The usefulness of neuron-specific enolase in cerebrospinal fluid to predict neurological prognosis in cardiac arrest survivors who underwent target temperature management: A prospective observational study

doi:10.1016/j.resuscitation.2019.09.027

Resuscitation

Volume 145, December 2019, Pages 185-191

https://doi.org/10.1016/j.resuscitation.2019.09.027 Get rights and content

Abstract

Aim

Cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels increase ahead of serum NSE levels in patients with severe brain injury. We examined the prognostic performance between CSF NSE and serum NSE levels in out-of-cardiac arrest (OHCA) survivors who had undergone target temperature management (TTM).

Methods

This single-centre prospective observational study included OHCA patients who had undergone TTM. NSE levels were assessed in blood and CSF samples obtained immediately (Day 0), and at 24 h (Day 1), 48 h (Day 2), and 72 h (Day 3) after return of spontaneous circulation (ROSC). The primary outcome was the 6-month neurological outcome.

Results

We enrolled 34 patients (males, 24; 70.6%), and 16 (47.1%) had a poor neurologic outcome. CSF NSE and serum NSE values were significantly higher in the poor outcome group compared to the good outcome group at each time point, except for serum Day 0. CSF NSE and serum NSE had an area under curve (AUC) of 0.819–0.972 and 0.648–0.920, respectively. CSF NSE prognostic performances were significantly higher than serum NSE levels at Day 1 and showed excellent AUC values (0.969; 95% confidence interval [CI] 0.844–0.999) and high sensitivity (93.8%; 95% CI 69.8–99.8) at 100% specificity.

Conclusion

We found CSF NSE values were highly predictive and sensitive markers of 6-month poor neurological outcome in OHCA survivors treated with TTM at Day 1 after ROSC. Therefore, CSF NSE levels at day 1 after ROSC can be a useful early prognosticator in OHCA survivors.

Introduction

Despite advances in post-cardiac arrest (CA) care, 50%–89% of OHCA patients die in hospital after the return of spontaneous circulation (ROSC), and 18% of survivors have been reported to have moderate to severe functional impairment at hospital discharge.1, 2, 3 The most common cause of death in OHCA patients with ROSC in hospitals has been reported to be withdrawal of life-sustaining therapy (WLST) for patients with perceived poor neurological prognosis, of whom 26% might have survived if life-sustaining therapy had not been interrupted and, of these, 64% might have had a functionally favourable survival.2, 4 The current international guidelines recommend that WLST be determined at least 72 h post-ROSC5, 6, 7 as, prior to 72 h, it is difficult to accurately distinguish patients with recoverable or irreversible injuries. Despite this recommendation, for reasons such as medical, economic, and social opportunity costs in relation to intensive care unit admission and the possibility of survival with severe brain injury, WLST prior to 72 h has been reported to be common.8, 9 Therefore, it is necessary to develop a tool that can accurately predict neurological outcomes earlier concerning comatose OHCA survivors.

To date, among available predictive tools, biomarkers such as neuron-specific enolase (NSE) have been widely used for patients after OHCA because there is no inter-observer variability and the results are easy to interpret.10, 11, 12, 13, 14, 15, 16

The Target Temperature Management after Cardiac Arrest (TTM) trial showed that serial NSE values were strong predictors of poor outcome after OHCA.¹³ The TTM trial also suggested that the best time point for serum NSE determination was 48 h or 72 h, and that the 24 h time point was too early to predict reliable outcomes.¹³ However, a number of previously published studies17, 18, 19, 20, 21 have reported that NSE is released from damaged neuron cells into the cerebrospinal fluid (CSF), and then released into the systemic circulation due to blood–brain barrier (BBB) disruption.18, 19, 20 In our previous study, we reported that the BBB began to be disrupted in the first 24 h after ROSC in patients with poor neurologic outcome.22, 23 Therefore, the CSF NSE level can be useful to predict neurologic outcome in cardiac arrest survivors even in the early hours before BBB disruption.²⁴

We hypothesised that the NSE levels measured in the CSF would change earlier with higher sensitivity than NSE levels measured in the serum. Therefore, we aimed to investigate the prognostic performance between serum NSE and CSF NSE for 6-month neurologic outcome in OHCA survivors who had undergone TTM.

