Saturday, April 12, 2008

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NEC dikategorikan oleh klasifikasi bell yang sudah dimodifikasi. Diagnosis dan klasifikasi dari NEC ditegakkan oleh 2 ahli neonatologis senior independen yang tidak mengetahui pembagian kelompok pada bayi tersebut. Jika mereka tidak setuju pada pengklasifikasian tersebut, dimintakan pendapat ketiga dari ahli neonatologis yang lain untuk mengambil keputusan. Gambaran demografi dan variabel klinis yang merupakan faktor resiko yang potensial untuk NEC secara abstrak prospektiv berasal dari data-data medis (medical record) menggunakan definisi berikut ini. Ibu yag menerima 2 dosis betamethason atau dexamethason yang diberikan > 24 jam sebelum melahirkan dipertimbangkan sudah dalam tahap steroid prenatal. Bayi dengan berat lahir >2SD dibawah rerata untuk usia kehamilan dipertimbangkan sebagai kecil usia kehamilan (KMK). Ruptur membran amnion/ketuban lama (prolong) didefinisikan sebagai pecahnya membran amnion >18 jam sebelum kelahiran. Chorioamnionitis didefinisikan sebagai demam maternal, cairan ketuban keruh dan berbau, dan pada hitung sel darah putih (Differential count) bergeser kekiri. Dan telah dikonfirmasi oleh ahli obstetri. Keadaan asfiksia didefinisikan sebagai berikut: (1) pH umbilicus < 7,0, (2) Apgar score < 3 pada 5 menit pertama, (3) manifestasi neurologis meliputi kejang hipotonis atau keadaan hipoxic-iskemia encepalopathy, dan (4) multipel organ failure. Surfaktan diberikan untuk syndrom distres pernapasan dalam 2 jam sesudah lahir dalam kasus bayi yang memerlukan ventilasi yang memerlukan suplemen oksigen dengan FiO2 > 0,40 dan memperlihatkan tipe perubahan radiologis semacam sindrom distres pernapasan. Indometasin diberikan jika didapatkan bayi dengan adanya PDA (patent ductus arteriosus) yang memperlihatkan pirau dari kiri ke kanan pada echokardiografi. Sepsis didiagnosa pada bayi dengan tanda klinis dari sepsis setelah proses randomisasi dan dari hasil kultur darah yang terbukti positif. Kejadian ini tidak terbatas dihubungkan dengan kematian atau NEC. Diutamakan hasilnya adalah kejadian dari kematian atau NEC (stadium > 2). Kematian dimasukkan sebagai hasil utama karena hal ini merupakan variabel kompetisi dari NEC.

PROBIOTIK DALAM NECROTIZING ENTEROCOLITIS (NEC)

Sampel- Penghitungan Dan Statistik

Data-data penulis memperlihatkan bahwa gabungan kejadian dari NEC atau kematian sekitar~23%. Set α error < style=""> NEC atau kematian sebanyak 50%, jumlah total yang dibutuhkan untuk memferifikasi hipotesis kami sekitar 338 (169 per arm dari penelitian).

Uji X2 digunakan untuk menganalisa data yang terkategorikan, along with Fisher’s exact tes when aplicable. Student’s t tes digunakan untuk data berikutnya. Sebuah model regresi logistik digunakan untuk menganalisa pengaruh perlakuan pada variabel hasil primer dan sekunder (kematian, NEC dan sepsis)

HASIL

Terdapat 417 BBLSR terdaftar di bagian PICU penulisselama 4-5 tahun masa penelitian. Dari sekian bayi tersebut, sebanyak 50 tak memenuhi syarat sebagai sampel (n=42) atau mengalami NEC sebelum usia 7 hari sesudah kelahiran (n=6), atau keluarga tidak setuju (n=2). Sehingga total 367 bayi yang terdaftar dalam percobaan: 180 dalam kelompok yang diteliti dan 187 dalam kelompok kontrol. 56 bayi dalam kelompok yang diteliti dan 61 bayi dari kelompok kontrol diberi asupan dari BANK ASI. Sedangkan kondisi klinis maternal, demografi bayi dan karakteristik klinis tidak berbeda diantara ke 2 kelompok (Tabel 1). Pada karakteristik klinik bayi tidak berbeda pada ke 2 kelompok bayi (Tabel 2). Tak satupun dari bayi-bayi yang menderita asfiksia mengidap NEC.

