Nama : Mahathir Musfira
NIM : 140610013
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.
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
issue? dengan jelas mengenai populasi yang dipelajari yaitu
An issue can be bayi berat lahir sangat rendah yang memenuhi
focused in term of standar kriteria kelayakan yang direkrut antara tahun
a. The population 2005 dan 2007 dari delapan pusat perawatan intensif
studied neonatal. Bayi yang usianya kurang dari 24 jam
b. The intervention dimasukkan jika berat lahir mereka kurang dari 1500
given g, membutuhkan perawatan intensif, dan orang tua
c. The comparator diberikan informed consent tertulis. Kriteria
given eksklusinya adalah diabetes maternal dan kelainan
kongenital mayor.
“Very-low-birth-weight infants who met predefined
eligibility 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 pada halaman 1874-1875.
Kelompok yang mendapatkan terapi insulin
menerima dosis tetap terus menerus infus insulin
(0,05 U per kilogram per jam), dengan dextrose 20%
intravena tambahan untuk mempertahankan
euglycemia (target kisaran, 4 sampai 8 mmol per
liter [72-144 mg per desiliter]) dalam 24 jam setelah
lahir sampai umur 7 hari. Insulin ASPART (Novo
Nordisk) digunakan, karena analog insulin ini
memiliki short half-life. Dextrose adalah diberikan
jika kadar glukosa darah menurun sampai kurang
1
dari 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 liter [47 mg per
desiliter]). Jika ada yang bertahan hiperglikemia (>
10 mmol per liter [180 mg per desiliter]), tingkat
infus glukosa dikurangi atau di infuskan 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 per liter (180 mg per desiliter) atau
kurang dari 2,6 mmol (47 mg per desiliter). Dokter
akan menentukan apakah laju infus dekstrosa harus
dikurangi atau ditambah atau jika terapi insulin harus
dimulai. Insulin dimulai hanya setelah dua kadar
glukosa lebih besar dari 10 mmol per liter dengan
menggunakan skala geser dan awal dosis 0,05 U per
kilogram per jam.
“Management of glucose control in both study
groups was predetermined in the protocol and
implemented through standard operating
procedures. Central venous access was required for
the per-protocol infusion of parenteral nutrition and
20% dextrose; thus, only infants with extant central
access were considered for inclusion in the study”
“Early-insulin group.
Infants who were randomly assigned to the
2
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 24
hours after birth until 7 days of age. Insulin aspart
(Novo Nordisk) was used, since this insulin analogue
has a short half-life. Dextrose was infused if blood
glucose levels decreased to less than 4.0 mmol per
liter (72 mg per deciliter), starting at 1 ml per
kilogram per hour,19 and insulin was discontinued if
this infusion did not prevent a drift toward
hypoglycemia (<2.6 mmol per liter [47 mg per
deciliter]). If there was persisting hyperglycemia
(>10 mmol per liter [180 mg per deciliter]), rates of
infusion of glucose were reduced or additional
insulin was infused”
“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
3
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”
c. Pada bagian kelompok kontrol 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 per liter (180 mg per desiliter) atau kurang
dari 2,6 mmol (47 mg per desiliter). Dokter akan
menentukan apakah laju infus dekstrosa harus
dikurangi atau ditambah atau jika terapi insulin harus
dimulai. Insulin dimulai hanya setelah dua kadar
glukosa lebih besar dari 10 mmol per liter dengan
menggunakan skala geser dan awal dosis 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
4
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
treatments bahwa penelitian dilakukan secara acak. Pengacakan
randomized? dicapai dengan 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 ≥ 25
minggu). Bayi secara acak ditugaskan untuk studi
Kelompok sesegera mungkin selama hari pertama
hidup.
“The study was an international, open-label,
randomized, controlled trial. Randomization was
achieved with the use of a 24-hour Internet based
program (www.thesealedenvelope.com) that used
minimization to reduce variability according to
center, birth weight (<1000 g or 1000 to 1500 g),
and gestational age (<25 weeks or ≥25 weeks).
Infants were randomly assigned to a study group as
soon as possible during the first day of life.”
3. Were all of the Yes (√) Can’t tell ( ) No ( )
patients who entered a. During the 7-day intervention period,
significantly more intravenous carbohydrate was
5
the trial properly infused in the early-insulin group than in the
control group (51±13 kcal per kilogram per day
accounted for at its
vs. 43±10 kcal per kilogram per day; P<0.001).
conclusion? However, there were no differences between the
study groups with regard to rates of either
a. Was follow up
protein or lipid infusion (Table 2).
complete? b. Subyek dianalisis sesuai dengan pengelompokan
b. Were patients awal yang dilakukan secara acak. Hal ini dijelaskan
analysed in the pada bagian pemantauan glukosa halaman 1875.
groups to which Kadar glukosa pada bayi di kelompok terapi awal
they were insulin diperiksa per jam setelah insulin dimulai,
randomised? namun interval waktu itu meningkat menjadi setiap 6
jam sekali jika kadar glukosa telah stabil. Kadar
glukosa pada bayi di kelompok kontrol diukur
sebagai klinis yang ditunjukkan, setidaknya tiga kali
sehari (setiap 8 jam) .