Section snippets

Study design and population

This was a prospective single-centre observational cohort study of adult comatose OHCA survivors treated with TTM at Chungnam National University Hospital, a 1365-bed tertiary care referral centre, in Daejeon, Korea, from December 2017 to November 2018. This study was approved by the Institutional Review Board of Chungnam National University Hospital (CNUH-2017-10-027). The inclusion criteria comprised OHCA patients >18 years old who had been treated using TTM. The exclusion criteria for this

Patient characteristics

A total of 41 adult comatose OHCA survivors were treated with TTM during the study period. Of these, 34 patients were enrolled in the present study, as shown in Fig. 1. At 6 months after ROSC, 18 (52.9%) patients were assessed as being in the good outcome group and 16 (47.1%) were assessed as being in the poor outcome group. The demographic and CA characteristics, stratified according to neurological outcome at 6 months, are shown in Table 1. Patients with good neurological outcome had a higher

Discussion

In this prospective observational study, NSE levels in both CSF and serum were significantly higher in the poor outcome group than the good outcome group at each time point, except serum NSE at Day 0. CSF NSE prognostic performances were significantly higher than serum NSE at Day 1 and showed excellent AUC values and high sensitivity at 100% specificity.

The international guidelines for post-OHCA care suggest various methods to predict the prognosis for OHCA survivors.²⁷ These methods include

Conclusion

CSF NSE values were shown to have early, high predictive, and high sensitivity values for predicting poor neurological outcome in comatose OHCA survivors treated with TTM. These values showed better performance that other serum biochemical markers such as NSE. A large sample, multi-centre study is warranted to identify the exact association between CSF NSE values and neurological outcomes.

Conflicts of interest statement

All authors declare no conflicts of interest.

Acknowledgement

None.

