CRITICAL APPRAISAL

EARLY INSULIN THERAPY IN VERY-LOW-BIRTH-WEIGHT

INFANTS

OLEH:

AHMAD ZAINI ARIF

1110017004

PRODI MAGISTER KEPERAWATAN

FAKULTAS KEPERAWATAN DAN KEBIDANAN
UNIVERSITAS NAHDLATUL ULAMA SURABAYA
2017
A. ARTIKEL JURNAL
Terlampir
Judul jurnal : Early Insulin Therapy in Very-Low-Birth-Weight Infants.
Publikasi : The New England Journal of Medicine Vol. 359, No. 18,
Page 1873-1884.

B. FORM CRITICAL APPRAISAL

A. Are the results of the trial valid?

(screening question)
1. Did the trial address Yes ( √ ) Can’t tell ( ) No ( )
a clearly focused a. Pada bagian studi populasi halaman 1874, tercantum dengan jelas
issue? mengenai populasi yang dipelajari yaitu bayi berat lahir sangat
An issue can be rendah yang memenuhi standar kriteria kelayakan yang direkrut
focused in term of antara tahun 2005 dan 2007 dari delapan pusat perawatan intensif
a. The population neonatal. Bayi yang usianya kurang dari 24 jam dimasukkan jika
studied berat lahir mereka kurang dari 1500 g, membutuhkan perawatan
b. The intensif, danorang tua diberikan informed consent tertulis. Kriteria
intervention eksklusinya adalah diabetes maternal dan kelainan kongenital
given mayor.
c. The comparator
“Very-low-birth-weight infants who met predefined eligibility
given
criteria were recruited between 2005 and 2007 from eight
neonatal intensive care centers. These centers were located in
Cambridge, Edinburgh, Leeds, and Luton (United Kingdom);
Leuven and Genk (Belgium); Amsterdam; and Barcelona. Infants
younger than 24 hours of age were included if their birth weight
was less than 1500 g, they required intensive care, and their
parents provided written informed consent. Exclusion criteria
were maternal diabetes and major fetal congenital abnormalities.”

b. Pada bagian intervensi halaman 1874, dijelaskan bahwa

manajemen kontrol glukosa di kedua studi kelompok ditentukan
dalam protokol dan dilaksanakan melalui prosedur operasi standar.
Akses vena sentral diperlukan untuk per-protokol infus nutrisi
parenteral dan dekstrosa 20%, dengan demikian, hanya bayi yang
masih ada akses sentral yang dipertimbangkan untuk dimasukkan
dalam penelitian.
Perlakuan pada kelompok terapi dan kelompok control dijelaskan
padahalaman 1874-1875. Kelompok yang mendapatkan terapi
insulin menerima dosis tetap terus menerusinfus insulin (0,05 U
per kilogram per jam),dengan dextrose 20% intravena tambahan
untuk mempertahankaneuglycemia (target kisaran, 4 sampai 8
mmol per liter 72-144 mg per desiliter) dalam 24jam setelah lahir
sampai umur 7 hari. Insulin ASPART (Novo Nordisk) digunakan,
karena analog insulin inimemiliki short half-life.Dextrose adalah
diberikan jika kadar glukosa darah menurun sampai kurangdari 4,0
mmol per liter (72 mg per desiliter), mulai pada 1 ml per kilogram
per jam, dan insulin dihentikan jika infus ini tidak mencegah
terjadinya hipoglikemia (<2,6 mmol per liter47 mg per desiliter).
Jika ada yang bertahan hiperglikemia (> 10 mmol per liter 180 mg
perdesiliter), tingkat infus glukosa dikurangi atau di infusekan
insulin tambahan.
Pada kelompok kontrol, bayi menerima perawatan standar di
mana dokter bertanggung jawab atas perawatan klinis kadar
glukosa yang lebih besar dari 10 mmol perliter (180 mg per
desiliter) atau kurang dari 2,6 mmol(47 mg perdesiliter). Dokter
akan menentukanapakah laju infus dekstrosaharus dikurangi atau
ditambah atau jika terapi insulinharus dimulai. Insulin dimulai
hanyasetelah dua kadar glukosa lebih besar dari 10 mmol per liter
dengan menggunakan skala geser dan awaldosis 0,05 U per
kilogram per jam.

