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Serum S 100 B: A Marker of Brain Damage in Traumatic Brain Injury with and without Multiple Trauma

Pelinka, Linda E.*; Toegel, Eva*; Mauritz, Walter; Redl, Heinz*

Clinical Aspects
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This prospective clinical study was conducted to determine whether S 100 B is a reliable serum marker for traumatic brain injury (TBI) with and without multiple trauma. Fifty-five trauma patients (Injury Severity Score [ISS] ≥24 and Glasgow Coma Score [GCS] ≤8) were classified by radiography, computer tomography, ultrasound, and neurology as TBI without multiple trauma (n = 23), TBI with multiple trauma (n = 23), or multiple trauma without TBI (n = 9). S 100 B was measured initially after trauma and daily for a maximum of 21 days. Both survivors and nonsurvivors had markedly increased S 100 B initially. All survivors returned to normal or moderately increased S 100 B levels within the first 48 h after trauma. In contrast, all nonsurvivors of isolated TBI had S 100 B values that either increased consistently or dropped and then increased again 48 h after the initial increase after trauma. There was no relationship between localization, extent, or severity of TBI and S 100 B. According to receiver operating characteristic curve analysis and calculation of the area under the curve (AUC), S 100 B is equally accurate for mortality prediction at 24, 48, and 72 h after trauma and is most accurate >84 h after trauma. Sensitivity/specificity for mortality prediction are more accurate in TBI without multiple trauma (AUC 0.802–0.971) than in TBI with multiple trauma (AUC 0.693–0.783). Thus, though S 100 B may be a reliable marker of brain damage in TBI without multiple trauma 24 h after trauma and thereafter, it appears to be less reliable in TBI with multiple trauma.

*Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Research Center for Traumatology of the Austrian Workers' Compensation Board; and Department of Anesthesiology and Critical Care Medicine, Lorenz Boehler Trauma Center of the Austrian Workers' Compensation Board, Vienna, Austria

Received 19 Mar 2002;

first review completed 11 Jun 2002; accepted in final form 29 Jul 2002

Address reprint requests to Linda E. Pelinka, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Research Center for Traumatology of the AUVA, Donaueschingenstrasse 13, A–1200 Vienna, Austria.

Financial support was provided by the Austrian Workers' Compensation Board.

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INTRODUCTION

In severe traumatic brain injury (TBI), reliable assessment of the patient's condition and continuous effective critical care are of the utmost importance in restricting the development of secondary brain insults (1). Though TBI monitoring has grown far more reliable in recent years, the extent of ongoing secondary brain insults still remains partially in the dark (2). On the one hand, it is well known that reliable clinical assessment is indeed limited in patients with TBI. On the other, computed tomography (CT), for all its diagnostic accuracy, places an immense strain on patients with TBI. Thus, CT is hardly suitable for frequent controls, not to mention the financial aspect. Clearly, a reliable marker for the development and extent of ongoing secondary brain insults would be a valuable asset for the management of patients with TBI in the critical care setting.

Almost 20 years ago, it was suggested that an ideal serum marker of TBI should be highly specific for the brain, highly sensitive for TBI, appear rapidly in the serum, and be released in a time-locked sequence with trauma (3). Though several substances have been studied (4,5), the ideal serum marker of TBI for the management of patients with TBI in the clinical care setting has yet to be found.

One marker of TBI that has been increasingly focused upon during recent years is S 100 B, a calcium-binding protein (6) present in high concentrations in astroglial cells and in Schwann cells (7). S 100 B has a biological half-life of 2 h. It is not influenced by hemolysis and it remains stable even if samples are not centrifuged and frozen immediately (8).

S 100 B increases in serum have been reported following global cerebral ischemia after cardiac arrest (9), hypothermic circulatory arrest (10), during cardiopulmonary bypass surgery (11), in stroke (12), and during aneurysmal subarachnoid hemorrhage (13). The temporal changes of serum S 100 B levels have been found to differ significantly between ischemic stroke and TBI (14). After TBI, serum S 100 B has been found to be increased in minor head trauma (15), as well as in severe TBI (16,17). In adults with TBI, some groups have measured and reported an S 100 B increase both in serum and in cerebrospinal fluid (18). In children, a very interesting recent study has reported increased S 100 B levels in the cerebrospinal fluid of children with severe TBI (19). Interestingly, it has recently been shown that serum S 100 B may also be increased immediately after multiple trauma without TBI (20).

In many cases, TBI is associated with multiple trauma. Though both TBI and multiple trauma have been studied extensively with regard to the cytokines (21,22), most studies on S 100 B have been limited to isolated TBI. To our knowledge, our study is the first to measure and compare the course of S 100 B in TBI with and without multiple trauma.

