SEVERE SEPSISもしくはSEPTIC SHOCKの患者において血清

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
Albumin Replacement in Patients with Severe Sepsis or Septic Shock
N Engl J Med 2014; 370:1412-1421
飯塚病院総合診療科 PGY 5
坂井正弘
監修：吉野俊平
J HOSPITALIST network Journal club
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
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
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
STEP2 論文の検索
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“Severe sepsis’’
“Septic shock”
“Albumin concentration”
で検索を行った
論文の選定
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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., and
Luciano Gattinoni, M.D. for the ALBIOS Study Investigators
N Engl J Med 2014; 370:14121421 April 10, 2014 DOI: 10.1056/NEJMoa1305727
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Abstract
Article
References
Citing Articles (52)
Letters
BACKGROUND
Although previous studies have suggested the potential advantages
of albumin administration in patients with severe sepsis, its efficacy
MEDIA IN THIS
ARTICLE
FIGURE 1
K
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
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化(concealment)されていたか
- 中央割り付け方式であり、隠化されている
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 components), with higher scores indicating more
severe organ dysfunction (Table S1 in the Supplementary Appendix). New organ failures were
defined as a change in a component score during 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
All the analyses were conducted on an intention-to-treat basis. Binary outcomes were compared 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 survival 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
介入群と対照群は同じ予後で開始したか
✤既知の予後因子は群間で似ていたか→Base-lineは同等か
Table 1. Characteristics of the Patients at Baseline.*
Characteristic
Albumin Group
(N = 903)
Crystalloid Group
(N = 907)
70
57–77
360 (39.9)
27±6
69
59–77
357 (39.4)
27±6
511 (56.6)
69 (7.6)
323 (35.8)
518 (57.1)
58 (6.4)
331 (36.5)
13 (1.4)
113 (12.5)
44 (4.9)
115 (12.7)
149 (16.5)
14 (1.5)
108 (11.9)
32 (3.5)
128 (14.1)
165 (18.2)
48
37–59
48
37–60
Age — yr
Median
Interquartile range
Female sex — no. (%)
Body-mass index†
Reason for ICU admission — no. (%)
Medical
Elective surgery
Emergency surgery
Preexisting condition — no. (%)‡
Liver disease
COPD
Chronic renal failure
Immunodeficiency
Congestive or ischemic heart disease
SAPS II score§
Median
Interquartile range
1414
n engl j med 370;15
nejm.org
april 10, 2014
介入群と対照群は同じ予後で開始したか
✤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
Table 1. (Continued.)
Characteristic
Physiological variable¶
Heart rate — beats/min
Mean arterial pressure — mm Hg
Central venous pressure — mm Hg
Urine output — ml/hr
Median
Interquartile range
Lactate — mmol/liter
Median
Interquartile range
Serum albumin — g/liter
Hemoglobin — g/dl
Central venous oxygen saturation — %
Median
Interquartile range
SOFA score∥
Median
Interquartile range
Organ dysfunction — no. (%)**
1 organ
2 organs
3 organs
4 organs
5 organs
Shock — no. (%)††
Mechanical ventilation — no. (%)
Fluid administration in previous 24 hr — no. (%)
Albumin
Synthetic colloids
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
*
Albumin Group
(N = 903)
Crystalloid Group
(N = 907)
105±22
74±16
10.0±4.9
106±20
73±15
9.8±4.7
50
20–100
50
25–100
2.3
1.4–4.2
24.1±6.3
10.9±2.1
2.5
1.6–4.3
24.2±6.2
11.0±2.0
73
65–79
73
68–80
8
6–10
8
5–10
188 (20.8)
361 (40.0)
236 (26.1)
89 (9.9)
29 (3.2)
565 (62.6)
709 (78.5)
208 (22.9)
303 (33.4)
248 (27.3)
115 (12.7)
33 (3.6)
570 (62.8)
737 (81.3)
153 (16.9)
452 (50.1)
176 (19.4)
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.
