severe sepsisもしくはseptic shockの患者にお...

SEVERE SEPSISもしくはSEPTIC SHOCKの患者において

血清アルブミン値 > 3.0 G/DLを維持することで

死亡率の改善に寄与するか

J HOSPITALIST network　Journal club

飯塚病院　総合診療科　PGY 5

坂井正弘監修：吉野俊平

Albumin Replacement in Patients with Severe Sepsis or Septic ShockN Engl J Med 2014; 370:1412-1421

症例

入院前はADLは自立していた81歳男性数日前より腰痛を自覚していた悪寒戦慄と全身の脱力感を主訴に救急搬送来院時、血圧 128/68mmHg、脈拍 110/min、整、体温 39.2呼吸数 28/min、SpO2 93％(RA)

右尿管結石による複雑性尿路感染症と診断し、入院入院6時間後、血圧低下、腎障害が出現し、大量補液および昇圧剤の投与を開始した

経過

腎瘻造設を試みるも成功せず、第2病日も血圧低下は持続大量補液は継続TP 4.2 g/dl、Alb 2.1 g/dlと低アルブミン血症が増悪し、全身の浮腫が増悪傾向であったその後、再度施行した腎瘻造設術が成功体液バランス調整目的に、一時的に晶質液に代えてアルブミン製剤を使用その後、血圧は安定化し、第4病日にはショック期を離脱

CLINICAL QUESTION

ショック期に一時的にアルブミン製剤を使用したが、アルブミン投与による血清Alb値の目標値は示されていない

血清Alb値を上昇させ、浮腫の原因となる低アルブミン血症を改善させることで、血管内ボリュームの適正化を図れないのか

Septic shockの患者において、ショック期にアルブミンを投与する際に、予後を改善しうる血清Alb値の目標値は存在するか

EBMの5STEP

STEP1　疑問の定式化 (PICO)

STEP2　論文の検索STEP3　論文の批判的吟味STEP4　症例への適応STEP5　STEP1～4の見直し

STEP1　疑問の定式化

P：Severe sepsisもしくはSeptic shockの患者I：ある血清アルブミン値を目標に、アルブミン投与を行う群C：アルブミン投与を行わない群O：死亡率

EBMの5STEP



STEP2　論文の検索

PubMed

“Severe sepsis’’

“Septic shock”

“Albumin concentration”で検索を行った

論文の選定

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BACKGROUNDAlthough previous studies have suggested the potential advantagesof albumin administration in patients with severe sepsis, its efficacyhas not been fully established.

Full Text of Background...

METHODSIn this multicenter, openlabel trial, we randomly assigned 1818patients with severe sepsis, in 100 intensive care units (ICUs), toreceive either 20% albumin and crystalloid solution or crystalloidsolution alone. In the albumin group, the target serum albuminconcentration was 30 g per liter or more until discharge from the ICUor 28 days after randomization. The primary outcome was death fromany cause at 28 days. Secondary outcomes were death from anycause at 90 days, the number of patients with organ dysfunction andthe degree of dysfunction, and length of stay in the ICU and thehospital.

Full Text of Methods...

RESULTSDuring the first 7 days, patients in the albumin group, as comparedwith those in the crystalloid group, had a higher mean arterialpressure (P=0.03) and lower net fluid balance (P<0.001). The totaldaily amount of administered fluid did not differ significantly betweenthe two groups (P=0.10). At 28 days, 285 of 895 patients (31.8%) inthe albumin group and 288 of 900 (32.0%) in the crystalloid group haddied (relative risk in the albumin group, 1.00; 95% confidence interval[CI], 0.87 to 1.14; P=0.94). At 90 days, 365 of 888 patients (41.1%) inthe albumin group and 389 of 893 (43.6%) in the crystalloid group haddied (relative risk, 0.94; 95% CI, 0.85 to 1.05; P=0.29). No significantdifferences in other secondary outcomes were observed between thetwo groups.

Full Text of Results...

CONCLUSIONSIn patients with severe sepsis, albumin replacement in addition tocrystalloids, as compared with crystalloids alone, did not improve therate of survival at 28 and 90 days. (Funded by the Italian MedicinesAgency; ALBIOS ClinicalTrials.gov number, NCT00707122.)

Full Text of Discussion...

