Are serial neuron-specific enolase levels associated with neurologic outcome of ECPR patients: A retrospective multicenter observational study

a b s t r a c t

Aim of the study: This study aims to evaluate whether Neuron-specific enolase level at 48 h after extracor- poreal cardiopulmonary resuscitation (ECPR) is associated with neurologic outcomes at 6 months after hospital discharge.

Methods: This was a retrospective, multicenter, observational study of adult patients who received ECPR between May 2010 and December 2016. In the two hospitals involved in this study, NSE measurements were a routine part of the protocol for patients who received ECPR. Serial NSE levels were measured in all patients with ECPR. NSE levels were measured 24, 48, and 72 h after ECPR. The primary outcome was Cerebral Performance Catego- ries (CPC) scale at 6 months after hospital discharge according to NSE levels at 48 h after ECPR.

Results: At follow-up 6 months after hospital discharge, Favorable neurologic outcomes of CPC 1 or 2 were ob- served in 9 (36.0%) of the 25 patients, and Poor neurologic outcomes of CPC 3, 4, or 5 were observed in 16 (64%) patients. NSE levels at 24 h in the favorable and poor neurologic outcome groups were 58.3 (52.5-73.2) ug/L and 64.2 (37.9-89.8) ug/L, respectively (p = 0.95). NSE levels at 48 h in the favorable and poor neurologic outcome groups were 52.1 (22.3-64.9) ug/L and 302.0 (62.8-360.2) ug/L, respectively (p = 0.01). NSE levels at 72 h were 37.2 (12.5-53.2) ug/L and 240.9 (75.3-370.0) ug/L, respectively (p < 0.01). In receiver operating char- acteristic (ROC) curve analysis, as the predictor of poor outcome, the optimal cut-off value for NSE level at 48 h was 140.5 ug/L, and the area under the curve (AUC) was 0.844 (p < 0.01). The optimal cut-off NSE level at 72 h was 53.2 ug/L, and the AUC was 0.897 (p < 0.01).

Conclusions: NSE level at 72 h displayed the highest association with neurologic outcome after ECPR, and NSE level at 48 h was also associated with neurologic outcome after ECPR.

(C) 2023 Published by Elsevier Inc.

  1. Introduction

According to the 2020 American Heart Association (AHA) guidelines, extracorporeal cardiopulmonary resuscitation can be consid- ered for select patients with refractory cardiac arrest [1]. Although there is insufficient evidence regarding the efficacy of ECPR, applying extracorporeal membrane oxygenation during cardiopulmo- nary resuscitation (CPR) may lead to a rapid improvement in blood flow and neurologic outcome [2]. However, maintaining ECMO is very

* Corresponding author at: Professor and Emergency Medicine department Konkuk University Medical Center, Konkuk University School of Medicine 120-1, Neungdong-ro, Gwangjin-gu, Seoul, Republic of Korea.

E-mail address: [email protected] (Y.H. Lee).

1 Han Bit Kim and Jeong Hoon Yang contributed equally to this work.

expensive, and the supply of ECMO is limited compared with the de- mand for ECMO. Therefore, it is important to predict neurologic out- come as soon as possible and make early decisions pertaining to the maintenance of ECMO in order to inform next treatment steps and min- imize resource wastage [3]. Neurologic assessment of patients with re- covery of spontaneous circulation (ROSC) after cardiac arrest is performed with several factors in mind based on clinical examination [4,5]. However, most patients receiving ECMO during post-CPR care are unconscious and/or receive Sedative infusion, making it difficult to assess neurologic status [6,7]. In predicting poor neurologic outcomes in Post-cardiac arrest syndrome (PCAS) with conventional CPR, the AHA guidelines recommend that Neuron-specific enolase levels can be used in combination with factors such as physical examination, electrophysiology, brain imaging, and other biomarkers [1]. NSE is cur- rently the most studied biomarker for predicting neurologic outcome 0735-6757/(C) 2023 Published by Elsevier Inc.

after cardiac arrest [6]; it is produced by dying neurons and levels pos- itively correlate with nerve damage severity and malignant electroen- cephalogram changes [8]. Moreover, many studies have found that high NSE levels are associated with poor neurologic outcomes in pa- tients with brain injury due to PCAS, traumatic brain injury, or stroke [9-12]. Most studies of NSE and PCAS have focused on conventional CPR. However, more recently, while studies have been conducted on the relationship between the neurologic outcome of PCAS in ECPR and NSE, most are still unknown, yet [3,13].

Thus, this study investigates whether serial NSE levels after ECPR are associated with the neurologic outcomes of ECPR patients. We hypoth- esized that NSE levels at 48 h after ECPR is associated with neurologic outcomes at 6 months after hospital discharge.

