Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Neuroprognostication of hypoxic–ischaemic coma in the therapeutic hypothermia era

Nature Reviews Neurology volume 10, pages 190–203 (2014)Cite this article

Subjects

Key Points

  • Therapeutic hypothermia (TH) influences the time course of neurological recovery after cardiac arrest, and the influence of added sedation is also of paramount importance

  • Standard modalities for assessing prognosis might be influenced by the use of TH

  • Promising tools for prognostication in the era of TH include certain blood biomarkers, brainstem reflexes, somatosensory evoked potentials, EEG reactivity, and neuroimaging findings

  • Clinicians should use a multimodal approach to prognosticate for individual patients

  • To improve generalizability of prognostic modalities, future studies should record, in a standardized fashion, the time before return of spontaneous circulation, the fraction of patients with out-of-hospital arrest, and other patient characteristics

  • Standardization of terminology, procedures and outcome measures using common data elements in future prospective research investigations will improve comparisons—and potentially allow pooling of data—across studies

Abstract

Neurological prognostication after cardiac arrest has always been challenging, and has become even more so since the advent of therapeutic hypothermia (TH) in the early 2000s. Studies in this field are prone to substantial biases—most importantly, the self-fulfilling prophecy of early withdrawal of life-sustaining therapies—and physicians must be aware of these limitations when evaluating individual patients. TH mandates sedation and prolongs drug metabolism, and delayed neuronal recovery is possible after cardiac arrest with or without hypothermia treatment; thus, the clinician must allow an adequate observation period to assess for delayed recovery. Exciting advances have been made in clinical evaluation, electrophysiology, chemical biomarkers and neuroimaging, providing insights into the underlying pathophysiological mechanisms of injury, as well as prognosis. Some clinical features, such as pupillary reactivity, continue to provide robust information about prognosis, and EEG patterns, such as reactivity and continuity, seem promising as prognostic indicators. Evoked potential information is likely to remain a reliable prognostic tool in TH-treated patients, whereas traditional serum biomarkers, such as neuron-specific enolase, may be less reliable. Advanced neuroimaging techniques, particularly those utilizing MRI, hold great promise for the future. Clinicians should continue to use all the available tools to provide accurate prognostic advice to patients after cardiac arrest.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Forest plots showing FPR and sensitivity of predictors of neurological outcome after cardiac arrest, with and without TH.
Figure 2: Fibre tractography using a thalamic region of interest.
Figure 3: A suggested approach to the comatose post-cardiac arrest patient, with and without therapeutic hypothermia.

Similar content being viewed by others

References

  1. Wijdicks, E. F., Hijdra, A., Young, G. B., Bassetti, C. L. & 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 67, 203–210 (2006).

    CAS  PubMed  Google Scholar 

  2. Deakin, C. D. et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 4. Adult advanced life support. Resuscitation 81, 1305–1352 (2010).

    PubMed  Google Scholar 

  3. Tortorici, M. A., Kochanek, P. M. & Poloyac, S. M. Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit. Care Med. 35, 2196–2204 (2007).

    CAS  PubMed  Google Scholar 

  4. Arpino, P. A. & Greer, D. M. Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest. Pharmacotherapy 28, 102–111 (2008).

    CAS  PubMed  Google Scholar 

  5. Cronberg, T. et al. Neurological prognostication after cardiac arrest—recommendations from the Swedish Resuscitation Council. Resuscitation 84, 867–872 (2013).

    PubMed  Google Scholar 

  6. Arnoldus, E. P. & Lammers, G. J. Postanoxic coma: good recovery despite myoclonus status. Ann. Neurol. 38, 697–698 (1995).

    CAS  PubMed  Google Scholar 

  7. Morris, H. R., Howard, R. S. & Brown, P. Early myoclonic status and outcome after cardiorespiratory arrest. J. Neurol. Neurosurg. Psychiatry 64, 267–268 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Levy, D. E. et al. Predicting outcome from hypoxic–ischemic coma. JAMA 253, 1420–1426 (1985).

    CAS  PubMed  Google Scholar 

  9. Plum, F. & Posner, J. B. The diagnosis of stupor and coma. Contemp. Neurol. Ser. 10, 1–286 (1972).

    CAS  PubMed  Google Scholar 

  10. Greer, D. M. et al. Clinical examination for outcome prediction in nontraumatic coma. Crit. Care Med. 40, 1150–1156 (2012).

    PubMed  Google Scholar 

  11. Greer, D. M. et al. Clinical examination for prognostication in comatose cardiac arrest patients. Resuscitation 84, 1546–1551 (2013).

    PubMed  PubMed Central  Google Scholar 

  12. Peberdy, M. A. et al. Part 9: post-cardiac arrest care: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 122 (Suppl. 3), S768–S786 (2010).

