kuliah asma121005 (nxpowerlite)
DESCRIPTION
umiTRANSCRIPT
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Tatalaksana jangka panjang Asma Anak
Dr H Bambang Supriyatno SpAK
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Bahasan
• Konsep inflamasi dan remodeling pada asma
• Klasifikasi asma• Tujuan tatalaksana• Longterm management:
Kapan?Obat Efek sampingHow early?
• Terapi inhalasi: kendala
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PERKEMBANGAN DEFINISI ASMA
OBSTRUKSI SALURAN RESPIRATORIK YANG REVERSIBEL SECARA SPONTAN ATAU SETELAH PENGOBATAN TERATASI
1950-an
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PENYAKIT EPISODIK, OBSTRUKSI AKIBAT MENINGKATNYA RESPONS BRONKUS THD STIMULI (HIPERREAKTIF BRONKUS)
KEADAAN KRONIK DITANDAI BRONKOSPASME BERULANG AKIBAT PENYEMPITAN LUMEN SALURAN RESPIRATORIK SEBAGAI RESPONS TERHADAP SUATU STIMULI YANG TIDAK MENYEBABKAN PENYEMPITAN YANG SAMA PADA ORANG LAIN
KONSEP PENCEGAHAN BRONKOSPASME
WHO, 1975
INFLAMASI KRONIS : LESI INFLAMASI DI SALURAN RESPIRATORIK INFILTRAT SELULER, EDEMA, KERUSAKAN EPITEL, BAHKAN FIBROSIS
PENGGUNAAN ANTI-INFLAMASI
1970-an
1960-an
1990-an
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Suatu keadaan wheezing episodik dan/atau batuk yang mana asma adalah yang paling mungkin, sedangkan sebab lain yang lebih jarang telah dapat disingkirkan
International Pediatric Asthma Consensus Group Arch Dis Child 1992;67:240-8.
International Pediatric Consensus Statement on the
Management of Childhood Asthma
Wheezing berulang dan/atau batuk persisten yang mana asma adalah yang paling mungkin, sedangkan sebab lain yang lebih jarang telah dapat disingkirkan
Warner dkk. Pediatr Pulmonol 1998;25:1-7
1989:
1992:
1998:
DEFINISI OPERASIONAL
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Inflamasi kronik saluran respiratorik
Banyak sel dan elemen seluler berperan (sel mast, eosinofil, limfosit T)
Pada orang rentan, inflamasi kronik episodik wheezing berulang, batuk, sesak nafas, rasa dada tertekan
Berhubungan dengan penyempitan saluran respiratorik yang luas dan bervariasi irreversibel sebagian atau teratasi spontan / pengobatan
GINA, 2002
Inflamasi kronik saluran respiratorik
Banyak sel dan elemen seluler berperan (sel mast, eosinofil, limfosit T)
Pada orang rentan, inflamasi kronik episodik wheezing berulang, batuk, sesak nafas, rasa dada tertekan
Berhubungan dengan penyempitan saluran respiratorik yang luas dan bervariasi irreversibel sebagian atau teratasi spontan / pengobatan
GINA, 2002
2002
Definisi sangat lengkap penerapan klinis sulit dan tidak praktis terutama untuk bayi dan
anak
Definisi sangat lengkap penerapan klinis sulit dan tidak praktis terutama untuk bayi dan
anak
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Inflamasi
Deskuamasi epitel
Mucus plug
Penebalan membrana basalis
Infiltrasi netrofil dan eosinofilHipertrofi dan konstriksi
otot polos
Edema
Hiperplasi kelenjar mukus
Barnes PJ
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Inflamasi pada asma
Barnes PJ
Inflamasi kronis
Perubahan struktur
Inflamasi akut
Respons steroid
Waktu
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AsmaNormal
Gambaran inflamasi
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Bahasan
• Konsep inflamasi dan remodeling pada asma• Klasifikasi asma• Tujuan tatalaksana• Longterm management:
Kapan?Obat Efek sampingHow early?