  1. Methods
    1. Study population

This was a retrospective, multicenter, observational study of adult patients who underwent ECPR at the Hallym University Medical Center (HUMC) and Samsung Medical Center (SMC) between May 2010 and December 2016. This study was approved by the institutional review boards of HUMC (HUMC 2015i128) and SMC (2017-11-088-002).

Trained study abstractors collected the clinical and laboratory data using a standardized case report form (Appendix 1). Abstractors were blinded to the hypothesis of the study at the time of data collection. Questions about data entry fields or disagreements between abstractors were discussed until consensus was achieved. All patients who under- went ECPR were included. After ECPR, brain computed tomography (CT) was performed to confirm the absence of other brain lesions such as subarachnoid hemorrhage . The exclusion criteria included:

(a) under 18 years of age; (b) previous CPC score >= 2; (c) not performed brain CT; (d) SAH on brain CT; (e) not performed serial NSE measure- ment every 24 h up to 72 h or missing data; (f) cause of death other

than brain death or unknown cause. Thus, 25 patients who received ECPR with veno-arterial ECMO were enrolled (Fig. 1).

    1. Definitions and outcomes

In this study, ECPR was defined as successful veno-arterial ECMO im- plantation and pump-on with chest compression during the index pro- cedure in patients with cardiac arrest. Even if ROSC occurred during ECMO implantation, the pump-on process was not interrupted [14,15]. ECMO pump-on was defined as cessation of chest compression after ECMO implantation and activation. Resuscitation was performed in the same way as described in our previous studies [16]. The arrest to ECMO pump-on time was defined as the time from cardiac arrest to the time the ECMO pump was turned on. Targeted temperature man- agement was implemented using a commercially available Surface cooling device (Arctic Sun(R); Medivance Corp., Louisville, CO, USA). Out- come was defined using the Glasgow-Pittsburgh Cerebral Performance Categories (CPC) scale at 6 months after hospital discharge. CPC scores of 1-2 were classified as favorable neurologic outcomes. CPC scores of 3, 4, and 5 were classified as poor neurologic outcomes. The CPC scale was measured by two independent neurologists at discharge, and follow-up CPC assessment after six months was performed while treating the patient through re-visiting or, if not feasible, by conducting a telephone interview.

    1. ECPR procedure

The CPR team was first activated at the onset of CPR. Conditions that subsequently activated the ECMO team included CPR lasting >10 min, refractory cardiogenic shock after successful resuscitation, or recurrent cardiac arrest. The ECMO team consisted of cardiologists, cardiovascular surgeons, intensivists, specialized nurses, and perfusionists. The ECMO team leader evaluated the patient together with the CPR team leader and decided whether to conduct ECMO. ECPR was performed when witnessed cardiac arrest was evident, there was no response after

Image of Fig. 1

Fig. 1. The study flow diagram. ECPR, extracorporeal cardiopulmonary resuscitation; CT, computed tomography; NSE, neuron-specific enolase.

conventional CPR for >10 min, and the cause of cardiac arrest was judged to be reversible. ECPR was suspended under the following con- ditions: a Life expectancy of <6 months, terminal malignancy, unwitnessed cardiac arrest, poor physical activity prior to cardiac arrest, an unprotected airway, or CPR was performed for >60 min from the first cardiac arrest. A percutaneous vascular approach using the Seldinger technique was first attempted in all cases with the femoral vessels the most used vascular access. When ECMO implantation was successfully performed, chest compression was stopped. The initial number of revo- lutions per minute of the ECMO device was adjusted to obtain a cardiac index of >2.2 L/min/m2 of body surface area, central mixed venous ox- ygen saturation of >70%, and a mean arterial pressure of >65 mmHg. Blood pressure was measured continuously using an arterial catheter, arterial blood gas analysis was performed in the artery of the right arm to estimate cerebral oxygenation. Additional fluids, blood transfu- sion and/or catecholamines (norepinephrine, epinephrine or dobuta- mine) were supplied to maintain intravascular volume and/or to achieve a mean arterial pressure of >65 mmHg, if necessary. If hypoper- fusion of the leg was suspected, as noted on physical examination and Doppler ultrasound of the femoral artery, an additional 7-9 Fr percuta- neous catheter distal to the ECMO arterial cannula was placed into the superficial femoral artery. After ECMO implantation, approaches to treat the underlying cause of cardiac arrest, including percutaneous cor- onary intervention, Coronary artery bypass grafting, heart transplanta- tion, and non-cardiopulmonary surgery, were performed.