    PubMed  Google Scholar 

  13. Zandbergen, E. G. et al. Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology 66, 62–68 (2006).

    CAS  PubMed  Google Scholar 

  14. Cronberg, T., Horn, J., Kuiper, M. A., Friberg, H. & Nielsen, N. A structured approach to neurologic prognostication in clinical cardiac arrest trials. Scand. J. Trauma Resusc. Emerg. Med. 21, 45 (2013).

    PubMed  PubMed Central  Google Scholar 

  15. Nolan, J. P. et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary. Resuscitation 81, 1219–1276 (2010).

    PubMed  Google Scholar 

  16. Becker, L. B. et al. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation 124, 2158–2177 (2011).

    PubMed  PubMed Central  Google Scholar 

  17. Booth, C. M., Boone, R. H., Tomlinson, G. & Detsky, A. S. Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. JAMA 291, 870–879 (2004).

    CAS  PubMed  Google Scholar 

  18. Morrison, L. J. et al. Validation of a rule for termination of resuscitation in out-of-hospital cardiac arrest. N. Engl. J. Med. 355, 478–487 (2006).

    CAS  PubMed  Google Scholar 

  19. Farrell, B., Godwin, J., Richards, S. & Warlow, C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J. Neurol. Neurosurg. Psychiatry 54, 1044–1054 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Jennett, B. & Bond, M. Assessment of outcome after severe brain damage. Lancet 1, 480–484 (1975).

    CAS  PubMed  Google Scholar 

  21. Alexander, M. P., Lafleche, G., Schnyer, D., Lim, C. & Verfaellie, M. Cognitive and functional outcome after out of hospital cardiac arrest. J. Int. Neuropsychol. Soc. 17, 364–368 (2011).

    PubMed  PubMed Central  Google Scholar 

  22. Fugate, J. E. et al. Cognitive outcomes of patients undergoing therapeutic hypothermia after cardiac arrest. Neurology 81, 40–45 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Nielsen, N. et al. Target Temperature Management after out-of-hospital cardiac arrest—a randomized, parallel-group, assessor-blinded clinical trial—rationale and design. Am Heart J. 163, 541–548 (2012).

    PubMed  Google Scholar 

  24. Moulaert, V. R., Verbunt, J. A., van Heugten, C. M. & Wade, D. T. Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review. Resuscitation 80, 297–305 (2009).

    PubMed  Google Scholar 

  25. Becker, L. B. et al. Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation 124, 2158–2177 (2011).

    PubMed  PubMed Central  Google Scholar 

  26. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N. Engl. J. Med. 346, 549–556 (2002).

  27. Bernard, S. A. et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J. Med. 346, 557–563 (2002).

    PubMed  Google Scholar 

  28. Sessler, D. I. Complications and treatment of mild hypothermia. Anesthesiology 95, 531–543 (2001).

    CAS  PubMed  Google Scholar 

  29. Fukuoka, N., Aibiki, M., Tsukamoto, T., Seki, K. & Morita, S. Biphasic concentration change during continuous midazolam administration in brain-injured patients undergoing therapeutic moderate hypothermia. Resuscitation 60, 225–230 (2004).

    CAS  PubMed  Google Scholar 

  30. Fritz, H. G. et al. The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs. Anesth. Analg. 100, 996–1002 (2005).

    CAS  PubMed  Google Scholar 

  31. Samaniego, E. A., Mlynash, M., Caulfield, A. F., Eyngorn, I. & Wijman, C. A. Sedation confounds outcome prediction in cardiac arrest survivors treated with hypothermia. Neurocrit. Care 15, 113–119 (2011).

    PubMed  PubMed Central  Google Scholar 

  32. Boyles, A. L., Harris, S. F., Rooney, A. A. & Thayer, K. A. Forest Plot Viewer: a new graphing tool. Epidemiology 22, 746–747 (2011).

    PubMed  Google Scholar 

  33. Fugate, J. E. et al. Predictors of neurologic outcome in hypothermia after cardiac arrest. Ann. Neurol. 68, 907–914 (2010).

    PubMed  Google Scholar 

  34. Wu, O. et al. Predicting clinical outcome in comatose cardiac arrest patients using early noncontrast computed tomography. Stroke 42, 985–992 (2011).

    PubMed  PubMed Central  Google Scholar 

  35. Wu, O. et al. Comatose patients with cardiac arrest: predicting clinical outcome with diffusion-weighted MR imaging. Radiology 252, 173–181 (2009).

    PubMed  PubMed Central  Google Scholar 

  36. Rossetti, A. O., Oddo, M., Logroscino, G. & Kaplan, P. W. Prognostication after cardiac arrest and hypothermia: a prospective study. Ann. Neurol. 67, 301–307 (2010).

    PubMed  Google Scholar 

  37. Kamps, M. J. et al. Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature. Intensive Care Med. 39, 1671–1682 (2013).

    CAS  PubMed  Google Scholar 

  38. Rossetti, A. O., Carrera, E. & Oddo, M. Early EEG correlates of neuronal injury after brain anoxia. Neurology 78, 796–802 (2012).

