Original Contribution

S-100 and neuron-specific enolase levels in carbon

monoxiderelated brain injury
Zeynep Cakir MD
a
, Sahin Aslan MD
a,

, Zuhal Umudum MD
b
, Hamit Acemoglu MD
c
,
Ayhan Akoz MD
a
, Sule Turkylmaz MD
a
, Nurnnsa ztrk MD
b
a
Department of Emergency Medicine, Ataturk University, Medical School, 25090 Erzurum, Turkey
b
Department of Biochemistry, Ataturk University, Medical School, 25090 Erzurum, Turkey
c
Department of Medical Education, Ataturk University, Medical School, 25090 Erzurum, Turkey
Received 23 August 2008; revised 24 October 2008; accepted 26 October 2008
Abstract
Introduction: Carbon monoxide (CO) toxicity may cause persistent injuries in tissues sensitive to
hypoxia. Neuropsychiatric sequelae may be observed in about 67% of cases after severe CO exposure.
Aim: The aims of this study were to demonstrate the usefulness of S-100 and neuron-specific enolase
(NSE) in CO intoxications, show the degree of neurological response, and determine the indications for
hyperbaric oxygen treatment (HBOT) as biochemical markers.
Results: The S-100 and NSE levels of the sera of 30 patients were studied upon admittance and at the
third and sixth hours. S-100 levels were found to be high in all 3 analyses. There was no significant
change in NSE levels. When the S-100 levels were compared with Glasgow Coma Scale levels, a
strong negative correlation was found for all hours (r = 0.7, 0.8; P = .00). The correlation between S-
100 and carboxyhemoglobin levels at the initial hour was found to be statistically significant (r = 0.4;
P = .01). The S-100 levels in patients receiving HBOT showed a considerable decrease compared with
those in patients not receiving the treatment. The same decrease was valid for NSE, although it
was insignificant.
Conclusion: S-100 may be useful in evaluating intoxications as an early biochemical marker in CO
intoxications, as well as in the differential diagnosis due to other causes, and in determining
HBOT indications.
2010 Elsevier Inc. All rights reserved.
1. Introduction
It has been reported in many countries that intoxications
caused by carbon monoxide (CO) gas released after
incomplete burning of carbon-containing fuels are the reasons
for more than half of fatal intoxications [1-3]. In spite of
precautions taken in many industrialized countries, such as the
United States and those in Europe, mortality and morbidity
rates have still been high [4]. In our country, particularly in our
region, where long and hard winter conditions are observed,
CO intoxications frequently occur [5].
Acute CO toxicity may result in earlier and persistent
injury in tissues that have high oxygen consumption and are
sensitive to hypoxia, such as the brain, heart, muscle, and
kidney. In survivors after severe CO exposure, some remain
asymptomatic, whereas 67% have psychiatric sequels [6-8].

Corresponding author. Tel.: +90 04423166333/1461; fax: +90

04423166340.
E-mail address: sahinaslan29@hotmail.com (S. Aslan).
www.elsevier.com/locate/ajem
0735-6757/$ see front matter 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.ajem.2008.10.032
American Journal of Emergency Medicine (2010) 28, 6167
The treatment of CO intoxication consists of supportive
treatment by normobaric oxygen treatment or hyperbaric
oxygen treatment (HBOT). In manyrecent studies, it is justified
that severe CO intoxications should be treated with hyperbaric
oxygen [1,3,9]. However, this treatment policy presents
problems in the way the diagnosis of severe intoxication is
determined [3,10]. The existence of biochemical markers that
may reflect brain injury may provide additional evidence in
detecting neurological response and may lead to the decision
regarding which patients should be sent to HBOT [10].
S-100, a glial cytoplasmic protein, and neuron-specific
enolase (NSE), a glycolytic enzyme, are useful biochemical
markers to demonstrate cerebral injury observed under
conditions such as head trauma, cerebral infarct, cardiac
arrest, and cardiac surgery [10-13].
This study has been aimed to identify whether the severity
of neurological symptoms correlates with NSE and S-100
levels and whether HBOT affects these levels.