    1. Serial NSE measurement

NSE levels were measured in all patients who underwent ECPR. In the two hospitals involved in this study, NSE measurements were a rou- tine part of the protocol for patients who received ECPR. Serial NSE mea- surements were performed 24, 48, and 72 h after ECMO pump-on. Each measurement was performed within 3 h before and after the scheduled time of measurement. Blood samples with hemolysis were excluded and blood samples were obtained again in these cases. Quantitative as- sessment of NSE was performed using an electroluminescence immu- noassay (DIAsource NSE-IRMA Kit, DIAsource Immunoassays S.A., Rue du Bosquet, 2, B-1348 Louvain-la-Neuve, Belgium).

    1. Statistical analyses

All statistical analyses were performed using the R software version

included in this study (Fig. 1). The mean age of patients was 47.5+- 14 years, and 72.0% were male. Among the 25 patients, 9 (36.0%) had fa- vorable neurologic outcomes and 16 (64.0%) had poor neurologic out- comes. Neurologic outcomes did not change during follow-up after six months. There were no significant differences in age, sex, previous med- ical history, or initial GCS score between favorable and poor neurologic outcome groups. There was a significant difference in body mass (22.9+- 3.4 vs. 26.2+-3.3, p = 0.03) (Table 1).

There were no significant differences in the ratios of out-of-hospital cardiac arrest (OHCA), witness cardiac arrest, bystander cardiac arrest, Initial shockable rhythm, defibrillation, and cardiac arrest. There were also no significant differences in the ECMO to pump-on times (Table 1). Initial laboratory findings, including lactic acid, hemoglobin, total bilirubin, blood urea nitrogen, creatinine, PT, INR, and aPTT showed no significant differences between favorable and poor neurologic outcome

groups (Table 2).

There was no significant difference in NSE levels 24 h after ECMO pump-on, however NSE levels at 48 h significantly differed between fa- vorable and poor neurologic outcome groups (52.1[22.3-64.9] ug/L vs. 302.0[62.8-360.2] ug/L, p = 0.01). NSE levels at 72 h were also signifi- cantly different between groups (37.2[12.5-53.2] ug/L vs. 240.9 [75.3-370.0] ug/L, p < 0.01) (Table 2 and Fig. 2).

On the ROC curve, NSE level at 24 h had an optimal cut-off value of

83.0 ug/L, AUC 0.479 (p < 0.01), NSE level at 48 h had an optimal cut- off value of 140.5 ug/L, AUC 0.844 (p < 0.01), and NSE level at 72 h had an optimal cut-off value of 53.2 ug/L, AUC 0.897 (p < 0.01) (Fig. 3).

  1. Discussion

We found that elevated NSE levels were associated with poor neu- rologic outcomes in patients who underwent ECPR. NSE level elevation at 72 h showed the highest association with poor neurologic outcome (AUC 0.897, p < 0.01), and NSE level elevation at 48 h was also associ- ated with poor neurologic outcome (AUC 0.844, p < 0.01).

NSE levels are helpful in predicting neurologic outcomes in post- cardiac arrest patients. In predicting neurologic outcomes following conventional CPR, the AHA guidelines recommend that NSE levels be used in combination with various other neurologic examination

Table 1

General characteristics of patients.

4.0.3 for Windows (R Foundation for Statistical Computing, Vienna,

Austria). Frequency analyses were conducted to identify participants’ characteristics. Nominal variables are presented as counts and percent- ages of the total numbers. Continuous variables without normal distri- bution are presented as medians and interquartile ranges. We used the Kolmogorov-Smirnov test to evaluate the distribution of continuous variables, and conducted a cross-analysis to identify the impact of the variables on neurologic outcomes. In addition, all variables were compared using the chi-squared or Fisher’s exact test and Wilcoxon rank-sum test at a significance level of p < 0.05. Receiver operating

Favorable neurologic outcome (N = 9)

Poor neurologic P outcome

(N = 16)

characteristic (ROC) curves were constructed to determine the diagnos- tic accuracy of NSE and lactate in predicting a patient’s neurologic out- come. Youden’s index was used to determine the cut-off values. The maximum index value was used to select the optimal cutoff value.

Statistical significance was set at P < 0.05.