Tabel 3 memperlihatkan hasil dari penelitian melalui analisis logistik regresi. Tingkat kejadian kematian atau NEC secara signifikan lebih rendah pada kelompok probiotik ketika dibandingkan dengan kelompok kontrol (9 dari 180[5%] dibanding 24 dari 187 [12.8%],secara respectiv; P = .009). Tingkat kejadian NEC juga lebih rendah pada kelompok yang diteliti dibanding pada kelompok kontrol (2 dari 180 [1.2%] dibanding 10 dari 186 [5.3%], dengan respetively; P = .04). didapatkan 6 kasus NEC berat (Bell stadium 3) pada kelompok kontrol dan tak satupun pada kelompok probiotik (P = .03 oleh analisis bivariate). Tingkat kejadian dari hasil kultur yang terbukti sepsis secara signifikan lebih rendah pada kelompok yang diteliti (probiotik) (P = .03). Tak satupun dari kultur yang positif tadi menumbuhkan actobacillus atau spesies Bifidobacterium. Tingkat kejadian NEC atau sepsis lebih rendah pada kelompok probiotik (24 dari 180 [13.3]dibanding 46 dari 187 [24.6%],respectibely; P< .03). Tingkat kejadian kematian, NEC, atau sepsis secara signifikan juga lebih rendah pada kelompok probiotik (31 dari 180 [17.2%] dibanding 60 dari187 [32.1%], repectively; P <.009).

Tabel 1. Klinis maternal dan demografi bayi dan karakteristik klinis

karakteristik

Kelompok Diteliti

( N = 180 )

Kelompok Kontrol

( N = 187 )

Ketuban pecah dini, n(%)

53 (29.4)

43 (23.0)

Preeklamsia, n(%)

26 (14.4)

24 (12.8)

Prenatal Steroid, n(%)

121 (67.2)

114 (61.0)

SCTP, n(%)

104 (57.8)

100 (53.5)

Multipregnancy, n(%)

34 (18.9)

33 (17.6)

Chorioamnionitis, n(%)

9 (5.0)

10 (5.3)

Laki-laki, n(%)

84 (46.7)

100 (53.5)

Kecil Masa Kehamilan, n(%)

42 (23.3)

41 (22.8)

Usia kehamilan, mgg

28.5 + 2.5*

28.2 + 2.5*

Berat lahir, gr

1104 + 242*

1071 + 243*

Apgar (5 menit)

<3

41

44

4-6

41

49

>7

98

94

Asfiksia, n(%)

4 (2.2)

6 (3.2)

Ph

7.29 + 1*

7.29 + 11*

Tak satupun dari perbedaan diatas yang secara statistik signifikan (P>.05)

*Nilai adalah rerata + SD

Tabel 2.variabel klinis pada kelompok bayi yang diteliti (Probiotik).

Variabel

Kelompok yg Diteliti

( N = 180 )

Kelompok Kontrol

( N = 187 )

Usia terdaftar,* hari

Nothing per oral, hari

Total parenteral nutisi, hari

Jumlah makanan 14 hari ml/kg$


DISKUSI

Penelitian kami memeperlihatkan bahwa infloran mengurangi tingkat kejadian (insidensi) dan severitas dari NEC pada BBLSR. Kami juga menemukan bahwa kelompok yang diteliti (studi) memiliki insidensi lebih rendah terhadap NEC dan sepsis. Menurut data penulis, jumlah yang diperlukan untuk merawat untuk mencegah 1 kasus NEC adalah 27, dan jumlah yang diperlukan untuk merawat untuk mencegah 1 kematian karena NEC adalah 31.

Meskipun banyak variabel berhubungan dengan perkembangan NEC, hanya prematuritas dan berat lahir rendah yang secara konstan diidentifikasi dalam penelitian case control. Faktor-faktor lain yang dihubungkan dengan peningkatan resiko NEC seperti kelahiran pervaginam, kebutuhan dukungan ventilator mekanik, pemberian glukokortikoid dan indometasin selama kehidupan minggu pertama, tidak digunakannya cateter arteri umbilicalis, nilai APGAR score yang rendah pada 5 menit pertama. Karena penelitian saat ini didesain secara acak (random), trial control, faktor-faktor resiko ini didistribusikan secara acakdan diperlihatkan tanpa adanya perbedaan diantara 2 kelompok.

Sebuah patogenesis yang diusulkan sebagai komponen utama pada NEC adalah interaksi bakteri dengan usus yang prematur. sebuah fakta bahwa NEC tidak terjadi di uterus meskipun stres dan ingesti fetal sebanyak 150 ml/kg/hari terhadap cairan amniom yang mengandung protein, karbohidrat dan lemak, imunoglobulin, dan elektrolit memberi kesan bahwa kolonisasi bakteri adalah faktor penting pada patogenesis penyakit ini. Sebuah percobaan pada binatang terhadap NEC memperlihatkan kebutuhan untuk kolonisasi bakteri apda perkembangan dari NEC.

