Biochemical markers and somatosensory evoked potentials in patients after cardiac arrest: The role of neurological outcome scores

Journal of the Neurological Sciences 305 (2011) 80–84

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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Biochemical markers and somatosensory evoked potentials in patients after cardiac arrest: The role of neurological outcome scores Obaida R. Rana a,⁎,1, Erol Saygili a,1, Johannes Schiefer b, Nikolaus Marx a, Patrick Schauerte a a b

Department of Cardiology, RWTH Aachen University, Aachen, Germany Department of Neurology, RWTH Aachen University, Aachen, Germany

a r t i c l e

i n f o

Article history: Received 14 September 2010 Received in revised form 22 February 2011 Accepted 1 March 2011 Available online 26 March 2011 Keywords: Biochemical markers Somatosensory evoked potentials (SSEP) Cardiac arrest Glasgow Outcome Score (GOS) Glasgow-Pittsburgh Cerebral Performance Categories (GP-CPC)

a b s t r a c t Biochemical markers, e.g. NSE or S100B, and somatosensory evoked potentials (SSEP) are considered promising candidates for neurological prognostic predictors in patients after cardiac arrest (CA). The Utstein Templates recommend the use of the Glasgow-Pittsburgh Cerebral Performance Categories (GP-CPC) to divide patients according to their neurological outcome. However, several studies investigating biochemical markers and SSEP are based on the Glasgow Outcome Score (GOS). We noticed that many studies failed to exclude patients who died without certified brain damage from patients classified as poor outcome, instead including all patients who died into this category. Therefore, we summarized the published NSE cut-off values and the derived sensitivity and specificity to predict poor outcome of those studies which only included patients with certified brain death in GOS-1 or GP-CPC-5 (group A) vs. those studies which did not differentiate between death from any cause or death due to primary brain damage (group B). On average, mean NSE cut-off values and sensitivity were higher (56 ± 35 ng/ml, 56 ± 18%) in group A than in group B (41 ± 17 ng/ml, 44± 25%), respectively. The specificity remained equally high in both groups. In analogy, the average sensitivity of SSEP to predict poor outcome was higher in group A (76 ± 11%) than in group B (50 ± 15%), while the specificity was similar in both groups. Conclusively, inclusion of deaths without certified brain damage after CA in neurological outcome studies will lead to underestimation of the prognostic power of biochemical or electrophysiological markers for brain damage. A modified GOS and GP-CPC score might help to avoid this bias. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Cardiac arrest (CA) is the leading cause of death in Europe and the USA affecting about 750.000 people annually [1]. The rate of restoration of spontaneous circulation (ROSC) has risen in the past decades due to considerable efforts to establish and improve of rescue chains comprising both layman and professional emergency services [2]. The trade-off of improved ROSC may be an increasing number of patient suffering from various degrees of brain damage after successful resuscitation [3]. Several clinical outcome scores, electrophysiological techniques, and imaging methods have attempted to predict the presence, degree and course of neurological outcome after CA [4]. This has recently been complemented by neural tissue derived biomarkers such as neuron-specific enolase (NSE) and S-100B [5]. The Utstein Consensus Conference participants recommend the use of the Glasgow-Pittsburgh Cerebral Performance Categories

⁎ Corresponding author at: Department of Cardiology, RWTH Aachen University, Pauwelsstr. 30, D-52074 Aachen, Germany. Tel.: +49 241 80 35142; fax: +49 241 80 82303. E-mail address: [email protected] (O.R. Rana). 1 Both authors contributed equally to this work. 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.03.007

(GP-CPC) to record the outcome of patients after CA, CPR and ROSC [6]. However, several studies evaluating biochemical markers and electrophysiological techniques for the prediction of outcome after CA are based on the Glasgow Outcome Score (GOS) [7–14]. Although both scores provide comparative categories (though more refined in the GP-CPC), a significant number of outcome studies using the GOS do not include patients with severe cerebral disability to the category of poor outcome [9,11,13,14]. Furthermore, while the GP-CPC defines death, certified brain dead or dead by traditional criteria as worst category (CPC 5) the Glasgow Outcome Score is less specific and defines the worst outcome level (GOS 1) simply as death irrespective of whether this was due to brain damage or other causes or both [6,7]. Unfortunately, many clinical studies using the GP-CPC do not restrict GP-CPC 5 to certified brain dead [15–18], which may dilute sensitivity and specificity of scores and parameters to predict neurologic outcome. E.g., if patients after CA who die because of other reasons than brain damage are included to GP-CPC 5 the cutoff values or sensitivities for biochemical markers or electrophysiological recordings such as SSEP of brain damage may have been calculated too low. Therefore, the present study was conducted to evaluate if clinical studies investigating biochemical markers or SSEP for the prediction of neurological outcome have taken care of this slight but important distinction.