Our aim was to determine whether S 100 B is a reliable serum marker for TBI and, if so, whether it is reliable both in TBI with and without multiple trauma.

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MATERIALS AND METHODS

According to Austrian law, ethics committee approval would not have been required because no clinical decisions were based upon the results. S 100 B was measured in blood drawn for routine evaluations and did not require additional sampling. Nevertheless, the protocol of the study was submitted to and approved by the Ethics Committee of the Austrian Workers' Compensation Board. The need for informed consent was waived by the Ethics Committee.

From January 1999 through July 2000, 55 patients (Injury Severity Scoore [ISS] ≥24 and Glasgow Coma Score [GCS] ≤8 in TBI) admitted to our trauma center were included in this prospective study. Depending upon their pattern of trauma, patients were classified as TBI without multiple trauma (n = 23), TBI with multiple trauma (n = 23), and multiple trauma without TBI (controls; n = 9).

The following criteria were required for inclusion: TBI and/or multiple trauma, and 8 h or less before admittance. Multiple trauma was defined as trauma to one body region with an Abbreviated Injury Score (AIS) >3 plus trauma to two other body regions with AIS >1, adding up to a minimal ISS of 24. Cerebral CT was carried out at admission in all patients, including those without TBI. Multiple trauma was diagnosed radiologically, by ultrasound, and/or by CT. TBI was defined as trauma to the brain with an AIS >3, verified by the cerebral CT at admission. All CT examinations were performed by the same radiologist and were classified according to the criteria defined by Gentry and co-workers (23).

All TBI patients with and without multiple trauma presented with one or more of the following CT diagnoses: contusion diameter ≥5 cm, multiple contusions (diameter ≥2 cm) extra-axial hematoma (subdural or epidural), diffuse hemorrhage (intracerebral or intraventricular), and cerebral edema with displacement of midline and/or compression of cisterns and/or effacement of sulci.

Clinical, radiological, and neurological examination and assessment of the GCS were carried out at admission to our trauma center by the attending senior trauma surgeon. Ventilation and hemodynamics were managed by the attending anesthesiologist. All patients were examined by cerebral CT and subsequently were either transferred to the critical care unit immediately or after surgery, depending upon the treatment required. Patients were included in the study as long as they required critical care or for a maximum of 21 days. CT scans were repeated after neurosurgical intervention and whenever the clinical course required. All patients were continuously monitored in the critical care unit. Laboratory checks as well as neurological follow-ups by the same neurologist were carried out daily.

S 100 B was determined from venous blood. The first sample was drawn at admission and daily thereafter at the same time. All samples were centrifuged and serum was frozen to –72°C and stored for analysis. The serum concentration of S 100 B was measured by a commercially available monoclonal immunoluminometric assay (LIA-mat Sangtec 100; AB Sangtec Medical, Bromma, Sweden). The sensitivity range is 0.02–20 μg/L and the normal range is ≤0.12 μg/L

To determine whether there was any correlation between the level and/or the course of S 100 B and intracranial pathology, each patient's S 100 B levels were plotted separately in line graphs and were compared with the corresponding clinical, neurological, and CT findings. In “Results,” patients are identified by their case numbers (#1–#55).

To compare survivors with nonsurvivors, the median levels of S 100 B measured during various predefined time periods after TBI with and without multiple trauma or after multiple trauma without TBI were plotted in bar graphs. One S 100 B value per patient was included for each time period. These predefined time periods were 0–12 h (equivalent to <12 h after trauma), 13–36 h (equivalent to 24 h after trauma), 37–60 h (equivalent to 48 h after trauma), 61–84 h (equivalent to 72 h after trauma), and >84 h after trauma.

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Statistical methods

Data are shown as medians, 25%, and 75% percentiles. Differences between survivors and nonsurvivors within the predefined time periods were evaluated by Mann-Whitney U Test, and P < 0.05 was considered significant. No correction with regard to multiple test application was used.

Cut-off S 100 B plasma levels for prediction of mortality as well as positive and negative predictive values for mortality were determined separately for different time periods after trauma (<12, 24, 48, 72, and >84 h) by receiver operating characteristic (ROC) curve analysis (24) of the maximum plasma level during these time periods after trauma. The ROC curve plots sensitivity against 100 minus specificity, using a range of “cut-off” values for a positive prediction. It was performed using Medcalc statistical software (Medcalc Software, Mariakerke, Belgium). The area under the curve (AUC) is a measure of the accuracy of prediction with 0.5 by chance alone and increasing to 1 as the accuracy increases to 100% sensitivity and specificity.

