BACKGROUND: Despite marked advances in intensive cardiology care, current options for outcome prediction in cardiac arrest survivors remain significantly limited. The aim of our study was, therefore, to compare the day-specific association of neuron-specific enolase (NSE) with outcomes in out-of-hospital cardiac arrest (OHCA) survivors treated with hypothermia. METHODS: Eligible patients were OHCA survivors treated with targeted temperature management at 33 °C for 24 h using an endovascular device. Blood samples for NSE levels measurement were drawn on days 1, 2, 3, and 4 after hospital admission. Thirty-day neurological outcomes according to the Cerebral Performance Category (CPC) scale and 12-month mortality were evaluated as clinical end points. RESULTS: A total of 153 cardiac arrest survivors (mean age 64.2 years) were enrolled in the present study. Using ROC analysis, optimal cutoff values of NSE for prediction of CPC 3-5 score on specific days were determined as: day 1 > 20.4 mcg/L (sensitivity 63.3%; specificity 82.1%; P = 0.002); day 2 > 29.0 mcg/L (72.5%; 94.4%; P < 0.001); and day 3 > 20.7 mcg/L (94.4%; 86.7%; P < 0.001). The highest predictive value, however, was observed on day 4 > 19.4 mcg/L (93.5%; 91.0%; P < 0.001); NSE value >50.2 mcg/L at day 4 was associated with poor outcome with 100% specificity and 42% sensitivity. Moreover, NSE levels measured on all individual days also predicted 12-month mortality (P < 0.001); the highest predictive value for death was observed on day 3 > 18.1 mcg/L (85.3%; 72.0%; P < 0.001). Significant association with prognosis was found also for changes in NSE at different time points. An NSE level on day 4 > 20.0 mcg/L, together with a change > 0.0 mcg/L from day 3 to day 4, predicted poor outcome (CPC 3-5) with 100% specificity and 73% sensitivity. CONCLUSIONS: Our results suggest that NSE levels are a useful tool for predicting 30-day neurological outcome and long-term mortality in OHCA survivors treated with targeted temperature management at 33 °C. The highest associations of NSE with outcomes were observed on day 4 and day 3 after cardiac arrest.

Cardiovascular Center Na Homolce Hospital Roentgenova 2 15000 Prague Czech Republic

See more in PubMed

Grasner JT, Lefering R, Koster RW, Masterson S, Bottiger BW, Herlitz J, Wnent J, Tjelmeland IB, Ortiz FR, Maurer H, et al. EuReCa ONE-27 Nations, ONE Europe, ONE Registry: A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe. Resuscitation. 2016;105:188–95. doi: 10.1016/j.resuscitation.2016.06.004. PubMed DOI

Stub D, Bernard S, Duffy SJ, Kaye DM. Post cardiac arrest syndrome: a review of therapeutic strategies. Circulation. 2011;123(13):1428–35. doi: 10.1161/CIRCULATIONAHA.110.988725. PubMed DOI

Callaway CW, Donnino MW, Fink EL, Geocadin RG, Golan E, Kern KB, Leary M, Meurer WJ, Peberdy MA, Thompson TM, et al. Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(18 Suppl 2):S465–482. doi: 10.1161/CIR.0000000000000262. PubMed DOI PMC

Nolan JP, Neumar RW, Adrie C, Aibiki M, Berg RA, Bottiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC, et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation. 2008;79(3):350–79. doi: 10.1016/j.resuscitation.2008.09.017. PubMed DOI

Dragancea I, Rundgren M, Englund E, Friberg H, Cronberg T. The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest. Resuscitation. 2013;84(3):337–42. doi: 10.1016/j.resuscitation.2012.09.015. PubMed DOI

Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–63. doi: 10.1056/NEJMoa003289. PubMed DOI

Hypothermia After Cardiac Arrest Study Group Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–56. doi: 10.1056/NEJMoa012689. PubMed DOI

Nolan JP, Soar J, Cariou A, Cronberg T, Moulaert VR, Deakin CD, Bottiger BW, Friberg H, Sunde K, Sandroni C. European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015: Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015. Resuscitation. 2015;2015(95):202–22. doi: 10.1016/j.resuscitation.2015.07.018. PubMed DOI

Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med. 2013;369(23):2197–206. doi: 10.1056/NEJMoa1310519. PubMed DOI

Zandbergen EG, Hijdra A, Koelman JH, Hart AA, Vos PE, Verbeek MM, de Haan RJ. Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology. 2006;66(1):62–8. doi: 10.1212/01.wnl.0000191308.22233.88. PubMed DOI

Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;67(2):203–10. doi: 10.1212/01.wnl.0000227183.21314.cd. PubMed DOI

Stammet P, Collignon O, Hassager C, Wise MP, Hovdenes J, Aneman A, Horn J, Devaux Y, Erlinge D, Kjaergaard J, et al. Neuron-specific enolase as a predictor of death or poor neurological outcome after out-of-hospital cardiac arrest and targeted temperature management at 33 degrees C and 36 degrees C. J Am Coll Cardiol. 2015;65(19):2104–14. doi: 10.1016/j.jacc.2015.03.538. PubMed DOI

