International Journal of Legal Medicine

, Volume 133, Issue 3, pp 871–881 | Cite as

Post-mortem in situ stability of serum markers of cerebral damage and acute phase response

  • Benjamin OndruschkaEmail author
  • Lina Woydt
  • Michael Bernhard
  • Heike Franke
  • Holger Kirsten
  • Sabine Löffler
  • Dirk Pohlers
  • Niels Hammer
  • Jan Dreßler
Original Article


The aim of the given study was to test the in situ stability of biochemical markers of cerebral damage and acute phase response in the early post-mortem interval to assess their usability for forensic pathology. A monocentric, prospective study investigated post-mortem femoral venous blood samples at four time points obtained within 48 h post-mortem starting at the death of 20 deceased, using commercial immunoassays for the ten parameters: S100 calcium-binding protein B (S100B), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), C-reactive protein (CRP), procalcitonin (PCT), ferritin, soluble tumor necrosis factor receptor type 1 (sTNFR1), and lactate dehydrogenase (LDH). Significant changes in serum levels were observed only later than 2 h after death for all markers. Inter-laboratory comparability was high, and intra-assay precision was sufficient for most markers. Most of the biomarker levels depended on the severity of hemolysis and lipemia but were robust against freeze-thaw cycles. Serum levels increased with longer post-mortem intervals for S100B, NSE, ferritin, sTNFR1, and LDH (for all p < 0.001) but decreased over this period for CRP (p = 0.089) and PCT (p < 0.001). Largely unchanged median values were found for GFAP (p = 0.139), BDNF (p = 0.106), and IL-6 (p = 0.094). Serum levels of CRP (p = 0.059) and LDH (p = 0.109) did not differ significantly between the final ante-mortem (resuscitation) and the first post-mortem sample (moment of death). Collecting the post-mortem blood sample as soon as possible will reduce the influence of post-mortem blood changes. Serum GFAP for detection of cerebral damage as well as serum IL-6 and CRP as proof of acute phase response seemed to be preferable due to their in situ stability in the first 2 days after death.


Acute phase response Intra-individual stability Post-mortem biochemistry Serum Thanatochemistry Traumatic brain injury 



The authors would like to thank Ms. Aqeeda Singh (Department of Anatomy, University of Otago, New Zealand) for proofreading the paper as a native speaker and Prof. Ralph Burkhardt (Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Germany) for his kind support in aliquot checking of serum interference indices.

Compliance with ethical standards

All experiments were conducted in accordance with the human and ethical principles of the University of Leipzig (no. 388/15-ek).

Conflict of interest

BO has received reimbursement of travel costs from Randox Laboratories. The authors declare no competing interests.