2. Materials and methods
2.1. Patients
Thirty adult patients who were admitted to emergency
service with CO intoxication between March and June 2007
were included in this prospective clinical study. The diagnosis
of CO intoxication was established according to history,
clinical characteristics, and blood carboxyhemoglobin (COHb)
levels. Those who had a previous diagnosis of a neuropsychia-
trical disease were excluded from the study. Patient demo-
graphics, source of CO, period of exposure to CO, time elapsed
in reaching the emergency unit, smoking habits, existence of
chronic or other accompanying diseases, symptoms at
presentation, systemic and neurological examination findings,
Glasgow Coma Scale (GCS), electrocardiogram (ECG)
findings, blood COHb, S-100 and NSE levels, other
laboratory results, and the modes of treatment were recorded.
The patients received HBOT and/or normobaric oxygen
treatment. The indication of HBOTwas determined according
to international guidelines [14]; patients with a COHb level of
greater than 20% and those with any neurological deficit
(including loss of consciousness and syncope), metabolic
acidosis, hypotension, evidence of myocardial ischemia, and
pregnancy at any gestational week were given HBOT. Patients
with HBOT indication received this treatment immediately
after stabilization, initially compressed to 3.0 atmospheres
absolute (atm abs) (304 kPa) for 50 minutes, followed by
60 minutes at 2.0 atm abs (203 kPa) and once a day thereafter,
making a total of 4 or 5 sessions (2.0 atm abs for 90 minutes).
2.2. Blood samples and biochemical measurements
Blood samples were obtained for S-100 and NSE first
when the patients presented to the emergency unit (at hour 0)
and then at the third and sixth hours. These samples were
centrifuged at 4000 rpm for 10 minutes and the serum was
dissociated and kept at 4C for no more than 24 hours. The S-
100 and NSE levels were measured by the ELISA method
(S-100, Bio Vendor; and NSE, DRG Diagnostics). Blood
samples also underwent analyses for measurements of CK,
CK-MB, troponin I, and COHb levels. Normal levels of S-
100 and NSE are less than 5 pg/L and 9 g/L, respectively.
2.3. Statistical analysis
Data were analyzed using the SPSS for Windows version
11.5 program. Demographic data were expressed as number,
percentage, and mean and SD. We compared the concentra-
tions of NSE and S-100 protein between groups using the
Mann-Whitney's rank sum test and the comparison within
the groups using the Wilcoxon's rank sum test. Pearson
correlation was used to analyze GCS, COHb levels, exposure
Table 1 Characteristics of the 30 CO-intoxicated patients
Patient characteristics
Age, mean (SD), y 31.80 (11.69)
Sex, no. (%)
Female 19 (63.3)
Male 11 (36.7)
Source of CO, no. (%)
Hot water heater 17 (56.7)
Stove 13 (43.3)
Exposure time, mins, mean (SD) 2.48 (3.44)
Access to emergency unit, mins, mean (SD) 2.51 (3.07)
Smoking habit, no. (%)
No user 22 (73.3)
User 8 (26.7)
Comorbidity, no. (%)
No 28 (93.3)
Yes 2 (6.7)
Symptoms-findings, no. (%)
Neurologic 9 (30.0)
Neurologic + GIS 13 (43.3)
Cardiac + neurologic + GIS 3 (10.0)
Neurologic + nonspecific 5 (16.7)
Glasgow Coma Score, mean (SD) 13.67 (2.59)
ECG findings, no. (%)
Absent 22 (73.3)
Sinus tachycardia 8 (26.7)
ST changes 0 (0.0)
COHb level, mean (SD), % 24.76 (13.20)
Cardiac biomarker elevation, no. (%)
Absent 26 (86.7)
Present 4 (13.3)
Hyperbaric oxygen therapy, no. (%)
No 12 (40.0)
Yes 18 (60.0)
Estimated COHb level at end of exposure to
CO, mean (SD), %
43.40 (11.66)
GIS indicates gastrointestinal system.
62 Z. Cakir et al.
time, and S-100 and NSE levels. P values less than .05 were
considered statistically significant.
3. Results
Thirty patients with the diagnosis of CO intoxication
were included in the study. Nineteen of the patients (63.3%)
were women, with a mean (SD) age of 31.8 (11.6) years
(range, 19-65 years). All intoxications had accidental
causes. The main characteristics of the patients are presented
in Table 1.
Eight cases had loss of consciousness of varying levels on
admission. In cases without loss of consciousness, at least
one of the following neurological symptoms of headache,
dizziness, confusion, speech disorder, and numbness and
neurological findings of dysarthria, loss of strength, and
cooperation difficulty was observed. In all patients, there was
at least one neurological symptom or finding. The initial
COHb measurements of 16 patients were greater than 20%.