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ORIGINAL ARTICLE

Albumin Replacement in Patients with Severe Sepsis or Septic

Shock

Pietro Caironi, M.D., Gianni Tognoni, M.D., Serge Masson, Ph.D., Roberto Fumagalli, M.D., Antonio Pesenti, M.D.,Marilena Romero, Ph.D., Caterina Fanizza, M.Stat., Luisa Caspani, M.D., Stefano Faenza, M.D., Giacomo Grasselli, M.D.,Gaetano Iapichino, M.D., Massimo Antonelli, M.D., Vieri Parrini, M.D., Gilberto Fiore, M.D., Roberto Latini, M.D., andLuciano Gattinoni, M.D. for the ALBIOS Study InvestigatorsN Engl J Med 2014; 370:14121421 April 10, 2014 DOI: 10.1056/NEJMoa1305727

Abstract Article References Citing Articles (52) Letters

MEDIA IN THISARTICLE

FIGURE 1

Serum Albumin Levelsthrough Day 28 andNet Fluid Balancethrough Day 7.

FIGURE 2

Probability of Survivalfrom Randomizationthrough Day 90.

ARTICLE ACTIVITY52 articles have citedthis article

EBMの5STEP



論文の背景アルブミンの体内での働きとして…

　- 膠質浸透圧を維持し、様々な内因性・外因性物質の　キャリアとしての働き

Mol Pharmacol 1975;11:824-32. 　- 抗酸化・抗炎症作用　- 活性酸素や窒素化合物に対するスカベンジャー作用

J Biol Chem 1961;236:PC5. Clin Sci (Lond) 1998;95:459-65.

Proc Natl Acad Sci USA 1992;89:7674-7.

　- 酸塩基平衡でのバッファー作用J Appl Physiol 1976;40:762-7.

論文の背景

集中治療領域でのアルブミンに関する話題…

　- Critical illnessの患者において4％アルブミンの投与は安全　- Severe sepsisの患者では有意ではないが、死亡率が低い　傾向があった

N Engl J Med. 2004; 350: 2247-56. (SAFE study) 　- Critical illnessの患者において、Alb 3.0 g/dl以上に保つこと　が有用である可能性あり

Crit Care Med. 2006; 34: 2536-40.

PATIENT: INCLUSION

イタリアにある100施設のICU

呼吸器、腹腔、尿路、その他に少なくとも1つ感染が　証明された、もしくは疑う所見がある

SIRS基準を2つ以上満たすSOFA scoreのいずれかを満たす　respiratory score>1、hematologic score>1

　hepatic score>1、cardiovascular score equal to 1、3 or4　　renal score>1

SOFA SCORE THE SEQUENTIAL ORGAN FAILURE ASSESSMENT SCORE

PATIENT: EXCLUSION

18歳以下終末期の患者アルブミン投与に対する既知の有害事象を有する患者アクティブな状態の頭部外傷後を有する患者に生じた　　

Severe sepsis or septic shock

うっ血性心不全(New York Heart Association class of 3 or 4)

肝硬変、吸収不良症候群、ネフローゼ症候群、熱傷Inclusion criteriaを満たしてから24時間以上経過した症例宗教上の問題他の研究に登録された患者

INTERVENTION

Day28もしくはICU退室まで、20％アルブミン+晶質液をAlb 3.0 g/dlを維持するように投与

COMPARISON

Day28もしくはICU退室まで、晶質液のみを投与

OUTCOME

Primary outcome：28日死亡率Secondary outcome：90日死亡率、臓器不全を有する　患者数、臓器障害の程度、ICU入室期間、入院期間

Tertiary outcome：腎代替療法の実施、AKIの発症率　　人工呼吸器装着の期間、昇圧剤・強心剤の投与中止　　までの期間

論文のPICO

P：ICUに入室している18歳以上の患者で、Severe Sepsis

　の診断基準を満たしたものI：Day28もしくはICU退室まで、20％アルブミン+晶質液　をAlb 3.0 g/dlを維持するように投与

C：Day28もしくはICU退室まで、晶質液のみを投与O：28日死亡率

統計学的分析方法

P < 0.05であれば、統計的有意差ありと判断power 80%、28日死亡率を45%、ARR 7.5%を想定サンプルサイズ 1350人と算出

倫理的配慮

全ての患者に対して、研究登録の前に書面を含めたインフォームドコンセントを行った

インフォームドコンセントの手続きや研究プロトコールは、研究を行った各施設の倫理委員会で承認された

介入群と対照群は同じ予後で開始したか

患者はランダム割り付けされていたか　- ランダム割り付けされているランダム割り付けは隠蔽化(concealment)されていたか　- 中央割り付け方式であり、隠蔽化されている


既知の予後因子は群間で似ていたか→Base-lineは同等か

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 370;15 nejm.org april 10, 20141414

crystalloids were administered whenever it was clinically indicated by the attending physician. The administration of synthetic colloids was not allowed. All other treatments were at the discre-tion of the attending physician.

