Serum neuron-specific enolase as predictor of outcome in comatose cardiac-arrest survivors: a prospective cohort study

Cédric Daubin, Charlotte Quentin, Stéphane Allouche, Olivier Etard, Cathy Gaillard, Amélie Seguin, Xavier Valette, Jean-Jacques Parienti, Fabrice Prevost, Michel Ramakers, Nicolas Terzi, Pierre Charbonneau, Damien du Cheyron, Cédric Daubin, Charlotte Quentin, Stéphane Allouche, Olivier Etard, Cathy Gaillard, Amélie Seguin, Xavier Valette, Jean-Jacques Parienti, Fabrice Prevost, Michel Ramakers, Nicolas Terzi, Pierre Charbonneau, Damien du Cheyron

Abstract

Background: The prediction of neurological outcome in comatose patients after cardiac arrest has major ethical and socioeconomic implications. The purpose of this study was to assess the capability of serum neuron-specific enolase (NSE), a biomarker of hypoxic brain damage, to predict death or vegetative state in comatose cardiac-arrest survivors.

Methods: We conducted a prospective observational cohort study in one university hospital and one general hospital Intensive Care Unit (ICU). All consecutive patients who suffered cardiac arrest and were subsequently admitted from June 2007 to February 2009 were considered for inclusion in the study. Patients who died or awoke within the first 48 hours of admission were excluded from the analysis. Patients were followed for 3 months or until death after cardiopulmonary resuscitation. The Cerebral Performance Categories scale (CPC) was used as the outcome measure; a CPC of 4-5 was regarded as a poor outcome, and a CPC of 1-3 a good outcome. Measurement of serum NSE was performed at 24 h and at 72 h after the time of cardiac arrest using an enzyme immunoassay. Clinicians were blinded to NSE results.

Results: Ninety-seven patients were included. All patients were actively supported during the first days following cardiac arrest. Sixty-five patients (67%) underwent cooling after resuscitation. At 3 months 72 (74%) patients had a poor outcome (CPC 4-5) and 25 (26%) a good outcome (CPC 1-3). The median and Interquartile Range [IQR] levels of NSE at 24 h and at 72 h were significantly higher in patients with poor outcomes: NSE at 24 h: 59.4 ng/mL [37-106] versus 28.8 ng/mL [18-41] (p < 0.0001); and NSE at 72 h: 129.5 ng/mL [40-247] versus 15.7 ng/mL [12-19] (p < 0.0001). The Receiver Operator Characteristics (ROC) curve for poor outcome for the highest observed NSE value for each patient determined a cut-off value for NSE of 97 ng/mL to predict a poor neurological outcome with a specificity of 100% [95% CI = 87-100] and a sensitivity of 49% [95% CI = 37-60]. However, an approach based on a combination of SSEPs, NSE and clinical-EEG tests allowed to increase the number of patients (63/72 (88%)) identified as having a poor outcome and for whom intensive treatment could be regarded as futile.

Conclusion: NSE levels measured early in the course of patient care for those who remained comatose after cardiac arrest were significantly higher in patients with outcomes of death or vegetative state. In addition, we provide a cut-off value for NSE (> 97 ng/mL) with 100% positive predictive value of poor outcome. Nevertheless, for decisions concerning the continuation of treatment in this setting, we emphasize that an approach based on a combination of SSEPs, NSE and clinical EEG would be more accurate for identifying patients with a poor neurological outcome.

Figures

Figure 1
Figure 1
Profile of the study.
Figure 2
Figure 2
Frequency of different neurological outcome categories in relation to the individual highest measurement of NSE.
Figure 3
Figure 3
Receiver operating characteristic curves for different peak serum NSE cut-off values (ng/mL) to predict poor neurological outcome.
Figure 4
Figure 4
Predictors of poor outcome according to different clinical-EEG, NSE and SSEPs combinations. * included: myoclonus at 24 h, and absence of pupillary light reflex or corneal reflex, tonic-clonic seizures and malignant EEG pattern at 72 h.