Shinozaki K, Oda S, Sadahiro T, Nakamura M, Hirayama Y, Abe R, Tateishi Y, Hattori N, Shimada T, Hirasawa H. S-100B and neuron-specific enolase as predictors of neurological outcome in patients after cardiac arrest and return of spontaneous circulation: a systematic review. Crit Care. 2009;13(4):R121. doi: 10.1186/cc7973. PubMed DOI PMC

Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet. 1975;1(7905):480–4. doi: 10.1016/S0140-6736(75)92830-5. PubMed DOI

DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44(3):837–45. doi: 10.2307/2531595. PubMed DOI

Rundgren M, Cronberg T, Friberg H, Isaksson A. Serum neuron specific enolase - impact of storage and measuring method. BMC Res Notes. 2014;7:726. doi: 10.1186/1756-0500-7-726. PubMed DOI PMC

Mlynash M, Buckwalter MS, Okada A, Caulfield AF, Venkatasubramanian C, Eyngorn I, Verbeek MM, Wijman CA. Serum neuron-specific enolase levels from the same patients differ between laboratories: assessment of a prospective post-cardiac arrest cohort. Neurocrit Care. 2013;19(2):161–6. doi: 10.1007/s12028-013-9867-5. PubMed DOI

Stern P, Bartos V, Uhrova J, Bezdickova D, Vanickova Z, Tichy V, Pelinkova K, Prusa R, Zima T. Performance characteristics of seven neuron-specific enolase assays. Tumour Biol. 2007;28(2):84–92. doi: 10.1159/000098441. PubMed DOI

Huntgeburth M, Adler C, Rosenkranz S, Zobel C, Haupt WF, Dohmen C, Reuter H. Changes in neuron-specific enolase are more suitable than its absolute serum levels for the prediction of neurologic outcome in hypothermia-treated patients with out-of-hospital cardiac arrest. Neurocrit Care. 2014;20(3):358–66. doi: 10.1007/s12028-013-9848-8. PubMed DOI

Cronberg T, Rundgren M, Westhall E, Englund E, Siemund R, Rosen I, Widner H, Friberg H. Neuron-specific enolase correlates with other prognostic markers after cardiac arrest. Neurology. 2011;77(7):623–30. doi: 10.1212/WNL.0b013e31822a276d. PubMed DOI

Storm C, Nee J, Jorres A, Leithner C, Hasper D, Ploner CJ. Serial measurement of neuron specific enolase improves prognostication in cardiac arrest patients treated with hypothermia: a prospective study. Scand J Trauma Resusc Emerg Med. 2012;20:6. doi: 10.1186/1757-7241-20-6. PubMed DOI PMC

Daubin C, Quentin C, Allouche S, Etard O, Gaillard C, Seguin A, Valette X, Parienti JJ, Prevost F, Ramakers M, et al. Serum neuron-specific enolase as predictor of outcome in comatose cardiac-arrest survivors: a prospective cohort study. BMC Cardiovasc Disord. 2011;11:48. doi: 10.1186/1471-2261-11-48. PubMed DOI PMC

Tiainen M, Roine RO, Pettila V, Takkunen O. Serum neuron-specific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke. 2003;34(12):2881–6. doi: 10.1161/01.STR.0000103320.90706.35. PubMed DOI

Bouwes A, Binnekade JM, Kuiper MA, Bosch FH, Zandstra DF, Toornvliet AC, Biemond HS, Kors BM, Koelman JH, Verbeek MM, et al. Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Ann Neurol. 2012;71(2):206–12. doi: 10.1002/ana.22632. PubMed DOI

Oksanen T, Tiainen M, Skrifvars MB, Varpula T, Kuitunen A, Castren M, Pettila V. Predictive power of serum NSE and OHCA score regarding 6-month neurologic outcome after out-of-hospital ventricular fibrillation and therapeutic hypothermia. Resuscitation. 2009;80(2):165–70. doi: 10.1016/j.resuscitation.2008.08.017. PubMed DOI

Mortberg E, Zetterberg H, Nordmark J, Blennow K, Rosengren L, Rubertsson S. S-100B is superior to NSE, BDNF and GFAP in predicting outcome of resuscitation from cardiac arrest with hypothermia treatment. Resuscitation. 2011;82(1):26–31. doi: 10.1016/j.resuscitation.2010.10.011. PubMed DOI

Steffen IG, Hasper D, Ploner CJ, Schefold JC, Dietz E, Martens F, Nee J, Krueger A, Jorres A, Storm C. Mild therapeutic hypothermia alters neuron specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients. Crit Care. 2010;14(2):R69. doi: 10.1186/cc8975. PubMed DOI PMC

Pfeifer R, Franz M, Figulla HR. Hypothermia after cardiac arrest does not affect serum levels of neuron-specific enolase and protein S-100b. Acta Anaesthesiol Scand. 2014;58(9):1093–100. doi: 10.1111/aas.12386. PubMed DOI