OUTCOMESThe primary outcome measure was death from any cause at 28 days after randomization. The principal secondary outcome measure was death from any cause at 90 days after randomization. Additional secondary outcomes were the number of patients with organ dysfunction and the de-gree of dysfunction and the length of stay in the ICU and the hospital. The severity of systemic illness was assessed with the use of the Simpli-fied Acute Physiology Score, with scores ranging from 0 to 163 and higher scores indicating more severe illness.16 Organ function was assessed daily with the use of the Sequential Organ Failure Assessment (SOFA) score,17 which ranges from 0 to 4 for each of five components (respiratory, coagulation, liver, cardiovascular, and renal com-ponents), with higher scores indicating more severe organ dysfunction (Table S1 in the Sup-plementary Appendix). New organ failures were defined as a change in a component score dur-ing the study from a baseline score of 0, 1, or 2 to a score of 3 or 4.5,18,19 Tertiary outcomes, which were assessed in post hoc analyses, included the

use of renal-replacement therapy, the incidence of acute kidney injury, the duration of mechanical ventilation, and the time to suspension of the ad-ministration of vasopressor or inotropic agents.

STATISTICAL ANALYSISWe originally determined that a sample of 1350 pa-tients would provide the study with 80% power to detect an absolute between-group difference of 7.5 percentage points in mortality at 28 days, on the basis of an estimated baseline mortality of 45%, with a two-sided P value of less than 0.05 indicating statistical significance. The study pro-tocol specified the possibility of increasing the sample to 1800 patients on the basis of a recom-mendation by the data and safety monitoring board during an interim analysis.

All the analyses were conducted on an inten-tion-to-treat basis. Binary outcomes were com-pared with the use of the chi-square test, and continuous outcomes with the use of the Wilcoxon rank-sum test. Comparisons of fluid volumes and physiological data over time were performed with the use of a two-factor analysis of variance for repeated measurements. We calculated sur-vival estimates according to the Kaplan–Meier method and compared them using a log-rank test. We performed an adjusted analysis using robust Poisson regression for binary outcomes. In a post hoc analysis, the primary and principal

Table 1. Characteristics of the Patients at Baseline.*

CharacteristicAlbumin Group

(N = 903)Crystalloid Group

(N = 907)

Age — yrMedian 70 69Interquartile range 57–77 59–77

Female sex — no. (%) 360 (39.9) 357 (39.4)Body-mass index† 27±6 27±6Reason for ICU admission — no. (%)

Medical 511 (56.6) 518 (57.1)Elective surgery 69 (7.6) 58 (6.4)Emergency surgery 323 (35.8) 331 (36.5)

Preexisting condition — no. (%)‡Liver disease 13 (1.4) 14 (1.5)COPD 113 (12.5) 108 (11.9)Chronic renal failure 44 (4.9) 32 (3.5)Immunodeficiency 115 (12.7) 128 (14.1)Congestive or ischemic heart disease 149 (16.5) 165 (18.2)

SAPS II score§Median 48 48Interquartile range 37–59 37–60

The New England Journal of Medicine Downloaded from nejm.org at Pfizer Japan Inc. on March 17, 2015. For personal use only. No other uses without permission.

Copyright © 2014 Massachusetts Medical Society. All rights reserved.


既知の予後因子は群間で似ていたか→Base-lineは同等かAlbumin Replacement in Severe Sepsis or Septic Shock

n engl j med 370;15 nejm.org april 10, 2014 1415

Table 1. (Continued.)

