Log in | Register

Secretoneurin as a marker for hypoxic brain injury after cardiopulmonary resuscitation

Julia Hasslacher| Georg Franz Lehner| Ulrich Harler| Ronny Beer| Hanno Ulmer| Rudolf Kirchmair| Reiner Fischer-Colbrie| Romuald Bellmann| Stefan Dunzendorfer| Michael Joannidis
Original
Volume 40, Issue 10 / October , 2014

Pages 1518 - 1527

Abstract

Purpose

The neuropeptide secretoneurin (SN) shows widespread distribution in the brain. We evaluated whether SN is elevated after cardiopulmonary resuscitation (CPR) and could serve as a potential new biomarker for hypoxic brain injury after CPR.

Methods

This was a prospective observational clinical study. All patients admitted to a tertiary medical intensive care unit after successful CPR with expected survival of at least 24 h were consecutively enrolled from September 2008 to April 2013. Serum SN and neuron-specific enolase were determined in 24 h intervals starting with the day of CPR for 7 days. Neurological outcome was assessed with the Cerebral Performance Categories Scale (CPC) at hospital discharge.

Results

A total of 134 patients were included with 49 % surviving to good neurological outcome (CPC 1–2). SN serum levels peaked within the first 24 h showing on average a sixfold increase above normal. SN levels were significantly higher in patients with poor (CPC 3–5) than in patients with good neurological outcome [0–24 h: 75 (43–111) vs. 38 (23–68) fmol/ml, p < 0.001; 24–48 h: 45 (24–77) vs. 23 (16–39) fmol/ml, p < 0.001]. SN determined within the first 48 h showed a receiver operating characteristic (ROC) area under the curve (AUC) of 0.753 (0.665–0.841). NSE in the first 72 h had a ROC-AUC of 0.881 (0.815–0.946). When combining the two biomarkers an AUC of 0.925 (0.878–0.972) for outcome prediction could be reached.

Conclusions

SN is a promising early biomarker for hypoxic brain injury. Further studies will be required for confirmation of these results.

