Neuron-specific enolase and S-100b in prolonged targeted temperature management after cardiac arrest: A randomised study

doi:10.1016/j.resuscitation.2017.11.052

Resuscitation

Volume 122, January 2018, Pages 79-86

https://doi.org/10.1016/j.resuscitation.2017.11.052 Get rights and content

Highlights

•
Serum levels of NSE and S100b are unaffected by prolonged targeted management compared to standard duration TTM.
•
Biomarker levels at day 1, 2 and 3 after cardiac arrest and daily changes of NSE until day 2 were the best predictors of neurological outcome.
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The biomarkers NSE and S-100b remain reliable prognosticators, even in the case of prolonged TTM after cardiac arrest.

Abstract

Background

We aimed to investigate the impact of prolonged targeted temperature management (TTM) in cardiac arrest patients on release of serum levels of NSE and S-100b and their prognostic performances.

Methods

This is a substudy of the Targeted Temperature Management for 24 vs 48 h trial. NSE and S-100b levels were analysed retrospectively in serum samples collected upon admission, at 24, 48, and 72 h after reaching the target temperature of 33 ± 1 °C. The primary outcome was biomarker serum concentrations and secondary outcome was the cerebral performance category score after 6 months.

Results

115 patients from two centres were analysed. NSE and S-100b levels did not differ between TTM groups at any single time-point. Poor outcome patients had higher biomarker levels at 24, 48, and 72 h: NSE: 9.73 (7.2; 10.9) versus 20.40 (12.7; 27.2), 8.86 (6.6; 9.6) versus 17.47 (11.1; 37.3) and 6.23 (5.3; 8.5) versus 31.05 (12.8; 52.5) respectively and S-100b: 0.09 (0.07; 0.11) versus 0.23 (0.19; 0.39), 0.08 (0.07; 0.09) versus 0.18 (0.15; 0.33) and 0.07 (0.06; 0.08) versus 0.13 (0.09; 0.23). The daily changes in NSE from admission to Day 2 after the cardiac arrest (CA) were also related to the outcome (p = 0.003 and p = 0.02). The best prediction of outcome was found at 72 h for NSE and at 24 h as well as 48 h for S100b.

Conclusions

No clinically relevant differences were found in the levels of NSE or S-100b between standard and prolonged TTM. Prognostic reliability of NSE and S-100b was unaltered by prolonged TTM.

Introduction

Out-of-hospital cardiac arrest (OHCA) affects an estimated 400,000 people in Europe each year [1], and with a mere 10% survival rate, it is a major cause of death. Two landmark studies from 2002 [2], [3] demonstrated that targeted temperature management (TTM) at 33 °C for 12–24 h improved the neurological outcome and survival in comatose OHCA patients admitted to the intensive care unit (ICU). Consequently, TTM at 33 ° for 24 h became the standard treatment in post-cardiac arrest therapy worldwide, albeit with a low level of evidence. The TTM-trial from 2013 [4], randomising 950 OHCA patients, demonstrated that there was no difference in the neurological outcome, whether the patients were cooled to 33 or 36 °C. As a result, the most recent guidelines now recommend TTM at 32–36 °C for at least 24 h in OHCA patients [5]. Besides the optimal TTM temperature, duration of TTM is another big question within post-resuscitation care research. In search of an answer to this question, a study including 355 OHCA patients [6] reported no difference in the neurological outcome of prolonged TTM for 48 h versus standard duration of TTM for 24 h.

The introduction of TTM changed the reliability of the known prognosticators, and the importance of further investigations on prognosticators in this new setting is therefore important to secure safety in prognostication. The blood concentration of the two biomarkers, neuron-specific enolase (NSE) and protein S-100b, are associated with the neurological outcome and play an important role in prognostication due to their almost universal accessibility and low costs. The two largest studies on NSE and S-100b levels in OHCA patients to date [7], [8] reported that an intervention in the 33–36 °C span did not affect the levels of the two biomarkers to a clinically relevant degree, albeit the levels of S-100b were higher in patients treated with TTM to 33 °C at two of the three sample time-points.

