PERAN INHIBITOR HMG-CoA REDUKTASE DALAM PENURUNAN INTERLEUKIN-6 TERHADAP HASIL AKHIR KLINIS PENDERITA KONTUSIO SEREBRI TESIS PENELITI: SABRI 077102007

  PERAN INHIBITOR HMG-CoA REDUKTASE DALAM PENURUNAN INTERLEUKIN-6 TERHADAP HASIL AKHIR KLINIS PENDERITA KONTUSIO SEREBRI TESIS PENELITI: SABRI 077102007

  LEMBAR PENGESAHAN Judul Tesis : PERAN INHIBITOR HMG-CoA REDUKTASE DALAM PENURUNAN INTERLEUKIN-6 TERHADAP HASIL AKHIR KLINIS PENDERITA KONTUSIO SEREBRI Nama : SABRI NIM : 077102007 Program Studi : ILMU BEDAH SARAF Menyetujui Pembimbing I Pembimbing II Dr.dr. Suzy Indharty, M.Kes, Sp.BS_ Prof.Dr.dr.Iskandar Japardi,Sp.BS(K) NIP. 197302202005012001 NIP. 194903311977111001 Mengetahui / Mengesahkan : Ketua Departemen Ketua Program Studi Prof.Dr.dr.Iskandar Japardi,Sp.BS(K)Prof.dr.Abd Gofar Sastrodiningrat SpBS(K) NIP. 194903311977111001 Nip.194405071977031001

  SURAT KETERANGAN SUDAH DIPERIKSA HASIL PENELITIAN JUDUL:PERAN INHIBITOR HMG-CoA REDUKTASE DALAM PENURUNAN INTERLEUKIN-6 TERHADAP HASIL AKHIR KLINIS PENDERITA KONTUSIO SEREBRI PENELITI: SABRI DEPARTEMEN:ILMU BEDAH SARAF

  INSTITUSI:UNIVERSITAS SUMATERA UTARA Medan , Mei 2013 Konsultan Metodelogi Penelitian Fakultas Kedokteran USU Medan Dr.dr.Arlinda sari wahyuni, M.Kes

  ABSTRAK Nama:Sabri Program studi : Magister Kedokteran Klinik Judul : Peran inhibitor HMG-CoA reduktase dalam penurunan interleukin-6 terhadap hasil akhir klinis penderita kontusio serebri Tujuan:Menilai hasil akhir klinis pengobatan penderita kontusio serebri dengan terapi inhibitor HMG-CoA reduktase dengan parameter interleukin-6 serum Tempat penelitian:Departemen Bedah Saraf FK USU-RS.HAM, Depatemen Patologi Klinik FK USU-RS.HAM Subjek penelitian:50 orang penderita cedera kepala sedang dengan gambaran CT scan kontusio serebri Hasil: Pada penelitian ini didapat nilai GOS saat pulang untuk terapi standar 4,08±1,00 dan terapi standar tambah inhibitor HMG-CoA reduktase 4,13±1,09, terlihat kenaikan nilai kelompok standar tambah inhibitor HMG-CoA reduktase sangat kecil, secara statistik tidak bermakna (p=0,822). Nilai Barthel saat pulang untuk terapi standar 78,18±15,85 dan terapi standar tambah inhibitor HMG-CoA reduktase 82,38±11,79, terlihat ada kecendrungan kenaikan nilai Barthel pada kelompok inhibitor HMG-CoA reduktase namun tidak signifikan (p=0,429). Nilai MMSE saat pulang untuk standar 15,27±12,07 dan standar tambah inhibitor HMG-CoA reduktase 13,24±14,29 , disini terlihat nilai lebih rendah pada kelompok standar tambah inhibitor HMG-CoA reduktase, namum masih dalam katagori yang sama gangguan kognitif , secara statistik tidak bermakna (p=0,808). Nilai GOS 1 bulan terapi standar 4,81 ±0,39 dan standar tambah inhibitor HMG-CoA reduktase 4,90±0,30, sedikit kecendrungan lebih tinggi pada inhibitor HMG-CoA reduktase namun secara tidak bermakna (p=0,418). Nilai Barthel’s 1 bulan untuk terapi standar dijumpai 95,00±7,56 dan terapi standar tambah inhibitor HMG-CoA reduktase 96,67±5,55, hanya sedikit meningkat pada kelompok inhibitor HMG-CoA reduktase namun tidak bermakna (p=0,616). Nilai MMSE pada 1bulan dijumpai untuk terapi standar; kognitif normal 18(81,80%), gangguan kognitif ringan 3(13,60%), gangguan kognitigf berat 1(4,5%) sedangkan pada terapi standar tambah inhibitor HMG-CoA reduktase; kognitif normal 17(81,00%), gangguan kognitif ringan 4(19,00%) dan tidak gangguan kognitif berat, tidak dijumpai perbedaan signifikans (p=0,563). Pada penelitian ini, nilai interleukin -6 hari pertama 9,74±15,77 dan hari kelima 3,20 ±1,98 sedangkan pada kelompok standar tambah inhibitor HMG CoA reduktase dijumpai nilai interleukin-6 hari pertama 11,96±12,78 dan hari kelima 1,25±3,33, dijumpai nilai p=0,295 untuk interleukin-6 hari pertama dan p=0,834 untuk interlaeukin-6 hari ke -5 ,dengan demikian tidak ada perbedaan signifikan kadar interleukin hari pertama dan hari kelima setelah terapi inhibitor HMG-CoA reduktase walaupun terlihat kecendrungan penurunan nilai setelah terapi inhibitor HMG-CoA reduktase Simpulan:,Tidak terdapat korelasi yang bermakna antara perlakuan inhibitor HMG-CoA reduktase dengan hasil akhir klinis (GOS, Barthel Indeks dan MMSE). Tidak terdapat korelasi yang bermakna antara kadar interleukin-6 serum dengan hasil akhir klinis (GOS,Barthel Indeks dan MMSE), pada hari pertama dan hari kelima.