Keywords

References

  1. Girotra S, Nallamothu BK, Spertus JA, Li Y, Krumholz HM, Chan PS (2012) Trends in survival after in-hospital cardiac arrest. N Engl J Med 367:1912–1920
    • View reference on PubMed
    • View reference on publisher's website
  2. Nolan JP (2011) Optimizing outcome after cardiac arrest. Curr Opin Crit Care 17:520–526
    • View reference on PubMed
    • View reference on publisher's website
  3. Berdowski J, Berg RA, Tijssen JG, Koster RW (2010) Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of 67 prospective studies. Resuscitation 81:1479–1487
    • View reference on PubMed
    • View reference on publisher's website
  4. Kudenchuk PJ, Redshaw JD, Stubbs BA, Fahrenbruch CE, Dumas F, Phelps R, Blackwood J, Rea TD, Eisenberg MS (2012) Impact of changes in resuscitation practice on survival and neurological outcome after out-of-hospital cardiac arrest resulting from nonshockable arrhythmias. Circulation 125:1787–1794
    • View reference on PubMed
    • View reference on publisher's website
  5. Delhaye C, Mahmoudi M, Waksman R (2012) Hypothermia therapy: neurological and cardiac benefits. J Am Coll Cardiol 59:197–210
    • View reference on PubMed
    • View reference on publisher's website
  6. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Aneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Kober L, Langorgen J, Lilja G, Moller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H (2013) Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 369:2197–2206
    • View reference on PubMed
    • View reference on publisher's website
  7. Rittenberger JC, Callaway CW (2013) Temperature management and modern post-cardiac arrest care. N Engl J Med 369:2262–2263
    • View reference on PubMed
    • View reference on publisher's website
  8. Citerio G, Bakker J, Bassetti M, Benoit D, Cecconi M, Curtis JR, Hernandez G, Herridge M, Jaber S, Joannidis M, Papazian L, Peters M, Singer P, Smith M, Soares M, Torres A, Vieillard-Baron A, Timsit JF, Azoulay E (2014) Year in review in Intensive Care Medicine 2013: i. Acute kidney injury, ultrasound, hemodynamics, cardiac arrest, transfusion, neurocritical care, and nutrition. Intensive Care Med 40:147–159
  9. Shinozaki K, Oda S, Sadahiro T, Nakamura M, Hirayama Y, Abe R, Tateishi Y, Hattori N, Shimada T, Hirasawa H (2009) 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 13:R121
    • View reference on PubMed
    • View reference on publisher's website
  10. Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S (2006) 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
    • View reference on PubMed
    • View reference on publisher's website
  11. Steffen IG, Hasper D, Ploner CJ, Schefold JC, Dietz E, Martens F, Nee J, Krueger A, Jorres A, Storm C (2010) 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
    • View reference on PubMed
    • View reference on publisher's website
  12. Zellner T, Gartner R, Schopohl J, Angstwurm M (2013) NSE and S-100B are not sufficiently predictive of neurologic outcome after therapeutic hypothermia for cardiac arrest. Resuscitation 84:1382–1386
    • View reference on PubMed
    • View reference on publisher's website
  13. Fischer-Colbrie R, Laslop A, Kirchmair R (1995) Secretogranin II: molecular properties, regulation of biosynthesis and processing to the neuropeptide secretoneurin. Prog Neurobiol 46:49–70
    • View reference on PubMed
    • View reference on publisher's website
  14. Kirchmair R, Benzer A, Troger J, Miller C, Marksteiner J, Saria A, Gasser RW, Hogue-Angeletti R, Fischer-Colbrie R, Winkler H (1994) Molecular characterization of immunoreactivities of peptides derived from chromogranin A (GE-25) and from secretogranin II (secretoneurin) in human and bovine cerebrospinal fluid. Neuroscience 63:1179–1187
    • View reference on PubMed
    • View reference on publisher's website
  15. Fischer-Colbrie R, Kirchmair R, Kahler CM, Wiedermann CJ, Saria A (2005) Secretoneurin: a new player in angiogenesis and chemotaxis linking nerves, blood vessels and the immune system. Curr Protein Pept Sci 6:373–385
    • View reference on PubMed
    • View reference on publisher's website
  16. Moons KG, Royston P, Vergouwe Y, Grobbee DE, Altman DG (2009) Prognosis and prognostic research: what, why, and how? BMJ 338:b375
    • View reference on PubMed
    • View reference on publisher's website
  17. Kirchmair R, Hogue-Angeletti R, Gutierrez J, Fischer-Colbrie R, Winkler H (1993) Secretoneurin–a neuropeptide generated in brain, adrenal medulla and other endocrine tissues by proteolytic processing of secretogranin II (chromogranin C). Neuroscience 53:359–365
    • View reference on PubMed
    • View reference on publisher's website
  18. Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, Cassan P, Coovadia A, D’Este K, Finn J, Halperin H, Handley A, Herlitz J, Hickey R, Idris A, Kloeck W, Larkin GL, Mancini ME, Mason P, Mears G, Monsieurs K, Montgomery W, Morley P, Nichol G, Nolan J, Okada K, Perlman J, Shuster M, Steen PA, Sterz F, Tibballs J, Timerman S, Truitt T, Zideman D (2004) Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries. A statement for healthcare professionals from a task force of the international liaison committee on resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa). Resuscitation 63:233–249
    • View reference on PubMed
    • View reference on publisher's website
  19. Nolan JP, Soar J, Zideman DA, Biarent D, Bossaert LL, Deakin C, Koster RW, Wyllie J, Bottiger B (2010) European Resuscitation Council guidelines for resuscitation 2010 section 1. Executive summary. Resuscitation 81:1219–1276
    • View reference on PubMed
    • View reference on publisher's website
  20. Fugate JE, Wijdicks EF, Mandrekar J, Claassen DO, Manno EM, White RD, Bell MR, Rabinstein AA (2010) Predictors of neurologic outcome in hypothermia after cardiac arrest. Ann Neurol 68:907–914
    • View reference on PubMed
    • View reference on publisher's website
  21. Rossetti AO, Oddo M, Logroscino G, Kaplan PW (2010) Prognostication after cardiac arrest and hypothermia: a prospective study. Ann Neurol 67:301–307
    • View reference on PubMed