    CAS  PubMed  Google Scholar 

  39. Oksanen, T. et al. Predictive power of serum NSE and OHCA score regarding 6-month neurologic outcome after out-of-hospital ventricular fibrillation and therapeutic hypothermia. Resuscitation 80, 165–170 (2009).

    PubMed  Google Scholar 

  40. Bouwes, A. et al. Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Ann. Neurol. 71, 206–212 (2012).

    PubMed  Google Scholar 

  41. Scheel, M. et al. The prognostic value of gray-white-matter ratio in cardiac arrest patients treated with hypothermia. Scand. J. Trauma Resusc. Emerg. Med. 21, 23 (2013).

    PubMed  PubMed Central  Google Scholar 

  42. Lee, B. K., Jeung, K. W., Lee, H. Y., Jung, Y. H. & Lee, D. H. Combining brain computed tomography and serum neuron specific enolase improves the prognostic performance compared to either alone in comatose cardiac arrest survivors treated with therapeutic hypothermia. Resuscitation 84, 1387–1392 (2013).

    CAS  PubMed  Google Scholar 

  43. Kim, J. et al. Prognostic performance of diffusion-weighted MRI combined with NSE in comatose cardiac arrest survivors treated with mild hypothermia. Neurocrit. Care 17, 412–420 (2012).

    PubMed  Google Scholar 

  44. Al Thenayan, E., Savard, M., Sharpe, M., Norton, L. & Young, B. Predictors of poor neurologic outcome after induced mild hypothermia following cardiac arrest. Neurology 71, 1535–1537 (2008).

    CAS  PubMed  Google Scholar 

  45. Schefold, J. C., Storm, C., Kruger, A., Ploner, C. J. & Hasper, D. The Glasgow Coma Score is a predictor of good outcome in cardiac arrest patients treated with therapeutic hypothermia. Resuscitation 80, 658–661 (2009).

    PubMed  Google Scholar 

  46. Sandroni, C. et al. Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 1: patients not treated with therapeutic hypothermia. Resuscitation 84, 1310–1323 (2013).

    PubMed  Google Scholar 

  47. Sandroni, C. et al. Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 2: patients treated with therapeutic hypothermia. Resuscitation 84, 1324–1338 (2013).

    PubMed  Google Scholar 

  48. Thomke, F. et al. Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus. BMC Neurol. 5, 14 (2005).

    PubMed  PubMed Central  Google Scholar 

  49. Krumholz, A., Stern, B. J. & Weiss, H. D. Outcome from coma after cardiopulmonary resuscitation: relation to seizures and myoclonus. Neurology 38, 401–405 (1988).

    CAS  PubMed  Google Scholar 

  50. Celesia, G. G., Grigg, M. M. & Ross, E. Generalized status myoclonicus in acute anoxic and toxic–metabolic encephalopathies. Arch. Neurol. 45, 781–784 (1988).

    CAS  PubMed  Google Scholar 

  51. Hui, A. C., Cheng, C., Lam, A., Mok, V. & Joynt, G. M. Prognosis following postanoxic myoclonus status epilepticus. Eur. Neurol. 54, 10–13 (2005).

    PubMed  Google Scholar 

  52. Greer, D. M. Unexpected good recovery in a comatose post-cardiac arrest patient with poor prognostic features. Resuscitation 84, e81–e82 (2013).

    PubMed  Google Scholar 

  53. Lucas, J. M. et al. Neurologic recovery after therapeutic hypothermia in patients with post-cardiac arrest myoclonus. Resuscitation 83, 265–269 (2012).

    PubMed  Google Scholar 

  54. Legriel, S. et al. Early EEG monitoring for detecting postanoxic status epilepticus during therapeutic hypothermia: a pilot study. Neurocrit. Care 11, 338–344 (2009).

    PubMed  Google Scholar 

  55. Ko, S. B. et al. Status epilepticus-induced hyperemia and brain tissue hypoxia after cardiac arrest. Arch. Neurol. 68, 1323–1326 (2011).

    PubMed  Google Scholar 

  56. Nordmark, J., Rubertsson, S., Mortberg, E., Nilsson, P. & Enblad, P. Intracerebral monitoring in comatose patients treated with hypothermia after a cardiac arrest. Acta Anaesthesiol. Scand. 53, 289–298 (2009).

    CAS  PubMed  Google Scholar 

  57. Ducasse, J. L., Marc-Vergnes, J. P., Cathala, B., Genestal, M. & Lareng, L. Early cerebral prognosis of anoxic encephalopathy using brain energy metabolism. Crit. Care Med. 12, 897–900 (1984).

    CAS  PubMed  Google Scholar 

  58. Buunk, G., van der Hoeven, J. G. & Meinders, A. E. Prognostic significance of the difference between mixed venous and jugular bulb oxygen saturation in comatose patients resuscitated from a cardiac arrest. Resuscitation 41, 257–262 (1999).