  Kata kunci:Kontusio serebri, interleukin-6, GOS,Barthel Indeks dan MMSE

  ABSTRACT Name: Sabri Study program: Magister of Clinical Medicine Title: The role of HMG-CoA reductase inhibitor in decreased of interleukin-6 to end result of clinical cerebral contusion Purpose: Evaluate treatment result of contusion cerebral patients with HMG-CoA reductase inhibitor with interleukin-6 serum as a parameter Place: Neurosurgery department FK USU-RS HAM, Clinical Pathology Department FK USU-RS HAM Subject: 50 patients of moderate head injury with head ct-scan show cerebral contusion Result: This research result GOS score when discharged for standard therapy is 4,08±1,00 and standard therapy with HMG-CoA reductase inhibitor is 4,13±1,09. This show a little elevation with standard therapy with HMG-CoA reductase inhibitor, statistic show not significant with p= 0,822. Barthel score when patient discharged for therapy standard is 78,18±15,85 and standard therapy with HMG-CoA reductase inhibitor is 82,38±11,79. There is a trend of Barthel score escalation on standard therapy with HMG-CoA reductase inhibitor but statistically not significant with p value= 0,429. MMSE score when discharged for therapy standard 15,27±12,07 and standard therapy with HMG-CoA reductase inhibitor 13,24±14,29, this show lower result result on the standard therapy with HMG-CoA reductase inhibitor, but still in the same category. Statistically, cognitive disturbance was not significant p= 0,808. One month GOS of standard therapy is 4,81±0,39 and standard therapy with HMG-CoA reductase inhibitor is 4,90±0,30, this show a little escalation on the grup that statistically not significant p value=0,418. One month Barthel index for therapy standard 95,00±7,56 and standard therapy with HMG-CoA reductase inhibitor 96,67±5,55, this show a little escalation on the standard therapy with HMG-CoA reductase inhibitor but not statistically not significant p=0,616. MMSE score after one month show on standard therapy: normal cognitive 18(81,8%), mild cognitive disturbance 3(13,6%) and severe cognitive disturbance 1 (4,5%). On standard therapy with HMG-CoA reductase inhibitor, normal cognitive is 17 (81%), mild cognitive disturbance 4(19%) and no severe cognitive disturbance, with p value p= 0,563 so there is no significant statistic difference. This research show interleukin-6 value on day one is 9,74±15,77 and day five is 20 ±1,98, while on standard therapy with HMG-CoA reductase inhibitor show interleukin-6 value on day one is 11,96±12,78 and day five is 1,25±3,33, with p=0,295for interleukin-6 day one and p=0,834 for interleukin-6 day . So there is no significant diffrence of interleukin-6 value on day one and five after HMG-CoA reductase inhibitor although there is a decline value trend after HMG-CoA reductase inhibitor treatment.

  Conclusion: There is no significant correlation between treatment HMG CoA reductase inhibitor with clinical result (GOS, Barthel index and MMSE). There is no significant correlation between interleukin-6 serum value with clinical result (GOS, Barthel index and MMSE) on day one dan five Keyword: cerebral contussion, interleukin-6, GOS, Barthel index and MMSE

  LEMBAR PENGESAHAN..................................................................................................i SURAT KETERANGAN TELAH DIPERIKSA METODELOGI PENELITIAN.......ii UCAPAN TERIMA KASIH..............................................................................................iii ABSTRAK..........................................................................................................................v ABSTRACT.......................................................................................................................vi DAFTAR ISI.....................................................................................................................vii DAFTAR SINGKATAN....................................................................................................ix DAFTAR TABEL, GAMBAR, BAGAN............................................................................x