  1. 1.
    Coe J (1993) Post-mortem chemistry update. Emphasis on forensic application. Am J Forensic Med Pathol 14:91–111CrossRefGoogle Scholar
  2. 2.
    Palmiere C, Mangin P (2012a) Post-mortem chemistry update part I. Int J Legal Med 126:187–198CrossRefGoogle Scholar
  3. 3.
    Palmiere C, Mangin P (2012b) Post-mortem chemistry update part II. Int J Legal Med 126:199–215CrossRefGoogle Scholar
  4. 4.
    Maeda H, Zhu BL, Ishikawa T, Quan L, Michiue T (2009) Significance of post-mortem biochemistry in determining the cause of death. Legal Med 11:46–49CrossRefGoogle Scholar
  5. 5.
    Luna A (2009) Is post-mortem biochemistry really useful? Why is it not widely used in forensic pathology? Legal Med 11:27–30CrossRefGoogle Scholar
  6. 6.
    Ondruschka B, Schuch S, Pohlers D, Franke H, Dreßler J (2018) Acute phase response after fatal traumatic brain injury. Int J Legal Med 132:531–539.CrossRefGoogle Scholar
  7. 7.
    Ondruschka B, Sieber M, Kirsten H; Franke H, Dreßler J (2018) Measurement of cerebral biomarkers proving traumatic brain injuries in post-mortem body fluids. J Neurotrauma 35:2044–2055.CrossRefGoogle Scholar
  8. 8.
    Sieber M, Dreßler J, Franke, Pohlers D, Ondruschka B (2018) Post-mortem biochemistry of NSE and S100B. A supplemental tool for detecting a lethal traumatic brain injury? J Forensic Legal Med 55:65–73.CrossRefGoogle Scholar
  9. 9.
    Woodcock T, Morganti-Kossmann MC (2013) The role of markers of inflammation in traumatic brain injury. Front Neurol 4:18CrossRefGoogle Scholar
  10. 10.
    Tsokos M, Reichelt U, Jung R, Nierhaus A, Püschel K (2001) Interleukin-6 and C-reactive protein serum levels in sepsis-related fatalities during the early postmortem period. Forensic Sci Int 119:47–56.CrossRefGoogle Scholar
  11. 11.
    Tsokos M, Reichelt U, Nierhaus A, Püschel K (2001) Serum procalcitonin (PCT): a valuable biochemical parameter for the post-mortem diagnosis of sepsis. Int J Legal Med 114:237–243.CrossRefGoogle Scholar
  12. 12.
    Soar J, Nolan JP, Böttiger BW, Perkins GD, Loot C, Carli P, Pellis T, Sandroni C, Skrifvars MB, Smith GB, Sunde K, Deakin CD et al (2015) European resuscitation council guidelines for resuscitation 2015. Section 3. Adult advanced life support. Resuscitation 95:100–147CrossRefGoogle Scholar
  13. 13.
    Hess C, Krueger L, Unger M, Madea B (2017) Freeze- and -thaw stability and long-term-stability of 84 synthetic cannabinoids in serum. Drug Test Anal 9:1506–1511CrossRefGoogle Scholar
  14. 14.
    German Medical Assocation (2015) Revision of the “Guideline of the German Medical Association on quality assurance in medical laboratory examinations - Rili-BAEK”. J Lab Med 39:26–69Google Scholar
  15. 15.
    Ishikawa T, Hamel M, Zhu B-L, Li D-R, Zhao D, Michiue T, Maeda H (2008) Comparative evaluation of postmortem serum concentrations of neopterin and C-reactive protein. Forensic Sci Int 179:135–143CrossRefGoogle Scholar
  16. 16.
    Palmiere C, Bardy D, Mangin P, Augsburger M (2013) Value of sTREM-1, procalcitonin and CRP as laboratory parameters for postmortem diagnosis of sepsis. J Inf Secur 67:545–555Google Scholar
  17. 17.
    Bode-Jänisch S, Schütz S, Schmidt A, Tschernig T, Debertin AS, Fieguth A, Hagemeier L, Teske J, Suerbaum S, Klintschar M, Bange FC (2013) Serum procalcitonin levels in the postmortem diagnosis of sepsis. Forensic Sci Int 226:266–272CrossRefGoogle Scholar
  18. 18.
    Majdan M, Plancikova D, Brazinova A, Rusnak M, Nieboer D, Feigin V, Maas A (2016) Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis. Lancet Public Health 1:e76–e83CrossRefGoogle Scholar
  19. 19.