O.R. Rana et al. / Journal of the Neurological Sciences 305 (2011) 80–84

2. Methods 2.1. Literature research A Medline search of literature published before April 2010 was performed using the following search term: “biomarker out-ofhospital cardiac arrest” and “somatosensory evoked potentials cardiac arrest outcome”. The search included original articles but excluded those not in English, animal experimental studies and case reports.

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Table 2 The Glasgow-Pittsburgh Cerebral Performance Categories (GP-CPC). GP-CPC

Cerebral Performance Categories

GP-CPC 1 GP-CPC 2

Good cerebral performance. Able to work and lead a normal life. Moderate cerebral disability. Sufficient cerebral function for part-time work in sheltered environment or independent activities of daily life. Severe cerebral disability. Dependent on others for daily support because of impaired brain function. Coma, vegetative state. Death, certified brain dead or dead by traditional criteria.

GP-CPC 3 GP-CPC 4 GP-CPC 5

2.2. Glasgow Outcome Score (GOS) The GOS is based on a study of Janett and Bond published in 1975 [7]. Table 1 summarizes the 5-point score. 2.3. The Glasgow-Pittsburgh Cerebral Performance Categories (GP-CPC) The GP-CPC have become the most widely used approach to evaluate quality of life after successful resuscitation [6]. Clinicians designed these categories to evaluate CA survivors. Table 2 summarizes the 5-point score. 3. Results

limitation of NSE and S100B to predict an unfavourable outcome based on the GOS [13]. The authors of this study did not separate patients who died from any cause from patients who died because of brain damage. Since more than 50% of patients with poor outcome died, a significant number of non-brain damage related death may have substantially biased the predictive value of the measured biomarkers. Rech et al., investigating serum NSE as an early predictor of neurological outcome after in-hospital CA, failed to exclude patients without brain damage from GOS 1, which comprised approximately 70% of all included patients [14]. In summary, all but one study applying a modified GOS failed to exclude patients without certified brain damage from GOS 1 [12].

3.1. Studies evaluating biochemical markers to predict outcome after CA 3.3. The Glasgow-Pittsburgh Outcome Categories (GP-CPC) A PubMed search resulted in 20 original papers evaluating biochemical markers to predict outcomes after CA (Table 3). 7 studies used the GOS [8–14], which per se does not differentiate between death and brain death, while 4 studies using the GP-CPC did not restrict GP-CPC 5 to brain death [15–18]. Of all 20 studies, 13 studies did not further differentiate patients who died with respect to death by certified brain damage or death due to other reasons [8–11,13–18, 22–24], while 7 studies did [12,19–21,25–27].

In the large Prognosis in Postanoxic Coma Study Group (PROPAC) all patients with NSE levels N 33 μg/l had an unfavourable outcome defined as GOS 1–2 [10]. This cut-off value was subsequently recommended by the “Quality Standards Subcommittee of the American Academy of Neurology” [4]. Almost all patients with poor outcome died (349 of 356) but no distinction between death from any cause and death due to brain damage was made [10]. Since patients without significant brain damage may have had lower NSE values the derived cut-off value may have been chosen too low thus potentially decreasing sensitivity of this value. The study of Damian et al. referred outcome of patients to the GOS ratings after 3 months [8]. Bassetti et al. analyzed outcome as the best cerebral performance achieved at any time during a 1 year follow-up [11]. These authors rated GOS 1–2 as poor outcome but failed to differentiate between certified brain death and death from other causes. The study of Pfeifer et al. investigated the potential and