The initial mean GCS of cases and COHb at the emergency
unit are presented in Table 1.
The mean values of patients' sera for S-100 levels at the
initial, third, and sixth hours; the NSE levels at the same
hours; and changes in these values, along with other
characteristics of patients, are presented in Tables 2 and 3.
Twelve patients (40%) received HBOT. When a compar-
ison was made between patients receiving and those not
receiving HBOT regarding the change in S-100 levels with
time after the first session, the S-100 levels were found to
have decreased significantly in patients receiving HBOT.
Although the same decrease was seen for NSE, it was not as
significant as the decrease in S-100 levels (Fig. 1A and B).
Table 2 Changes in S-100 levels due to time and patient characteristics
Patient characteristics Initial Third hour Sixth hour
Mean SD Mean SD Mean SD
Sex
a
Female 88.62 86.17 53.93 37.32 35.29 19.04
Male 188.05 216.34 101.73 91.93 50.21 34.19
Source of CO Hot water heater 142.37 179.30 68.42 43.37 46.95 29.19
Stove 102.46 109.73 75.44 88.99 32.66 19.65
Smoking habit Not a user 108.49 111.36 73.24 73.82 39.22 23.98
User 170.70 235.26 66.56 39.27 44.98 32.71
ECG changes None 98.14 104.18 64.53 70.70 34.91 19.52
Tachycardia 199.15 233.85 90.52 48.66 56.84 35.73
Significant change in cardiac biomarkers
b
No 117.88 155.54 70.73 69.64 39.70 25.61
Yes 171.84 136.20 76.21 37.15 47.63 32.38
HBOT
b
Yes 175.36 180.31 93.98 76.80 47.23 29.50
No 49.65 19.24 37.68 14.76 31.05 16.76
a
For the comparison of third-hour levels between groups, P b .05.
b
For all comparisons between groups and within groups whether taken HBOT or not, P b .005.
Table 3 Changes in NSE levels due to time and patient characteristics
Patient characteristics Initial Third hour Sixth hour
Mean SD Mean SD Mean SD
Sex
a
Female 31.03 18.12 19.59 8.60 13.22 8.65
Male 43.64 26.07 33.99 23.16 26.71 13.85
Source of CO Hot water heater 39.64 26.04 28.60 19.97 19.19 14.77
Stove 30.44 13.97 20.00 10.04 16.82 9.13
Smoking habit Not a user 32.64 16.96 21.60 10.45 16.27 11.44
User 43.94 31.66 33.86 26.62 23.38 14.58
ECG finding None 35.03 22.95 24.13 18.30 18.41 13.96
Tachycardia 37.35 19.73 26.92 12.27 17.49 7.88
Significant change in cardiac biomarkers
b
No 31.82 17.21 22.16 11.38 16.90 10.81
Yes 60.58 34.36 42.52 33.96 26.40 20.82
HBOT
c
Yes 37.18 24.40 26.46 19.61 17.22 12.11
No 33.36 18.06 22.48 11.62 19.58 13.49
a
For comparisons between third and sixth hours, P b .05.
b
For comparisons of the initial levels of the groups, P b .005.
c
For all comparisons whether taken HBOT or not, P b .005.
63 S-100 and neuron-specific enolase levels in carbon monoxide
In all 8 patients with changes in consciousness when
admitted to the emergency unit, the S-100 levels were high
in all 3 measurements, and NSE levels were high in only
3 patients at the admittance hour; however, there were no
significant changes at the third- and sixth-hour measure-
ments. When S-100 levels at hours 0, 3, and 6 were
compared with their GCS on admission to the emergency
unit, a strong negative correlation was detected for all
3 hours (r = 0.7, 0.8; P = .000). The correlation curve of
the sixth hour is shown Fig. 2. When the NSE levels at the
same hours were compared with GCS levels, no significant
correlation was found (P N .05).
The correlation between S-100 and COHb levels at hour
0 was found to be significant (r = 0.4; P = .01). However, S-
100 level at the third and sixth hours and the NSE values at
hours 0, 3, and 6 had no correlation with COHb levels on
admission (P N .05).
Only 4 cases showed significant changes for cardiac
markers (troponin I N0.01 mg/dL and CK-MB/CK N5%).
When the significant changes in cardiac markers were
compared with S-100 and NSE levels at all hours, no
remarkable changes were found (P N .05).