    CAS  PubMed  Google Scholar 

  59. Gueugniaud, P. Y. et al. Prognostic significance of early intracranial and cerebral perfusion pressures in post-cardiac arrest anoxic coma. Intensive Care Med. 17, 392–398 (1991).

    CAS  PubMed  Google Scholar 

  60. Madl, C. et al. Improved outcome prediction in unconscious cardiac arrest survivors with sensory evoked potentials compared with clinical assessment. Crit. Care Med. 28, 721–726 (2000).

    CAS  PubMed  Google Scholar 

  61. Zandbergen, E. G., Koelman, J. H., de Haan, R. J. & Hijdra, A. SSEPs and prognosis in postanoxic coma: only short or also long latency responses? Neurology 67, 583–586 (2006).

    CAS  PubMed  Google Scholar 

  62. Robinson, L. R., Micklesen, P. J., Tirschwell, D. L. & Lew, H. L. Predictive value of somatosensory evoked potentials for awakening from coma. Crit. Care Med. 31, 960–967 (2003).

    PubMed  Google Scholar 

  63. Rothstein, T. L. The utility of median somatosensory evoked potentials in anoxic-ischemic coma. Rev. Neurosci. 20, 221–233 (2009).

    PubMed  Google Scholar 

  64. Young, G. B., Doig, G. & Ragazzoni, A. Anoxic–ischemic encephalopathy: clinical and electrophysiological associations with outcome. Neurocrit. Care 2, 159–164 (2005).

    PubMed  Google Scholar 

  65. Brunko, E. & Zegers de Beyl, D. Prognostic value of early cortical somatosensory evoked potentials after resuscitation from cardiac arrest. Electroencephalogr. Clin. Neurophysiol. 66, 15–24 (1987).

    CAS  PubMed  Google Scholar 

  66. Gendo, A. et al. Time-dependency of sensory evoked potentials in comatose cardiac arrest survivors. Intensive Care Med. 27, 1305–1311 (2001).

    CAS  PubMed  Google Scholar 

  67. Buchthal, F. & Rosenfalck, P. Spontaneous electrical activity of human muscle. Electroencephalogr. Clin. Neurophysiol. 20, 321–336 (1966).

    CAS  PubMed  Google Scholar 

  68. Sebel, P. S., de Bruijn, N. P. & Neville, W. K. Effect of hypothermia on median nerve somatosensory evoked potentials. J. Cardiothorac. Anesth. 2, 326–329 (1988).

    CAS  PubMed  Google Scholar 

  69. Tiainen, M., Kovala, T. T., Takkunen, O. S. & Roine, R. O. Somatosensory and brainstem auditory evoked potentials in cardiac arrest patients treated with hypothermia. Crit. Care Med. 33, 1736–1740 (2005).

    PubMed  Google Scholar 

  70. Bouwes, A. et al. Somatosensory evoked potentials during mild hypothermia after cardiopulmonary resuscitation. Neurology 73, 1457–1461 (2009).

    CAS  PubMed  Google Scholar 

  71. Leithner, C., Ploner, C. J., Hasper, D. & Storm, C. Does hypothermia influence the predictive value of bilateral absent N20 after cardiac arrest? Neurology 74, 965–969 (2010).

    PubMed  Google Scholar 

  72. Zanatta, P. et al. Pain-related somatosensory evoked potentials and functional brain magnetic resonance in the evaluation of neurologic recovery after cardiac arrest: a case study of three patients. Scand. J. Trauma Resusc. Emerg. Med. 20, 22 (2012).

    PubMed  PubMed Central  Google Scholar 

  73. Zanatta, P., Messerotti Benvenuti, S., Baldanzi, F. & Bosco, E. Pain-related middle-latency somatosensory evoked potentials in the prognosis of post anoxic coma: a preliminary report. Minerva Anestesiol. 78, 749–756 (2012).

    CAS  PubMed  Google Scholar 

  74. Madhok, J., Iyer, S., Thakor, N. V. & Maybhate, A. Characterization of neurologic injury using novel morphological analysis of Somatosensory Evoked Potentials. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2010, 2798–2801 (2010).

    PubMed  Google Scholar 

  75. Takai, N. et al. Auditory evoked potential P50 as a predictor of neurologic outcome in resuscitated cardiac arrest patients. J. Clin. Neurophysiol. 28, 302–307 (2011).

    PubMed  Google Scholar 

  76. Sakurai, A. et al. Reduced effectiveness of hypothermia in patients lacking the wave V in auditory brainstem responses immediately following resuscitation from cardiac arrest. Resuscitation 70, 52–58 (2006).

    PubMed  Google Scholar 

  77. Fischer, C. et al. Mismatch negativity and late auditory evoked potentials in comatose patients. Clin. Neurophysiol. 110, 1601–1610 (1999).

    CAS  PubMed  Google Scholar 

  78. Tzovara, A. et al. Progression of auditory discrimination based on neural decoding predicts awakening from coma. Brain 136, 81–89 (2013).

