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Lactate Dehydrogenase Predicts Early Hematoma Expansion and Poor Outcomes in Intracerebral Hemorrhage Patients

  • Heling Chu
  • Chuyi Huang
  • Jing Dong
  • Xiaobo Yang
  • Jun Xiang
  • Qiang DongEmail author
  • Yuping TangEmail author
Original Article
  • 13 Downloads

Abstract

This study aimed to investigate whether serum lactate dehydrogenase (LDH) levels predicted hematoma expansion and poor outcomes in intracerebral hemorrhage (ICH) patients. The differentially expressed proteins between patients with and without hematoma expansion were screened using proteomic analysis. Then the critical value of the target protein was determined by retrospectively analyzing the data from a derivation cohort. A prospective study on the validation cohort of three clinical centers was performed to investigate the association between the target protein and hematoma expansion and poor outcomes (modified Rankin Scale > 3) at 90 days by using univariate and multivariate logistic regression analyses. Among the 41 differentially expressed proteins, LDH A chain was upregulated, which is one of the two main subunits of LDH protein. Considering that it was easy to determine serum LDH levels, LDH was selected as the target protein. In the derivation cohort, LDH ≥ 220 U/L was selected as the critical value to predict hematoma expansion by using receiver operating characteristic analysis. A total of 366 ICH patients were enrolled in the validation cohort and LDH ≥ 220 U/L was positive in 127 patients (34.7%). The multivariate logistic regression analysis demonstrated LDH levels and LDH ≥ 220 U/L independently predicted hematoma expansion (p < 0.001) and poor outcomes (p < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of LDH ≥ 220 U/L for hematoma expansion and poor outcome prediction were 79.1%, 80.0%, 56.7%, 92.1%, and 79.8% and 53.3%, 78.2%, 63.0%, 70.7%, and 68.0%, respectively. In conclusion, LDH is a reliable predictor for early hematoma expansion and poor outcomes in patients with ICH.

Keywords

Intracerebral hemorrhage Hematoma expansion Lactate dehydrogenase Proteomic analysis Poor outcomes 

Notes

Funding

This research was supported by grants from the National Natural Science Foundation of China (No. 81500998) and Science and Technology Commission of Shanghai Municipality, China (No. 16140903200).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval and Patient Consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Fudan University Ethics Committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–76.CrossRefGoogle Scholar
  2. 2.
    Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373:1632–44.CrossRefGoogle Scholar
  3. 3.
    Hemphill JC 3rd, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032–60.CrossRefGoogle Scholar
  4. 4.
    Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175–81.CrossRefGoogle Scholar
  5. 5.
    Dowlatshahi D, Demchuk AM, Flaherty ML, Ali M, Lyden PL, Smith EE, et al. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology. 2011;76:1238–44.CrossRefGoogle Scholar
  6. 6.
    Delgado Almandoz JE, Yoo AJ, Stone MJ, Schaefer PW, Goldstein JN, Rosand J, et al. Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion: the spot sign score. Stroke. 2009;40:2994–3000.CrossRefGoogle Scholar
  7. 7.
    Sporns PB, Schwake M, Kemmling A, Minnerup J, Schwindt W, Niederstadt T, et al. Comparison of spot sign, blend sign and black hole sign for outcome prediction in patients with intracerebral hemorrhage. J Stroke. 2017;19:333–9.CrossRefGoogle Scholar
  8. 8.
    Morotti A, Charidimou A, Phuah CL, Jessel MJ, Schwab K, Ayres AM, et al. Association between serum calcium level and extent of bleeding in patients with intracerebral hemorrhage. JAMA Neurol. 2016;73:1285–90.CrossRefGoogle Scholar
  9. 9.
    Di Napoli M, Parry-Jones AR, Smith CJ, Hopkins SJ, Slevin M, Masotti L, et al. C-reactive protein predicts hematoma growth in intracerebral hemorrhage. Stroke. 2014;45:59–65.CrossRefGoogle Scholar
  10. 10.
    Silva Y, Leira R, Tejada J, Lainez JM, Castillo J, Dávalos A. Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage. Stroke. 2005;36:86–91.CrossRefGoogle Scholar
  11. 11.
    Xu X, Chen X, Zhang J, Zheng Y, Sun G, Yu X, et al. Comparison of the Tada formula with software slicer: precise and low-cost method for volume assessment of intracerebral hematoma. Stroke. 2014;45:3433–5.CrossRefGoogle Scholar
  12. 12.
    Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, Molina CA, Blas YS, Dzialowski I, et al. Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study. Lancet Neurol. 2012;11:307–14.CrossRefGoogle Scholar
  13. 13.
    Navarro P, Trevisan-Herraz M, Bonzon-Kulichenko E, Núñez E, Martínez-Acedo P, Pérez-Hernández D, et al. General statistical framework for quantitative proteomics by stable isotope labeling. J Proteome Res. 2014;3:1234–47.CrossRefGoogle Scholar
  14. 14.
    Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke. 1996;27:1783–7.CrossRefGoogle Scholar
  15. 15.
    Delcourt C, Huang Y, Arima H, Chalmers J, Davis SM, Heeley EL, et al. Hematoma growth and outcomes in intracerebral hemorrhage: the INTERACT1 study. Neurology. 2012;79:314–9.CrossRefGoogle Scholar
  16. 16.
    Fujii Y, Takeuchi S, Sasaki O, Minakawa T. TanakaR. Multivariate analysis of predictors of hematoma enlargement in spontaneous intracerebral hemorrhage. Stroke. 1998;29:1160–6.CrossRefGoogle Scholar
  17. 17.
    Huynh TJ, Aviv RI, Dowlatshahi D, Gladstone DJ, Laupacis A, Kiss A, et al. Validation of the 9-point and 24-point hematoma expansion prediction scores and derivation of the PREDICT a/B scores. Stroke. 2015;46:3105–10.CrossRefGoogle Scholar
  18. 18.
    Chu H, Xiang J, Wu P, Su J, Ding H, Tang Y, et al. The role of aquaporin 4 in apoptosis after intracerebral hemorrhage. J Neuroinflamm. 2014;11:184.CrossRefGoogle Scholar
  19. 19.
    Morotti A, Phuah CL, Anderson CD, Jessel MJ, Schwab K, Ayres AM, et al. Leukocyte count and intracerebral hemorrhage expansion. Stroke. 2016;47:1473–8.CrossRefGoogle Scholar
  20. 20.
    Rodriguez-Luna D, Rubiera M, Ribo M, Coscojuela P, Pagola J, Piñeiro S, et al. Serum low-density lipoprotein cholesterol level predicts hematoma growth and clinical outcome after acute intracerebral hemorrhage. Stroke. 2011;42:2447–52.CrossRefGoogle Scholar
  21. 21.
    Lampl Y, Paniri Y, Eshel Y, Sarova-Pinhas I. Cerebrospinal fluid lactate dehydrogenase levels in early stroke and transient ischemic attacks. Stroke. 1990;21:854–7.CrossRefGoogle Scholar
  22. 22.
    Thoresen M, Liu X, Jary S, Brown E, Sabir H, Stone J, et al. Lactate dehydrogenase in hypothermia-treated newborn infants with hypoxic-ischaemic encephalopathy. Acta Paediatr. 2012;101:1038–44.CrossRefGoogle Scholar
  23. 23.
    Muiz AJ, Abdullah J, Naing NN, Ghazaime G, Ariff AR. Spontaneous intracerebral hemorrhage in northeast Malaysian patients: a four-year study. Neuroepidemiology. 2003;22:184–95.CrossRefGoogle Scholar
  24. 24.
    Miyoshi N, Tanigawa T, Nishioka S, Maruyama K, Eguchi E, Tanaka K, et al. Association of salivary lactate dehydrogenase level with systemic inflammation in a Japanese population. J Periodontal Res. 2018;53:487–94.CrossRefGoogle Scholar
  25. 25.
    Manerba M, Di Ianni L, Govoni M, Roberti M, Recanatini M, Di Stefano G. Lactate dehydrogenase inhibitors can reverse inflammation induced changes in colon cancer cells. Eur J Pharm Sci. 2017;96:37–44.CrossRefGoogle Scholar
  26. 26.
    Valvona CJ, Fillmore HL, Nunn PB, Pilkington GJ. The regulation and function of lactate dehydrogenase a: therapeutic potential in brain tumor. Brain Pathol. 2016;26:3–17.CrossRefGoogle Scholar
  27. 27.
    Lin H, Muramatsu R, Maedera N, Tsunematsu H, Hamaguchi M, Koyama Y, et al. Extracellular lactate dehydrogenase a release from damaged neurons drives central nervous system angiogenesis. EBioMedicine. 2018;27:71–85.CrossRefGoogle Scholar
  28. 28.
    Brouwers HB, Chang Y, Falcone GJ, Cai X, Ayres AM, Battey TW, et al. Predicting hematoma expansion after primary intracerebral hemorrhage. JAMA Neurol. 2014;71:158–64.CrossRefGoogle Scholar
  29. 29.
    Morotti A, Dowlatshahi D, Boulouis G, Al-Ajlan F, Demchuk AM, Aviv RI, et al. Predicting intracerebral hemorrhage expansion with noncontrast computed tomography: the BAT score. Stroke. 2018;49:1163–9.CrossRefGoogle Scholar
  30. 30.
    Morotti A, Boulouis G, Romero JM, Brouwers HB, Jessel MJ, Vashkevich A, et al. Blood pressure reduction and noncontrast CT markers of intracerebral hemorrhage expansion. Neurology. 2017;89:548–54.CrossRefGoogle Scholar
  31. 31.
    Morotti A, Brouwers HB, Romero JM, Jessel MJ, Vashkevich A, Schwab K, et al. Intensive blood pressure reduction and spot sign in intracerebral hemorrhage: a secondary analysis of a randomized clinical trial. JAMA Neurol. 2017;74:950–60.CrossRefGoogle Scholar
  32. 32.
    Meretoja A, Churilov L, Campbell BC, Aviv RI, Yassi N, Barras C, et al. The spot sign and tranexamic acid on preventing ICH growth--AUStralasia trial (STOP-AUST): protocol of a phase II randomized, placebo-controlled, double-blind, multicenter trial. Int J Stroke. 2014;9:519–24.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neurology, Huashan Hospital, State Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina
  2. 2.Department of Neurology, Shanghai East HospitalTongji University School of MedicineShanghaiChina
  3. 3.Department of Neurology, Jinshan HospitalFudan UniversityShanghaiChina
  4. 4.Department of Chinese Integrative Medicine, Zhongshan HospitalFudan UniversityShanghaiChina

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