“Management of glucose control in both studygroups was

predetermined in the protocol andimplemented through standard
 operating procedures.Central venous access was required for
theper-protocol infusion of parenteral nutrition and20% dextrose;
thus, only infants with extant centralaccess were considered for
inclusion in thestudy”
“Early-insulin group.
Infants who were randomly assigned to the earlyinsulin group
received a fixed-dose continuous nfusion of insulin (0.05 U per
kilogram per hour), with additional intravenous 20% dextrose to
maintain euglycemia (target range, 4 to 8 mmol per liter [72 to
144 mg per deciliter]) from within 24hours after birth until 7 days
of age. Insulin aspart(Novo Nordisk) was used, since this
insulinanalogue has a short half-life.Dextrose wasinfused if blood
glucose levels decreased to lessthan 4.0 mmol per liter (72 mg per
deciliter), startingat 1 ml per kilogram per hour,19 and insulinwas
discontinued if this infusion did not preventa drift toward
hypoglycemia (<2.6 mmol per liter[47 mg per deciliter]). If there
was persisting hyperglycemia (>10 mmol per liter [180 mg
perdeciliter]), rates of infusion of glucose were reducedor
additional insulin was infused”

“Control Group
Infants who were randomly assigned to the controlgroup received
standard care in which the physicianwho was responsible for
clinical care reviewedglucose levels that were greater than 10
mmol perliter (180 mg per deciliter) or less than 2.6 mmol(47 mg
per deciliter). The physician would determinewhether the rate of
infusion of dextroseshould be reduced or increased or if insulin
therapyshould be initiated. Insulin was initiated onlyafter two
glucose levels were greater than 10 mmolper liter with the use of a
sliding scale and an initialdose of 0.05 U per kilogram per hour”

c.Pada bagian kelompok control halaman 1875, dijelaskan mengenai

perlakuan yang diberikan pada kelompok control atau kelompok
 pembanding. Seperti yang telah dijelaskan pada poin b diatas,
Pada kelompok kontrol, bayi menerima perawatan standar di mana
dokter bertanggung jawab atas perawatan klinis kadar glukosa
yang lebih besar dari 10 mmol perliter (180 mg per desiliter) atau
kurang dari 2,6 mmol (47 mg perdesiliter). Dokter akan
menentukan apakah laju infus dekstrosa harus dikurangi atau
ditambah atau jika terapi insulinharus dimulai. Insulin dimulai
hanyasetelah dua kadar glukosa lebih besar dari 10 mmol per liter
dengan menggunakan skala geser dan awaldosis 0,05 U per
kilogram per jam.

“Control Group
Infants who were randomly assigned to the control group received
standard care in which the physician who was responsible for
clinical care reviewed glucose levels that were greater than 10
mmol per liter (180 mg per deciliter) or less than 2.6 mmol (47 mg
per deciliter). The physician would determine whether the rate of
infusion of dextrose should be reduced or increased or if insulin
therapy should be initiated. Insulin was initiated only after two
glucose levels were greater than 10 mmol per liter with the use of
a sliding scale and an initial dose of 0.05 U per kilogram per
hour”