    PubMed  Google Scholar 

  79. Hockaday, J. M., Potts, F., Epstein, E., Bonazzi, A. & Schwab, R. S. Electroencephalographic changes in acute cerebral anoxia from cardiac or respiratory arrest. Electroencephalogr. Clin. Neurophysiol. 18, 575–586 (1965).

    CAS  PubMed  Google Scholar 

  80. Synek, V. M. Value of a revised EEG coma scale for prognosis after cerebral anoxia and diffuse head injury. Clin. Electroencephalogr. 21, 25–30 (1990).

    CAS  PubMed  Google Scholar 

  81. Scollo-Lavizzari, G. & Bassetti, C. Prognostic value of EEG in post-anoxic coma after cardiac arrest. Eur. Neurol. 26, 161–170 (1987).

    CAS  PubMed  Google Scholar 

  82. Scozzafava, J., Hussain, M. S., Brindley, P. G., Jacka, M. J. & Gross, D. W. The role of the standard 20 minute EEG recording in the comatose patient. J. Clin. Neurosci. 17, 64–68 (2010).

    PubMed  Google Scholar 

  83. Rossetti, A. O., Oddo, M., Liaudet, L. & Kaplan, P. W. Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia. Neurology 72, 744–749 (2009).

    PubMed  Google Scholar 

  84. Stecker, M. M. et al. Deep hypothermic circulatory arrest: I. Effects of cooling on electroencephalogram and evoked potentials. Ann. Thorac. Surg. 71, 14–21 (2001).

    CAS  PubMed  Google Scholar 

  85. Rundgren, M., Rosen, I. & Friberg, H. Amplitude-integrated EEG (aEEG) predicts outcome after cardiac arrest and induced hypothermia. Intensive Care Med. 32, 836–842 (2006).

    PubMed  Google Scholar 

  86. Rundgren, M., Westhall, E., Cronberg, T., Rosen, I. & Friberg, H. Continuous amplitude-integrated electroencephalogram predicts outcome in hypothermia-treated cardiac arrest patients. Crit. Care Med. 38, 1838–1844 (2010).

    PubMed  Google Scholar 

  87. Mani, R., Schmitt, S. E., Mazer, M., Putt, M. E. & Gaieski, D. F. The frequency and timing of epileptiform activity on continuous electroencephalogram in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia. Resuscitation 83, 840–847 (2012).

    PubMed  Google Scholar 

  88. Abend, N. S. et al. Electroencephalographic monitoring during hypothermia after pediatric cardiac arrest. Neurology 72, 1931–1940 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Rossetti, A. O., Urbano, L. A., Delodder, F., Kaplan, P. W. & Oddo, M. Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest. Crit. Care 14, R173 (2010).

    PubMed  PubMed Central  Google Scholar 

  90. Cloostermans, M. C., van Meulen, F. B., Eertman, C. J., Hom, H. W. & van Putten, M. J. Continuous electroencephalography monitoring for early prediction of neurological outcome in postanoxic patients after cardiac arrest: a prospective cohort study. Crit. Care Med. 40, 2867–2875 (2012).

    PubMed  Google Scholar 

  91. Hofmeijer, J., Tjepkema-Cloostermans, M. C. & van Putten, M. J. Burst-suppression with identical bursts: a distinct EEG pattern with poor outcome in postanoxic coma. Clin. Neurophysiol. http://dx.doi.org/10.1016/j.clinph.2013.10.017.

  92. Tjepkema-Cloostermans, M. C., van Meulen, F. B., Meinsma, G. & van Putten, M. J. A Cerebral Recovery Index (CRI) for early prognosis in patients after cardiac arrest. Crit. Care 17, R252 (2013).

    PubMed  PubMed Central  Google Scholar 

  93. Alvarez, V., Oddo, M. & Rossetti, A. O. Stimulus-induced rhythmic, periodic or ictal discharges (SIRPIDs) in comatose survivors of cardiac arrest: characteristics and prognostic value. Clin. Neurophysiol. 124, 204–208 (2013).

    PubMed  Google Scholar 

  94. Wennervirta, J. E. et al. Hypothermia-treated cardiac arrest patients with good neurological outcome differ early in quantitative variables of EEG suppression and epileptiform activity. Crit. Care Med. 37, 2427–2435 (2009).

    PubMed  Google Scholar 

  95. Ermes, M. et al. Prediction of poor outcome using detector of epileptiform EEG in ICU patients resuscitated after cardiac arrest. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2007, 3056–3059 (2007).

    PubMed  Google Scholar 

  96. Shin, H. C., Jia, X., Nickl, R., Geocadin, R. G. & Thakor Ast, N. V. A subband-based information measure of EEG during brain injury and recovery after cardiac arrest. IEEE Trans. Biomed. Eng. 55, 1985–1990 (2008).

    PubMed  PubMed Central  Google Scholar 

  97. Kawai, M., Thapalia, U. & Verma, A. Outcome from therapeutic hypothermia and EEG. J. Clin. Neurophysiol. 28, 483–488 (2011).