Flora mikrobiologi intstinum merupakan faktor penting pada mekanisme pertahanan host melawan infeksi bakteri. Lawrence dkk memperlihatkan bahwa kolonisasi usus dengan jumlah sedikit dan keberadaan spesies bakteri dapat dihambat oleh lingkungan yang steril. Mereka berspekulasi bahwa kondisi lingkungan yang kurang steril di NICU menyebabkan kolonisasi intestinal dengan absorbsi dari toksin bakteri yang hidup yang mungkin merusak illeum imatur, menyebabkan perkembangan dari NEC. Hay dkk dan Miller dkk mengobservasi perubahan baik kuantitatif maupun kualitatifpada flora fecal sebelum terjadinya NEC. Mereka mengobservasi sebuah kemunduran pada variasi spesies dan pergeseran kearah predominan dari enterobactericiae sebelum terjadinya NEC. Gewalb dkk melaporkan bahwa bifidobacterium dan lactobacillus ditemukan pada bekas popok atau sandaran dari bayi pada <5%>

Mekanisme potensial yang mana probiotik mungkin melindungi bayi beresiko tinggi dari perkembangan NEC termasuk didalamnya peningkatan barier mukosa terhadap perpindahan bakteri dan produknya melewati mukosa, pengelluaran secara kompetitif patogen yang potensial, modifikasi respon host terhadap produk mikroba dan peningkatan nutrisi enteral yang menghambat pertumbuhan dari berbagai kuman patogen seperti klebsiella pneumoniae, Escherichia coli, dan Candida albicans.

Ada faktor-faktor lai ndari data-data penelitian yang mendukung bahwa invasi mikroba sebagai faktor yang memiliki peranan kejadian NEC. Observasi ini mengemukakan bahwa perubahan flora mikroba melalui makanan enteral semacam probiotik mungkin menguntungkan. Akantetapi, ada kekurangan dalampercobaan klinik untuk mengkonfirmasi hipotesis ini.

Infloran telah dipakai sebagai probiotik untuk mengurangi tingkat insidensi NEC oleh hayes. Dalam penelitian itu, seperempat tablet infloran diberikan ke semua bayi yang terdaftar di NICU. Hasilnya memperlihatkan penurunan yang signifikan dari NEC dan NEC yang berhubungan dengan kematian pada pengobatan infloran ketika dibandingkan dengan kelompok kontrol. Kesimpulan dari penelitian ini mendukung dugaan percobaan random trial-control untuk memperbarui kemanjuran dari penelitian kami.

Dalam penelitian multicenter-double blind baru-baru ini . 585 bayi dengan usia gestasi <33>2 minggu ketika diacak /random dengan pemberian placebo atau Lactobcillusrhamnosus GG 1x/hari dari mulai makan sampai akhir(disharge). Pengukuran hasil meliputi insidensi ISK, sepsis bakeri dan NEC. Tidak ada perbedaan signifikan dintara kelompok probiotik dan placebo dalam hal 3 variabel tadi. Namun rerata kejadian pada kelompok kontrol untuk 2 variabel (NEC: 1,4%; Sepsis: 3,4%), yang memerlukan jauh lebih banyak sampel untuk membuktikan hipotesis mereka.ada percobaan lain diantara percobaab tersebut dengan penelitian kami . kami menggunakan infloran sebuah probiotik dari hasil kultur dari bekas dudukan neonatus dan mengandung L acidophilus dan B infantis. Perbedaan lain dari usia bayi yang terdaftar ntuk diteliti. Pada penelitian kami usia bayi bayi 1 minggu dan 2 minggu untuk penelitian mereka.

Penelitian kami memperlihatkan bahwa kelompok yang diteliti(studi) memiliki tingkat insidensi yang lebih rendah dari NEC dan SEPSIS. Mekanisme dari kemanjuran probiotik dalam mengurangi tingkat insidensi sepsis pada BBLSR mungkin sama dengan NEC dan memungkinkan terjadinya peningkatan dari kolonisasi mikroflora yang diinginkan seperti Streptococcus salivarius.

Meskipun wagner dkk menyarankan bahwa masalah keamanan penanganan dengan probiotik perlu ditujukan kepada host dengan kondisi imunodefisiensi seperti neonatus, kami tidak mengobservasi komplikasi (seperti sepsis karena Lactobacillus atau Bifidobacterium) karena infloran ini. Namun, percobaan kami tidak mempunyai kekuatan mengevaluasi keamanan dalam hal resiko yang mungkin karena kejadian sepsis lactobacillus atau sepsis Bifidobacterium.

Kami mengobservasi 6 bayi dengan NEC sebelum masuk ke percobaan dan pemberian makanan enteral.5 dari mereka memiliki berat <1000gr.>

KESIMPULAN

Pemberian infloran oral pada BBLSR mengurangiinsidensi dan severitas dari NEC,dan infloran sebagai probiotik melindungi BBLSR dari NEC.

ACKNOWLEDGMENTS

Penelitian ini didukung oleh Research Department of China Medical University Hospital (grant DMR90140)

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