References

    1. Wijdicks Neurology 2006 13these 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;67:203–210. doi: 10.1212/.
    1. Zandbergen EG, Hijdra A, Koelman JH, Hart AA, Vos PE, Verbeek MM, de Haan RJ. PROPAC Study Group. Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology. 2006;66:62–68.
    1. Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brainstem auditory evoked potentials in cardiac arrest patients treated with hypothermia. Crit Care Med. 2005;33:1736–1740. doi: 10.1097/01.CCM.0000171536.63641.D9.
    1. Koht A, Schatz W, Schmidt G, Schramm J, Watanabe E. Effects of etomidate, midazolam, and thiopental on median nerve somatosensory evoked potentials and the additive effects of fentanyl and nitrous oxide. Anesth Analg. 1988;67:435–441.
    1. Sloan TB, Fugina ML, Toleikis JR. Effects of midazolam on median nerve somatosensory evoked potentials. Br J Anaesth. 1990;64:590–593. doi: 10.1093/bja/64.5.590.
    1. Stecker MM, Cheung AT, Pochettino A, Kent GP, Patterson T, Weiss SJ, Bavaria JE. Deep hypothermic circulatory arrest: I. Effects of cooling on electroencephalogram and evoked potentials. Ann Thorac Surg. 2001;71:14–21. doi: 10.1016/S0003-4975(00)01592-7.
    1. Kottenberg-Assenmacher E, Armbruster W, Bornfeld N, Peters J. Hypothermia does not alter somatosensory evoked potential amplitude and global cerebral oxygen extraction during marked sodium nitroprusside-induced arterial hypotension. Anesthesiology. 2003;98:1112–1118. doi: 10.1097/00000542-200305000-00013.
    1. Zandbergen EG, de Haan RJ, Stoutenbeek CP, Koelman JH, Hijdra A. Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet. 1998;352:1808–1812. doi: 10.1016/S0140-6736(98)04076-8.
    1. Rundgren M, Karlsson T, Nielsen N, Cronberg T, Johnsson P, Friberg H. Neuron specific enolase and S-100B as predictors of outcome after cardiac arrest and induced hypothermia. Resuscitation. 2009;80:784–789. doi: 10.1016/j.resuscitation.2009.03.025.
    1. Fogel W, Krieger D, Veith M, Adams HP, Hund E, Storch-Hagenlocher B, Buggle F, Mathias D, Hacke W. Serum neuron-specific enolase as early predictor of outcome after cardiac arrest. Crit Care Med. 1997;25:1133–1138. doi: 10.1097/00003246-199707000-00012.
    1. Schoerkhuber W, Kittler H, Sterz F, Behringer W, Holzer M, Frossard M, Spitzauer S, Laggner AN. Time course of serum neuron-specific enolase. A predictor of neurological outcome in patients resuscitated from cardiac arrest. Stroke. 1999;30:1598–1603. doi: 10.1161/01.STR.30.8.1598.
    1. Rosén H, Sunnerhagen KS, Herlitz J, Blomstrand C, Rosengren L. Serum levels of the brain-derived proteins S-100 and NSE predict long-term outcome after cardiac arrest. Resuscitation. 2001;49:183–191. doi: 10.1016/S0300-9572(00)00348-8.
    1. Meynaar IA, Oudemans-van Straaten HM, van der Wetering J, Verlooy P, Slaats EH, Bosman RJ, van der Spoel JI, Zandstra DF. Serum neuron-specific enolase predicts outcome in post-anoxic coma: a prospective cohort study. Intensive Care Med. 2003;29:189–195.
    1. Tiainen M, Roine RO, Pettilä V, Takkunen O. Serum neuron-specific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke. 2003;34:2881–2886. doi: 10.1161/01.STR.0000103320.90706.35.
    1. Zingler VC, Krumm B, Bertsch T, Fassbender K, Pohlmann-Eden B. Early prediction of neurological outcome after cardiopulmonary resuscitation: a multimodal approach combining neurobiochemical and electrophysiological investigations may provide high prognostic certainty in patients after cardiac arrest. Eur Neurol. 2003;49:79–84. doi: 10.1159/000068503.
    1. Pfeifer R, Börner A, Krack A, Sigusch HH, Surber R, Figulla HR. Outcome after cardiac arrest: predictive values and limitations of the neuroproteins neuron-specific enolase and protein S-100 and the Glasgow Coma Scale. Resuscitation. 2005;65:49–55. doi: 10.1016/j.resuscitation.2004.10.011.
    1. Rech TH, Vieira SR, Nagel F, Brauner JS, Scalco R. Serum neuron-specific enolase as early predictor of outcome after in-hospital cardiac arrest: a cohort study. Crit Care. 2006;10:R133. doi: 10.1186/cc5046.
    1. Auer J, Berent R, Weber T, Porodko M, Lamm G, Lassnig E, Maurer E, Mayr H, Punzengruber C, Eber B. Ability of neuron-specific enolase to predict survival to hospital discharge after successful cardiopulmonary resuscitation. CJEM. 2006;8:13–18.
    1. Reisinger J, Höllinger K, Lang W, Steiner C, Winter T, Zeindlhofer E, Mori M, Schiller A, Lindorfer A, Wiesinger K, Siostrzonek P. Prediction of neurological outcome after cardiopulmonary resuscitation by serial determination of serum neuron-specific enolase. Eur Heart J. 2007;28:52–58.
    1. Oksanen T, Tiainen M, Skrifvars MB, Varpula T, Kuitunen A, Castrén M, Pettilä 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;80:165–170. doi: 10.1016/j.resuscitation.2008.08.017.
    1. Martens P, Raabe A, Johnsson P. Serum S-100 and neuron-specific enolase for prediction of regaining consciousness after global cerebral ischemia. Stroke. 1998;29:2363–2366. doi: 10.1161/01.STR.29.11.2363.