    PubMed  Google Scholar 

  98. Crepeau, A. Z. et al. Continuous EEG in therapeutic hypothermia after cardiac arrest: prognostic and clinical value. Neurology 80, 339–344 (2013).

    PubMed  Google Scholar 

  99. Hovland, A., Nielsen, E. W., Kluver, J. & Salvesen, R. EEG should be performed during induced hypothermia. Resuscitation 68, 143–146 (2006).

    PubMed  Google Scholar 

  100. Rittenberger, J. C., Popescu, A., Brenner, R. P., Guyette, F. X. & Callaway, C. W. Frequency and timing of nonconvulsive status epilepticus in comatose post-cardiac arrest subjects treated with hypothermia. Neurocrit. Care 16, 114–122 (2012).

    PubMed  PubMed Central  Google Scholar 

  101. Kessler, S. K. et al. Short-term outcome prediction by electroencephalographic features in children treated with therapeutic hypothermia after cardiac arrest. Neurocrit. Care 14, 37–43 (2011).

    PubMed  PubMed Central  Google Scholar 

  102. Fatovich, D. M., Jacobs, I. G., Celenza, A. & Paech, M. J. An observational study of bispectral index monitoring for out of hospital cardiac arrest. Resuscitation 69, 207–212 (2006).

    PubMed  Google Scholar 

  103. Chollet-Xemard, C. et al. Bispectral index monitoring is useless during cardiac arrest patients' resuscitation. Resuscitation 80, 213–216 (2009).

    PubMed  Google Scholar 

  104. Leary, M. et al. Neurologic prognostication and bispectral index monitoring after resuscitation from cardiac arrest. Resuscitation 81, 1133–1137 (2010).

    PubMed  Google Scholar 

  105. Stammet, P., Werer, C., Mertens, L., Lorang, C. & Hemmer, M. Bispectral index (BIS) helps predicting bad neurological outcome in comatose survivors after cardiac arrest and induced therapeutic hypothermia. Resuscitation 80, 437–442 (2009).

    PubMed  Google Scholar 

  106. Aibiki, M. et al. Good neurological recovery of a post-cardiac arrest patient with very low bispectral index values and high suppression ratios after resumption of spontaneous circulation. Resuscitation 83, e87–e88 (2012).

    CAS  PubMed  Google Scholar 

  107. Seder, D. B., Fraser, G. L., Robbins, T., Libby, L. & Riker, R. R. The bispectral index and suppression ratio are very early predictors of neurological outcome during therapeutic hypothermia after cardiac arrest. Intensive Care Med. 36, 281–288 (2010).

    PubMed  Google Scholar 

  108. Schmechel, D., Marangos, P. J. & Brightman, M. Neurone-specific enolase is a molecular marker for peripheral and central neuroendocrine cells. Nature 276, 834–836 (1978).

    CAS  PubMed  Google Scholar 

  109. Schmechel, D., Marangos, P. J., Zis, A. P., Brightman, M. & Goodwin, F. K. Brain endolases as specific markers of neuronal and glial cells. Science 199, 313–315 (1978).

    CAS  PubMed  Google Scholar 

  110. Ramont, L. et al. Effects of hemolysis and storage condition on neuron-specific enolase (NSE) in cerebrospinal fluid and serum: implications in clinical practice. Clin. Chem. Lab. Med. 43, 1215–1217 (2005).

    CAS  PubMed  Google Scholar 

  111. Tiainen, M., Roine, R. O., Pettila, V. & Takkunen, O. Serum neuron-specific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 34, 2881–2886 (2003).

    CAS  PubMed  Google Scholar 

  112. Steffen, I. G. et al. 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 14, R69 (2010).

    PubMed  PubMed Central  Google Scholar 

  113. Rundgren, M. et al. Neuron specific enolase and S-100B as predictors of outcome after cardiac arrest and induced hypothermia. Resuscitation 80, 784–789 (2009).

    CAS  PubMed  Google Scholar 

  114. Auer, J. et al. Ability of neuron-specific enolase to predict survival to hospital discharge after successful cardiopulmonary resuscitation. CJEM 8, 13–18 (2006).

    PubMed  Google Scholar 

  115. Cronberg, T. et al. Neuron-specific enolase correlates with other prognostic markers after cardiac arrest. Neurology 77, 623–630 (2011).

    CAS  PubMed  Google Scholar 

  116. Almaraz, A. C., Bobrow, B. J., Wingerchuk, D. M., Wellik, K. E. & Demaerschalk, B. M. Serum neuron specific enolase to predict neurological outcome after cardiopulmonary resuscitation: a critically appraised topic. Neurologist 15, 44–48 (2009).