• Terapi inhalasi: kendala
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Diagnosis of Asthma
“Cough and/or wheezing that:
•episodic,
•nocturnal (variability),
•reversibility
•with atopic family”
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Klasifikasi Asma
• Derajat serangan (Akut) RinganSedangBeratAncaman henti
napas
• Klasifikasi penyakit (kronis)Asma episodik jarangAsma episodik seringAsma persisten
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Klasifikasi penyakitParameter klinis
dan uji fungsi paruAsma
episodik jarangAsma persisten
Asma episodik sering
Frekuensi < 1x /bulan Setiap hari> 1x /bulan
Lamanya < 1 minggu Setiap hari >1 minggu
Antar serangan Tanpa gejala Gejala malam hari gejala(+)
Tidur dan aktivitas Normal tergangguMungkin terganggu
Pemeriksaan fisis Normal AbnormalMungkin abnormal
Pengendali Tidak perlu Steroid/kombinasiSteroid/kombinasi
Fungsi paru (diluar serangan)
PEF/FEV1 >80%PEF/FEV1 <60%
Variabilitas 20-30%PEF/FEV1 60-80%
Variabilitas (serangan) >15% > 50%> 30%
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Bahasan
• Konsep inflamasi dan remodeling pada asma• Klasifikasi asma• Tujuan tatalaksana• Longterm management:
Kapan?Obat Efek sampingHow early?
• Terapi inhalasi: kendala
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Tujuan tatalaksana asma
• Gejala kronik minimal (idealnya tidak ada)
• Serangan akut minimal (jarang)
• Kunjungan ke UGD tidak pernah
• Penggunaan ß2-agonis minimal
• Aktivitas tidak terhambat
• Uji fungsi paru normal (mendekati)
• Efek samping obat minimal
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Meningkatkan Kualitas Hidup
tujuan akhir…….
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Penghindaran alergen
Imuno terapi
Farmako terapi
Pendidikan
Tatalaksana asma
BIAYA
GINA, 2002
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Bahasan
• Konsep inflamasi dan remodeling pada asma• Klasifikasi asma• Tujuan tatalaksana• Longterm management:
Kapan?Obat Efek sampingHow early?
• Terapi inhalasi: kendala
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Cost ?
Availability ?
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Kapan??
Klasifikasi Pengendali (Controller)
Pelega (Reliever)
Asma episodik jarang
tidak Ya
Asma episodik sering
Ya Ya
Asma persisten Ya Ya
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Fig. Lung function (V´maxFRC) at infancy and 6 years of age expressed in Z-scores by wheezing
group: ●, never wheeze; ▲, transient early wheeze; ■, late onset wheeze; ♦, persistent wheeze. (*P < .05 vs never wheeze group; **P < .05 vs never, late, and persistent wheeze groups.)
-1.20 1 2 3 4 5 6
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4Z
-Sco
reNever
Late Onset
Persistent
Transient
Age (yrs)
Taussig LM, et al. JACI 2003; 111:661-675
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Bahasan
• Konsep inflamasi dan remodeling pada asma• Klasifikasi asma• Tujuan tatalaksana• Longterm management:
Kapan?Obat Efek sampingHow early?
• Terapi inhalasi: kendala
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Medikamentosa
• Bronkodilator
• Antiinflamasi
• Antiremodeling
• Anti IgE
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TREATING ASTHMA
with Bronchodilators alone
is like
Painting over rust !!!
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Anti-inflamasi
• Antihistamin
• Disodium Cromoglycate (DSCG)
• Kortikosteroid
• Anti PDE 4 (Phosphodiesterase)
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Long-term placebo-controlled trial of ketotifen in the management of preschool children with asthma
Loftus BG, Price JF
J Allergy Clin Immunol 1987; 79:350-5
The results suggest that:
“Ketotifen has no place in the management of young children with frequent asthma”
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Inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma:
a systematic review.
Tasche MJA, Uijen JHJ, Bernsen RMD, de Jongste JC, van der Wouden JC.
Thorax 2000; 55:913-20
“Insufficient evidence that DSCG has a beneficial effect as maintenance treatment
in children with asthma”
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Bagaimana Peran Kortikosteroid ????
