MMP-9, brain edema, and length of hospital stay of patients with spontaneous supratentorial intracerebral hemorrhage after hematoma evacuation along with the administration of tigecycline
Background: The high plasma level of matrix metalloproteinses–9 (MMP-9) is believed to disrupt the blood-brain barrier (BBB) and cause brain edema, as well as increase patient’s length of hospital stay (LOS). Tigecycline showed ability to reduce the MMP-9 level on study in animals. This study aimed to evaluate whether tigecycline can reduce the plasma levels of MMP-9; brain edema; and LOS of patients with supratentorial spontaneous intracerebral hemorrhage (SSICH).
Methods: A randomized clinical trial (RCT) was conducted on 72 SSICH patients who underwent hematoma evacuation in eleven hospitals in Jakarta; 100 mg tigecycline (n=35) or 2 g fosfomycine (n=37) administered intravenously before skin incision as an prophylactic antibiotics to avoid post-operative infections. Plasma levels of MMP-9 were measured in all subjects before and on the first and seventh day after the surgery. Reduction of brain edema was assessed by comparing the extent of brain edema on computed tomography scan (CT scan) before and CT scan after surgery. The length of stay (LOS) was recorded at the time of hospital discharge either survive or death. Data were analyzed using Mann-Whitney and Chi-Square test.
Results: There were non-significant statistical differences between two groups in the proportion of subjects with reduced MMP-9 levels on the first day (48% vs 50%; p=0.902; OR=1.1) and seventh day after the surgery (33% vs 48%; p=0.296; OR=1.9); proportion of the subjects with brain edema reduction (86% vs 80%, p=0.58); LOS (median 12 days vs 13 days, p=0.256; LOS ≥15 days 40% vs 27%; p=0.243; OR=1.81; NNT=8).
Conclusion: On SSICH patients who underwent hematoma evacuation, tigecycline did not either reduce MMP-9 levels and brain edema or shorthen LOS.
Silver FL, Norris JW, Lewis AJ, Hachinski VC. Early mortality following stroke: a prospective review. Stroke. 1984;15(3):492–6. https://doi.org/10.1161/01.STR.15.3.492
Minematsu K. Evacuation of intracerebral hematoma is likely to be beneficial. Stroke. 2003;34(6):1567–8. https://doi.org/10.1161/01.STR.0000074549.37517.54
Sulejczak D, Grieb P, Walski M, Frontczak-Beniewicz M. Apoptotic death of cortical neurons following surgical brain injury. Folia Neuropathol. 2008;46(3):213–9.
Frontzack-Beniewicz M, Chrapusta SJ, Sulejzak D. Long-term consequences of surgical brain injury characteristics of the neurovascular unit and formation and demise of glial scar in a rat model. Folia Neuropathol. 2011;49(3):204–18.
Meyer S, Verheyden G, Brinkmann N, Dejaeger E, de Weerdt W, et al. Functional and motor outcome 5 years after stroke is equivalent to outcome at 2 months: Follow-up of the collaborative evaluation of rehabilitation in stroke across Europe. Stroke. 2015;46:1613–9. https://doi.org/10.1161/STROKEAHA.115.009421
Petrovska-Cvetkovska D, Dolnenc-Baneva N, Nikodijevic D, Chepreganova-Changovska T. Correllative study between serum matrix metalloproteinase – 9 value and neurologic deficit in acute primary supratentorial intracerebral haemorrhage. Sec Med Sci. 2014.
Copin JC, Rebetez MML, Turck N, Robin X, Sanchez JC, Schaller K, et al. Matrix metalloproteinae 9 and cellular fibronectin plasma concentrations are predictors of the composite endpoint of length of stay and death in the intensive care unit after severe traumatic brain injury. Scan J Trauma, Resc and Emerg Med. 2012;80(83). DOI: 10.1186/1757-7241-20-83
Yong VW, Giuliani F, Xue M, Bar-Or A, Metz LM. Experimental models of neuroprotection relevant to multiple sclerosis. Neurology. 2007;68(Suppl 3):S32–7. https://doi.org/10.1212/01.wnl.0000275230.20635.72
Wang J, Tsirka SE. Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain. 2005;128(Pt7):1622–33. https://doi.org/10.1093/brain/awh489
Simonetti O, Cirioni O, Lucarini G, Orlando F, Ghiselli R, Silvestri C, et al. Tigecycline accelerates staphylococcal-infected burn wound healing through matrix metalloproteinase-9 modulation. J Antimicrob Chemother.2012;67:191–201. https://doi.org/10.1093/jac/dkr440
Saekhu M, Mahyuddin H, Ronokusumo TAS, Sastroasmoro S. Tigecycline reduces tumor necrosis factor alpha level and inhospital mortality of patients with spontaneous supratentorial intracerebral hemorrhage. Med J Indones. 2016;25(2):69–75. https://doi.org/10.13181/mji.v25i2.1351
Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke. 1996;27(8):1304–5. https://doi.org/10.1161/01.STR.27.8.1304
Madiyono B, Moeslichan S, Sastroasmoro S, Budiman I, Purwanto SH. Perkiraan besar sampel. In: Sastroasmoro S, Ismael S, editors. Dasar-dasar metodologi penelitian klinis. 5th ed. Jakarta: CV Sagung Seto; 2014. p. 352–95.