    PubMed  Google Scholar 

  117. Daubin, C. et al. Serum neuron-specific enolase as predictor of outcome in comatose cardiac-arrest survivors: a prospective cohort study. BMC Cardiovasc. Disord. 11, 48 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Einav, S., Kaufman, N., Algur, N. & Kark, J. D. Modeling serum biomarkers S100 beta and neuron-specific enolase as predictors of outcome after out-of-hospital cardiac arrest: an aid to clinical decision making. J. Am. Coll. Cardiol. 60, 304–311 (2012).

    CAS  PubMed  Google Scholar 

  119. Mlynash, M. et al. Serum neuron-specific enolase levels from the same patients differ between laboratories: assessment of a prospective post-cardiac arrest cohort. Neurocrit. Care 19, 161–166 (2013).

    CAS  PubMed  Google Scholar 

  120. Rana, O. R., Saygili, E., Schiefer, J., Marx, N. & Schauerte, P. Biochemical markers and somatosensory evoked potentials in patients after cardiac arrest: the role of neurological outcome scores. J. Neurol. Sci. 305, 80–84 (2011).

    CAS  PubMed  Google Scholar 

  121. Derwall, M., Stoppe, C., Brucken, D., Rossaint, R. & Fries, M. Changes in S-100 protein serum levels in survivors of out-of-hospital cardiac arrest treated with mild therapeutic hypothermia: a prospective, observational study. Crit. Care 13, R58 (2009).

    PubMed  PubMed Central  Google Scholar 

  122. Mortberg, E. et al. S-100B is superior to NSE, BDNF and GFAP in predicting outcome of resuscitation from cardiac arrest with hypothermia treatment. Resuscitation 82, 26–31 (2011).

    PubMed  Google Scholar 

  123. Shinozaki, K. et al. Serum S-100B is superior to neuron-specific enolase as an early prognostic biomarker for neurological outcome following cardiopulmonary resuscitation. Resuscitation 80, 870–875 (2009).

    CAS  PubMed  Google Scholar 

  124. Funk, G. C. et al. The strong ion gap and outcome after cardiac arrest in patients treated with therapeutic hypothermia: a retrospective study. Intensive Care Med. 35, 232–239 (2009).

    PubMed  Google Scholar 

  125. Hasper, D., von Haehling, S., Storm, C., Jorres, A. & Schefold, J. C. Changes in serum creatinine in the first 24 hours after cardiac arrest indicate prognosis: an observational cohort study. Crit. Care 13, R168 (2009).

    PubMed  PubMed Central  Google Scholar 

  126. Donnino, M. W. et al. Effective lactate clearance is associated with improved outcome in post-cardiac arrest patients. Resuscitation 75, 229–234 (2007).

    CAS  PubMed  Google Scholar 

  127. Oda, Y. et al. Prediction of the neurological outcome with intrathecal high mobility group box 1 and S100B in cardiac arrest victims: a pilot study. Resuscitation 83, 1006–1012 (2012).

    CAS  PubMed  Google Scholar 

  128. Stammet, P. et al. Circulating microRNAs after cardiac arrest. Crit Care Med. 40, 3209–3214 (2012).

    CAS  PubMed  Google Scholar 

  129. Sulaj, M., Saniova, B., Drobna, E. & Schudichova, J. Serum neuron specific enolase and malondialdehyde in patients after out-of-hospital cardiac arrest. Cell. Mol. Neurobiol. 29, 807–810 (2009).

    CAS  PubMed  Google Scholar 

  130. Hastbacka, J. et al. Serum matrix metalloproteinases in patients resuscitated from cardiac arrest. The association with therapeutic hypothermia. Resuscitation 83, 197–201 (2012).

    PubMed  Google Scholar 

  131. Engel, H. et al. Serum procalcitonin as a marker of post-cardiac arrest syndrome and long-term neurological recovery, but not of early-onset infections, in comatose post-anoxic patients treated with therapeutic hypothermia. Resuscitation 84, 776–781 (2013).

    CAS  PubMed  Google Scholar 

  132. Annborn, M. et al. Procalcitonin after cardiac arrest—an indicator of severity of illness, ischemia–reperfusion injury and outcome. Resuscitation 84, 782–787 (2013).

    CAS  PubMed  Google Scholar 

  133. Greer, D. et al. Clinical MRI interpretation for outcome prediction in cardiac arrest. Neurocrit. Care 17, 240–244 (2012).

    PubMed  Google Scholar 

  134. Choi, S. P. et al. The density ratio of grey to white matter on computed tomography as an early predictor of vegetative state or death after cardiac arrest. Emerg. Med. J. 25, 666–669 (2008).

    CAS  PubMed  Google Scholar 

  135. Torbey, M. T., Selim, M., Knorr, J., Bigelow, C. & Recht, L. Quantitative analysis of the loss of distinction between gray and white matter in comatose patients after cardiac arrest. Stroke 31, 2163–2167 (2000).

    CAS  PubMed  Google Scholar 

  136. Yanagawa, Y., Un-no, Y., Sakamoto, T. & Okada, Y. Cerebral density on CT immediately after a successful resuscitation of cardiopulmonary arrest correlates with outcome. Resuscitation 64, 97–101 (2005).