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Peningkatan uji fungsi paru (FEV1)
Pauwels et al, NEJM 1997
Pulmicort® 100 g bid
Pulmicort® 400 g bid
Pulmicort® 100 g bid+ Oxis® 9 g bid
Pulmicort® 400 g bid+ Oxis® 9 g bid
%
pre
dic
ted
70
75
80
85
90
-1 0 1 2 3 6 9 12Months
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0
0.1
0.2
0.3
0.4
0.5
0.6
Baseline BDP
Peningkatan 2 reseptor
Baraniuk et al AJRCCM, 1997
2-r
ecep
tor
/ acti
n r
ati
o
* p < 0.04
100 µg for 3 days
*
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Serangan Akut Asma
4
13
0
2
4
6
8
10
12
14
Seretide FP + Montelukast
No
. o
f p
atie
nts
exp
erie
nci
ng
an
as
thm
a ex
acer
bat
ion
s
Penggunaan obat 2 agonis
Ringdal et al, Respir Med 2003
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Pauwels et al, NEJM 1997
Penurunan serangan asmaPenurunan serangan asma
40
0
10
20
30
Exa
cerb
atio
ns
/ p
atie
nt
/ ye
ar
Pulmicort® 100 g bid
Pulmicort® 100 g bid+ Oxis® 9 g bid
Pulmicort® 400 g bid
Pulmicort® 400 g bid+ Oxis® 9 g bid
Increasing Pulmicort® dose: p <0.001Adding Oxis®: p <0.001Pulmicort® 800 vs. Pulmicort® 200 + Oxis® p = 0.76 (NS)
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”Real life” variability in asthmaSymptoms and use of reliever medication
Exacerbation
Oral course of corticosteroids
Effect of inhaled corticosteroids during periods of worsening
Exacerbation
Threshold for exacerbation treatment
Attenuation or prevention of exacerbations
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Kualitas hidup (KS +LABA)
*p<0.01 vs baseline†p<0.05 vs placeboStatus fungsional
meningkat
Status fungsionalmenurun
Mea
n F
SIIR
sco
re
Mahajan et al. Pediatr Asthma Allergy Immunol 1998
0
Anak sakit kronik
Anak sehat
80
90
100
0 12Waktu (minggu)
84
PlaceboSalmeterol 50 µg bid
**
*
*
*
207 anak, 57% menerima steroid inhaler
FSIIR, functional status IIR
† †
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Kips et al, AJRCCM 2000
Adding formoterol to budesonideAdding formoterol to budesonidedoes not mask inflammationdoes not mask inflammation
Months
SputumEosinophils
(%)
SputumEG2+ cells
(%)
0.0
2.5
5.0
7.5
0
5
10
151 2 3 6 9
1 2 3 6 9
Pulmicort® 400 g bid
Pulmicort® 100 g bid +Oxis® 9 g bid
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Gambaran patologi sebelum dan sesudah pengobatan steroid
Laitinen LA et al, J Allergy Clin Immunol 1992
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Perbaikan epitel pasca steroid
sebelum sesudahP Howarth, 1999P Howarth, 1999
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• Memperbaiki pengendalian asma pada anak
• Bukti-bukti penelitian:
meningkatkan PEF (pagi dan sore)
meningkatkan FEV1 (pagi dan sore)
mengurangi variasi diurnal FEV1
mengurangi gejala
menurunkan frekuensi serangan asma
mengurangi pengunaan obat pelega (2 agonis)
Meningkatkan kualitas hidup
Kortikosteroid
FEV1, forced expiratory volume in 1 secondPEF, peak expiratory flow
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Bahasan
• Konsep inflamasi dan remodeling pada asma• Klasifikasi asma• Tujuan tatalaksana• Longterm management:
Kapan?Obat Efek sampingHow early?
• Terapi inhalasi: kendala
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Efek samping
• Suara parau
• Iritasi farings
• Kandidiasis
• Sakit kepala
• Gangguan pertumbuhan??
Longterm steroid……
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Bahasan
• Konsep inflamasi dan remodeling pada asma• Klasifikasi asma• Tujuan tatalaksana• Longterm management:
Kapan?Obat Efek sampingHow early?
• Terapi inhalasi: kendala
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Steroid dosis rendah
Steroid dosis medium
Steroid dosis rendah + LABA
steroid dosis rendah+ ALTR
steroid dosis rendah+TSR
Steroid dosis tinggi
steroid dosis medium + LABA
Steroid dosis medium + ALTR
Steroid dosis medium + TSR
STEROID ORAL
Longterm management
PNAA,2004
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Fig. 6. Hypothetical peak prevalence by age for the 3 different wheezing phenotypes. The prevalence for each age interval should be the area under the curve. This does not
imply that the groups are exclusive.
AsmaNon-AtopicWheezers
TransientWheezers
Umur (tahun)
Keja
dia
n w
heezi
ng
0 3 6 11
Wheezing berulang
• Major :• Dermatitis atopi• Orang tua asma
• Minor• Eosinofil darah ↑• Wheezing• Rinitis alergika
• Asma: jika• 2 major atau• 1 major +2 minor
Taussig LM, et al. JACI 2003; 111:661-675
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Bahasan
• Konsep inflamasi dan remodeling pada asma• Klasifikasi asma• Tujuan tatalaksana• Longterm management:
Kapan?Obat Efek sampingHow early?
• Terapi inhalasi: kendala
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Kendala
• Aspek tenaga medis– Persepsi salah – Kehilangan pasien
• Aspek obat-obatan– Ketersediaan– Distribusi– Harga
• Aspek komunitas– Berbahaya– Adiksi– Sosio-kultur
• Penunjang– Algoritme sulit– Kendala alat penunjang
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MERAH
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KUNING
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MERAH
BIRU
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Gambar Apakah ini ???