OHCA, n (%)

Witness, n (%)

5 (55.6)

9 (100.0)

4 (25.0)

13 (81.2)



Bystander, n (%)

7 (77.8)

13 (81.2)


3. Results

Initial shockable rhythm, n (%)

4 (57.1)

5 (35.7)


Defibrillation, n (%)

6 (66.7)

11 (68.8)


Of the 357 patients who underwent ECPR during hospitalization at Cardiac arrest cause, n (%) 0.23

Cardiac 6 (66.7) 15 (93.8)

HUMC and SMC. Two patients under 18 years of age, 14 patients with Non-cardiac 3 (33.3) 1 (6.2)

previous CPC >= 3, 241 patients without brain CT, 16 patients of SAH on

Arrest to ECMO pump-on time,

45.0 (19.0-48.0)

48.0 (20.0-64.0)


brain CT, 34 patients with not performed serial NSE measurement or

missing data, and 26 patients with cause of death other than brain

min, median (IQR)

Initial Glasgow Coma Scale

3.0 (3.0-3.0)

3.0 (3.0-3.0)


Dyslipidemia 0 (0.0) 2 (12.5) 0.74

Current smoker 3 (33.3) 5 (31.2) 1.00

Demographics Age, years




Gender (male), n (%)

5 (55.6)

13 (81.2)


Body mass index, kg/m2




Medical history, n (%)

Diabetes mellitus

1 (11.1)

4 (25.0)



3 (33.3)

7 (43.8)



0 (0.0)

3 (18.8)


Previous myocardial infarction 0 (0.0) 2 (12.5) 0.74

Resuscitation characteristics

death or unknown cause were excluded. Thus, 25 patients were

OHCA, out-of-hospital cardiac arrest; ECMO, extracorporeal membrane oxygenation.

Table 2

Laboratory findings in patients.

Initial laboratory data

lactate, mmol/L

11.2 (10.5-13.7)

10.4 (7.6-13.8)


Hemoglobin before ECMO,

14.5 (11.8-15.1)

13.8 (13.1-15.5)



Hemoglobin after ECMO, g/dl

11.0 (10.0-11.9)

12.5 (11.6-13.7)


Total bilirubin, mg/dl

0.3 (0.3-0.5)

0.7 (0.4-1.0)


Blood urea nitrogen, mg/dl

12.0 (9.8-18.4)



Creatinine, mg/dl

1.2 (1.0-1.4)

1.4 (1.3-1.9)


PT, s

13.7 (13.4-15.5)

13.5 (13.2-13.6)



1.3 (1.0-1.5)

1.1 (1.0-0.1.3)


aPTT, s

54.6 (30.2-104.1)

38.3 (34.4-46.3)



7.1 (6.9-7.3)

7.0 (6.9-7.2)


PaO2, mmHg

82.5 (50.0-153.9)

25.5 (12.3-88.1)


PaCO2, mmHg

53.4 (31.6-70.5)

69.0 (39.0-87.0)


Bicarbonate, mmol/L

13.3 (10.6-19.3)

19.3 (10.0-24.6)


Serial NSE level, ug/L

24 h NSE level

58.3 (52.5-73.2)

64.2 (37.9-89.8)


48 h NSE level

52.1 (22.3-64.9)

302 (62.8-360.2)


72 h NSE level

37.2 (12.5-53.2)

240 (75.3-370.0)


Favorable Neurologic Outcome (N = 9)

Poor Neurologic P Outcome

(N = 16)

methods [1]. In most post-cardiac arrest patients, it is difficult to per- form Neurologic examinations because target temperature manage- ment is performed, and sedatives and Muscle relaxants are used [6,7]. In these situations, using NSE levels confers an advantage in predicting neurologic outcomes. With this, the unnecessary wastage of medical re- sources may be prevented.

There have been several previous studies on NSE in patients with PCAS, and elevated NSE levels were associated with poor neurologic outcome [6,12,17-25]. Serial NSE measurements were more accurate than single NSE measurements in predicting poor neurologic outcomes. Previous studies for serial NSE measurements on conventional CPR pa- tients showed that either 48 or 72 h had the highest Predictive power for neurologic outcome [26-29]. On the other hand, there have been few studies on the association between NSE levels and neurologic out- come in ECPR patients, and the number of enrolled patients has been small [3,7,13,30]. ECPR is also associated with hemolysis of erythrocytes and thrombocytes, which may further elevate NSE levels [3,13].

Floerchinger et al. studied the association between NSE levels mea- sured within 48 h after ECPR and neurologic outcomes in 134 patients [13]. It was found that the higher the NSE level at 24 h, the higher the serum free hemoglobin level, which indicates hemolysis. Nevertheless,

ECMO, extracorporeal membrane oxygenation; PT, prothrombin time; INR, international normalized ratio; aPTT, activated partial thromboplastin time; NSE, neuron-specific enolase.

there was a significant difference in NSE levels at 48 h correlating with the presence or absence of brain injury. The cut-off value of the NSE

Image of Fig. 2

Fig. 2. Boxplots of peak neuron-specific enolase levels as time course between favorable and poor neurologic outcome groups. NSE levels at 48 h significantly differed between groups (52.1[22.3-64.9] ug/L vs. 302.0[62.8-360.2] ug/L, p = 0.01). NSE levels at 72 significantly differed between groups (37.2[12.5-53.2] ug/L vs. 240.9[75.3-370.0] ug/L, p < 0.01).