Provatopoulou X, Gounaris A, Kalogera E, Zagouri F, Flessa I, Goussetis E, et al. Circulating levels of matrix metalloproteinase-9 (MMP-9), neutrophil gelatinase-associated lipocalin (NGAL) and their complex MMP-9/NGAL in breast cancer disease. BMC Cancer. 2009;9:390. https://doi.org/10.1186/1471-2407-9-390
Umeano O, Phillips-Bute B, Hailey CE, Sun W, Gray MC, Roulhac-Wilson B, et al. Gender and age interact to affect early outcome after intracerebral hemorrhage. PLoS One. 2013;8(11):e81664. https://doi.org/10.1371/journal.pone.0081664
Ganti L, Jain A, Yerragondu N, Jain M, Bellolio MF, Gilmore RM, et al. Female gender remains an independent risk factor for poor outcome after acute nontraumatic intracerebral hemorrhage. Neurol Res Intl. 2013;2013(219097):1–7. https://doi.org/10.1155/2013/219097
Tetri S, Juvela S, Saloheimo P, Pyhtinen J, Hillbom M. Hipertension and diabetes as predictor of early death after spontaneous intracerebral hemorrhage. J Neurosurg. 2009;110(3):411–7. https://doi.org/10.3171/2008.8.JNS08445
Togha M, Bakhtavar K. Factor associated with in-hospital mortality following intracerebral hemorrhage: a three year study in Tehran, Iran. BMC Neurology. 2004;4(9):1–5. https://doi.org/10.1186/1471-2377-4-9
Sakaguchi T, Toma M, Yoshida T, Omura H, Takasu H. Metal shelate with tetracycline derivates part VII: The structure of tetracycline chelates. Chem Pharma Bulletin. 1958;6(1):1–9. https://doi.org/10.1248/cpb.6.1
Grenier D, Huot MP, Mayrand D. Iron-chelating activity of tetracycline and its impact on the susceptibility of Actinobacillus actinomycetemcomitans to these antibiotics. Antimicrob Agents Chemother. 2000;44(3):763–6. https://doi.org/10.1128/AAC.44.3.763-766.2000
Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotics properties and their clinical implication. J Am Acad Dermatol. 2006;54(2):256–65. https://doi.org/10.1016/j.jaad.2005.10.004
da Silva LM, Nunes Salgado HR. Tigecycline: a review of properties, applications, and analitycal methods. Ther Drug Monit. 2010;32(3):282–8. https://doi.org/10.1097/FTD.0b013e3181dda54f
Chang JJ, Emanuel BA, Mack WJ, Tsivgoulis G, Alexandrov AV. Matrix metalloproteinase-9: dual role and temporal profile in intracerebral hemorrhage. J Stroke Cerebrovasc Dis. 2014;23(10):2498–505. https://doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.005
Lakhan SE, Kirchgessner A, Tepper D, Leonard A. Matrix metalloproteinases and blood-brain barrier disruption in acute eschemic stroke. Front Neurol. 2013;4(32):1–15. doi: 10.3389/fneur.2013.00032
Ingeman A, Andersen G, Hundborg HH, Svendsen ML, Johnsen SP. In-hospital medical complication, length of stay, and mortality among stroke unit patients. Stroke. 2011;42(11):3214–8. https://doi.org/10.1161/STROKEAHA.110.610881
Stein M, Misselwitz B, Hamann GF, Kolodziej MA, Reinges MHT, Uhl E. Defining prolonged length of acute care stay for surgically and conservatively treated patients with spontaneous intracerebral hemorrhage: a population-based analysis. BioMed Res Int. 2016;2016(9095263):1–6. https://doi.org/10.1155/2016/9095263
Chan CL, Ting HW, Huang HT. The definition of a prolonged intensive care unit stay for spontaneous intracerebral hemorrhage patients: an application with National Health Insurance Reasearch database. BioMed Res Int. 2014;2014(891725):1–9. https://doi.org/10.1155/2014/164081
Kim HT, Lee JM, Koh EJ, Choi HY. Surgery versus conservative treatment for supratentorial intracerebral hemorrhage in spot sign positive patients. J Korean Neurosurg Soc. 2015;58(4):309–15. https://doi.org/10.3340/jkns.2015.58.4.309
Hollborn M, Wiedemann P, Bringmann A, Kohen L. Chemotactic and cytotoxic effects of minocycline on human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2010;51(5):2721–9. https://doi.org/10.1167/iovs.09-4661
Lively S, Schlichter LC. The microglial activation state regulates migration and role of matrix-dissolving enzymes for invasion. J Neuroinflammation. 2013;10:75. https://doi.org/10.1186/1742-2094-10-75
Barkho BZ, Munoz AE, Li X, Li L, Cunningham LA, Zhao X. Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote differentiation and migration of adult neural progenitor in response to the chemokines. Stem Cells. 2008;26(12):3139–49. https://doi.org/10.1634/stemcells.2008-0519
Lee SR, Kim HY, Rogowska J, Zhao BQ, Bhide P, Parent JM, et al. Involment of matrix metalloproteinase in neuroblast migration from the subventricular zone after stroke. J Neurosci. 2006;26913):3491–5. DOI: 10.1523/JNEUROSCI.4085-05.2006
Andres RH, Guzman R, Ducray AD, Mordasini P, Gera A, Barth A, et al. Cell replacement therapy for intracerebral hemorrhage. Neurosurg Focus. 2008;24(3–4):E15. https://doi.org/10.3171/foc/2008/24/3-4/e15
Patil CG, Alexander AL, Hayden Gephart MG, Lad SP, Arrigo RT, Boakye M. A population-based study of inpatient outcomes after operative managemant of nontraumatic intracerebral hemorrhage in the United States. World Neurosurg. 2012;78(6):640–5. https://doi.org/10.1016/j.wneu.2011.10.042
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