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RESULTS

The patients suffering from TBI with and without multiple trauma or from multiple trauma without TBI were similar in age and gender distribution. Severity of trauma and prognosed mortality according to the combined Trauma Score and ISS (TRISS) were higher in the patients suffering from TBI with multiple trauma than in patients suffering from TBI without multiple trauma or from multiple trauma without TBI (Table 1). Regarding the S 100 B level at admission, there were no significant differences between the groups. Actual mortality for patients with TBI without multiple trauma was clearly higher than predicted by TRISS, whereas actual mortality was lower than predicted by TRISS for TBI with multiple trauma. Actual and predicted mortality were similar for multiple trauma without TBI.

Table 1

Table 1

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TBI without multiple trauma

In all patients suffering from TBI without multiple trauma (n = 23; 13 survivors and 10 nonsurvivors), S 100 B was increased initially after trauma. However, survivors differed markedly from nonsurvivors in their further course of S 100 B (Figs. 1, A and B, and 2).

Fig. 1

Fig. 1

Fig. 2

Fig. 2

The course of S 100 B for each survivor is presented in Figure 1A. S 100 B remained increased for 24 to 48 h after trauma, then dropped and remained below 1 μg/L. The degree by which S 100 B drops after the initial increase after trauma in relationship to time, i.e., the downward slope in the course of S 100 B, varied from patient to patient. Only one survivor (#43) showed a late temporary S 100 B increase (days 14 and 15). Though his cerebral CT and neurological status remained unchanged, the patient's laboratory values and clinical condition deteriorated due to acute respiratory distress syndrome and acalculous cholecystitis. Later, when the patient's clinical condition improved, S 100 B dropped.

Although the nonsurvivors showed a similar initial increase of S 100 B after trauma as the survivors, the further course of S 100 B differed markedly (Fig. 1B). The nonsurvivors had S 100 B levels that either remained increased or dropped after the initial increase after trauma and then increased again 48 h after trauma or earlier.

In two nonsurvivors (#26 and #31), S 100 B dropped temporarily, remaining low for several days. Interestingly, this paralleled clinical and CT improvement. One of these two nonsurvivors (#26), showed a terminal S 100 B increase, which paralleled clinical and CT deterioration and an intra-cranial pressure (ICP) increase 48 h before death. However, the other nonsurvivor (#31) showed this terminal S 100 B increase much earlier at 24 h prior to any other signs of deterioration and 5 days before death. Unfortunately, this patient was transferred and thus no further blood samples were gained.

Survivors were also compared with nonsurvivors by their respective median levels of S 100 B measured during various predefined time periods after trauma (Fig. 2). S 100 B differed significantly between survivors and nonsurvivors after 48 h (P = 0.0239), 72 h (P = 0.0373), and >84 h (0.0250).

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TBI with multiple trauma

As in TBI without multiple trauma (n = 23; 15 survivors and 8 nonsurvivors), S 100 B was initially increased after trauma in all patients suffering from TBI with multiple trauma Though survivors differed from nonsurvivors, this difference was not as pronounced as in TBI without multiple trauma (Figs. 1C and D, and 3).

Fig. 3

Fig. 3

The individual course of S 100 B for each survivor is shown in Figure 1C. After an initial peak, S 100 B remained increased until 24 to 48 h after trauma, then it dropped and remained low.

Again, the nonsurvivors followed a different course (Fig. 1D). Three of five nonsurvivors (#4, #18, and #41) whose samples were drawn within the first 2 h after trauma had high initial S 100 B levels followed by a sharp drop during the first 24 h after trauma. Unfortunately, the initial sample in the fourth nonsurvivor (#34) was drawn 9 h after trauma and thus an initial S 100 B increase may have been missed. Unlike the nonsurvivors of TBI without multiple trauma, neither of the nonsurvivors of TBI with multiple trauma (#4 and #34) showed a terminal rise in S 100 B even though TBI was the cause of death. In contrast, the nonsurvivors whose cause of death was multi-organ failure (#41 and #18) showed a clear S 100 B increase.

When survivors were compared with nonsurvivors during predefined time periods after trauma (Fig. 3), both showed the highest S 100 B levels during the first 12 h after trauma. The difference in S 100 B between survivors and nonsurvivors was borderline significant 72 h after trauma (P = 0.0887) and was not significant at any other point in time.