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Interleukin-6 as a Potential Predictor of Neurologic Outcomes in Cardiac Arrest Survivors Who Underwent Target Temperature Management
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Citation Excerpt :
In this study, the AUC of IL-6 for prognosis prediction immediately (IL-60) after ROSC was 0.810, with 75.0% (95% CI 53.3–90.2) sensitivity and 80.0% (95% CI 56.3–94.3) specificity with respect to poor neurologic outcome. The AUC and sensitivity of IL-6 for prognosis prediction immediately after ROSC were not inferior to those of serum NSE (25,26). Although the AUC of IL-60 for prognosis prediction was high, the sensitivity/specificity was relatively poor.
Serum interleukin-6 (IL-6) is a cytokine released in response to an inflammatory stimulus or tissue injury. IL-6 levels are known to increase in patients with brain injury.
We investigated the neurologic outcomes associated with serum IL-6 levels in out-of-hospital cardiac arrest (OHCA) survivors who underwent target temperature management (TTM).
This was a prospective single-center observational study from October 2018 to November 2019 in a cohort of 45 patients. Serum inflammatory markers (IL-6, C-reactive protein, white blood cells) were determined in samples obtained immediately and at 24, 48, and 72 h after the return of spontaneous circulation (ROSC). Poor neurologic outcome, defined as Cerebral Performance Category 3–5 at 3 months after cardiac arrest, was the primary outcome.
Among 45 patients enrolled in this study, 25 (55.6%) patients showed a poor neurologic outcome. IL-6 levels were significantly higher in the poor neurologic outcome group immediately (IL-6₀) after ROSC. The area under the curve (AUC) value of IL-6₀ was the highest among those of serum IL-6, CRP, and WBC at each time point. The IL-6 levels for predicting poor neurologic outcome had a sensitivity of 75.0%, with 80% specificity at IL-6₀. The AUC of IL-6₀ was 0.810 (95% confidence interval 0.664–0.913), with a cutoff value of 346.7 pg mL⁻¹.
Serum IL-6 level immediately after ROSC was a highly specific and sensitive marker for the 3-month poor neurologic outcome, and may be a useful early predictive marker of neurologic outcome in OHCA survivors treated with TTM.
Impact of low and high partial pressure of carbon dioxide on neuron-specific enolase derived from serum and cerebrospinal fluid in patients who underwent targeted temperature management after out-of-hospital cardiac arrest: A retrospective study
2020, Resuscitation
Citation Excerpt :
To investigate a neuroprotective role of PaCO2 in OHCA survivors treated with TTM, the impact of high PaCO2 on serum neuron-specific enolase (NSE) was analysed by two previous randomised controlled trials (RCTs).3,8 Our previously published study reported the usefulness of cerebrospinal fluid (CSF) biomarkers in predicting neurological outcomes.16,17 Furthermore, Geocadin et al. suggested that CSF samples have the advantage that the biomarker need not be transported across the blood–brain barrier (BBB) for detection, thus greatly reducing contamination, despite being harder to obtain.18
In a previous study, low and high-normal arterial carbon dioxide tension (PaCO₂) were not associated with serum neuron-specific enolase (NSE) in cardiac arrest survivors. We assessed the effect of PaCO₂ on NSE in cerebrospinal fluid (CSF) and serum.
This was a retrospective study. PaCO₂ for the first 24 h was analysed in four means, qualitative exposure state (qES), time-weighted average (TWA), median, and minimum–maximum (Min–Max). These subgroups were divided into low (LCO₂) and high PaCO₂ (HCO₂) groups defined as PaCO₂ ≤ 35.3 and PaCO₂ > 43.5 mmHg, respectively. NSE was measured at 24, 48, and 72 h (sNSE_24,48,72 and cNSE_24,48,72) from return of spontaneous circulation (ROSC). The primary outcome was the association between PaCO₂ and the NSE measured at 24 h after ROSC.
Forty-two subjects (male, 33; 78.6%) were included in total cohort. PaCO₂ in TWA subgroup was associated with cNSE_24,48,72, while PaCO₂ in the other subgroup were only associated with cNSE₂₄. PaCO₂ and cNSE in qES subgroup showed good correlation (r = −0.61; p < 0.01), and in TWA, median, and Min–Max subgroup showed moderate correlations (r = −0.57, r = −0.48, and r = −0.60; p < 0.01). Contrastively, sNSE was not associated and correlated with PaCO₂ in all analysis. Poor neurological outcome in LCO₂ was significantly higher than HCO₂ in qES, TWA, and median subgroups (p < 0.01, p < 0.01, and p = 0.02).
Association was found between NSE and PaCO₂ using CSF, despite including normocapnic ranges; TWA of PaCO₂ may be most strongly associated with CSF NSE levels. A prospective, multi-centre study is required to confirm our results.
Cerebrospinal fluid lactate dehydrogenase as a potential predictor of neurologic outcomes in cardiac arrest survivors who underwent target temperature management
2020, Journal of Critical Care
