Elsevier

Resuscitation

Volume 168, November 2021, Pages 206-213
Resuscitation

Clinical paper
Neuron-specific enolase and long-term neurological outcome after OHCA – A validation study

https://doi.org/10.1016/j.resuscitation.2021.09.001Get rights and content

Abstract

Aims

To investigate what NSE levels predict long-term neurological prognosis at 24, 48 and 72 hours after ROSC in a cohort of out-of-hospital cardiac arrest and to validate previously suggested NSE cut-offs, including the latest ERC guidelines (2021).

Methods

Patients admitted to intensive care units in four hospitals in Southern Sweden between 2014–2018 were included. Blood samples were handled by a single local laboratory. The primary outcome was neurological outcome according to the Cerebral Performance Category (CPC) scale at 2–6 months after cardiac arrest.

Results

368 patients were included for analysis. A ≤2% false positive rate for the prediction of poor neurological outcome was achieved with an NSE cut-off value of >101 μg/L at 48 hours and >80 μg/L at 72 hours. The cut-off suggested by the recent ERC guidelines of >60 μg/L at 48 and/or 72 hours generated a false positive rate of 4.3% (95 %CI 0.9–7.4%).

Conclusion

A local validation study of the ability of serum levels of neuron-specific enolase to predict long-term poor neurological outcome after out-of-hospital cardiac arrest generated higher cut-offs than suggested by previous publications.

Introduction

Cardiac arrest is a major cause of mortality in the world. Comatose survivors of cardiac arrest admitted to ICU have about 50% mortality.1 Early mortality due to circulatory failure accounts for a third of cases. The remainder generally occurs later and are attributed to brain injury.2 Few patients meet the criteria for brain death. Instead, the majority of deaths attributed to brain injury are a result of the withdrawal of life-sustaining therapies (WLST) due to poor neurological prognosis and futile intensive care.2

The European Resuscitation Council (ERC) recommend a multimodal neuro prognostication no earlier than 72 hours after cardiac arrest.3 Blood biomarkers are easily sampled, often analysed at low cost, are not affected by sedative drugs and provide a numeric value not confounded by subjective interpretation. Neuron-Specific Enolase (NSE) is currently the only recommended biomarker. NSE is an enzyme mainly found in neuronal- and neuroendocrine cells, and levels are elevated after brain injury. NSE is also found in erythrocytes and malignant tumours, including neuroendocrine and small cell lung cancer. Hence levels may also be elevated due to haemolysis and tumours.

In patients with good neurological outcome, NSE typically decreases after 24 h, whereas NSE continues to increase in patients with poor outcome peaking at 48–96 hours. Results from early studies on patients resulted in guidelines suggesting NSE > 33 μg/L within three days after cardiac arrest predicted poor outcome with no false-positives.4 In patients treated with TTM, higher cut-offs have been reported, but results are conflicting.5., 6., 7., 8., 9., 10., 11., 12., 13. In a large, blinded sub-study of the TTM-trial, NSE ≥ 48 μg/L at 48 hours and ≥38 μg/L at 72 hours predicted poor long-term neurological outcome with a false-positive rate (FPR) ≤2%.5 In the largest study to date, NSE > 90 μg/L on day 3 predicted poor outcome with FPR 0.5% and outliers were described.6 Both the absolute change in NSE and the ratio of NSE change predicts neurological outcome.5., 14., 15., 16. A small study reported a 48:24 hour NSE ratio of ≥1.7 and a 72:24 hour NSE ratio of ≥1.3 to be 100% specific for poor outcome.14 In the most recent ERC guidelines,17 the multimodal prognostication algorithm suggests the cut-off NSE > 60 μg/L at 48 hours and/or 72 hours after ROSC to predict poor neurological outcome and increasing NSE levels 24–48 h or 24/48–72 h further support a likely poor outcome.

Studies on NSE levels have used different measuring techniques. NSE levels differ between laboratory methods.18., 19. Guidelines have long suggested that local laboratories create their own cut-offs through local validation studies, but no such studies have been published.17., 20. In the Region of Skane, Sweden, multimodal neuro prognostication of comatose survivors of cardiac arrest is performed according to ERC guidelines, including serum NSE levels analysed in the local laboratory.