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Multiple trauma without TBI

Interestingly, S 100 B was initially increased after trauma in all patients with multiple trauma without TBI (n = 9; 8 survivors and 1 nonsurvivor;Figs. 1E and 4).

Fig. 4

Fig. 4

The individual course of S 100 B for each survivor is shown in Figure 1E. As in TBI and with and without multiple trauma, S 100 B was initially increased, remained increased for 24 to 48 h, then dropped and remained low in all survivors.

We are unable to present any data on the course in nonsurvivors because the only nonsurvivor (#40) died within the first 8 h after trauma.

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ROC analysis

According to the ROC analysis, the sensitivity and specificity of S 100 B for the prediction of death after TBI (Table 2) is equally unreliable for TBI with and without multiple trauma <12 h after trauma (AUC 0.69). However, for TBI without multiple trauma, the sensitivity and specificity of S 100 B for the prediction of death grows much more reliable 24 h after trauma, and thereafter (AUC 0.80), is equally reliable during different time periods after trauma (24, 48, 72 h) and is most accurate >84 h after trauma. In contrast, the sensitivity and specificity of S 100 B for the prediction of death are lower (smaller AUC) for TBI with multiple trauma. Whereas sensitivity and specificity of S 100 B are close to 100% >84 h after trauma for TBI without multiple trauma, they do not improve further for TBI with multiple trauma. The cut-off levels for separation of survivors from nonsurvivors decrease with time after trauma.

Table 2

Table 2

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DISCUSSION

Our aim was to determine whether S 100 B is a reliable serum marker for TBI and, if so, whether it is reliable both in TBI with and without multiple trauma. Our three patient groups (TBI without multiple trauma, TBI with multiple trauma, and multiple trauma without TBI) were comparable with regard to age, gender distribution, and initial S 100 B levels. They differed in trauma severity, predicted mortality according to TRISS, and in actual mortality. The highest actual mortality was seen in TBI without multiple trauma, where actual mortality was almost three times higher than predicted by TRISS. This is due to the fact that TRISS underestimates mortality when trauma is limited to TBI. Possibly, it also reflects the fact that we determine TRISS at admission to the emergency room. Almost all our TBI patients arrived intubated and ventilated, and hemodynamic stabilization was underway. The resulting Revised Trauma Score, which is more favorable than prior to intubation, is an important value in the subsequent calculation of TRISS.

We found that S 100 B may indeed be an reliable serum marker for the management of patients suffering from TBI without multiple trauma. The course of S 100 B may be useful for the daily assessment of TBI on the one hand and for the prediction of outcome on the other. However, we also found that S 100 B appears to be less reliable for the management of patients suffering from TBI with multiple trauma. Our most striking findings are:

  • All nonsurvivors of TBI without multiple trauma had S 100 B levels which either remained increased or dropped temporarily after the initial increase after trauma and then increased again when additional secondary brain damage developed.
  • All trauma survivors had S 100 B levels that dropped and remained low 48 h after trauma or earlier.
  • All trauma patients, regardless of whether they were suffering from TBI or not, had an initial increase of S 100 B after trauma.

None of the 36 survivors studied had increased S 100 B later than 48 h after trauma. The only exception was a brief increase in S 100 B in one patient (#43), which occurred after a surgical procedure. In contrast, all nonsurvivors with isolated TBI had S 100 B values that either remained increased or decreased temporarily (following the initial increase after trauma) and then increased again. These findings are in accordance with the preliminary results published by Raabe and co-workers (25).

Interestingly, one nonsurvivor (#31) had a phase of marked clinical improvement. During that phase, S 100 B dropped. However, S 100 B began to increase again 24 h before the first clinical signs of deterioration appeared (5 days before death). Three similar cases have been reported (26). We agree that the daily course of S 100 B is of the utmost clinical relevance and that increasing or persistingly high levels signal ongoing secondary brain damage, regardless of continuous therapy (17). The level of S 100 B over 14 days has been reported to correlate with the severity of TBI (18). In contrast, we compared each patient's daily S 100 B level with the CT and neurological findings on the same day, and we did not find any correlation. In our opinion, the general course rather than individual S 100 B levels provide information both on the condition and outcome of TBI.

Although survivors of TBI with and without multiple trauma followed similar courses of S 100 B, nonsurvivors did not. On the one hand, there were no survivors with increased S 100 B later than 48 h after trauma (with the exception of one patient with a short increase after surgery), i.e., S 100 B was never falsely positive. On the other hand, there were two nonsurvivors with normal S 100 B, i.e., S 100 B was falsely negative twice. Surprisingly, S 100 B remained normal in both of these nonsurvivors, who were suffering from TBI with multiple trauma, even though TBI was the actual cause of death. Due to the small number and early death of some patients, our information on the nonsurvivors of TBI with multiple trauma is more limited than on the nonsurvivors of TBI without multiple trauma. This is also reflected in ROC analysis, which calculated lower sensitivity/specificity and thus a smaller AUC for patients with TBI and multiple trauma. Of course, these findings need to be verified in a larger patient population.

