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Abstract

Background: The sequential organ failure assessment score (SOFA) is increasingly used
as an endpoint in intensive care randomized controlled trials (RCTs). Although serially
measured SOFA is independently associated with mortality in observational cohorts, the
association between treatment effects on SOFA vs. effects on mortality has not yet been
quantified in RCTs. The aim of this study was to quantify the relationship between SOFA
and mortality in RCTs and to identify which SOFA derivative best reflects between-group
mortality differences. Methods: The review protocol was prospectively registered
(Prospero CRD42016034014). We performed a literature search (up to May 1, 2016) for
RCTs reporting both SOFA and mortality, and analyzed between-group differences in
these outcomes. Treatment effects on SOFA and mortality were calculated as the
between-group SOFA standardized difference and log odds ratio (OR), respectively. We
used random-effects meta-regression to (1) quantify the linear relationship between RCT
treatment effects on mortality (logOR) and SOFA (i.e. responsiveness) and (2) quantify
residual heterogeneity (i.e. consistency, expressed as I2). Results: Of 110 eligible RCTs,
87 qualified for analysis. Using all RCTs, SOFA was significantly associated with
mortality (slope=0.49 (95% CI 0.17; 0.82), p=0.006,I2 =5%); the overall mortality effect
explained by SOFA score (R2) was 9%. Fifty-eight RCTs used Fixed-day SOFA as an
endpoint (i.e. the score on a fixed day after randomization), 25 studies used Delta SOFA
as an endpoint (i.e. the trajectory from baseline score) and 15 studies used
otherBackground: The sequential organ failure assessment score (SOFA) is increasingly
used as an endpoint in intensive care randomized controlled trials (RCTs). Although
serially measured SOFA is independently associated with mortality in observational
cohorts, the association between treatment effects on SOFA vs. effects on mortality has
not yet been quantified in RCTs. The aim of this study was to quantify the relationship
between SOFA and mortality in RCTs and to identify which SOFA derivative best reflects
between-group mortality differences. Methods: The review protocol was prospectively
registered (Prospero CRD42016034014). We performed a literature search (up to May 1,
2016) for RCTs reporting both SOFA and mortality, and analyzed between-group
differences in these outcomes. Treatment effects on SOFA and mortality were calculated
as the between-group SOFA standardized difference and log odds ratio (OR),
respectively. We used random-effects meta-regression to (1) quantify the linear
relationship between RCT treatment effects on mortality (logOR) and SOFA (i.e.
responsiveness) and (2) quantify residual heterogeneity (i.e. consistency, expressed as I2).
Results: Of 110 eligible RCTs, 87 qualified for analysis. Using all RCTs, SOFA was
significantly associated with mortality (slope=0.49 (95% CI 0.17; 0.82), p=0.006,I2
=5%); the overall mortality effect explained by SOFA score (R2) was 9%. Fifty-eight
RCTs used Fixed-day SOFA as an endpoint (i.e. the score on a fixed day after
randomization), 25 studies used Delta SOFA as an endpoint (i.e. the trajectory from
baseline score) and 15 studies used other SOFA derivatives as an endpoint. Fixed-day
SOFA was not significantly associated with mortality (slope=0.35 (95% CI 0.04; 0.75),
p=0.08, I2 =12%) and explained 3% of the overall mortality effect (R2). Delta SOFA was
significantly associated with mortality (slope=0.70 (95% CI 0.26; 1.14), p=0.004,I2 =0%)
and explained 32% of the overall mortality effect (R2). Conclusions: Treatment effects on
Delta SOFA appear to be reliably and consistently associated with mortality in RCTs.