The aims of the study were:

  • (1)

    To investigate what NSE levels predict poor long-term (2–6 months) neurological prognosis at 24, 48, and 72 hours after ROSC in a cohort of patients admitted to intensive care after out-of-hospital cardiac arrest (OHCA).

  • (2)

    To validate previously suggested NSE cut-offs and FPRs to predict poor outcome, including the 2021 ERC guidelines.

We hypothesized that local cut-offs would not differ from previously suggested cut-offs.5., 17.

Section snippets

Patients

We conducted a retrospective multicentre observational study of post-cardiac arrest patients included in SWECRIT - a regional biobank aiming to include all adult (>18 years old) patients admitted to intensive care in four ICUs in Skane, Sweden, between 2014–2018. Post-cardiac arrest patients were identified by ICD-10 in the local intensive care registry. Patients who suffered OHCA were identified through medical notes. All sites performed percutaneous cardiac intervention (PCI), at one site PCI

Included patients

In 2014–2018, 624 adult patients were admitted to intensive care after OHCA, of which 554 were included in the SWECRIT biobank and patient database. At least one valid NSE sample was available for 368/554 patients (Fig. 1). 110/368 were identified as having suffered an unwitnessed arrest with first monitored rhythm asystole and/or retrospectively found to have had a non-cardiac cause of arrest.

Study population

Patient characteristics are described in Table 1. Overall, the group with NSE samples and the group

Discussion

In this validation study of the ability of NSE to predict long-term neurological outcome after OHCA, the main findings were: 1) NSE levels in comatose survivors of OHCA predicted poor outcome at 24, 48 and 72 hours after ROSC, with the best accuracy at 48 hours. At 48 hours, a cut-off of 101 μg/L had a FPR ≤2%. At 72 hours, a cut-off of 80 μg/L had a FPR ≤2%. 2). Contrary to our hypothesis, cut-off values in this study population were higher than most previously published studies.5., 7., 8., 9.

Limitations

The present study is limited by its retrospective design. All samples were analysed in one central lab, which limits external validity in settings where this is not available. The quality of data was dependent on the quality of documentation in the patients’ medical notes. Thirty-three per cent of patients were excluded due to missing NSE samples, with a risk of selection bias when tests were ordered by the treating physician. However, the outcome was similar in the patients with and without

Conclusion

This local validation study of the ability of serum NSE to predict long-term poor neurological outcome generated higher cut-offs than suggested by previous publications, including the latest guidelines from the European Resuscitation Council. NSE cannot alone fully predict the functional consequences of anoxic brain injury after cardiac arrest, and neuro prognostication should be multimodal. Confounders including haemolysis should be considered when interpreting NSE values. Before implementing

Funding

Regional Research Support Region Skåne and Government funding of clinical research within the Swedish National Health Services (ALF).

Ethical statement

Regional Ethical Review Board Lund, Protocol 2014/46, 2015/267, and 2016/583. Patient consent was obtained through an opt-out decision, i.e. patients who regained consciousness received a letter with information to contact the investigators if they did not want to participate. For patients who never regained consciousness, consent was assumed.

CRediT authorship contribution statement

Emilie Lissner Östlund: Conceptualization, Methodology, Formal analysis, Writing – original draft, Visualization. Helena Levin: Project administration, Data curation, Methodology, Writing – review & editing. Niklas Nielsen: Conceptualization, Writing – review & editing. Attila Frigyesi: Methodology, Writing – review & editing. Anna Lybeck: Conceptualization, Methodology, Supervision, Funding acquisition, Resources, Writing – review & editing.

References (23)

Cited by (0)

1

Address: Department of Anesthesia and Intensive Care, Skane University Hospital, 221 85 Lund, Sweden.

2

Address: Department of Research & Education, Skane University Hospital, 221 85 Lund, Sweden.

3

Address: Department of Anesthesia and Intensive Care, Helsingborg Hospital, 251 87, Helsingborg, Sweden.

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