Image of Fig. 3

Fig. 3. R receiver operating characteristic curves for serum peak neuron-specific enolase (NSE) levels at 24 h, 48 h, and 72 h after extracorporeal cardiopulmonary resuscitation . The area under the ROC curve of peak NSE level at 24 h is 0.479(95% CI:0.184-0.775), at 48 h is 0.844(95% CI:0.687-1) and at 72 h is 0.897(95% CI:0.758-1).

level peak was presented as 100 ug/L, and the AUC value was presented as 0.73 (95% confidence interval 0.65-0.82). However, unlike in our study, neurologic outcome was not judged by CPC assessment but by Brain CT scan.

Schrage et al. described the association between NSE level and neu- rologic outcome of ECPR patients, dividing 129 patients into derivation and validation cohorts [3]. At 48 h, the cut-off NSE level value of 70 ug/L and AUC of 0.87 showed the highest Discriminatory power of neurologic outcome. However, unlike our study, favorable neurologic outcomes were defined as CPC 1, 2, and 3. In addition, unlike this study, which in- cluded only patients who underwent ECMO implantation during active CPR, both patients who underwent ECMO implantation during active CPR and those who underwent ECMO implantation within 6 h after resuscitation were included.

Petermichl et al. investigated patients who underwent ECMO im- plantation at the prehospital level [30]. They found that NSE levels

peaked at 48 h, and the discriminatory power between the CPC 1-2 group and the CPC 3-4 group at 72 h (p < 0.001) was higher than that at 48 h (p = 0.002). In another ECPR study, NSE level was measured on days 1, 3, and 7, and the NSE level elevation at 72 h showed the highest association with poor neurologic outcome [7].

In most studies on serial NSE, NSE level elevation at 48 h had the highest association with poor neurologic outcome, whereas in studies of ECPR, NSE level elevations at either 48 or 72 h had the highest associ- ation with poor neurologic outcome [3,13,30].

The particular strength of this study lies in the multicenter tracking of the serial trend of NSE only for patients who directly underwent ECMO during active CPR. Moreover, another strength was our long- term tracking of neurologic outcome for up to 6 months.

However, this study has several limitations. First, the sample size of 25 was very small because ECPR is relatively uncommon. In addition, Among the 357 patients who underwent ECPR, 241 patients who did

not undergo brain CT were excluded. Brain CT was performed to ex- clude patients with brain lesion such as SAH. However, as a result, 67% of patients were excluded. Therefore, the sample size is unlikely to rep- resent the entire ECPR population. We aimed to study whether NSE was associated with prognosis in the absence of brain lesions which are not associated with Hypoxic brain damage such as SAH. This is the strength of our study, but it also caused the disadvantage of increasing the num- ber of excluded patients. Thus, a large-scale prospective study with a larger sample size should be undertaken in the future. Second, there may be some differences that are hidden by the small sample size be- tween favorable neurologic outcome group and poor neurologic out- come group. As mentioned in the results, there was no statistically significant difference except body mass index. However, although not statistically significant, initial shockable rhythm rate was higher in the favorable neurologic outcome group (57.1% vs 35.7%), and the rate of cardiac cause arrest was lower in the favorable neurologic outcome group (66.7% vs 93.8%). These points should be considered in interpret- ing the results of this study. Third, there was no verification of results due to the small sample size. Fourth, the degree of hemolysis induced by ECMO could not be determined. Fourth, this study was not double- blinded at the time of data collection, which may have caused bias.

  1. Conclusions

With neurologic outcomes after ECPR, NSE levels at 72 h showed the highest association, while NSE levels at 48 h was also associated with neurologic outcome. This study is suggestive, and it warrants further study to find a relationship between NSE levels and neurologic out- comes after ECPR.


This work was supported by the Soonchunhyang University research fund.

CRediT authorship contribution statement

Han Bit Kim: Writing – review & editing, Writing – original draft, Vi- sualization, Formal analysis, Conceptualization. Jeong Hoon Yang: Writing – review & editing, Writing – original draft, Data curation. Young Hwan Lee: Writing – review & editing, Methodology, Conceptu- alization.

Declaration of Competing Interest

The authors have no conflict of interest to disclose.


We appreciate support and dedication in data collection from Nayeon Kim at Cancer Education Center, Samsung Medical Center.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2023.03.047.


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