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Gambar Apakah ini???
A. Kuda B. Katak
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Dampak positif terapi inhalasi
• Kualitas hidup
• Kualitas terapi
• Kualitas hidup
• Kualitas terapi
INHALASI
ORAL
Pasien
Keu
ang
an k
elu
arg
a
• Ke dokter lain• Ke luar negeri
(Mutu dokter anak Indonesia )
Asma stabil
Patient Get Patient (cerita mulut ke mulut)
-
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Tatalaksana (dalam penelitian)
• Anti IgE (Omalizumab)– rhuMAb-E25 (recombinant humanized
monoclonal antibody)– Kalau dengan steroid dan LABA tidak baik
• Anti-interleukin (IL-4, IL-5)– Proses penelitian
• Imunisasi (rekayasa genetik)– Penelitian
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Kesimpulan
• Asma: Inflamasi kronis dan remodeling• Ketotifen dan Disodium cromoglycate: kurang
bermanfaat sebagai tatalaksana jangka panjang
• Steroid dengan/atau kombinasi: obat pilihan sebagai tatalaksana jangka panjang
• Indonesia: Pedoman Nasional Asma Anak (UKK Respirologi IDAI)
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Harus Berjuang
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• Catatan:
Dibawakan pada Simposium Asma
Balikpapan, 8 Mei 2005
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Bone densitometry
• Bone densitometry – 3/38 cases (7.9%) DEXA: chronological age
below -1.0– 13/37 patients (35.1%) DEXA: lumbar spine
(L2-4) chronological age below -1.0
Longterm steroid……
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Biochemical markers of bone metabolism
• No significant:– serum osteocalcin– PINP – ALP – BALP– urine DPD/Cr ratio– NTx/Cr ratio
Longterm steroid……
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Petanda biokemis
400
350
300
250
200
150
100
50
0NTx/Cr
(nmol/mmol)ALP
(IU/L)P1NP(g/L)
BALP(IU/L)
OSTEO(ng/m)l
DPD/Cr(nmol/mmol)
Hasi
lKontrolKasusStandard error
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”No significant correlation between any of the
biochemical markers and DEXA z- score (chronological
or bone age)”
Longterm steroid……
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Chronological age lumbar Spinal (L2-L4)C
um
ula
tive P
rob
ab
ility
(%
)
Z-score
-4 -3 -2 -1 0 1 2 3 40
20
40
60
80
100Reference PopulationStudy Population
Cumulative probability graphs of lumbar spinal densityIn study population vs. reference population
Longterm steroid……
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Bone Age Lumbar Spine (L2-L4)C
um
ula
tive P
rob
ab
ility
(%
)
Z-score-4 -3 -2 -1 0 1 2 3 4
0
20
40
60
80
100Reference PopulationStudy Population
Cumulative probability graphs of lumbar spinal densityIn study population vs. reference population
Longterm steroid……
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Efikasi steroid
Keungtungan dosis
Efek samping
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Keuntungan steroid inhalasi
• Dosis rendah
• Langsung ke sal respiratorik
• Onset (awitan) cepat
• Efek samping sistemik minimal
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Modern view of Asthma
MucushypersecretionHyperplasia
Eosinophil
Mast cell
Allergen
Th2 cell
VasodilatationNew vessels
Plasma leak Oedema
Neutrophil
Mucus plug
Macrophage/dendritic cell
BronchoconstrictionHypertrophy / hyperplasia
Cholinergic reflex
Epithelial shedding
Subepithelialfibrosis
Sensory nerve activation
Nerve activation
Barnes PJ
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Rasionalisasi steroid + LABA
Smooth muscledysfunction
Airwayinflammation
• Bronchoconstriction• Bronchial hyperreactivity• Hyperplasia• Inflammatory mediator release
• Inflammatory cell infiltration / activation• Mucosa oedem• Cellular proliferation• Epithelial damage• Basement membrane thickening
Symptoms / exacerbations
LABA CS
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Evolving treatment options
1975
1980
1985
1990 19952000
Large use of short-acting
ß2-agonists
“Fear” of short-acting ß2-agonists
Singleinhaler therapy (Symbicort®)
ICS treatment introduced
1972
Adding LAßA to ICS therapy
Kips et al, AJRCCM 2000 Pauwels et al, NEJM 1997
Greening et al, Lancet 1992
Bronchospasm Inflammation Remodelling