CharacteristicAlbumin Group

(N = 903)Crystalloid Group

(N = 907)

Physiological variable¶Heart rate — beats/min 105±22 106±20Mean arterial pressure — mm Hg 74±16 73±15Central venous pressure — mm Hg 10.0±4.9 9.8±4.7Urine output — ml/hr

Median 50 50Interquartile range 20–100 25–100

Lactate — mmol/literMedian 2.3 2.5Interquartile range 1.4–4.2 1.6–4.3

Serum albumin — g/liter 24.1±6.3 24.2±6.2Hemoglobin — g/dl 10.9±2.1 11.0±2.0Central venous oxygen saturation — %

Median 73 73Interquartile range 65–79 68–80

SOFA score∥Median 8 8Interquartile range 6–10 5–10

Organ dysfunction — no. (%)**1 organ 188 (20.8) 208 (22.9)2 organs 361 (40.0) 303 (33.4)3 organs 236 (26.1) 248 (27.3)4 organs 89 (9.9) 115 (12.7)5 organs 29 (3.2) 33 (3.6)

Shock — no. (%)†† 565 (62.6) 570 (62.8)Mechanical ventilation — no. (%) 709 (78.5) 737 (81.3)Fluid administration in previous 24 hr — no. (%)

Albumin 153 (16.9) 176 (19.4)Synthetic colloids 452 (50.1) 479 (52.8)

* Plus–minus values are means ±SD. There were no significant differences between the two groups except with respect to central venous oxygen saturation (P = 0.02) and number of patients with organ dysfunction (P = 0.04). COPD denotes chronic obstructive pulmonary disease, and ICU intensive care unit.

† The body-mass index is the weight in kilograms divided by the square of the height in meters.‡ Among preexisting conditions, liver disease was defined as the presence of cirrhosis, portal hypertension, or previous

episodes of liver insufficiency; immunodeficiency as the concurrent presence of immunosuppressive diseases or receipt of immunosuppressive therapies; and congestive or ischemic heart disease as New York Heart Association class II.

§ The Simplified Acute Physiology Score (SAPS II)16 was used to assess the severity of systemic illness at baseline. Scores range from 0 to 163, with higher scores indicating more severe illness.

¶ Data on central venous pressure were available for 841 patients in the albumin group and 858 in the crystalloid group; data on lactate level, for 874 and 867, respectively; data on serum albumin level, for 821 and 813, respectively; data on hemoglobin level, for 893 and 894, respectively; and data on central venous oxygen saturation, for 798 and 802, respectively.

∥ The Sequential Organ Failure Assessment (SOFA) score17 includes subscores ranging from 0 to 4 for each of five components (respiratory, coagulation, liver, cardiovascular, and renal components), with higher scores indicating more severe organ dysfunction. The scoring was modified by excluding the assessment of cerebral failure (the Glasgow Coma Scale), which was not performed in these patients, and by decreasing to 65 mm Hg the mean arterial pressure threshold for a cardiovascular subscore of 1, for consistency with the hemodynamic targets as defined according to the early goal-directed therapy.15

** Organ dysfunctions were defined as a SOFA score of 2 or more on the respiratory component; 2 or more on the co-agulation component; 2 or more on the liver component; 1, 3, or 4 on the cardiovascular component; and 2 or more on the renal component.5 A score of 2 on the cardiovascular component was not included because that score is as-signed for the use of vasopressor drugs at low doses (a condition not considered to be strictly related to cardiovascu-lar dysfunction).

†† Shock at the time of randomization was defined as a score of 3 or 4 on the cardiovascular component of the SOFA.5



臓器障害を有する患者数やScvO2の値にわずかな差があるほかはほぼ同等

研究はどの程度盲検化されていたか

Open labelingのため盲検化なし

→治療者や評価者によるバイアスが入る可能性あり

研究完了時点で両群は予後のバランスがとれていたか

追跡は完了しているか　→追跡率、脱落率はどうか　追跡率 98.3％ vs 98.5％　脱落率 1.7％ vs 1.6％Intention to treat(ITT)解析されているか　→ITT解析である試験の早期中止はない