The GP-CPC have become the most widely used approach to evaluate quality of life after successful resuscitation [6]. Clinicians designed these categories to evaluate CA survivors. The GP-CPC evaluate only cerebral performance capabilities. These outcome categories are reliable and easy to obtain and often require only a telephone call to family members. Table 2 briefly describes the GP-CPC based on the recommended guidelines for uniform reporting of data from out-of-hospital CA (Utstein Style) [6]. Although GP-CPC 5 is defined as death, death due to hypoxic brain damage or by traditional criteria, many studies included patients who died of any reason in this category [15–18]. Yangawa et al. used the GP-CPC according to outcome of patients; however, the authors defined GP-CPC 5 as death and not brain death [15]. Derwall et al. assessed neurological outcome 14 days after CPR by the use of GP-CPC [16]. However, the authors did not define each GP-CPC, so that the readers are kept uninformed about the definition of each GP-CPC. Tiainen et al. evaluated the effect of therapeutic hypothermia on serum NSE and S100B protein levels in predicting unfavourable outcome after out-of-hospital CA [18], and Steffen et al. conducted an observational study comparing NSE levels in patients treated with mild hypothermia with historical non-hypothermia patients [17]. The authors of both papers assessed clinical outcome according to the GP-CPC, however, both papers referred to the work of Jannett and Bond [7], who proposed the GOS. On the other hand, only 3 studies using the GP-CPC included patients who died by certified brain damage to GP-CPC 5 [19–21].

Table 1 The Glasgow Outcome Score (GOS).

3.4. NSE cut off values, sensitivity and specificity predicting poor outcome in studies including patients with and without certified hypoxic brain death in GOS 1 or GP-CPC 5

3.2. Studies using the Glasgow Outcome Score (GOS)

GOS

Neurological outcome

GOS 1 GOS 2 GOS 3

Death Persistent vegetative state (unable to interact with environment) Severe disability (unable to live independently but able to follow commands) Moderate disability (able to live independently but unable to return to work) Mild or no disability (able to return to work)

GOS 4 GOS 5

Table 4 summarizes the published NSE cut off values (ng/ml) and the derived sensitivity (%), and specificity (%) to predict poor outcome of those studies which only included patients with certified brain death in GOS 1 or GP-CPC 5 (group A) vs. those studies which did not differentiate between death from any cause or death due to primary brain damage (group B). On average, mean NSE cut-off values were higher (56 ± 35 ng/ml, n = 4) in group A than in group B

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Table 3 Studies evaluating biochemical markers to predict outcome after CA.

Damian et al. [8] Turedi et al. [9] Zandbergen et al. [10] Bassetti et al. [11] Hachimi-Idrissi et al. [12] Pfeifer et al. [13] Rech et al. [14] Yanagawa et al. [15] Derwall et al. [16] Steffen et al. [17] Tiainen et al. [18] Prohl et al. [19] Reisinger et al. [20] Zingler et al. [21] Arnalich et al. [22] Auer et al. [23] Sulaj et al. [24] Böttiger et al. [25] Meynaar et al. [26] Martens et al. [27]

Outcome score

Differentiation of patients with certified brain death

Biomarker

Time to measure outcome after CPR

GOS GOS 1–2 vs. GOS 3–5 GOS GOS 1–2 vs. GOS 3–5 Modified GOS GOS 1–2 vs. GOS 3–5 GOS 1–2 vs. GOS 3–5 CPC 1–2 vs. CPC 3–5 CPC 1–2 vs. CPC 3–5 CPC 1–2 vs. CPC 3–5 CPC 1–2 vs. CPC 3–5 CPC 1–2 vs. CPC 3–5 CPC 1–2 vs. CPC 3 vs. CPC 4 CPC 1–3 vs. CPC 4–5 Survivors vs. non-survivors Survivors vs. non-survivors Survivors vs. non-survivors Brain damage vs. no brain damage Comatose vs. regained consciousness Death/vegetative state vs. regained consciousness

No No No No Yes No No No No No No Yes Yes Yes No No No Yes Yes Yes

S100B IMA and MDA NSE NSE S100B NSE and S100B NSE Biochemical–hematologic parameters S100B NSE NSE and S100B NSE and S100B NSE NSE and S100B Cell-free plasma DNA NSE NSE and MDA NSE and S100B NSE NSE and S100B

