Penurunan Kadar Matriks Metalloproteinase-9 dan D-Dimer Plasma setelah Pemberian Bromelin dan Korelasinya dengan Luaran Klinis pada Stroke Iskemik Akut

Abstract

Expression of Matrix Metalloproteinase9 (MMP9) due to ischemic conditions in the brain causes damage to the blood brain barrier, edema and widespread brain damage and is thought to worsen the clinical outcome. D-dimer as a fibrin-splitting end product contribute to thrombosis and are closely related to poor clinical outcome. This study was a double-blind clinical trial of acute ischemic stroke patients treated at RSUP H. Adam Malik Medan aiming to demonstrate decreased levels of MMP9 and D-dimer plasma after administration of Bromelin against standard therapy and correlation with clinical outcome. The study took place from April 1st, 2016 to April 30th, 2017. A total of 69 subjects were randomly assigned to 3 treatment groups, those who received additional treatment with Bromelin 500 mg, Bromelin 250 mg and Plasebo, each twice a day. Variable measurements were performed before and after 14 days of treatment. The mean of MMP9, D-dimer, mRS and BI values were descriptively reported, and the correlation of MMP9 and D-dimer level with mRS values was performed by Pearson correlation test, while against BI with Spearman correlation test. The subject consisted of 45 male (65.2%), with mean of age 57.46±10.93 years old. The mean level of MMP9 was 5.82±0.76 ng/ml; mean level of D-dimer was 703±1.227 ng/ml; mean of mRS value was 3±1.036. The average value of BI was 60±24.8. There was a very weak positive correlation between MMP9 and mRS (r = 0.12; p = 0.328), and very weak negative correlation between MMP9 and BI (r = - 0,06; p = 0,608). There was a moderate positive correlation between D-dimer and mRS value (r = 0.083; p = 0.495) and very weak negative correlation between D-dimer and BI value which is statistically not significant (r = - 0,05; p = 0,683). The mean level of MMP9 in the Bromelin 500 mg group (23 people) decreased significantly from 6.02±0.32 to 5.50±0.94 (p 0.028). The result of correlation test between decreasing level of MMP9 and mRS value after administration of Bromelin 500 mg showed a very weak negative correlation, statistically not significant (r = - 0.03; p = 0.905) and the correlation test with BI value showed very weak positive correlation and statistically not significant (r = 0.039; p = 0.859). The mean level of D-dimer decreased insignificantly from 650.7±976.79 to 575.00±674.83 (p = 0.743). The result of correlation between D-dimer level and mRS value showed weak positive correlation statistically not significant (r = 0.382; p = 0.072). The mean level of MMP9 in the Bromelin 250 mg group (23 people) decreased insignificantly from 5.62±1.037 to 5.14±1.3 (p = 0.183). The result of correlation test between decreasing level of MMP9 and mRS value after administration of Bromelin 250 mg showed a weak negative correlation, statistically not significant (r = - 0.351; p = 0.101) and the correlation test with BI value showed moderate positive correlation (r = 0.557; p = 0.006). The mean level of D-dimer decreased insignificantly from 757.22±1704.25 to 619.96±882.67 (p = 0.581). The result of correlation test between decreasing level of D-dimer with mRS value after administration of Bromelin 250 mg showed very weak positive correlation statistically not significant (r = 0.031; p = 0.887), and the correlation test with BI value showed very weak positive correlation and statistically not significant (r = 0.069; p = 0.755). The mean level of MMP9 in the Placebo group (23 persons) increased insignificantly from 5.82±0.71 to 5.91±0.83 (p = 0.616). The result of correlation test between increasing level of MMP9 with mRS value after administration of Placebo showed very weak positive correlation, statistically not significant (r = 0.114; p = 0.604) and the correlation test with BI value showed weak negative correlation and statistically not significant (r = 0.22; p = 0.308). The mean level of D-dimer in Placebo group increased insignificantly from 726.26±889.7 to 874.6±2065.25 (p = 0.538). The correlation test between increasing level of D-dimer and mRS value showed a moderate positive correlation (r = 0.592; p = 0.003), and the correlation test with BI value showed moderate negative and statistically not significant (r = - 0.562; p = 0.005). Conclusion: The level of MMP9 and D-dimer increased in acute ischemic stroke. The administration of 500 mg Bromelin significantly decreased the level of plasma MMP9 (p = 0.028) and correlated with improvement in clinical outcome although statistically not significant. Similarly, D-dimer level were decrease and correlated with improvements in clinical outcomes but were not statistically significant.