Supplementary Appendix – Caironi et al., pag. 7

Figure S1

910 Were assigned to receiveAlbumin

908 Were assigned to receiveCrystalloids

1818 Patients underwent randomization

621 Underwent randomization

between 6 and 24 hours

903 Were included in the analysis 907 Were included in the analysis

895 (99.1%) Were included in the analysis at 28 day

900 (99.2% Were included in the analysis at 28 day

888 (98.3%) Were included in the analysis at 90 day

893 (98.5%) Were includedin the analysis at 90 day

8 (0.9%) Were lost to follow-up





within 6 hours


within 6 hours


between 6 and 24 hours

7 Were excluded5 Were randomized twice2 Withdrew consent for the use of their data

5 Were treated as Crystalloids

19 Discontinued trial fluid2 Underwent randomization

without inclusion criteria6 Were withdrawn owing to

violation of exclusion criteria8 Were withdrawn owing to the

occurence of exclusion criteriaduring the trial

2 Were withdrawn for medicalreasons

1 Withdrew consent for receivingtrial fluid

1 Was excluded1 Was randomized twice

23 Discontinued trial fluid6 Underwent randomization

without inclusion criteria6 Were withdrawn owing to

violation of exclusion criteria6 Were withdrawn owing to the

occurence of exclusion criteriaduring the trial

4 Were withdrawn for medicalreasons

1 Withdrew consent for receivingtrial fluid

Figure S1. Randomization, Stratification, and Follow-up of Study Patients. Six patients were excluded after the end of the study as they had been already and previously randomized in the trial. Two patients withdrew consent for the use of their data after the end of the study. Due to the high number of participating centers (100 ICUs), and the potential heterogeneity between their organizational structures, no data on screened patients were collected.

治療介入は適切に行われたか

Day 1～28まで有意に介入群で血清アルブミン値が高い1日あたりの輸液バランスは介入群の方が低い(p < 0.001)



secondary outcomes were assessed in patients who had septic shock and those who did not have septic shock at the time of enrollment. Heterogeneity of treatment effects among sub-groups was assessed with the use of the test for a common relative risk. SAS software, version 9.2 (SAS Institute), was used for all the analyses.

R ESULT S

STUDY POPULATIONFrom August 2008 through February 2012, a total of 1818 patients with severe sepsis were random-

ly assigned to receive 20% albumin and crystal-loid solution (910 patients) or crystalloid solution alone (908) for fluid replacement. Per protocol, patient enrollment was stratified according to the interval between the time the patient met the clinical criteria for severe sepsis and random-ization: 6 hours or less (579 patients [31.8%]) versus more than 6 hours (1239 [68.2%]). A total of 8 patients were excluded from the analysis (2 patients in the albumin group owing to with-drawal of consent, and 5 in the albumin group and 1 in the crystalloid group owing to a ran-domization error) (Fig. S1 in the Supplementary Appendix).

After follow-up, data regarding death at 90 days were available for 888 of 903 patients (98.3%) in the albumin group and for 893 of 907 (98.5%) in the crystalloid group. Baseline characteristics were similar between the two study groups, except for a slight imbalance in the number of patients with organ dysfunction and values of central venous oxygen saturation (Table 1). The primary site of

34

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26

24

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00 4 8 12 16 28

Study Day

Seru

m A

lbum

in (g

/lite

r)

P<0.001

P<0.001

B

A

No. at RiskAlbuminCrystalloids

821813

677663

483464

335303

239217

198159

148130

107104


840844

789795

742735

701685

639635

586587

542529

20 24

Net

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id B

alan

ce (m

l)

5000

4000

3000

2000

1000

−1000

−2000

−3000

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1 2 3 4 5

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6 7

AlbuminCrystalloids

AlbuminCrystalloids

Figure 1. Serum Albumin Levels through Day 28 and Net Fluid Balance through Day 7.

Panel A shows the serum albumin concentration through day 28 in patients receiving albumin and crys-talloids or crystalloids alone. Day 0 was defined as the time of randomization. Data are medians, with I bars indicating interquartile ranges. The P value is for the between-group comparison performed with the use of a two-factor analysis of variance for repeated mea-surements to test time (29 days for serum albumin, including day 0) and group effects. Panel B shows the net fluid balance through day 7 for patients receiving albumin and crystalloids or crystalloids alone. The daily net fluid balance was calculated as the difference between the total amount of administered fluid (in-cluding 20% albumin; crystalloids; other blood prod-ucts, such as packed red cells, fresh-frozen plasma, or platelets; and other fluids) and the total amount of excreted fluid each day (including urinary output and other fluid losses, such as fluids potentially removed with continuous renal-replacement therapy, fluids lost as feces, aspirated gastric content, drainage fluids, and insensible perspiration). For day 1, the net fluid balance was computed from the time of randomiza-tion to day 1, which averaged 16 hours in the two study groups. The horizontal line in the boxes indi-cates the median, the top and bottom of the box the interquartile range, and I bars the 5th and 95th per-centile range. The P value is for the between-group comparison performed with the use of the two-factor analysis of variance for repeated measurements to test time (7 days) and group effects.





secondary outcomes were assessed in patients who had septic shock and those who did not have septic shock at the time of enrollment. Heterogeneity of treatment effects among sub-groups was assessed with the use of the test for a common relative risk. SAS software, version 9.2 (SAS Institute), was used for all the analyses.