2. Was the assignment Yes (√ ) Can’t tell ( ) No ( )

of patients to Pada bagian studi populasi halaman 1874, dijelaskan bahwa
treatments penelitian dilakukan secara acak. Pengacakan dicapai dengan
randomized? penggunaan program berbasis internet 24 jam
(www.thesealedenvelope.com) yang digunakan untuk mengurangi
variabilitas menurut pusat, berat badan lahir (<1000 g atau 1000
untuk 1500 g), dan usia kehamilan (<25 minggu atau ≥25minggu).
Bayi secara acak ditugaskan untuk studi Kelompok sesegera
mungkin selama hari pertama hidup.
 “The study was an international, open-label,randomized,
controlled trial. Randomization wasachieved with the use of a 24-
hour Internet basedp rogram (www.thesealedenvelope.com)
thatused minimization to reduce variability accordingto center,
birth weight (<1000 g or 1000 to1500 g), and gestational age
(<25 weeks or ≥25weeks). Infants were randomly assigned to a
studygroup as soon as possible during the first day oflife.”
3. Were all of the Yes (√) Can’t tell ( ) No ( )
patients who Pada bagian abstrak jurnal halaman 1873, dijelaskan bahwa semua
entered the trial subyek yang ikut dalam penelitian diperhitungkan dalam hasil dan
properly accounted kesimpulan. Dibandingkan dengan bayi dalam kelompok kontrol,
for at its bayi dalam kelompok terapi awal insulin memiliki rata-rata yang
conclusion? lebih rendah(± SD) kadar glukosa (6,2±1,4 vs 6,7±2,2 mmolper
a. Was follow up liter 112±25 vs 121±40 mg per desiliter, P=0,007). Lebih sedikit
complete? bayi pada kelompok terapi awal insulin yang memiliki
b. Were patients hiperglikemia selama lebih dari10% dari minggu pertama
analysed in the kehidupan (21% vs 33%, P=0,008). Lebih banyak bayi pada
groups to which kelompok terapi awal insulin mengalami episodehipo glikemia
they were (didefinisikan sebagai glukosa darah tingkat <2,6mmolper liter 47
randomised? mgper desiliter untuk>1jam) (29% dalam kelompok awal-insulin
vs 17% pada kelompok kontrol, P=0,005), dan peningkatan
hipoglikemia signifikan pada bayi dengan berat lahir lebih
dari1kg.Tidak ada perbedaan dalam analisis intention-to-treat
untuk hasil primer (mortalitas pada perkiraan tanggal pengiriman)
dan hasil sekunder (morbiditas).
Dalam analisis intention-to-treat, mortalitas pada 28 hari lebih
tinggi pada early insulin tersebut kelompok dibandingkan dengan
kelompok kontrol (P =0,04).

”Results
As compared with infants in the control group, infants in the early-
insulin group had lower mean (±SD) glucose levels (6.2±1.4 vs.
6.7±2.2 mmol per liter [112±25 vs.121±40 mg per deciliter], P =
 0.007). Fewer infants in the early-insulin group had
hyperglycemia for more than 10% of the first week of life (21% vs.
33%, P = 0.008).The early-insulin group had significantly more
carbohydrate infused (51±13 vs.43±10 kcal per kilogram per day,
P<0.001) and less weight loss in the first week(standard-deviation
score for change in weight, −0.55±0.52 vs. −0.70±0.47; P =
0.006).More infants in the early-insulin group had episodes of
hypoglycemia (defined as ablood glucose level of <2.6 mmol per
liter [47 mg per deciliter] for >1 hour) (29% inthe early-insulin
group vs. 17% in the control group, P = 0.005), and the increase
inhypoglycemia was significant in infants with birth weights of
more than 1 kg.There were no differences in the intention-to-treat
analyses for the primary outcome(mortality at the expected date of
delivery) and the secondary outcome (morbidity).In the intention-
to-treat analysis, mortality at 28 days was higher in the
earlyinsulingroup than in the control group (P = 0.04).”

a. Follow up dilakukan secara lengkap, dan dijelaskan pada bagan 1

halaman 1877.

b. Subyek dianalisis sesuai dengan pengelompokan awal yang

dilakukan secara acak. Hal ini dijelaskan pada bagian pemantauan
glukosa halaman 1875. Kadar glukosa pada bayi dikelompok terapi
awal insulin diperiksa per jam setelah insulin dimulai, namun
interval waktu itu meningkat menjadi setiap 6 jam sekali jika kadar
glukosatelah stabil. Kadar glukosa pada bayi dikelompok kontrol
diukur sebagai klinis yang ditunjukkan,setidaknya tiga kali sehari
(setiap 8 jam) .