“Glucose levels in infants in the early-insulin group
were checked hourly after insulin was initiated, but
the time interval was increased to every 6 hours once
glucose levels had stabilized. Glucose levels in
infants in the control group were measured as
clinically indicated, at least thrice daily (every 8
hours).”
Detailed Question
4. Were patients, health Yes ( ) Can’t tell ( ) No ( √ )
workers and study
personel “blind” to Pada penelitian ini, pengobatan tidak dilakukan
treatment? secara “blind”. Hal tersebut dijelaskan pada metode
6
c. Were the patients studi populasi halaman 1874. Pengobatan yang
d. Were the health dilakukan secara blind tidak layak, karena tidak akan
workers mencapai perbedaan yang memadai dalam kontrol
e. Were the study glukosa antara kelompok dan mungkin mengurangi
personel. keselamatan pasien.
“Blinding of the treatment allocation was not
feasible, since it would not achieve adequate
differences in glucose control between the groups
and might reduce patient safety.”
5. Were the groups Yes ( √) Can’t tell ( ) No ( )
similar at the start of
Pada tabel 1 dijelaskan mengenai karakteristik klinis
the trial?
dasar dari bayi dan ibu yang direkrut dalam
In term of other
penelitian. Karakteristik bayi tersebut berupa usia
factors that might
kehamilan ketika lahir, lingkar kepala bayi, jenis
effect the outcome
kelamin bayi, standar deviasi skor untuk berat badan
such as age, sex,
lahir, Indeks Risiko Klinis untuk Bayi (CRIB) skor
social class.
(skor berkisar dari 0 sampai 23, dengan skor yang
lebih tinggi menunjukkan lebih parah penyakit).
Karakteristik ibunya adalah ada tidaknya
korioamnionitis, ada tidaknya prolonged rupture of
membranes (PROM), dan menerima glukokortikoid
antenatal atau tidak.
6. Aside from the Yes (√ ) Can’t tell ( ) No ( )
experimental
Selain perlakuan yang dieksperimenkan, subyek
intervention, were the
diperlakukan sama. Hal itu dijelaskan pada tabel 2
groups treated
halaman 1880.
equally?
Kelompok kontrol dan kelompok terapi mendapatkan
7
beberapa 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 rationya
treatment effect? sebesar 0,61 dengan interval kepercayaan 95% :
What outcomes are 0.33-1.15 dan P 0,2. Sedangkan odds ratio pada
measured? kejadian sepsis sebesar 1.11 (0.69-1.8), 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 the As compared with infants in the control group,
estimate of the infants in the early-insulin group had lower mean
treatment effect? (±SD) glucose levels (6.2±1.4 vs. 6.7±2.2 mmol per
What are its liter [112±25 vs. 121±40 mg per deciliter], P =
confidence limits? 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 a blood glucose level of
<2.6 mmol per liter [47 mg per deciliter] for >1 hour)
(29% in the early-insulin group vs. 17% in the
control group, P = 0.005), and the increase in
8
hypoglycemia 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 earlyinsulin group than in the control
group (P = 0.04).
There was no difference in the outcome of mortality
at the expected date of delivery (18 of 192 infants in
the control group [9%] vs. 28 of 194 infants in the
early-insulin group [14%]; odds ratio, 0.61; 95% CI,
0.33 to 1.15; P = 0.2; The most common causes of
death before 28 days were overwhelming infection
and extreme prematurity. However, in subsequent as-
treated analyses, mortality was 10.4% (19 of 182
patients) among patients in the early-insulin group;
this rate was not significant as compared with the rate
among controls (odds ratio, 0.52; 95% CI, 0.24 to
1.12; P = 0.13) (Table 4).
C. Will the results help locally?
9. Can the results be Yes ( ) Can’t tell ( ) No (√)
applied to the local
population?
Do you think that the
patients covered by
the trial are similar
enough to your
population?
10. Were all clinically Yes ( ) No (√ )
important outcomes
considered?
9
If not, does this affect
the decision?
11. Are the benefits worth Yes ( ) No ( √ )
the harms and costs?
Adverse Events
This is unlikely to be
All reported major adverse events, apart from
addressed by the trial.
hypoglycemia, were related to the primary or
But what do you
secondary outcomes. There were no reported adverse
think?
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%). Episodes of hypoglycemia
were not associated with clinical signs of
hypoglycemia.
10