3 months At discharge 12 months 12 months At discharge 28 days 6 months 1 month 14 days At discharge 6 months 6 months 6 months 12 weeks 24 h and overall in-hospital mortality 48 h after ROSC 7 days 7 days During hospital stay 6 months

(41 ± 17 ng/ml, n = 6). Furthermore, the mean sensitivity of NSE predicting poor outcome was higher in group A (56 ± 18%, n = 4) than in group B (44 ± 25%, n = 4), while the specificity remained equally high in both groups (group A: 97 ± 6%, n = 4; group B: 99 ± 2%, n = 6).

studies which did not differentiate between death from any cause or death due to primary brain damage (group B). The average sensitivity of SSEP to predict poor outcome was higher in group A (76 ± 11%, n = 3) than in group B (50 ± 15%, n = 13), while the specificity was similar in both groups (A: 97 ± 5%, n = 3 vs. B: 99 ± 2%, n = 13).

3.5. Studies evaluating SSEP to predict poor outcome after CA

4. Discussion

The PubMed search resulted in 16 original papers evaluating SSEP to predict outcomes after CA (Table 5). Of these 16 studies 6 studies used the GOS [11,34–38] and 7 studies used the GP-CPC [21,28–33] to categorize the outcome of patients. Of all 16 studies, 13 studies did not further differentiate patients who died with respect to death by certified brain damage or death due to other reasons [11,29–40], while 3 studies did [21,26,28].

The present survey shows that most of the studies investigating biochemical markers and SSEP for the prediction of neurological

3.6. Sensitivity and specificity for SSEP predicting poor outcome in studies including patients with and without certified brain death in GOS 1 or GP-CPC 5 Table 6 summarizes the sensitivity (%) and specificity (%) of SSEP to predict poor outcome in those studies which only included patients with certified brain death in GOS 1 or GP-CPC 5 (group A) vs. those Table 4 NSE cut-off values, sensitivity and specificity predicting poor outcome in studies including patients with and without certified hypoxic brain death in GOS 1 or GP-CPC 5. Certified brain death in GOS 1 or GP-CPC 5

Cut/spe/ sen/day

Without certified brain death in GOS 1 or GP-CPC 5

Cut/spe/ sen/day

Prohl J, et al., 2007 [19] Zingler VC, et al., 2003 [21] Reisinger J, et al., 2007 [20] Meynaar IA, et al., 2003 [26] Martens P, et al., 1998 [27] Böttiger BW, et al., 2001 [25]

32/100/33/2 91/100/75/3

Rech et al. [14] Pfeifer et al. [13]

60/100/35/1 65/96/40/3

80/100/63/ peak NM

Sulaj et al. [24]

NM

Zandbergen et al. [10]

33/100/?/3

20/89/51/#

Auer et al. [23]

30/100/79/2

NM

Steffen et al. [17]

27/100/?/3

Bassetti et al. [11] Tiainen et al. [18]

NM 31/96/22/1

NM = not mentioned. #, 24 h after confirmed global cerebral ischemia. Cut = cut off value, spe = specificity, sen = sensitivity.

Table 5 Studies evaluating somatosensory evoked potentials (SSEP) to predict outcome after CA.

Zingler et al. [21] Daubin et al. [28] Madl et al. [29] Bauer et al. [30] Rossetti et al. [31] Tiainen et al. [32] Fugate et al. [33] Bassetti et al. [11] Samaniego et al. [34] Logi et al. [35] Young et al. [36] Fischer et al. [37] Zandbergen et al. [38] Nakabayashi et al. [39] Meynaar et al. [26] Sherman et al. [40] a

Outcome evaluations

Time to measure Differentiation of patients with certified outcome after CPR brain death

CPC 1–3 vs. CPC 4–5

Yes

12 weeks

CPC 1–3 vs. CPC 4–5

Yesa

6 months

CPC 1–2 vs. CPC 3–5 CPC 1–2 vs. CPC 3–5 CPC 1–2 vs. CPC 3–5

No No No

6 months ? 3–6 months

CPC 1–2 vs. CPC 3–5

No

6 months

CPC

No

At discharge

GOS 1–2 vs. GOS 3–5

No

12 months

GOS 1–2 vs. GOS 3–5

No

3 months

GOS 1–2 vs. GOS 3–5 GOS

No No

3 months 3 months

GOS

No

12 months

GOS

No

12 months

Glasgow Coma Scale No (GCS) Comatose vs. regained Yes consciousness presence or absence No of awakening

Patients who died b 72 h were excluded from the study.