“Glucose levels in infants inthe early-insulin group were checked

hourly afterinsulin was initiated, but the time interval
wasincreased to every 6 hours once glucose levelshad stabilized.
 Glucose levels in infants in thecontrol group were measured as
clinically indicated,at least thrice daily (every 8 hours).”
Detailed Question
4. Were patients, Yes ( ) Can’t tell ( ) No ( √ )
health workers and
study personel Pada penelitian ini, pengobatan tidak dilakukan secara “blind”. Hal
“blind” to tersebut dijelaskan pada metode studi populasi halaman 1874.
treatment? Pengobatan yang dilakukan secara blind tidak layak, karena tidak
c. Were the akan mencapai perbedaan yang memadai dalam kontrol glukosa
patients antara kelompok dan mungkin mengurangi keselamatan pasien.
d. Were the health “Blinding of the treatment allocation was not feasible, since it
workers would not achieve adequate differences in glucose control between
e. Were the study the groups and might reduce patient safety.”
personel.
5. Were the groups Yes ( √) Can’t tell () No ( )
similar at the start
Pada tabel 1 dijelaskan mengenai karakteristik klinis dasar dari bayi
of the trial?
dan ibu yang direkrut dalam penelitian. Karakteristik bayi tersebut
In term of other
berupa usia kehamilan ketika lahir, lingkar kepala bayi,
factors that might
jeniskelaminbayi, standar deviasi skor untuk berat badan lahir,
effect the outcome
Indeks Risiko Klinis untuk Bayi (CRIB) skor (skor berkisar dari 0
such as age, sex,
sampai 23, dengan skor yang lebih tinggi menunjukkanlebih parah
social class.
penyakit). Karakteristik ibunya adalah ada tidaknya korioamnionitis,
ada tidak nya prolonged rupture of membranes (PROM), dan
menerima gluko kortikoid antenatal atau tidak.
6. Aside from the Yes (√ ) Can’t tell ( ) No ( )
experimental Selain perlakuan yang dieksperimenkan, subyek diperlakukan sama.
intervention, were Hal itu dijelaskan pada tabel 2 halaman 1880.
the groups treated Kelompok control dan kelompok terapi mendapatkan beberapa
equally? perlakuan yang sama selain perlakuan terapi insulin. Perlakuannya
adalah pemberian cairan, karbohidrat, protein, lipid, dan susu.
B. What are the results?
7. How large was the Hasil perhitungan pada mortalitas, odds ratio nya sebesar
treatment effect? 0,61dengan interval kepercayaan 95% : 0.33-1.15 dan P 0,2.
 What outcomes are Sedangkan odds ratio pada kejadian sepsis sebesar 1.11 (0.69-1.8),
measured? necrotizing enterocolitis 0.92 (0.49-1.71), retinopathy 0.88 (0.42-
1.84), penyakit intracranial 0.83 (0.53-1.28), penyakit paru kronik
0.85(0.54-1.35).

8. How precise was Estimasi efek terapinya kurang tepat.

the estimate of the
treatment effect?
What are its
confidence limits?
C.Will the results help locally?
9. Can the results be Yes ( √ ) Can’t tell ( ) No ( )
applied to the local
Hasil dari penelitian ini dapat diterapkan pada populasi lokal, karena
population?
pasien local dapat memenuhi criteria pada penelitian ini, baik criteria
Do you think that
inklusi maupun eksklusi.
the patients covered
by the trial are
similar enough to
your population?
10. Were all clinically Yes ( √ ) No ( )
important outcomes
Pada bagian adverse event halaman 1878, dijelaskan bahwa semua
considered?
melaporkan efek samping utama, selain hipoglikemia, yang terkait
If not, does this
dengan hasil primer atau sekunder. Tidak ada yang melaporkan
affect the decision?
peristiwa merugikan berkaitan dengan trauma, infeksi edema, atau
terkait dengan sensor pemantauan glukosa yang diberikan
berkelanjutan. Tidak ada reaksi efeksamping serius yang tidak dapat
ditangani. Dokter melaporkan episode hipoglikemia (glukosa darah
<2,6 mmol perliter untuk> 1 jam), pada 17 bayi di kelompok terapi
awalinsulin(8,8%) (termasuk 2 yang memiliki protokol pelanggaran
dan 4 yang ditarik daristudi) dan 3 pada kelompok kontrol (1,6%).

“All reported major adverse events, apart from hypoglycemia, were

related to the primary or secondary outcomes. There were no
 reported adverse
events relating to trauma, infection, or edema associated with the
continuous glucose-monitoring
sensor. No unanticipated serious adverse reactions were suspected.
Clinicians reported episodes of hypoglycemia (blood glucose <2.6
mmol per liter for >1 hour), in 17 infants in the early-insulin group
(8.8%) (including 2 who had protocol violations and 4 who were
withdrawn from the study) and in 3 in the control group (1.6%).”
11. Are the benefits Yes () No ( √ )
worth the harms
Manfaat yang didapatkan dari penelitian ini tidak senilai dengan
and costs?
biaya yang dikeluarkan. Karena hasil yang didapatkan belum
This is unlikely to
maksimal, dan ada beberapa hal yang menunjukkan hasil yang tidak
be addressed by the
signifikan.
trial. But what do
you think?