    Blennow K, Brody DL, Kochanek PM, Levin H, McKee A, Ribbers GM, Yaffe K, Zetterberg H (2016) Traumatic brain injuries. Nat Rev Dis Primers 2:16084CrossRefGoogle Scholar
  20. 20.
    Chirica VI (2017) Useful markers to assess traumatic and hypoxic brain injury. Rom J Legal Med 25:146–151CrossRefGoogle Scholar
  21. 21.
    Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein R, Tyndall JA, Manley GT (2018) An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn 18:165–180CrossRefGoogle Scholar
  22. 22.
    Li DR, Zhu BL, Ishikawa T, Zhao D, Michiue T, Maeda H (2006a) Postmortem serum protein S100B levels with regard to the cause of death involving brain damage in medicolegal autopsy cases. Legal Med 8:71–77CrossRefGoogle Scholar
  23. 23.
    Li DR, Zhu BL, Ishikawa T, Zhao D, Michiue T, Maeda H (2006b) Immunohistochemical distribution of S-100 protein in the cerebral cortex with regard to the cause of death in forensic autopsy. Legal Med 8:78–85CrossRefGoogle Scholar
  24. 24.
    Goede A, Dreßler J, Sommer G, Schober K, Franke H, Ondruschka B (2015) Wundalterdiagnostik nach letalem Schädel-Hirn-Trauma. Rechtsmedizin 25:261–267CrossRefGoogle Scholar
  25. 25.
    Ondruschka B, Pohlers D, Sommer G, Schober K, Teupser D, Franke H, Dreßler J (2013) S100B and NSE as useful postmortem biochemical markers of traumatic brain injury in autopsy cases. J Neurotrauma 30:1862–1871CrossRefGoogle Scholar
  26. 26.
    Osuna E, Perez-Carceles MD, Luna A, Pounder DJ (1992) Efficacy of cerebro-spinal fluid biochemistry in the diagnosis of brain insult. Forensic Sci Int 52:193–198CrossRefGoogle Scholar
  27. 27.
    Raabe A, Kopetsch O, Groß U, Zimmermann M, Gebhart P (2003) Measurements of serum S-100B protein: effects of storage time and temperature on pre-analytical stability. Clin Chem Lab Med 41:700–703CrossRefGoogle Scholar
  28. 28.
    Beaudeux JL, Léger P, Dequen L, Gandjbakhch I, Coriat P, Foglietti MJ (2000) Influence of hemolysis on the measurement of S-100 protein and neuron-specific enolase plasma concentrations during coronary artery bypass grafting. Clin Chem 46:989–990Google Scholar
  29. 29.
    Missler U, Wiesmann M, Wittmann G (1999) Measurement of glial fibrillary acidic protein in human blood: analytical method and preliminary clinical results. Clin Chem 45:138–141Google Scholar
  30. 30.
    Ramont L, Thoannes H, Volondat, 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 43:1215–1217CrossRefGoogle Scholar
  31. 31.
    Verfaillie CJ, Delanghe JR (2010) Hemolysis correction factor in the measurement of serum neuron-specific enolase. Clin Chem Lab Med 48:891–892CrossRefGoogle Scholar
  32. 32.
    Korley FK, Diaz-Arrastia R, Wu AH, Yue JK, Manley GT, Sair HI, Van Eyk J, Everett AD et al (2016) Circulating brain-derived neurotrophic factor has diagnostic and prognostic value in traumatic brain injury. J Neurotrauma 33:215–225CrossRefGoogle Scholar
  33. 33.
    Failla MD, Conley YP, Wagner AK (2016) Brain-derived neurotrophic factor (BDNF) in traumatic brain injury-related mortality: interrelationships between genetics and acute systemic and central nervous system BDNF profiles. Neurorehabil Neural Repair 30:83–93CrossRefGoogle Scholar
  34. 34.
    Tsokos M (2007) Postmortem diagnosis of sepsis. Forensic Sci Int 165:155–164CrossRefGoogle Scholar
  35. 35.
    Mimasaka S, Funayama M, Hashiyada M, Nata M, Tsunenari S (2007) Significance of levels of IL-6 and IL-8 after trauma. A study of 11 cytokines post-mortem using multiplex immunoassay. Injury 38:1047–1051CrossRefGoogle Scholar
  36. 36.
    Schrag B, Roux-Lombard P, Schneiter D, Vaucher P, Mangin P, Palmiere C (2012) Evaluation of C-reactive protein, procalcitonin, tumor necrosis factor alpha, interleukin-6, and interleukin-8 as diagnostic parameters in sepsis-related fatalities. Int J Legal Med 126:505–512CrossRefGoogle Scholar