  2.5 Terapi Standar pada Cedera Kepala Sedang....................................................11

  2.8.5 Radikal Bebas…………………...………………………………..………..22

  2.8.4 Kalsium………………………………………….…………..……………..21

  2.8.3 Excitotoxicity/Glutamat…………………………………..………………..19

  2.8.2 Reperfusion injury/cytokine…………………………..…………………....17

  2.8.1 Nekrosis/apoptosis……………………………………..…………………..16

  2.8 Mediator-mediator dan mekanisme nya pada cedera otak sekunder.........................16

  2.7 Skala Fungsional “Barthel’s Index”& MMSE................................................15

  2.6 Skala Prognosis Glasgow(Glasgow Outcome Scale=GOS)............................12

  2.4 Penilaian Tingkat Kesadaran pada Cedera Otak..............................................9

  BAB I PENDAHULUAN

  2.3 Patofisiologi Cedera Kepala.............................................................................6

  2.2 Klasifikasi Cedera Kepala................................................................................6

  2.1 Definisi Cedera kepala......................................................................................6

  BAB II TINJAUAN PUSTAKA

  1.4 Mamfaat penelitian................................................................................................5

  1.3 Tujuan Penelitian.....................................................................................................5

  1.2 Rumusan Masalah..................................................................................................4

  1.1 Latar Belakang Penelitian......................................................................................1

  2.8.6 Gen exspresi,Sintesis protein dan Growth faktor….....................................24

  2.9 Strategi Farmakologi Pemilihan Neuroproteksi…......................................................24

  2.9.1 Apoptosis inhibitor…………………………………………….…….....24

  2.9.2 Alpha adrenoceptor antagonis………………..………………………..24

  2.9.3 Cholinergic agents…………………………………………………..…25

  2.9.4 Kinin antagonis………………………………………………………...25

  2.9.5 Cyclo-Oxygenase 2 inhibitors(COX-2 Inhibitor)……………………....27

  2.9.6 Intracellular Adhesion Molecule Antagonists........................................27

  2.9.7 N-Methyl-D-Aspartate (NMDA) Receptor Antagonists..........................27

  2.9.8 AMPA Receptor Antagonists...................................................................28

  2.9.9 Magnesium Sulfate..................................................................................28

  2.9.10 Dexanabinol..........................................................................................29

  2.9.11 Stratrienes.............................................................................................29

  2.9.12 Calcium Antagonists.............................................................................30

  2.9.13 LOE 908................................................................................................30

  2.9.14 MS 153..................................................................................................30

  2.9.15 Cyclosporin...........................................................................................30

  2.9.16 Antioxidants………………………………………………………....31

  2.9.17 Nitric Oxide Inhibitors………………………………………… …..31

  2.9.18 Growth Factors……………………………………………...… …..32

  2.10 Stati(HMG-CoA) Sebagai Neuroproteksi………………………………….............34

  2.11 Interleukin………………………………………………………….............…….....42

  2.12 Kerangka teori............................................................................................................46