Only 8 cases showed ECG changes (all were sinus
tachycardias); in these patients, the comparison for S-100
and NSE at all time intervals showed no significant
difference (P N .05).
4. Discussion
Tissue hypoxia after CO exposure is one of the most
common causes of toxic brain injury. Hippocampus, ganglia,
and the white substance are frequently affected in the central
nervous system [15,16]. This effect may result in many
neuropsychiatric disorders, such as acute neurological
symptoms, delayed encephalopathy, personality changes,
parkinsonism, and cognitive changes [1,15,17,18]. We
observed unconsciousness in 8 of our patients and we
found various neurological symptoms for the remaining.
Because a thorough neuropsychiatry evaluation is not
always possible, biochemical markers showing neuronal
Fig. 1 A, Time-dependent S-100 levels of the patients who have
taken hyperbaric oxygen therapy (HBOT) or those who have not.
B, Changes in NSE levels according to time in the patients who
have taken HBOT and those who have not.
Fig. 2 Correlation between Glasgow Coma Scale and S-100 at
the sixth hour.
64 Z. Cakir et al.
injury may provide objective data in determining brain
dysfunction. S-100 is a calcium-binding protein involved in
calcium homeostasis and predominantly produced by glial
cells within the brain. Neuron-specific enolase is a soluble
cytoplasmic protein with a still undefined function released
by neurons, neuroendocrine cells, and tumors. These
biomarkers reflect ischemic neuronal damage indirectly
perhaps mainly due to a mechanism that triggered by
hypoxia. Many studies have proven the efficacy of NSE and
S-100 in demonstrating acute neuronal injury in many
conditions such as head trauma, cerebral infarct, intracranial
hemorrhage and space-occupying lesions, cardiac arrest, and
cardiac surgery [10,11,19,20]. Studies with these biochem-
ical markers are limited for cases with CO intoxication.
Secretion of S-100 from astrocytes is stimulated under
metabolic stress (oxygen, serum, and glucose deprivation).
High S-100 levels lead to the induction of proinflammatory
cytokines such as IL-1 or tumor necrosis factor and
inflammatory stressrelated enzymes such as inducible nitric
oxide synthase [21]. A prominent role of this protein seems
to be the promotion of vascular inflammatory responses
through interaction with the receptor for advanced glycation
end products [22]. Although recent studies showing that
increases in S-100 in CO-intoxicated patients exist, studies
about this marker's role in the inflammatory process for this
intoxication are not enough. Furthermore, Thom et al [23-25]
showed that CO-mediated oxidative stress causes chemical
alterations for another mediator, myelin basic protein (MBP),
which initiates an adaptive immunologic response that leads
to a functional deficit. Also, the authors conclude that HBOT
prevents immune-mediated neurological deterioration after
CO poisoning because it partially prevents the acute
biochemical alterations in MBP. Albeit S-100 and MBP
are both markers of inflammatory process of the brain by
different mechanisms, a relationship between these media-
tors was also found [26].
Brvar et al [27,28] found a relationship between CO
intoxication and high levels of S-100 in their studies.
Moreover, there was a relationship with altered levels of
consciousness and high levels of S-100 [27]. Rasmussen et
al [10] investigated serum S-100 and NSE levels at the
initial, 12th, 24th, and 36th hours in 20 CO-intoxicated
patients and 20 controls and found very high S-100 and
NSE levels in 2 of their patients who died as a consequence
of intoxication. However, they reported that they could not
determine a considerable difference between CO intoxication
and control groups and they could not demonstrate a
significant correlation with the level of consciousness within
the group. As for the present study, the serum S-100 and
NSE levels of CO-intoxicated patients at hours 0, 3, and 6
were investigated. All 8 patients with loss of consciousness
had high S-100 levels at all times, whereas only 3 had high
NSE levels at the admittance hour.
When GCS levels were compared with S-100 levels at
all times, a strong negative correlation was found, but there
was no similar relation for NSE in our study. The results of 2
studies by Brvar et al [27,28] and our results are similar with
respect to sampling times and S-100 results. Rasmussen
et al [10] found similar NSE results with ours, but S-100
results were different. One of the reasons for this is the fact
that most of the patients in the study of Rasmussen et al [10]
were victims of fires at home, rendering the patients exposed
to cyanide intoxication, which may also play a role in loss of
consciousness, simultaneously with CO gas. In our study,
COintoxications originated from water heaters or stoves, and
no other toxic agents were in question. The other reason may
be related with the sampling time. The half-life of S-100 is
about 2 hours [10]. We think that an appropriate sampling
time was achieved for S-100 in our study (2.5 hours,
ranging between 0.5 and 18 hours). As a result, the level of
S-100 seems to be quite useful in determining early-period
neuronal injury in CO intoxications.