  37. 37.
    Fujita MQ, Zhu B-L, Ishida K, Quan L, Oritani S, Maeda H (2002) Serum C-reactive protein levels in postmortem blood—an analysis with special reference to the cause of death and survival time. Forensic Sci Int 130:160–166CrossRefGoogle Scholar
  38. 38.
    Astrup BS, Thomsen JL (2007) The routine use of C-reactive protein in forensic investigations. Forensic Sci Int 172:49–55CrossRefGoogle Scholar
  39. 39.
    Maeda H, Zhu B-L, Bessho Y, Ishikawa T, Quan L, Michiue T, Zhao D, Li D-R, Komatsu A (2008) Postmortem serum nitrogen compounds and C-reactive protein levels with special regard to investigation of fatal hyperthermia. Forensic Sci Med Pathol 4:175–180CrossRefGoogle Scholar
  40. 40.
    Uhlin-Hansen L (2001) C-reactive protein (CRP), a comparison of pre- and post-mortem blood levels. Forensic Sci Int 124:32–35CrossRefGoogle Scholar
  41. 41.
    Palmiere C, Augsburger M (2014) Markers for sepsis diagnosis in the forensic setting. State of the art. Croat Med J 55:103–114CrossRefGoogle Scholar
  42. 42.
    Schmidt S, Windgassen M, Nofer J-R, Pfeiffer H, Ribbecke S, Schmeling A (2015) Procalcitonin as a postmortem sepsis marker. A comparison of the validity of results obtained from blood serum, aqueous humour and cerebrospinal fluid. Int J Legal Med 129:117–123CrossRefGoogle Scholar
  43. 43.
    Ramsthaler F, Kettner M, Mall G, Bratzke H (2008) The use of rapid diagnostic test of procalcitonin serum levels for the postmortem diagnosis of sepsis. Forensic Sci Int 178:139–145CrossRefGoogle Scholar
  44. 44.
    Meisner M, Tschaikowsky K, Schnabel S, Schmidt J, Katalinic A, Schüttler J (1997) Procalcitonin - influence of temperature, storage, anticoagulation and arterial or venous asservation of blood samples on procalcitonin concentrations. Clin Chem Lab Med 35:597–602.CrossRefGoogle Scholar
  45. 45.
    Madea B, Musshoff F (2007) Post-mortem biochemistry. Forensic Sci Int 165:165–171CrossRefGoogle Scholar
  46. 46.
    Flanagan RJ (2017) Post-mortem biochemistry and toxicology. Arab J For Sci For Med 1:540–552Google Scholar
  47. 47.
    Hanrieder J, Wetterhall M, Enblad P, Hillered L, Bergquist J (2009) Temporally resolved differential proteomic analysis of human ventricular CSF for monitoring traumatic brain injury biomarker candidates. J Neurosci Methods 177:469–478CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Benjamin Ondruschka
    • 1
    Email author
  • Lina Woydt
    • 1
  • Michael Bernhard
    • 2
  • Heike Franke
    • 3
  • Holger Kirsten
    • 4
    • 5
  • Sabine Löffler
    • 6
  • Dirk Pohlers
    • 7
  • Niels Hammer
    • 8
    • 9
    • 10
  • Jan Dreßler
    • 1
  1. 1.Medical Faculty, Institute of Legal MedicineUniversity of LeipzigLeipzigGermany
  2. 2.Emergency DepartmentHeinrich Heine University DuesseldorfDuesseldorfGermany
  3. 3.Rudolf Boehm Institute of Pharmacology and ToxicologyUniversity of LeipzigLeipzigGermany
  4. 4.Institute for Medical Informatics, Statistics and EpidemiologyUniversity of LeipzigLeipzigGermany
  5. 5.LIFE Center (Leipzig Interdisciplinary Research Cluster of Genetic Factors, Phenotypes and Environment)University of LeipzigLeipzigGermany
  6. 6.Institute of AnatomyUniversity of LeipzigLeipzigGermany
  7. 7.Center of Diagnostics GmbHKlinikum ChemnitzChemnitzGermany
  8. 8.Department of AnatomyUniversity of OtagoDunedinNew Zealand
  9. 9.Department of Orthopedic and Trauma SurgeryUniversity Hospital of LeipzigLeipzigGermany
  10. 10.Fraunhofer Institute for Machine Tools and Forming TechnologyDresdenGermany

Personalised recommendations