Ekspresi Matriks Metalloproteinase9 (MMP9) akibat kondisi iskemik di otak menyebabkan kerusakan sawar darah otak, edema dan meluasnya kerusakan otak dan diduga memperburuk luaran klinis. D-dimer sebagai produk akhir pemecahan fibrin berkontribusi menyebabkan thrombosis dan erat hubungannya dengan buruknya luaran klinis. Penelitian ini merupakan uji klinik tersamar ganda terhadap pasien stroke iskemik akut yang dirawat di RSUP H. Adam Malik Medan yang bertujuan untuk membuktikan penurunan kadar MMP9 dan D-dimer plasma setelah penambahan Bromelin terhadap terapi yang standar dan korelasinya dengan luaran klinis. Penelitian berlangsung periode 1 April 2016 hingga 30 April 2017. Sejumlah 69 subjek dibagi secara random ke dalam 3 kelompok perlakuan yaitu kelompok yang mendapat terapi tambahan Bromelin 500 mg, 250 mg dan Plasebo dengan dosis 2 kali sehari. Pengukuran variabel dilakukan sebelum dan sesudah 14 hari perlakuan. Rerata kadar MMP9, D-dimer, nilai mRS dan BI dilaporkan secara deskriptif, dan korelasi kadar MMP9 dan D-dimer dengan nilai mRS dilakukan dengan Uji korelasi Pearson, sedangkan terhadap BI dengan uji korelasi Spearman. Keseluruhan subjek (n=69) terdiri dari 45 orang (65,2%) laki-laki, rerata usia 57,46±10,93 tahun. Rerata kadar MMP9 adalah 5,82±0,76 ng/ml; Rerata kadar D-dimer 703±1,227 ng/ml; Rerata nilai mRS adalah 3±1,036. Rerata nilai BI adalah 60±24,8.Terdapat korelasi positif sangat lemah kadar MMP9 dengan mRS (r = 0,12; p = 0,328),dan korelasi negatif sangat lemah antara kadar MMP9 dengan BI (r = – 0,06; p = 0,608). Terdapat korelasi positif sedang antara D-dimer dengan mRS (r 0,083; p 0,495) dan korelasi negatif sangat lemah kadar D-dimer dengan nilai BI yang secara statistik tidak signifikan (r = - 0,05; p = 0,683). Rerata kadar MMP9 pada Kelompok Bromelin 500 mg (23 orang) menurun secara signifikan dari 6,02±0,32 menjadi 5,50±0,94 (p = 0,028). Hasil uji korelasi penurunan kadar MMP9 dengan mRS setelah mendapat Bromelin 500 mg menunjukkan korelasi negatif sangat lemah yang tidak signifikan (r = - 0,03; p = 0,905) dan dengan BI berkorelasi positif sangat lemah dan tidak signifikan (r = 0,039; p = 0,859). Rerata kadar D-dimer menurun secara tidak signifikan dari 650,7±976,79 menjadi 575,00±674,83 (p = 0,743). Hasil uji korelasi kadar D-dimer dengan mRS menunjukkan korelasi positif lemah secara tidak signifikan (r = 0,382; p = 0,072). Rerata kadar MMP9 pada Kelompok Bromelin 250 mg (23 orang) menurun secara tidak signifikan dari 5,62±1,037 menjadi 5,14±1,3 (p = 0,183). Hasil uji korelasi penurunan kadar MMP9 dengan mRS setelah mendapat Bromelin 250 mg menunjukkan korelasi negatif lemah yang tidak signifikan (rn = – 0,351; p = 0,101) dan dengan BI berkorelasi positif sedang secara signifikan (r = 0,557 ; p = 0.006). Rerata kadar D-dimer menurun secara tidak signifikan dari 757,22±1704,25 menjadi 619,96±882,67 (p = 0,581). Hasil uji korelasi penurunan kadar D-dimer dengan mRS setelah mendapat Bromelin 250 mg menunjukkan korelasi positif sangat lemah yang tidak signifikan (r = 0,031; p = 0,887), dan dengan BI berkorelasi positif sangat lemah dan tidak signifikan (r = 0,069; p = 0,755). Rerata kadar MMP9 pada Kelompok Plasebo (23 orang) meningkat secara tidak signifikan dari 5,82±0,71 menjadi 5,91±0,83 (p = 0,616). Hasil uji korelasi peningkatan kadar MMP9 dengan mRS setelah mendapat Plasebo menunjukkan korelasi positif sangat lemah yang tidak signifikan (r = 0,114; p = 0,604) dan dengan BI berkorelasi negatif lemah dan tidak signifikan (r = 0,22; p = 0,308). Rerata kadar D-dimer meningkat secara tidak signifikan dari 726,26±889,7 menjadi 874,6±2065,25 (p = 0,538). Hasil uji korelasi peningkatan kadar D-dimer dengan mRS menunjukkan korelasi positif sedang secara signifikan (r = 0,592 ; p = 0,003), dan dengan BI berkorelasi negatif sedang namun secara statistik tidak signifikan (r = - 0,562; p = 0,005). Kesimpulan: Kadar MMP9 dan D-dimer meningkat pada stroke iskemik akut. Penambahan Bromelin 500 mg menurunkan kadar MMP9 plasma secara signifikan (p = 0,028) dan berkorelasi dengan perbaikan luaran klinis meskipun secara statistik tidak signifikan. Demikian juga kadar D-dimer menurun dan berkorelasi dengan perbaikan luaran klinis namun secara statistik tidak signifikan.