In our research, the increase in NSE levels for the HBOT
group was not as obvious as that in S-100 levels. Why?
Recent studies showed that the highest NSE serum values
were found 6 hours postinjury, denoting that NSE serum
level seems to reflect only the direct neuronal damage after
traumatic brain injury in a time-dependent manner [29].
Besides, a strong relationship was found between NSE and
IL- 6 values in serum, suggesting that neurons may
participate in the inflammatory response after trauma.
Thus, the authors concluded that although S-100 seems to
be more closely associated with the degree of cerebral
damage and the neurological outcome, NSE correlates more
significantly with the release of immunologic factors,
suggesting that these markers may have a distinct origin as
well as physiological and functional significance [12]. In our
study, we investigated the serum NSE levels at the initial,
third, and sixth hours. Because the half-life of NSE is
24 hours [10] and previous studies show that the correlation
exists 6 hours postinjury [12], we avow that we did not
choose correct sampling hours for NSE. We might find a
closer relationship between CO intoxication and NSE levels
if we analyzed the levels after 6 hours.
Carboxyhemoglobin measurements at the time of actually
reaching the emergency unit may not always correlate with
symptoms, findings, and prognosis in acute CO intoxications
[2,14,30,31]. In the recent study by Weaver et al [30], COHb
did not correlate with 6-week cognitive outcome. Carbox-
yhemoglobin begins to degrade in the period after exposure,
while oxygen support during the transfer to the hospital also
accelerates this degradation. In the present study, when S-
100 and NSE levels were compared with COHb levels, only
S-100 level at admittance hour was found to be positively
correlated with COHb levels. The reason for this may be the
oxygen supports that began during transport. Neither the
2 studies of Brvar et al nor that of Rasmussen et al compared
COHb levels with S-100 and NSE levels.
Almost all studies recommend HBOT in severe CO
intoxications [14,30-35]. However, there is no consensus on
patients considered as severe CO intoxication. Furthermore,
there is no certain idea even about what COHb levels should be
65 S-100 and neuron-specific enolase levels in carbon monoxide
[14]. The only agreement is the treatment of patients in coma
states on admission due to CO intoxication [27,33]. On the
other hand, HBOT was considered to be of no use in patients
resuscitated for arrest secondary to CO intoxication and
patients with temporary loss of consciousness [27,36]. In a
study carried out by Weaver et al [34], it has been emphasized
that it will be beneficial for all patients to receive HBOT,
without considering the severity of intoxication.
We showed that high S-100 levels found at the early
stages of acute neurologic injury have significantly been
reduced by the use of HBOT. Because the fall of this
protein, which is also a neuronal inflammation determinant,
correlated well with the use HBOT, it is not wrong to argue
that HBOT also has an anti-inflammatory effect on the brain
in CO-intoxicated patients. Hopkins et al [37] showed that
CO-intoxicated patients with the absence of the 4 allele
benefit much from HBOT. Similarly, we found that patients
with high S-100 levels seem to benefit more from HBOT.
Currently, because it is impossible to study apo4 allele in the
emergency department, obtaining S-100 levels is also hard.
Thus, we suggest that unless S-100 levels are widely
available, HBOT should be recommended to all the
indicated patients.
This study has some limitations. We did not evaluate
long-term neurologic sequels of CO intoxication. It is true
that S-100containing cell types have also been identified
outside the central nervous system and there are physiolo-
gical stimuli for release of S-100 into the serum, which are
not related to central nervous system diseases such as stress,
fasting, critically ill patients, cardiac arrest, and extracranial
injuries without brain injury [11-13,21]. Thus, this may have
affected our results.
In conclusion, S-100 levels are parallel with the severity
of cerebral response to CO intoxication. Hyperbaric oxygen
treatment seems to have an anti-inflammatory effect on the
brain in CO-intoxicated patients. However, we think that
further studies are needed to determine if S-100 is an
effective biomarker in CO intoxication. As for NSE, new
studies with appropriate working hours are necessary.
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67 S-100 and neuron-specific enolase levels in carbon monoxide
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