In an effort to transfer these findings from the bench to the bed, i.e., to the critical care setting, we believe that any increase of S 100 B later than 24 h after trauma may be an alarm sign indicating cerebral deterioration or even impending death in TBI without multiple trauma. This potential predictive value of S 100 B is shown by the good sensitivity/specificity and AUC calculated with the ROC analysis for 24, 48, 72, and >84 h after trauma (up to 0.97 AUC, with a maximum achievable value of 1). Different ROC cut-off values (between 2.2 and 0.79 μg/L) were found for these four time periods after trauma. The AUC of less than 0.9 at 24, 48, and 72 h after trauma results from two nonsurvivors (Fig. 1A, #31 and #26) who had very low S 100 B levels during these time periods after trauma (paralleled by a very good clinical course). S 100 B in these two nonsurvivors did not increase until >84 h after trauma. Interestingly, this S 100 B increase appeared before there was any other indication of cerebral problems.

Though it has always been assumed that the initial increase in S 100 B after trauma is attributable to TBI, this has not actually been proven in a clinical study. To the best of our knowledge, no study to date has ever differentiated between isolated TBI and TBI with multiple trauma. Interestingly, we found that S 100 B is always increased during the first 24 h after multiple trauma, regardless of whether it is associated with TBI or not. Thus, no reliable information on TBI can be gained from S 100 B until later than 24 h after trauma. As pointed out earlier, it is the further course of S 100 B that may indeed provide reliable information.

S 100 B was also increased in the nine patients with multiple trauma but without TBI. This is in accordance with a clinical study recently published that reported that S 100 B was increased in 17 patients with multiple trauma without TBI (20). Thus, we agree that S 100 B may be difficult to interpret immediately after multiple trauma and that S 100 B values determined later than 24 h after trauma may be more reliable with respect to TBI. In our opinion, the initial increase of S 100 B in these patients could reflect cerebral hypoperfusion resulting from posttraumatic hypotensive shock. As pointed out earlier, all patients were examined by CT upon admittance. All patients classified as multiple trauma without TBI had negative CT findings as well as negative neurological findings. One could argue that magnetic resonance imaging (MRI) is more sensitive than CT (27) and thus would have detected brain damage that might have been overlooked. However, MRI is not yet standard of care upon admission of severely traumatized patients. Furthermore, none of the patients suffering from multiple trauma without TBI ever showed any neurological signs or any increase of S 100 B that would have warranted another CT or MRI (28).

Regarding a possible relationship between S 100 B and intracranial pathology, the results reported are heterogeneous, ranging from no correlation at all (29) to correlation (30), and even differences in the course of S 100 B corresponding to different types of cortical lesions (16). A relationship between S 100 B levels and severity of TBI, determined by correlation with the GCS, has also been reported by some authors (31). However, when we compared each patient's S 100 B levels with CT results and GCS on the same day, we found no relationship between S 100 B levels and the localization, extent, or severity of TBI. In our study, initial S 100 B values were highest in nonsurvivors of TBI with multiple trauma, followed by the survivors of TBI with multiple trauma. Interestingly, the highest initial S 100 B value by far was found in a survivor of TBI without multiple trauma (#28) who was suffering from a gunshot wound to the brain. Though not among the most severely injured patients in the study, he was the only one with penetrating instead of blunt TBI.

During the first hours after severe trauma, serum S 100 B is increased in all patients, including those without TBI. The initial S 100 B increase earlier than 24 h after trauma does not correlate with the severity of TBI and is not necessarily even a reliable sign of TBI. Reliable information regarding TBI can be gained only from the course of S 100 B beginning later than 24 h after trauma. S 100 B could be a reliable serum marker both for daily management and for prediction of outcome of patients suffering from TBI without multiple trauma. According to our findings, S 100 B does not appear to be equally reliable for management and prediction of outcome of patients suffering from TBI with multiple trauma.

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ACKNOWLEDGMENTS

The authors thank Georg Siakos, MD and Laith Hamid, MD for neurological and radiological evaluation and follow-up, and Ilse Jung, MSc for statistical evaluation.

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Keywords:

Traumatic brain injury; secondary brain damage; multiple trauma; S 100 B

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