Citation Excerpt :
In the present study, the AUC and sensitivity of CSF LDH at 48 h after ROSC were 0.941 (95% CI, 0.806–0.992) and 94.1% (95% CI, 71.3–99.9), respectively, with 100% specificity. The AUC and sensitivity for prognosis prediction of CSF LDH at 48 h after ROSC were higher than those of serum NSE in the previous studies and not inferior to those of CSF NSE [31,32]. LDH level is an easy and quick measurable biomarker, but NSE analysis has limited availability in routine laboratories.
Cerebrospinal fluid (CSF) lactate dehydrogenase (LDH) levels increase in patients with brain injury. We investigated neurologic outcomes associated with CSF LDH levels in out-of-hospital cardiac arrest (OHCA) survivors who underwent target temperature management (TTM).
This was a prospective single-centre observational study from April 2018 to May 2019 on a cohort of 41 patients. CSF and serum LDH samples were obtained immediately (LDH₀) and at 24 (LDH₂₄), 48 (LDH₄₈), and 72 h (LDH₇₂) after return of spontaneous circulation (ROSC). Neurologic outcomes were assessed at 3 months after ROSC using the Cerebral Performance Category scale.
Twenty-one patients had a poor neurologic outcome. CSF LDH levels were significantly higher in the poor neurologic outcome group at each time point. The area under the curve (AUC) of CSF LDH₄₈ was 0.941 (95% confidence interval [CI], 0.806–0.992). With a cut off value of 250 U/L, CSF LDH₄₈ had a high sensitivity (94.1%; 95% CI, 71.3–99.9) at 100% specificity.
CSF LDH level at 48 h was a highly specific and sensitive marker for 3-month poor neurologic outcome. This may constitute a useful predictive marker for neurologic outcome in OHCA survivors treated with TTM.
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Ultra-early neurologic outcome prediction of out-of-hospital cardiac arrest survivors using combined diffusion-weighted imaging findings and quantitative analysis of apparent diffusion coefficient
2020, Resuscitation
This study examined whether the presence of cortical necrosis (CN) on ultra-early diffusion-weighted imaging (DWI) and the severity of cytotoxic oedema (CytE) with cerebral oedema (CbrE), measured using quantitative analysis of apparent diffusion coefficient (ADC), could predict neurological outcomes before targeted temperature management in out-of-hospital cardiac arrest survivors (OHCAs).
In this retrospective study, the first DWI with ADC scans was performed within 6 h; the second was obtained between 72 and 96 h after return of spontaneous circulation. The primary outcome was neurological outcomes at 6 months after OHCA. The % voxels of ADC value (PV) was calculated; CbrE and CytE values were > or < than 650⁻⁶ mm²/s, respectively. The best performance PV was obtained from CytE (thld-CytE) and CbrE values (thld-CbrE). Prognostic performances of CN, thld-CytE, thld-CbrE, and converted scores were calculated in combination. The changes in DWI findings and the difference between the PV (ΔPV) from the first and second DWI were analysed.
Thirty-six patients were included. CN (area under receiver operating characteristic curve [AUC] = 0.800), thld-CytE (PV420; AUC = 0.730), and thld-CbrE (PV1090; AUC = 0.775) showed meaningful performance, and the combined score showed best performance for poor outcome prediction (AUC = 0.956). DWI findings of CN patients was worse at the second DWI. ΔPV significantly increased in the poor outcome group, CN patients, and the group including both, thld-CytE and thld-CbrE.
In OHCAs, ultra-early DWI with ADC could successfully predict poor neurological outcomes by combining scores of CN, thld-CytE, and thld-CbrE.
The crystal ball is filled with CSF
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Clinical paperThe usefulness of neuron-specific enolase in cerebrospinal fluid to predict neurological prognosis in cardiac arrest survivors who underwent target temperature management: A prospective observational study

Abstract

Aim

Methods

Results

Conclusion

Introduction

Section snippets

Study design and population

Patient characteristics

Discussion

Conclusion

Conflicts of interest statement

Acknowledgement

Resuscitation

Resuscitation

J Clin Neurosci

J Am Coll Cardiol

Resuscitation

Resuscitation

J Stroke Cerebrovasc Dis

J Clin Neurosci

J Neurol Sci

Resuscitation

Clin Chim Acta

Resuscitation

Resuscitation

Resuscitation

Ann Thorac Surg

Heart disease and stroke statistics-2018 update: a report from the American Heart Association

Circulation

Heart disease and stroke statistics-2012 update: a report from the American Heart Association

Circulation

Neurological prognostication after cardiac arrest in the era of target temperature management

Curr Neurol Neurosci Rep

Clinical paper
The usefulness of neuron-specific enolase in cerebrospinal fluid to predict neurological prognosis in cardiac arrest survivors who underwent target temperature management: A prospective observational study