    1. Shinozaki K, Oda S, Sadahiro T, Nakamura M, Abe R, Nakada TA, Nomura F, Nakanishi K, Kitamura N, Hirasawa H!. Serum S-100B is superior to neuron-specific enolase as an early prognostic biomarker for neurological outcome following cardiopulmonary resuscitation. Resuscitation. 2009;80:870–875. doi: 10.1016/j.resuscitation.2009.05.005.
    1. Grubb NR, Simpson C, Sherwood RA, Abraha HD, Cobbe SM, O'Carroll RE, Deary I, Fox KA. Prediction of cognitive dysfunction after resuscitation from out-of-hospital cardiac arrest using serum neuron-specific enolase and protein S-100. Heart. 2007;93:1268–1273. doi: 10.1136/hrt.2006.091314.
    1. Cummins RO, Chamberlain DA, Abramson NS, Allen M, Baskett P, Becker L, Bossaert L, Delooz H, Dick W, Eisenberg M. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein Style. Task Force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Ann Emerg Med. 1991;20:861–874.
    1. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270:2957–2963. doi: 10.1001/jama.270.24.2957.
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. Prognosis in acute organ-system failure. Ann Surg. 1985;202:685–693. doi: 10.1097/00000658-198512000-00004.
    1. Daubin C, Guillotin D, Etard O, Gaillard C, du Cheyron D, Ramakers M, Bouchet B, Parienti JJ, Charbonneau P. A clinical and EEG scoring system that predicts early cortical response (N20) to somatosensory evoked potentials and outcome after cardiac arrest. BMC Cardiovasc Disord. 2008;8:35. doi: 10.1186/1471-2261-8-35.
    1. Synek VM. EEG abnormality grades and subdivisions of prognostic importance in traumatic and anoxic coma in adults. Clin Electroencephalogr. 1988;19:160–166.
    1. Synek VM. Prognostically important EEG coma patterns in diffuse anoxic and traumatic encephalopathies in adults. J Clin Neurophysiol. 1988;5:161–174. doi: 10.1097/00004691-198804000-00003.
    1. Thömke F, Marx JJ, Sauer O, Hundsberger T, Hägele S, Wiechelt J, Weilemann SL. Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus. BMC Neurol. 2005;5:14. doi: 10.1186/1471-2377-5-14.
    1. Simel DL, Samsa GP, Matchar DB. Likelihood ratios with confidence: sample size estimation for diagnostic test studies. J Clin Epidemiol. 1991;44:763–770. doi: 10.1016/0895-4356(91)90128-V.
    1. Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F. Predicting outcome from hypoxic-ischemic coma. JAMA. 1985;253:1420–1426. doi: 10.1001/jama.253.10.1420.
    1. Edgren E, Hedstrand U, Kelsey S, Sutton-Tyrrell K, Safar P. Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group. Lancet. 1994;343:1055–1059. doi: 10.1016/S0140-6736(94)90179-1.
    1. Chen R, Bolton CF, Young B. Prediction of outcome in patients with anoxic coma: a clinical and electrophysiologic study. Crit Care Med. 1996;24:672–678. doi: 10.1097/00003246-199604000-00020.
    1. Fischer C, Luauté J, Némoz C, Morlet D, Kirkorian G, Mauguière F. Improved prediction of awakening or nonawakening from severe anoxic coma using tree-based classification analysis. Crit Care Med. 2006;34:1520–1524. doi: 10.1097/01.CCM.0000215823.36344.99.
    1. Jorgensen EO, Holm S. Resuscitation. The natural course of neurological recovery following cardiopulmonary. Resuscitation. 1998;36:111–122. doi: 10.1016/S0300-9572(97)00094-4.
    1. Madl C, Kramer L, Domanovits H, Woolard RH, Gervais H, Gendo A, Eisenhuber E, Grimm G, Sterz F. Improved outcome prediction in unconscious cardiac arrest survivors with sensory evoked potentials compared with clinical assessment. Crit Care Med. 2000;28:721–6. doi: 10.1097/00003246-200003000-00020.
    1. Nakabayashi M, Kurokawa A, Yamamoto Y. Immediate prediction of recovery of consciousness after cardiac arrest. Intensive Care Med. 2001;27:1210–1214. doi: 10.1007/s001340100984.
    1. Robinson LR, Micklesen PJ, Tirschwell DL, Lew HL. Predictive value of somatosensory evoked potentials for awakening from coma. Crit Care Med. 2003;31:960–967. doi: 10.1097/01.CCM.0000053643.21751.3B.
    1. Madl C, Grimm G, Kramer L, Yeganehfar W, Sterz F, Schneider B, Kranz A, Schneeweiss B, Lenz K. Early prediction of individual outcome after cardiopulmonary resuscitation. Lancet. 1993;341:855–858. doi: 10.1016/0140-6736(93)93061-5.
    1. Rossetti AO, Oddo M, Logroscino G, Kaplan PW. Prognostication after cardiac arrest and hypothermia: a prospective study. Ann Neurol. 2010;67:301–307.
    1. Steffen IG, Hasper D, Ploner CJ, Schefold JC, Dietz E, Martens F, Nee J, Krueger A, Jörres 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:R69. doi: 10.1186/cc8301.
    1. Rundgren M, Westhall E, Cronberg T, Rosén I, Friberg H. Continuous amplitude-integrated electroencephalogram predicts outcome in hypothermia-treated cardiac arrest patients. Crit Care Med. 2010;38:1838–1844. doi: 10.1097/CCM.0b013e3181eaa1e7.

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