  BAB III KERANGKA KONSEP DAN DEFINISI OPERASIONAL

  3.1 Definisi Konsepsional Variable Penelitian.............................................47

  3.2 Definisi Operasional Varable Penelitian ..................................................47

  3.3 Hipotesis……………………………………………………………. ...48

  BAB IV METODE PENELITIAN

  4.1 Tempat dan Waktu Penelitian…………………………………….………...49

  4.2 Populasi dan Subjek penelitian…………….……………….……………....49

  4.3 Kriteria Inklusi….........................................................................................…49

  4.4 Kriteria Eksklusi………...……………………………………………..….…50

  4.5 Kriteria Drop Out……..………………………………………………...……50

  4.6 Metode Penelitian.......................................………………………….............50

  4.7 Alur penelitian/ Kerangka Operasionl.............................................................52

  4.8 Kerangka Konseptual……………………………………………………......53

  4.9 Pengolahan Data..............................................................................................54

  4.10 Pelaksanaan Penelitian...................................................................................54

  4.11 Prosedur Pemeriksaan Interleukin-6(IL-6)....................................................54

  4.12 Informed Consent atau Ethical Clearance ………………………………...57

  BAB V. HASIL PENELITIAN

  5.1 Distribusi Menurut Umur………….…………………………………………58

  5.2 Distribusi Menurut Jenis Kelamin……………………………….………..…58

  5.3 Distribusi Menurut Hari Rawatan…………………………………………...59

  5.4 Distribusi GCS Masuk……………………………………………………….59

  5.5 GOS Saat Pulang……………………………………………………………..60

  5.6 Barthel’s dan MMSE Saat Pulang……………………………………...……60

  5.7 GOS dan Barthel’s Saat Satu Bulan……………………………………..…...61

  5.8 MMSE Saat Satu Bulan…………………………………………………...…62

  5.9 Kadar Interleukin-6 Serum Hari Pertama dan Kelima…………………….…62

  5.10 Hasil Analisis Korelasi IL-6 dengan GOS,Barthel, MMSE………….…….63

  BAB VI PEMBAHASAN

  6.1 Karateristik Subjek yang Diteliti………………………………………..…...65

  6.2 GOS Saat Pulang ……………………………………………………………66

  6.3 Barthel’s Saat Pulang……………………………………………………......66

  6.4 MMSE Saat Pulang………………………………………………………….66

  6.5 GOS Saat Satu Bulan………………………………………………………..67

  6.6 Barthel’s Saat Satu Bulan…………………………………………………...67

  6.7 MMSE Saat Satu Bulan……………………………………………………..67

  6.8 Hubungan Kadar IL-6 dengan Terapi Inhibitor HMG-CoA Reduktase…...68

  6.9 Hubungan IL-6 dengan GOS,Barthel, MMSE………………………………68

  BAB VII SIMPULAN DAN SARAN

  6.1 Simpulan……………………………………………………………………..70

  6.2 Saran…………………………………………………………………………70 DAFTAR PUSTAKA........................................................................................................71 LAMPIRAN....................................................................................................74a,b,c,d,e,f,g

  AMPA: Amino-3-hydroxy-5-methyl-4- isoxazolepropionate BFGF: Basic fibroblast growth factor BBB: Blood brain barrier BDNF: Brain- Derivate Neurotrophic Factor COX-2: Cyclo-oxygenase-2 CRF: Corticotrophine –realising factor DNA: Deoxiribo nucleic acid Enos: Endothelial isoform of nitric oxide synthase GDNF:Glial Derived Neurotrophic Factor GMP:Cyclic guadinosine monophosphate GOS:Glasgow outcome scale GCS:Glasgow Coma Scale GDNF:Glial Derived Neurotrophic Factor HMG-CoA:3-hydroxy-3-methyglutaryl coenzyme A HSP:Head shock protein HNE:Hydroxynonenanl

  IL-6: Interleukin-6

  ICAM-1: Intercellular adhesion molecule 1 PPI :Proton Pump Inhibitrt PIP2:Phosphatidile inositol biphosphate PTNE:Phosphate and tension homolog TNF alpha:Tumor necrosis factor LKT: Leukotrienes LIF: Leukemia inhibitory factor MMPs:Matrix metalloproteinase MPTP:Metil phenil tetra hidro piridin(suatu neurotoxin dopaminergik) NMDA: N-methyl-D-aspartate NO: Nitrix oxide NSAID:Non steroid anti immflamatory drug NGF:Nerve growth factor NGF-1Insuline Like Growth Factor-1 NF-Kb:Nuclear factor kappa B PKB: Protein kinase B PI3K: Phosphoinositide-3-kinase ROS: Reactive oxigen spesies SOD: Superoxida dismustase

  VEGF: Vascular endothelial growth factor

  VEGFR2: Vascular endothelial growth factor receptor 2 Vwf: von Willebrand Factor

  DAFTAR TABEL 1.

  Tabel 1. Nilai GCS………………………………………..……………….......11 2. Tabel 2. Nilai GOS dan GOS Extended...............................................................16 3. Tabel 5. Efek Neuroprotektive Statin...................................................................46

  DAFTAR GAMBAR 4.

  Gambar 1. Faktor-Faktor yang Mempengaruhi Prognosis Setelah Cedera Otak.8

  5. Gambar 2. Beberapa Gambaran Cedera Apoptosis pada Neuron .......................19 6.

  Gambar 3. Mekanisme dan Mediator-Mediator Sekunder pada Cedera Saraf….20

  DAFTAR BAGAN 7.

  Bagan 1. Penatalaksanaan Cedera Kepala Sedang Non Operatif.........................11

  8. Bagan 2. Induksi Glutamate pada Cedera saraf Akut..........................................22

  9. Bagan 3. Ringkasan Jalur Sinyal Neuroprotektive yang Dipengaruhi oleh Fibrine

  Growth Factor(FGF. ............................................................................................35 10.

  Bagan 4. Jalur Metabolisme Mevalonat...............................................................37 11. Bagan 5. Mekanisme Statin pada Metabolisme Lemak dan Sinyal Sel pada

  Neuroprotektive.....................................................................................................39

  12. Bagan 6. Efek Statin pada Cedera Kepala............................................................45 13.

  Bagan 7. Kerangka Teori....................................................................................48 14. Bagan 8. Alur Penelitian......................................................................................55 15. Bagan 9. Kerangkan Konseptual..........................................................................56