The aim of the present study was to investigate whether prolonged TTM would reduce NSE and S-100b serum levels or cause changes in the biomarker levels over time. Furthermore, we wanted to explore the prognostic performance of the two biomarkers at specific time-points as well as their progression over time from one sample to the next. We hypothesised that prolonged TTM for 48 h would reduce the serum levels of NSE and S-100b, as compared to the standard 24-h duration of TTM.

Section snippets

Patients

All the patients included in the present study were a subset of the patients (n = 355) included in the randomised multicentre study, “Targeted Temperature Management for 48 vs 24 h and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial” (the TTH48 trial) [6]. TTH48 compares the effect on the neurological outcomes of 24 vs. 48 h of TTM at 33 ± 1 °C. In the present prospective study, a total of 159 patients were enrolled in the ICUs at Aarhus University Hospital,

Results

A total of 159 patients treated with TTM for 24 or 48 h at 33 °C were enrolled in the TTH48 trial during the study period, at both Aarhus and Stavanger. Blood samples were collected from 128 of these patients; 115 were included in the final statistical analysis (Fig. 1). At the 6-month follow-up, 79 patients (69%) had a good neurological outcome (CPC score 1 or 2) while 36 had a poor neurological outcome (CPC score 3–5). No significant differences were found in the baseline characteristics (Table

Discussion

In the present study, we found no statistically significant attenuating effect of 48 h of TTM on NSE and S-100b levels, as compared to the standard 24-h TTM. We found that higher NSE and S-100b levels predicted poor neurological outcome at the specific time points t24, t48, and t72. Likewise, a rise in NSE levels from t24 to t48 predicted a poor neurological outcome. Prolonged TTM did not alter the prognostic performance of the two biomarkers.

A relatively small Finnish study [12] randomised

Conclusion

Prolonged targeted temperature management for 48 h at 33 °C after an out-of-hospital cardiac arrest did not attenuate the levels of NSE and S-100b, as compared to the standard 24-h TTM, nor did it affect the changes over time at a clinically relevant level. The NSE and S-100b levels at all time-points, except at admission, as well as daily changes over time up until 48 h after reaching target temperature, predicted outcome at 6 months in both standard 24-h TTM, and prolonged 48-h TTM. This

Conflicts of interest

Christophe H. V. Duez received funding for research in neuroprognostication from the private foundations the Viggo and Helene Bruun Foundation, the Lily Benthine Lunds Foundation of 1st of June 1978, the Director Jacob Madsen & Wife Olga Madsen Foundation and the Grocer A. V. Lykfeldt and Wife Foundation. The foundations had no influence on the study design, execution, analysis or interpretation of the data. Co-authors had nothing to disclose.

Acknowledgement

We wish to thank the staff at the ICUs in Stavanger University Hospital and Aarhus University Hospital.

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Blood samples for measuring S-100b and NSE were drawn upon patient admission, 24 h, 48 h and 72 h after the patient reached the target temperature. Details of the lab procedures have been published previously.8 Measurement ranges were .3–740 μg/l for NSE and .02–39 μg/l for S-100b.
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^☆: A Spanish translated version of the abstract of this article appears as Appendix in the final online version at https://doi.org/10.1016/j.resuscitation.2017.11.052

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Clinical paperNeuron-specific enolase and S-100b in prolonged targeted temperature management after cardiac arrest: A randomised study☆

Highlights

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

Conclusion

Conflicts of interest

Acknowledgement

Resuscitation

Resuscitation

J Am Coll Cardiol

Resuscitation

Resuscitation

Resuscitation

Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia

N Engl J Med

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest

N Engl J Med

Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest

N Engl J Med

Clinical paper
Neuron-specific enolase and S-100b in prolonged targeted temperature management after cardiac arrest: A randomised study☆