R ESULT S

STUDY POPULATIONFrom August 2008 through February 2012, a total of 1818 patients with severe sepsis were random-

ly assigned to receive 20% albumin and crystal-loid solution (910 patients) or crystalloid solution alone (908) for fluid replacement. Per protocol, patient enrollment was stratified according to the interval between the time the patient met the clinical criteria for severe sepsis and random-ization: 6 hours or less (579 patients [31.8%]) versus more than 6 hours (1239 [68.2%]). A total of 8 patients were excluded from the analysis (2 patients in the albumin group owing to with-drawal of consent, and 5 in the albumin group and 1 in the crystalloid group owing to a ran-domization error) (Fig. S1 in the Supplementary Appendix).

After follow-up, data regarding death at 90 days were available for 888 of 903 patients (98.3%) in the albumin group and for 893 of 907 (98.5%) in the crystalloid group. Baseline characteristics were similar between the two study groups, except for a slight imbalance in the number of patients with organ dysfunction and values of central venous oxygen saturation (Table 1). The primary site of

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26

24

22

20

18

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00 4 8 12 16 28

Study Day

Seru

m A

lbum

in (g

/lite

r)

P<0.001

P<0.001

B

A


821813

677663

483464

335303

239217

198159

148130

107104


840844

789795

742735

701685

639635

586587

542529

20 24

Net

Flu

id B

alan

ce (m

l)

5000

4000

3000

2000

1000

−1000

−2000

−3000

0

1 2 3 4 5

Study Day

6 7

AlbuminCrystalloids

AlbuminCrystalloids

Figure 1. Serum Albumin Levels through Day 28 and Net Fluid Balance through Day 7.

Panel A shows the serum albumin concentration through day 28 in patients receiving albumin and crys-talloids or crystalloids alone. Day 0 was defined as the time of randomization. Data are medians, with I bars indicating interquartile ranges. The P value is for the between-group comparison performed with the use of a two-factor analysis of variance for repeated mea-surements to test time (29 days for serum albumin, including day 0) and group effects. Panel B shows the net fluid balance through day 7 for patients receiving albumin and crystalloids or crystalloids alone. The daily net fluid balance was calculated as the difference between the total amount of administered fluid (in-cluding 20% albumin; crystalloids; other blood prod-ucts, such as packed red cells, fresh-frozen plasma, or platelets; and other fluids) and the total amount of excreted fluid each day (including urinary output and other fluid losses, such as fluids potentially removed with continuous renal-replacement therapy, fluids lost as feces, aspirated gastric content, drainage fluids, and insensible perspiration). For day 1, the net fluid balance was computed from the time of randomiza-tion to day 1, which averaged 16 hours in the two study groups. The horizontal line in the boxes indi-cates the median, the top and bottom of the box the interquartile range, and I bars the 5th and 95th per-centile range. The P value is for the between-group comparison performed with the use of the two-factor analysis of variance for repeated measurements to test time (7 days) and group effects.



サンプルサイズは十分か

目標の症例数は集められたただ、結果には有意差は　つかなかった

28日時点で観察された死亡率が予想より低く、そのため研究がUnderpowerとなった可能性がある



The findings in our trial may appear to con-tradict those of the predefined subgroup analysis from the SAFE study,5 which suggested a sur-vival advantage with an albumin-based strategy during severe sepsis. The plausibility of this hy-pothesis was supported by the significant hemo-dynamic advantages observed23 and by further investigations showing that the correction of hypoalbuminemia reduced the severity of organ

dysfunction.4,6 Similar beneficial effects were also suggested by a large meta-analysis, which concluded that the use of albumin-containing solutions could be associated with lower mortal-ity than that seen with other fluid regimens.24

Our results confirm that administration of albumin produces small but significant hemody-namic advantages. A significantly greater pro-portion of patients in the albumin group than in

Table 2. Outcomes.