1 month During hospital stay At discharge

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Table 6 Sensitivity and specificity for somatosensory evoked potentials (SSEP) predicting poor outcome in studies including patients with and without certified hypoxic brain death in GOS 1 or GP-CPC 5. Certified brain death in GOS 1 or GP-CPC 5

Parameters

Sens. (%)

Spec. (%)

Daubin C, et al., 2008 [28] Zingler VC, et al., 2003 [21] Meynaar IA, et al., 2003 [26]

Bilateral absence of cortical responses Bilateral absence of cortical responses N20 absent

79 85 64

92 100 100

Without certified brain death in GOS 1 or GP-CPC 5

Parameters

Sens. (%)

Spec. (%)

Young GB, et al., 2005 [36] Madl C, et al., 2000 [29] Bassetti C, et al., 1996 [11] Bauer E, et al., 2003 [30] Fischer C, et al., 2006 [37] Nakabayashi M, et al., 2001 [39] Fugate JE, et al., 2010 [33] Rossetti AO, et al., 2010 [31] Samaniego EA, et al., 2010 [34] Tiainen M, et al., 2005 [32] Sherman AL, et al., 2000 [40] Zandbergen EG, et al., 2006 [38] Logi F, et al., 2003 [35]

N20 absent N20 absent bilaterally N20 absent bilaterally N20 absent N20 absent bilaterally N20 absent bilaterally N20 absent bilaterally N20 absent bilaterally N20 absent N20 absent N1 absent bilaterally N20 absent bilaterally N20 absent bilaterally

57 37a 51a 51a 31 82 20a 46a 64 58a,b 55 48c 47

92 100 100a 100a 100 100 100a 100a 100 100a,b 100 100 100

a b c

Values were calculated from raw data extensively expressed in the paper. Value calculated from patients treated with and without hypothermia. Prevalence for poor outcome and absence of N20 and N70 72 h after CPR.

outcome after CA failed to exclude patients without certified brain death from the group of patients with poor outcome. If deaths after CA are included in neurological outcome studies without certifying brain damage, this will lead to an underestimation of the calculated cut-off values and sensitivities of biochemical markers and SSEP for predicting neurological outcome. In 1991 the GP-CPC were proposed to complement the GOS. The GOS was first introduced by Janett and Bond in 1975 [7]. The main difference between both scores is that GOS does not further differentiate the cause of death in GOS 1, whereas GP-CPC 5 acknowledges death due to brain death vs. death by any cause. Consequently, many studies investigating biochemical markers or SSEP for the prediction of neurological outcome included patients who died either from primary brain damage or death from any cause [15–18,29–33]. We thus propose a modification of the GOS and the GP-CPC score in order to allow a more stringent use: In studies evaluating neurological outcome by biochemical or clinical markers it is of upmost importance to differentiate between death with certified brain damage and death without certified brain damage (e.g. cardiogenic and/or septic shock, pulmonary embolism, aortic dissection). Hypoxic brain damage should be documented by neurological investigations, cranial CT/MRI, electrophysiological evaluations and/ or transcranial Doppler (TCD) ultrasonography. Only patients with certified brain damage should be included in GOS 1. GOS 1 may be specified into subgroup 1a (death from any cause) and 1b (death with certified brain damage). Likewise, the GP-CPC score category 5 should be divided into 5a (death from any cause) and 5 b (death with certified brain death). While studies depending on the GP-CPC mostly included GP-CPC 3 into the group of poor outcome together with GP-CPC 4–5, studies using the GOS classification included patients with GOS 3 (~ GP-CPC 3) to patients with good outcome together with GOS 4–5. In future studies, a consensus may be established to align the complementary categories of the 2 scores, in order to make comparison between studies more easy. 5. Conclusions Inclusion of deaths without certified brain damage after CA in neurological outcome studies will lead to underestimation of the prognostic power of biochemical or electrophysiological markers for

brain damage. A modified GOS and GP-CPC score might help to avoid this bias.

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