Fixed-day SOFA was the most frequently reported outcome among the reviewed RCTs,
but was not significantly associated with mortality. Based on this study, we recommend
using Delta SOFA rather than Fixed-day SOFA as an endpoint in future RCTs. Keywords:
Critical care trials, Multiple organ failure, Sepsis, Surrogate endpoints
SOFA derivatives as an endpoint. Fixed-day SOFA was not significantly associated with
mortality (slope=0.35 (95% CI 0.04; 0.75), p=0.08, I2 =12%) and explained 3% of the
overall mortality effect (R2). Delta SOFA was significantly associated with mortality
(slope=0.70 (95% CI 0.26; 1.14), p=0.004,I2 =0%) and explained 32% of the overall
mortality effect (R2). Conclusions: Treatment effects on Delta SOFA appear to be reliably
and consistently associated with mortality in RCTs. Fixed-day SOFA was the most
frequently reported outcome among the reviewed RCTs, but was not significantly
associated with mortality. Based on this study, we recommend using Delta SOFA rather
than Fixed-day SOFA as an endpoint in future RCTs. Keywords: Critical care trials,
Multiple organ failure, Sepsis, Surrogate endpoints

Abstrak
Latar Belakang: Penilaian kegagalan organ berurutan skor (SOFA) semakin digunakan
sebagai titik akhir di intensif
peduli percobaan terkontrol acak (RCT).Meskipun serial diukur SOFA secara independen
terkait dengan kematian di
kohort obser4).Kami melakukan literatur
pencarian (sampai dengan 1 Mei 2016) untuk RCT melaporkan kedua SOFA dan
kematian, dan dianalisis perbedaan antara kelompok di
hasil ini. Efek pengobatan terhadap SOFA dan mortalitas dihitung sebagai antara
kelompok SOFA standar
Perbedaan dan peluang log ratio (OR), masing-masing.Kami menggunakan random-efek
meta-regvasional, hubungan antara efek pengobatan terhadap SOFA vs efek pada
kematian belum pernah
diukur dalam RCT.Tujuan dari penelitian ini adalah untuk mengukur hubungan antara
SOFA dan mortalitas pada RCT dan
mengidentifikasi derivatif SOFA paling mencerminkan perbedaan mortalitas antara
kelompok.
Metode: Tinjauan protokol secara prospektif terdaftar (Prospero CRD4201603401resi
untuk (1) mengukur linier
hubungan antara efek pengobatan RCT pada kematian (logOR) dan SOFA (yaitu
responsiveness) dan (2) mengukur
residual heterogenitas (yaitu konsistensi, dinyatakan sebagai I 2).
Hasil: Dari 110 RCT memenuhi syarat, 87 memenuhi syarat untuk analisis.Menggunakan
semua RCT, SOFA secara bermakna dikaitkan dengan kematian
(kemiringan = 0,49 (95% CI 0,17; 0,82), p = 0,006, I 2 = 5%);efek kematian secara
keseluruhan dijelaskan oleh skor SOFA (R 2) adalah 9%.
Lima puluh delapan RCT digunakan Fixed-hari SOFA sebagai titik akhir (yaitu skor pada
hari yang tetap setelah pengacakan), 25 studi digunakan
Delta SOFA sebagai titik akhir (yaitu lintasan dari skor awal) dan 15 studi digunakan
derivatif SOFA lainnya sebagai
endpoint.Fixed-hari SOFA tidak bermakna dikaitkan dengan mortalitas (kemiringan =
0,35 (95% CI -0,04; 0,75), p = 0,08,
Aku 2 = 12%) dan menjelaskan 3% dari efek kematian secara keseluruhan (R 2). Delta
SOFA secara bermakna dikaitkan dengan kematian
(kemiringan = 0.70 (95% CI 0,26; 1,14), p = 0,004, I 2 = 0%) dan menjelaskan 32% dari
efek kematian secara keseluruhan (R 2).
Kesimpulan: efek pengobatan dari Delta SOFA tampaknya andal dan konsisten dikaitkan
dengan mortalitas pada RCT.
Fixed-hari SOFA adalah hasil yang paling sering dilaporkan di antara RCT Ulasan, tapi
tidak signifikan
terkait dengan kematian. Berdasarkan penelitian ini, kami sarankan menggunakan Delta
SOFA daripada Tetap-hari SOFA sebagai
endpoint di RCT masa depan.
Kata kunci: uji coba perawatan kritis, kegagalan organ Beberapa, Sepsis, Titik akhir
pengganti
* Correspondence: h.degrooth@vumc.nl
1 Departemen Perawatan Intensif, VU University Medical Center, De Boelelaan
1117, 1081 HV Amsterdam, Belanda
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de Grooth et al. Perawatan Kritis (2017) 21:38
DOI 10,1186 / s13054-017-1609-1