Outcome Albumin Group Crystalloid GroupRelative Risk

(95% CI) P Value

Primary outcome: death at 28 days — no./total no. (%) 285/895 (31.8) 288/900 (32.0) 1.00 (0.87–1.14) 0.94

Secondary outcomes

Death at 90 days — no./total no. (%) 365/888 (41.1) 389/893 (43.6) 0.94 (0.85–1.05) 0.29

New organ failures — no./total no. (%)* 0.99

None 372/836 (44.5) 383/841 (45.5)

1 organ 283/836 (33.9) 287/841 (34.1)

2 organs 130/836 (15.6) 123/841 (14.6)

3 organs 40/836 (4.8) 36/841 (4.3)

4 organs 10/836 (1.2) 11/841 (1.3)

5 organs 1/836 (0.1) 1/841 (0.1)

SOFA score† — 0.23

Median 6.00 5.62

Interquartile range 4.00–8.50 3.92–8.28

SOFA subscore†

Cardiovascular — 0.03

Median 1.20 1.42


Respiratory — 0.63

Median 2.00 2.00


Renal — 0.15

Median 0.83 0.75


Coagulation — 0.04

Median 0.64 0.50


Liver — 0.02

Median 0.28 0.20


Length of stay — days

In ICU — 0.42

Median 9 9

Interquartile range 4–18 4–17

In hospital‡ — 0.65

Median 20 20

Interquartile range 10–36 9–38



RRR、ARR、NNTはそれぞれいくらか

0.2％0.63％32.0％ 31.8％ 500

28日死亡率には有意差は認めなかった

SECONDARY/TERTIARY OUTCOMEの評価T h e n e w e ngl a nd j o u r na l o f m e dic i n e


of data from the 1121 patients with septic shock showed significantly lower mortality at 90 days in the albumin group than in the crystalloid group. Conversely, in the subgroup of patients with se-vere sepsis without shock, mortality appeared to be higher among those who were treated with albumin than among those treated with crystal-loids alone, although the difference was far from significant. This analysis was not prespecified, and therefore it may be characterized by well-known biases. Nonetheless, a state of shock asso-ciated with severe sepsis represents a well-defined clinical entity. Moreover, if the oncotic, anti-inflammatory, and nitric oxide–scavenging prop-erties of albumin are of clinical importance, these may be maximally exploited in the condi-tions that are the most severe, such as cardiovas-cular dysfunction.

Our trial has certain limitations. First, we in-cluded the use of albumin solutions with a greater concentration than those used in the SAFE study (20% vs. 4%). Consequently, the volume of albu-min solution that was administered was mark-

edly lower than that administered in the SAFE study, since our goal was to correct hypoalbu-minemia and not to directly replace intravascu-lar volume. Second, the observed mortality at 28 days was lower than originally expected, thereby increasing the likelihood that the study was un-derpowered. Finally, only approximately one third of the patients were enrolled during the early phase of severe sepsis.

In conclusion, the use of albumin in addition to crystalloids to correct hypoalbuminemia, as compared with the use of crystalloids alone, in patients with severe sepsis during their stay in the ICU did not provide a survival benefit at 28 or 90 days, despite improvements in hemodynamic variables. The clinical benefit of albumin that was seen in the post hoc analysis of the subgroup of patients with septic shock warrants further confirmation.

Supported by the Italian Medicines Agency.Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.We thank Nicola Bottino, M.D., Giuseppe Breda, M.D.,

Davide Chiumello, M.D., Stefania Crotti, M.D., Sergio De Chiara, M.D., Alfredo Lissoni, M.D., Francesca Pagan, M.D., Mauro Panigada, M.D., Riccarda Russo, M.D., Monica Savioli, M.D., Alberto Sicignano, M.D., Daniela Tubiolo, M.D., and all the residency and nursing staff of the Rianimazione Generale Emma Vecla, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda–Ospedale Maggiore Policlinico, Milan (coordinating center), for support in monitoring the ran-domization process and study compliance; Paola Bruzzone, M.D., Federico Polli, M.D., and Federica Tallarini, M.D., of the Dipartimento di Anestesia, Rianimazione e Terapia del Dolore, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Milan, and Tommaso Mauri, M.D., of the Dipartimento di Medicina Perioperatoria e Terapia Intensiva, Azienda Ospedaliera S. Gerardo di Monza, for help in data-quality as-sessment; Luisella Pirozzi of the Consorzio Mario Negri Sud, Santa Maria Imbaro, and Marina Leonardelli of the Dipartimento di Anestesia, Rianimazione e Terapia del Dolore, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Milan, for support in monitoring study compliance and retriev-ing outcome data; Paolo Cadringher and Eleonora Carlesso, M.Sc., of the Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Università degli Studi, Milan, for pri-mary support in creating and managing electronic clinical re-search forms; Jean-Louis Vincent, M.D., of the Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Peter M. Suter, M.D., of the University of Geneva, Geneva, Maria Grazia Valsecchi of the Dipartimento di Medicina Clinica e Prevenzione, Università degli Studi di Milano-Bicocca, Milan, and Amedeo Santosuosso of the Dipartimento di Giurisprudenza, Università degli Studi di Pavia, Pavia, for serving on the data and safety monitoring board; the study patients and their relatives for their participa-tion; and the physicians and nursing staff of the participating centers for their cooperation.