    PubMed  Google Scholar 

  137. Metter, R. B., Rittenberger, J. C., Guyette, F. X. & Callaway, C. W. Association between a quantitative CT scan measure of brain edema and outcome after cardiac arrest. Resuscitation 82, 1180–1185 (2011).

    PubMed  PubMed Central  Google Scholar 

  138. Hald, J. K., Brunberg, J. A., Dublin, A. B. & Wootton-Gorges, S. L. Delayed diffusion-weighted MR abnormality in a patient with an extensive acute cerebral hypoxic injury. Acta Radiol. 44, 343–346 (2003).

    CAS  PubMed  Google Scholar 

  139. Greer, D. M. MRI in anoxic brain injury. Neurocrit. Care 1, 213–215 (2004).

    PubMed  Google Scholar 

  140. Mlynash, M. et al. Temporal and spatial profile of brain diffusion-weighted MRI after cardiac arrest. Stroke 41, 1665–1672 (2010).

    PubMed  PubMed Central  Google Scholar 

  141. Els, T., Kassubek, J., Kubalek, R. & Klisch, J. Diffusion-weighted MRI during early global cerebral hypoxia: a predictor for clinical outcome? Acta Neurol. Scand. 110, 361–367 (2004).

    PubMed  Google Scholar 

  142. Wijdicks, E. F., Campeau, N. G. & Miller, G. M. MR imaging in comatose survivors of cardiac resuscitation. AJNR Am. J. Neuroradiol. 22, 1561–1565 (2001).

    CAS  PubMed  Google Scholar 

  143. Topcuoglu, M. A., Oguz, K. K., Buyukserbetci, G. & Bulut, E. Prognostic value of magnetic resonance imaging in post-resuscitation encephalopathy. Intern. Med. 48, 1635–1645 (2009).

    PubMed  Google Scholar 

  144. Yenari, M. A. et al. Diffusion- and perfusion-weighted magnetic resonance imaging of focal cerebral ischemia and cortical spreading depression under conditions of mild hypothermia. Brain Res. 885, 208–219 (2000).

    CAS  PubMed  Google Scholar 

  145. Jarnum, H. et al. Diffusion and perfusion MRI of the brain in comatose patients treated with mild hypothermia after cardiac arrest: a prospective observational study. Resuscitation 80, 425–430 (2009).

    PubMed  Google Scholar 

  146. Wijman, C. A. et al. Prognostic value of brain diffusion-weighted imaging after cardiac arrest. Ann. Neurol. 65, 394–402 (2009).

    PubMed  PubMed Central  Google Scholar 

  147. Greer, D. et al. Serial MRI changes in comatose cardiac arrest patients. Neurocrit. Care 14, 61–67 (2011).

    PubMed  Google Scholar 

  148. Greer, D. M. et al. Hippocampal magnetic resonance imaging abnormalities in cardiac arrest are associated with poor outcome. J. Stroke Cerebrovasc. Dis. 22, 899–905 (2012).

    PubMed  Google Scholar 

  149. Heradstveit, B. E. et al. Repeated magnetic resonance imaging and cerebral performance after cardiac arrest—a pilot study. Resuscitation 82, 549–555 (2011).

    PubMed  Google Scholar 

  150. Gofton, T. E. et al. Functional MRI study of the primary somatosensory cortex in comatose survivors of cardiac arrest. Exp. Neurol. 217, 320–327 (2009).

    PubMed  Google Scholar 

  151. Norton, L. et al. Disruptions of functional connectivity in the default mode network of comatose patients. Neurology 78, 175–181 (2012).

    CAS  PubMed  Google Scholar 

  152. Achard, S. et al. Hubs of brain functional networks are radically reorganized in comatose patients. Proc. Natl Acad. Sci. USA 109, 20608–20613 (2012).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr Jennifer E. Fugate and Dr Alejandro Rabinstein from the Mayo Clinic for sharing their original data from their study. We would also like to thank Dr Mark R. J. R. Bouts of the MGH Athinoula A. Martinos Centre for his assistance in the literature review. We would also like to thank the Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care for funding support.

Author information

Authors and Affiliations

  1. Department of Neurology, Yale University School of Medicine, LLCI 912, 15 York Street, New Haven, 06520, CT, USA

    David M. Greer

  2. Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, MA, USA

    Eric S. Rosenthal

  3. Athinoula A. Martinos Centre for Biomedical Imaging, 149 13th Street CNY 2301, Charlestown, 02129, MA, USA

    Ona Wu

Authors
  1. David M. Greer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric S. Rosenthal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ona Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data for the article, provided substantial contributions to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to David M. Greer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greer, D., Rosenthal, E. & Wu, O. Neuroprognostication of hypoxic–ischaemic coma in the therapeutic hypothermia era. Nat Rev Neurol 10, 190–203 (2014). https://doi.org/10.1038/nrneurol.2014.36

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2014.36

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing