC13 
guidelines. The external validation already performed has the limitation of being applied to a 
preselected population; nevertheless it showed that the SNC13 have a potential impact for 
reducing frequency of CT scans22. In order to complement the previous study we designed 
this multicenter prospective study that will collect enough data to support the safety and 
efficacy of the SNC13. The study is pragmatic in nature, including all adult patients with GCS 
9-13 within 24h of head injury, with very few exclusion criteria. 
The second important aim was to compare the SNC13 to the other 6 guidelines. Different 
guidelines applied to the same population will perform with very different results, as previous 
studies have already shown23,24. The first aspect to be discussed in this comparative work is 
how many patients of this TBI population could be managed according to different guidelines. 
Both NOC, NICE and CCRH guidelines have strict inclusion criteria that may exclude a 
substantial portion of the TBI patients leaving physicians with no other choice than CT. 
Nevertheless, more flexible guidelines with no exclusion criteria like CHIP prediction rule or 
the NCWFNS guidelines have been proven to only marginally reduce the number of CTs. 
Nevertheless, beside restricted inclusion criteria, the NICE guidelines have shown to be one 
of the better performing guidelines for reducing CT frequancy23.  

In the SNC13 guidelines, all patients could be managed with no exclusion criteria pre-defined, 
except for the time frame of 24h. According to previous studies, we would have expected a 
S100B negative rate for about 30% of sampled patients but, considering the new grading of 
patients, we expect better performances. 
S100B is not the perfect biomarker for mTBI considering its low specificity. The perfect 
biomarker should be able to be brain specific, easily detectable, have a high sensitivity for 
intracranial complications and adverse outcome, with 100% negative predictive value and 
high clinical specificity. In recent years researchers agree on the possibility of defining a brain 
biomarker-panel; it therefore is fundamental to compare a well-studied biomarker as S100B 
with other new biomarkers. . The present study includes the most promising of these. 
Strength and limitations  
The main strength of this study is its design being an adequately powered multicenter study. 
Another important aspect is that it tests the SCN13 in the health care system for which it was 
intended for.  
However every study has its limitation: a proper validation should be performed with a 
randomized study design; however this method would be ethically questionable. 
The SNC13 were designed primarily for the Scandinavian health care system and its validity 
outside Scandinavia cannot be assumed. 
Biomarker analysis will only be performed in a pre-defined subgroup of patients. This could 
lead to selection bias; however, the remaining patients do not have any theoretical advantage 
in management with biomarker results.   
 
 

Variable 
Data Format 
Demografic/anamnestic variables 
 
Age 
Years (continuous) 
Gender 
Male/female 
Cause of injury 
Patient report 
Pedestrian/cyclist versus vehicle 
Yes/no 
Ejected from vehicle 
Yes/no 
Fall 
Yes/no 
Fall >1m 
Yes/no 
Signs of skull fracture 
Yes/no 
Contusion of the skull 
Yes/no 
Fracture above clavicles 
Yes/no 
Alcohol/drug intoxication 
Yes/no 
Ethanol levels 
mmol/l (continuous) 
LOC* 
Yes/no 
Duration LOC 
Minutes (continuous) 
Amnesia 
Yes/no 
Duration Amnesia 
Minutes (continuous) 
Persistent anterograd amnesia 
Yes/no 
Headache 
Yes/no 
Worsening headache 
Yes/no 
Vomiting episodes 
Number (continuous) 
Neurological deficit 
Yes/no 
Pretraumatic seizure 
Yes/no 
Posttraumatic seizure 
Yes/no 
GCS 
Number (continuous) 
GCS deterioration** 
Number (continuous) 
Antiplatlet medication 
Yes/no 
Anticoagulation therapy 
Yes/no 
Drug registration 
Drug name 
Bleeding disorder 
Yes/no 
Shunt-treatment 
Yes/no 
 
 
Dismissed*** 
Yes/no 
S100B 
μg/L (continuous) 
CT 
Yes/no 
Admitted 
Yes/no 
Other causes to admission than TBI 
Yes/no 
Length of admission 
Days (continuous) 
Complications during admission 
Yes/no 
 
 
 
 
 
 
* LOC= loss of conciousness 
** deterioration of GCS 2 after injury 
*** dismissed with no intervention (CT or 
admission) 
 
Table 1. variables studied 
 
 

 
CCHR 
NOC 
NICE 
CHIP 
NCWFNS 
NEXUS II 
SNC13 
Inclusion 
criteria 
Age ≥ 16 
 
Presenting within 24h 
of head injury 
Age ≥ 18 
 
Presenting 
within 24h 
of head 
injury 
 
GCS 15 
Age ≥ 18 
 
Age ≥ 16 
 
Presenting 
within 24h of 
head injury 
 
 
GCS 13-14 or 
GCS 15 and 
LOC or 
amnesia or 
pst-traumatic 
seizure or 
vomiting or 
severe 
headache or 
alcohol/drug 
intoxication or 
coagulopathy/ 
oral 
anticoagulants 
or injury 
above the 
clavicle or 
neurological 
deficit 
Age ≥ 18 
 
Presenting 
within 12h 
of head 
injury 
 
GCS 14-15 
Age ≥ 18 
 
 
 
 
 
 
GCS 15 
Age ≥ 18 
 
Presenting 
within 24h of 
head injury 
 
GCS 9-15 
Exclusion 
criteria  
-No clear history of 
trauma as primary 
event 
-Penetrating skull 
injury or depressed 
fracture 
-bleeding disorder or 
oral anticoagulants 
- neurological deficit 
 
GCS ≤14 
 
 
 
 
 
Primary 
outcomes 
Any need for 
neurological 
intervention 
Acute 
traumatic 
intracranial 
lesion on 
CT 
 
Any 
intracranial 
traumatic 
finding on CT 
 
Any 
intracranial 
injury on 
CT 
Any 
neurosurgical 
intervention 
Secondary 
outcomes 
Clinically relevant 
brain injury on CT 
 
 
All 
neurosurgical 
intervention 
after initial CT 
 
 
Any non-
neurosurgical 
intracranial 
traumatic 
complications 
Table 2. inclusion criteria, exclusion criteria, primary outcomes, secondary outcomes 
 
 

Clinical findings 
CCHR 
NOC 
NICE 
CHIP 
NCWFNS 
NEXUS 
II 
SNC 2013 
Age 
≥65 
>60 
≥65 
≥60 major 
40-60 minor 
>60 
≥65 
≥65 and 
anti-
platelet 
treatment 
Pedestrian/cyclist 
versus vehicle 
Minor 
 
Minor 
Major 
 
 
 
Ejected from 
vehicle 
Minor 
 
Minor 
Major 
 
 
 
Fall >1m 
Minor 
 
Minor 
Minor 
 
 
 
Signs of skull 
fracture 
Any 
Any 
Any 
Any 
Any 
Any 
Any 
Contusion of the 
skull 
 
 
 
 
 
Any 
 
Fracture above 
clavicles 
 
Any 
 
 
 
 
 
Alcohol/drug 
intoxication 
Any 
 
 
 
Any 
 
 
LOC* 
Inclusion 
Inclusion 
Inclusion 
Minor 
Any 
 
Low risk 
Amnesia 
Retrograde 
> 30 min 
Antegrade Retrograde 
> 30 min 
≥4h major 
2-<4h 
minor 
Any 
- 
- 
Headache 
 
Severe 
 
 
Any 
 
 
Vomiting 
episodes 
>2 
Any 
>2 
Major 
Any 
>2 
>2 and 
GCS 14 
low-risk 
Neurological 
deficit 
Excluded 
Excluded 
Any 
Minor 
Any 
Any 
Any 
Pretraumatic 
seizure 
 
 
 
 
Yes 
 
 
Posttraumatic 
seizure 
Excluded 
Any 
Any 
major 
Any 
 
Any 
GCS <15 
After 2h 
Exclusion 
After 2h 
≥2 points 
deterioration 
Major 
1point=minor 
Always 
Always 
14 and no 
other 
risk-
factor= 
low risk 
Antiplatlet 
medication 
 
 
 
 
 
 
And ≥65y  
Anticoagulation 
therapy 
Exclusion 
- 
Any 
Major 
Any 
Any 
Any 
Bleeding disorder 
Exclusion 
 
 
Major 
 
 
Any 
Shunt-treatment 
 
 
 
 
Any previous 
neurosurgical 
intervention 
 
Yes 
Table 3. Comparison of the 7 guidelines used in clinical practice for initial screening of TBI.  
 
 

 
 
 
 
Figure 1: Algorythm for eligibility  
 
 
Patients with head 
injury seeking the ED 
Patients eligible: 
Age≥18 
GCS 9-15 
Injury within 24h 
Patients enrolled 
Data registration 
Total number of patients 
to analyze  
Missed patients 
Excluded patients: 
-refusal 
-no Swedish citizen 
Patients lost to follow 
up 
Follow up 
(after 3 months) 
Tx 
T1 
T2 
T0 
Validation analysis 
Primary endpoint 
Comparison guidelines-  
Secondary endpoint 
Comparison biomarkers- 
Secondary endpoint 
 
Improved guidelines- 
 Secondary endpoint 
 

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