903907

733729

647652

597598

567676

556551

545538

535521

529511

523504

0 10 20 30 40 50

Days since Randomization

Prob

abili

ty o

f Sur

viva

l

60 70 80 90

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.0

Albumin

P=0.39

Crystalloids

Figure 2. Probability of Survival from Randomization through Day 90.

The graph shows the Kaplan–Meier estimates for the probability of sur-vival among patients receiving albumin and crystalloids and among those receiving crystalloids alone. The P value was calculated with the use of the log-rank test.



90日死亡率も有意に改善することはできなかった

(41.1％ vs 43.6％、p = 0.29)

SECONDARY/TERTIARY OUTCOMEの評価

介入群では、心血管系のSOFA subscore (1.20 vs 1.42、p = 0.03)

が低く、凝固系 (0.64 vs 0.50、p = 0.04) と肝 (0.28 vs 0.20、P = 0.02)

のSOFA subscoreが高かった介入群で、昇圧剤・強心剤投与中止までの期間が短かった (3 vs 4、p = 0.007)

その他のSecondary/Tertiary outcome（臓器不全を有する患者数、ICU入室期間、入院期間、腎代替療法の実施、AKIの発症率、人工呼吸器装着の期間）には有意差はなかった

OTHERS

割り当て当初にSeptic shockを合併している患者は、介入群で90日死亡率が低かった(43.6％ vs 49.9％、p = 0.03)

介入群で、ランダム化後6時間以内にターゲットのMAP

により早く到達し、初めの7日間はMAPはより高く、　一方脈拍数はより低かった

STEP3のまとめベースの2群間にはわずかな差はあるものの、極端にどちらかに有利・不利をもたらすものではなさそう

Open labelingのため、治療者や評価者などのバイアスが入る可能性あり

20%アルブミンの投与を行い、血清アルブミン値を3.0 g/dl以上に保つことは、Severe sepsisやSeptic shock患者の90日までの死亡率を改善させることはできなかった

ただ、限定的な血行動態上の利点はありそう発症早期にSeptic shockを合併した患者にとって、20％アルブミンの投与はもしかしたら有用であるかもしれない

EBMの5STEP



STEP4　症例への適応

研究患者は自身の診療における患者と似ていたか　- 本症例はInclusion criteiriaを満たし、Exclusion

criteriaの該当項目はなかった　- Baseline characteristicsの患者群と大きな相違はない患者にとって重要なアウトカムはすべて考慮されたか　- 考慮されている

STEP4　症例への適応見込まれる治療の利益は、考えられる害やコストに見合うか　- Primary outcomeに有意差なく、利益が乏しい印象　- 発症早期にSeptic shockを合併した患者においては　 90日死亡率を改善するかもしれないが、あくまで　 Post hoc subgroup解析の結果本症例で、血清アルブミン値を3.0 g/dl以上に　　　　

保つことの意義は乏しいか

EBMの5STEP



STEP5　STEP1～4の見直し

STEP1　問題の定式化　- Severe sepsisもしくはSeptic shockの患者における、血清アルブミン値　の目標値に疑問を抱いたSTEP2　論文の検索　- PubMedを用いて短時間で検索できたSTEP3　論文の批判的吟味　- JAMA user’s guideを用いて論文の内的妥当性を検討したSTEP4　情報の患者への適応　- 批判的吟味の結果、血清アルブミン値を3.0 g/dl以上に保つことの　意義は乏しいと判断

まとめ20%アルブミンの投与を行い、血清アルブミン値を3.0

g/dl以上に保つことは、Severe sepsisやSeptic shock患者の90日までの死亡率を改善させることはできなかった

現時点では、上記の患者群において血清アルブミン値を3.0 g/dl以上に保つ意義は乏しそう

発症早期にSeptic shockを合併した患者においては90日死亡率を改善するかもしれないが、今後の研究が待たれる

severe sepsisもしくはseptic shockの患者にお...

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