  22. Edgren E, Hedstrand U, Kelsey S, Sutton-Tyrrell K, Safar P (1994) Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group. Lancet 343:1055–1059
    • View reference on PubMed
    • View reference on publisher's website
  23. Stiell IG, Nesbitt LP, Nichol G, Maloney J, Dreyer J, Beaudoin T, Blackburn J, Wells GA (2009) Comparison of the cerebral performance category score and the health utilities index for survivors of cardiac arrest. Ann Emerg Med 53:241–248
    • View reference on PubMed
    • View reference on publisher's website
  24. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27:157–172
    • View reference on PubMed
    • View reference on publisher's website
  25. Shyu WC, Lin SZ, Chiang MF, Chen DC, Su CY, Wang HJ, Liu RS, Tsai CH, Li H (2008) Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2/Stat3 pathway in murine models of stroke. J Clin Invest 118:133–148
    • View reference on PubMed
    • View reference on publisher's website
  26. Marti E, Ferrer I, Blasi J (2001) Differential regulation of chromogranin A, chromogranin B and secretoneurin protein expression after transient forebrain ischemia in the gerbil. Acta Neuropathol 101:159–166
    • View reference on PubMed
  27. Egger M, Schgoer W, Beer AG, Jeschke J, Leierer J, Theurl M, Frauscher S, Tepper OM, Niederwanger A, Ritsch A, Kearney M, Wanschitz J, Gurtner GC, Fischer-Colbrie R, Weiss G, Piza-Katzer H, Losordo DW, Patsch JR, Schratzberger P, Kirchmair R (2007) Hypoxia up-regulates the angiogenic cytokine secretoneurin via an HIF-1alpha- and basic FGF-dependent pathway in muscle cells. FASEB J 21:2906–2917
    • View reference on PubMed
    • View reference on publisher's website
  28. Ischia R, Gasser RW, Fischer-Colbrie R, Eder U, Pagani A, Cubeddu LX, Lovisetti-Scamihorn P, Finkenstedt G, Laslop A, Winkler H (2000) Levels and molecular properties of secretoneurin-immunoreactivity in the serum and urine of control and neuroendocrine tumor patients. J Clin Endocrinol Metab 85:355–360
    • View reference on PubMed
  29. Bottiger BW, Mobes S, Glatzer R, Bauer H, Gries A, Bartsch P, Motsch J, Martin E (2001) Astroglial protein S-100 is an early and sensitive marker of hypoxic brain damage and outcome after cardiac arrest in humans. Circulation 103:2694–2698
    • View reference on PubMed
    • View reference on publisher's website
  30. Mortberg E, Zetterberg H, Nordmark J, Blennow K, Rosengren L, Rubertsson S (2011) S-100B is superior to NSE, BDNF and GFAP in predicting outcome of resuscitation from cardiac arrest with hypothermia treatment. Resuscitation 82:26–31
    • View reference on PubMed
    • View reference on publisher's website
  31. Rosen H, Sunnerhagen KS, Herlitz J, Blomstrand C, Rosengren L (2001) Serum levels of the brain-derived proteins S-100 and NSE predict long-term outcome after cardiac arrest. Resuscitation 49:183–191
    • View reference on PubMed
    • View reference on publisher's website
  32. Tiainen M, Roine RO, Pettila V, Takkunen O (2003) Serum neuron-specific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 34:2881–2886
    • View reference on PubMed
    • View reference on publisher's website
  33. Haimoto H, Hosoda S, Kato K (1987) Differential distribution of immunoreactive S100-alpha and S100-beta proteins in normal nonnervous human tissues. Lab Invest 57:489–498
    • View reference on PubMed
  34. Hayashida H, Kaneko T, Kasaoka S, Oshima C, Miyauchi T, Fujita M, Oda Y, Tsuruta R, Maekawa T (2010) Comparison of the predictability of neurological outcome by serum procalcitonin and glial fibrillary acidic protein in postcardiac-arrest patients. Neurocrit Care 12:252–257
    • View reference on PubMed
    • View reference on publisher's website
  35. Rana OR, Schroder JW, Baukloh JK, Saygili E, Mischke K, Schiefer J, Weis J, Marx N, Rassaf T, Kelm M, Shin DI, Meyer C, Saygili E (2013) Neurofilament light chain as an early and sensitive predictor of long-term neurological outcome in patients after cardiac arrest. Int J Cardiol 168:1322–1327
    • View reference on PubMed
    • View reference on publisher's website
  36. Gilje P, Gidlof O, Rundgren M, Cronberg T, Al-Mashat M, Olde B, Friberg H, Erlinge D (2014) The brain-enriched microRNA miR-124 in plasma predicts neurological outcome after cardiac arrest. Crit Care 18:R40
    • View reference on PubMed
    • View reference on publisher's website
  37. Schoerkhuber W, Kittler H, Sterz F, Behringer W, Holzer M, Frossard M, Spitzauer S, Laggner AN (1999) Time course of serum neuron-specific enolase. A predictor of neurological outcome in patients resuscitated from cardiac arrest. Stroke 30:1598–1603
    • View reference on PubMed
    • View reference on publisher's website
  38. Casmiro M, Maitan S, De PF, Cova V, Scarpa E, Vignatelli L (2005) Cerebrospinal fluid and serum neuron-specific enolase concentrations in a normal population. Eur J Neurol 12:369–374
    • View reference on PubMed
    • View reference on publisher's website
  39. Zandbergen EG, de Haan RJ, Hijdra A (2001) Systematic review of prediction of poor outcome in anoxic-ischaemic coma with biochemical markers of brain damage. Intensive Care Med 27:1661–1667
  40. Ramont L, Thoannes H, Volondat A, Chastang F, Millet MC, Maquart FX (2005) 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
    • View reference on PubMed
    • View reference on publisher's website
  41. Oksanen T, Tiainen M, Skrifvars MB, Varpula T, Kuitunen A, Castren M, Pettila V (2009) 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
    • View reference on PubMed
    • View reference on publisher's website
  42. Tiainen M, Roine RO, Pettila V, Takkunen O (2003) Serum neuron-specific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke 34:2881–2886
    • View reference on PubMed
    • View reference on publisher's website
  43. Lemiale V, Dumas F, Mongardon N, Giovanetti O, Charpentier J, Chiche JD, Carli P, Mira JP, Nolan J, Cariou A (2013) Intensive care unit mortality after cardiac arrest: the relative contribution of shock and brain injury in a large cohort. Intensive Care Med 39:1972–1980

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement