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Can S-100B serum protein help to save cranial CT resources in a peripheral trauma centre? A study and consensus paper
  1. B Müller1,
  2. D S Evangelopoulos2,
  3. K Bias1,
  4. A Wildisen1,
  5. H Zimmermann2,
  6. A K Exadaktylos2
  1. 1Department of Surgery, Regional Hospital Sursee, Lucerne, Switzerland
  2. 2Department of Emergency Medicine, Inselspital, Bern, Switzerland
  1. Correspondence to Dr D S Evangelopoulos, Department of Emergency Medicine, Inselspital, CH-3010 Bern, Switzerland; ds.evangelopoulos{at}gmail.com

Abstract

Background Cranial CT (CCT) is the gold standard to rule out traumatic brain injury. The serum level of the protein S-100B has recently been proposed as promising marker of traumatic brain injury. We prospectively investigated whether it might be a reliable tool for CCT triage in mild brain injury at a peripheral trauma centre with limited CT resources.

Methods Patients with mild head injury and a Glasgow Coma Score of 13–15 admitted to the emergency department of a peripheral trauma centre were enrolled. Blood samples for S-100B analysis were obtained after clinical evaluation. The cut-off level for positive S-100B was 0.105 μg/l. All patients underwent CCT. The relationship between clinical findings, CCT results and S-100B levels was evaluated.

Results 233 patients were enrolled. Median time between injury and sampling was 137 min. CCT was positive in 22 (9%) patients. Of these, 19 (8%) had positive serum S-100B levels. Overall, S-100B had a specificity of 12.2% and a sensitivity of 86.4%, with a positive predictive value of 12.8% and a negative predictive value of 85.7% as a selection tool for CCT triage in patients with mild head injury.

Conclusion The S-100B serum level showed a high sensitivity and negative predictive value in the screening of patients with mild head injury. The use of serum S-100B as a biomarker for CCT triage may improve patient screening and decrease the number of CCT scans performed. This would reduce unnecessary radiation exposure and free up capacity in the emergency rooms of peripheral hospitals to enable them to cope better with multiple admissions.

  • Mild head injury
  • GCS
  • treatment protocol
  • S-100B
  • CCT triage
  • management
  • emergency department management
  • trauma
  • trauma
  • head

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Introduction

Head injuries causing traumatic brain injury (TBI) remain one of the most common reasons for emergency hospital admission.1 2

The best approach to the evaluation and diagnosis of mild head injuries remains controversial. Cranial CT (CCT) is considered the standard diagnostic tool.3 Norlund et al reported that the use of early CCT in mild head injury patients was more cost effective than 24 h admission.4 Extensive use of CT scanning may, however, increase costs and radiation exposure. Several studies report that pathological findings at CCT scan are made in only 3–20% of mild head injury patients.5 6 Although the infrastructure of Level A trauma centres permits parallel, accurate CT screening, multiple admissions requiring routine CCT screening of mild traumatic head injuries may overwhelm emergency room (ER) capacity in peripheral trauma centres.

S-100B is a member of a multigenic family of low molecular weight, calcium-modulated proteins (S-100 proteins), characterised by two calcium binding sites of the helix-loop-helix (‘EF-hand type’) conformation. These intracellular proteins occur as dimers and posses a highly conserved amino acid sequence. Their expression and distribution is cell-specific, and they play a major role in the regulation of protein phosphorylation, transcription, Ca2+ homoeostasis, cell growth and inflammatory response.7 8

S-100B was recently introduced as a reliable biological marker for detection and outcome prediction in TBI patients.9–12 The protein has a half-life of about 120 min and 98% sensitivity 3 h after trauma.13 14 Several studies have shown that it may also be a marker for the detection of extracranial injuries.15 16

We performed a prospective study to investigate whether the S-100B serum level is a reliable biological marker, and, in addition to the initial clinical assessment, may thus improve CCT triage and increase the screening capacity of peripheral ERs. Our hypothesis was that patients with a mild head injury, a Glasgow Coma Scale (GCS) of 13–15 and normal serum S-100B would not have benefited from a CCT scan.

Materials and methods

Between January 2008 and August 2009, all patients with mild head trauma admitted to the ER of our regional trauma centre were consecutively enrolled. According to our in-house policy, all patients with head injuries undergo CCT.3 All adult patients (≥16 years) with mild head trauma (GCS of 13–15) were included in the study. Most common CCT scan findings were skull fractures, localised epidural, subdural haematomas and isolated subarachnoid haematomas.3 17 18 Patients suffering from cancer, stroke or other neurological diseases, or presenting with intracranial bleeds with a diameter greater than 5 mm or >1 bleed, a history of inherited coagulopathy or anticoagulant therapy, platelet aggregation inhibitor therapy or intoxication were excluded.7 19 Patients with late admissions to the ER and/or multiple associated injuries were also excluded from the study group.16 20

After thorough clinical examination by the ER physician, blood samples for the determination of S-100B serum levels were collected from all patients and the time interval between the accident and ER admission was recorded. After centrifugation, S-100B was determined in serum by an electrochemiluminescence immunoassay on a Modular Analytics E411 automated analyser (Elecsys S-100, Roche Diagnostics AG, Rotkreuz, Switzerland).

Based on other studies on S-100B, a serum concentration of 0.105 μg/l was selected as cut-off for the presence of relevant TBI. Levels above this cut-off were regarded as positive.21–23

After blood sampling, all patients underwent a CCT scan (GE 64-row, multislice) according to the ER protocol.3

After clinical and serological data collection, statistical analysis for the determination of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) was performed.

Results

In all, 300 patients with mild head trauma and a GCS of 13–15 were admitted to our ER between January 2008 and August 2009. Sixty-seven were excluded from this study because of cancer, stroke or other neurological disease, leaving 233 for analysis. Of the patients, 143 were men and 90 were women. The median age was 48.4 years (range 11–97; 25–75% quartile 24–72).

Median time between admission and blood sampling was 77 min (25–75% quartile 60–120).

A positive S-100B level in the blood was found in 169/233 (72.5%) mild head injury patients (>0.105 μg/l). Findings in the remaining patients were negative. There were 22/233 (9.4%) positive CCT scans and the remainder were negative.

Previous studies on S-100B have distinguished three different population groups (normal, borderline and pathological) based on the protein's values.24 25 Since our aim was examine weather S-100B could serve as reliable serum marker supporting clinical examination and improving CCT triage, we divided our population in three main groups based on the median serum S-100B level and clinical and CCT results (table 1, figure 1).

Table 1

Study groups' characteristics

Figure 1

Flow chart for S-100 based protocol for screening patients with mild head injury in the ER of a peripheral hospital.

Group A consisted of 64/233 (27.8%) patients with no clinical symptoms and a median S-100B concentration of 0.081 μg/l (25–75% quartile 0.065–0.102). In all, 49/233 (21.0%) had negative S-100B values and 15/233 (6.4%) had positive values. None of these patients had findings at CCT scan. Due to the small increase in S-100B and the absence of clinical findings, these patients would not normally undergo CCT scan.

Group B included 147/233 (63.1%) subjects with negative and positive clinical findings and a median S-100B concentration of 0.354 μg/l (25–75% quartile 0.138–0.488). Of these, 129/233 (55.4%) had positive and 18/233 (7.7%) had negative S-100B serum values. As in Group A, all CCT scans in this group were negative.

Group C consisted of 22/233 (9.4%) patients with positive clinical findings, a median S-100B concentration of 0.479 μg/l (25–75% quartile 0.153–0.702) and positive findings at CCT scan. Of these, 19/233 (8.3%) had positive and 3/233 (1.3%) negative S-100B serum values (tables 2 and 3).

Table 2

Cranial CT and S-100B serum concentration

Table 3

Positive clinical findings and S-100B serum concentration

Statistical analysis demonstrated a sensitivity of 86.4% but a specificity of only 12.2% for S-100B in the detection of mild TBI. A PPV of only 12.8% was found, while the NPV was 85.7%. False-positive S-100B serum values were found in 144/233 (61.8%) patients. Of these, 15/233 (6.4%) belonged to Group A, showing positive S-100B serum values. The remaining 129/233 (55.4%) with positive serum S-100B values belonged to Group B. False-negative S-100B serum values were reported only in 3/233 (1.3%) patients, all in Group C.

Discussion

Our results show that the serum S-100B level—despite its low specificity (12.2%) and PPV (12.8%)—demonstrated a high sensitivity (86.4%) and NPV (85.7%) for mild TBI, and may therefore be a reliable marker that might considerably assist in initial clinical examination and effective CCT triage.11

In a prospective multicentre study comprising 1309 patients, Biberthaler et al found a sensitivity of 99% and also reported a higher NPV than that of our study group.23 In a review of six prospective studies on serum S-100B including Biberthaler's results, Unden et al reported a specificity of 12%, but their sensitivity value of 98.2% and NPV of 99.5% were higher than ours.14 Since similar cut-off S-100B serum values were used in all studies, one possible explanation for the differences from our results may be the large number of patients included in these studies.

A further explanation may be the time between the accident and blood sampling. Although our median time was 77 min, two of our three false-negative S-100B serum values were in patients in whom the interval was very much longer than the median.13 14 The first was in a patient with a subdural haematoma at CCT and an S-100B serum concentration of 0.055 μg/l. Thorough re-examination of his records showed that he was transferred to our ER from a district hospital and that the real interval between trauma and blood sampling was 11.5 h, hence the low S-100B serum level. Similarly, for the second subject, although a serum concentration of 0.037 μg/l was measured, his medical records revealed that the head trauma had occurred 48 h before ER admission. The half-life of S-100B is about 2 h13; it is therefore reasonable that the level measured in patients with small intracranial lesions arriving at the ER with some delay may be below the cut-off level. For such purposes, the maximum interval between trauma and blood sampling should be 3 h, as applied by Unden et al, to achieve a high sensitivity and NPV for S-100B.14 Sensitivity in our sample increased from 86.4% to 95.5% when the two above patients were excluded.

Unlike these two patients, the sampling interval in the third was 60 min; CCT detected an undisplaced fracture of the frontal bone. Surprisingly, although serum S-100B is a biomarker of neural tissue damage, a concentration of only 0.038 μg/l (below the cut-off value) was determined in this patient. Similar cases of false-negative S-100B serum values have been reported in other studies.23

Although clinical examination and GCS are the mainstay for the assessment of initial status, clinical symptoms such as headache, vomiting, nausea, amnesia and loss of consciousness have been shown to be inadequate as triage tools for CCT (6–10% positive CCTs) and do not reliably identify patients with possible TBI.3 6 The additional information obtained by using a reliable biological serum marker would support clinical examination and improve CCT triage.14 26

In 2009, our group proposed ‘the Bernese Trauma Unit Protocol’ for mild head injury.27 The application of S-100B as an additional tool for patient screening and CT triage led to the development of a modified protocol that may assist in decreasing the number of unnecessary CT scans in a limited-resources peripheral hospital (figure 1).

We found that unnecessary CCT scans were performed in 36% of patients. Thorough clinical examination would have avoided CCT scans in 28%, and determination of S-100B would have excluded a further 8%. Freeing up resources in this way would increase capacity during multiple admissions of patients with mild head injury in ERs in peripheral hospitals.

Limitations

Our study has certain important limitations. It included a relatively small number of patients and was restricted to a specific subpopulation of patients with mild head injury. It was not randomised and did not include an in-depth cost analysis. Determining S-100B is not unproblematic because its role in non-head-related injuries is under discussion. Moreover, patients with no other obvious injuries may present with elevated serum protein concentrations. Axonal injuries, even in patients without a history of percussive trauma to the head, and extensive soft tissue injuries have also been shown to elevate S-100B levels.16 28 29 The interval between injury and blood sample collection is another important issue for S-100B. As shown above, for two patients in our study group, a false negative S-100B value was obtained due to delayed blood sample collection. For delayed ER admissions, serum S-100B concentration cannot be regarded as a reliable marker of mild TBI.17

Conclusion

The mainstay of management on admission to the ER are clinical examination and CCT. The use of serum S-100B as a biomarker for CCT triage may improve patient screening and decrease the number of CCT scans performed. This would reduce unnecessary radiation exposure and free up capacity in the ERs of peripheral hospitals to enable them to cope better with multiple admissions.

Acknowledgments

We would like to thank Alistair Reeves for his language revisions and critical input.

References

View Abstract

Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Regional Hospital Sursee, Lucerne, Switzerland.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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