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
Supplementary Appendix – Caironi et al., pag. 7
Figure S1
1818 Patients
underwent randomization
✤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
910 Were assigned to receive
Albumin
289 Underwent
randomization
within
6 hours
621 Underwent
randomization
between
6 and 24 hours
7 Were excluded
5 Were randomized twice
2 Withdrew consent for the use of their
data
5 Were treated as Crystalloids
19 Discontinued trial fluid
2 Underwent randomization
without inclusion criteria
6 Were withdrawn owing to
violation of exclusion criteria
8 Were withdrawn owing to the
occurence of exclusion criteria
during the trial
2 Were withdrawn for medical
reasons
1 Withdrew consent for receiving
trial fluid
903 Were included in the analysis
→ITT解析である
✤試験の早期中止はない
8 (0.9%) Were lost
to follow-up
895 (99.1%) Were included
in the analysis at 28 day
7 (0.8%) Were lost
to follow-up
888 (98.3%) Were included
in the analysis at 90 day
908 Were assigned to receive
Crystalloids
290 Underwent
randomization
within
6 hours
618 Underwent
randomization
between
6 and 24 hours
1 Was excluded
1 Was randomized twice
23 Discontinued trial fluid
6 Underwent randomization
without inclusion criteria
6 Were withdrawn owing to
violation of exclusion criteria
6 Were withdrawn owing to the
occurence of exclusion criteria
during the trial
4 Were withdrawn for medical
reasons
1 Withdrew consent for receiving
trial fluid
907 Were included in the analysis
7 (0.8%) Were lost
to follow-up
900 (99.2% Were included
in the analysis at 28 day
7 (0.8%) Were lost
to follow-up
893 (98.5%) Were included
in the analysis at 90 day
Figure S1. Randomization, Stratification, and Follow-up of Study Patients.
Serum Al
20
18
16
14
P<0.001
治療介入は適切に行われたか
Albumin
Crystalloids
0
0
4
8
12
16
20
24
28
198
159
148
130
107
104
Study Day
The
at Risk
n e w e ng l a n d j o uNo.
r na
l o f m e dic i n e
Albumin
Crystalloids
821
813
677
663
483
464
335
303
239
217
B Figure 1. Serum Albumin Levels through Day 28
A
and Net Fluid
5000 Balance through Day 7.
34
32
Net Fluid Balance (ml)
30
Serum Albumin (g/liter)
28
26
24
22
20
18
16
14
Albumin
Crystalloids
P<0.001
0
0
4
8
12
16
20
24
28
198
159
148
130
107
104
Study Day
No. at Risk
Albumin
Crystalloids
821
813
677
663
483
464
335
303
239
217
B
5000
Albumin
Panel A shows the serum albumin concentration
Crystalloids
400028 in patients receiving albumin and crysthrough day
talloids or crystalloids alone. Day 0 was defined as the
3000
time of randomization. Data are medians, with I bars
indicating2000
interquartile ranges. The P value is for the
between-group comparison performed with the use
1000 analysis of variance for repeated meaof a two-factor
surements to test time (29 days for serum albumin,
including day0 0) and group effects. Panel B shows the
net fluid−1000
balance through day 7 for patients receiving
albumin and crystalloids or crystalloids alone. The
daily net−2000
fluid balance was calculated as the difference
between the totalP<0.001
amount of administered fluid (in−3000albumin; crystalloids; other blood prodcluding 20%
4
1
2
3
5
6
7
ucts, such as packed red cells, fresh-frozen plasma, or
Dayof
platelets; and other fluids) and the total Study
amount
excreted
No.
at Riskfluid each day (including urinary output and
other
removed639
Albuminfluid losses, such
742
586
542
840 as fluids
789 potentially
701
Crystalloids
735
587
529
635
844
795
685
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 randomizasecondary outcomes were assessed in patients
tion to day 1, which averaged 16 hours in the two
had septic
shock
study groups. Thewho
horizontal
line in the
boxes and
indi- those who did not
septic
shockof the
at box
the the
time of enrollment.
cates the median,have
the top
and bottom
interquartile range,
and I bars the 5th
95th per- effects among subHeterogeneity
of and
treatment
centile range. Thegroups
P value is
for
the
between-group
was assessed with the use of the test for
comparison performed with the use of the two-factor
a common relative risk. SAS software, version
analysis of variance for repeated measurements to test
(SAS
Institute), was used for all the analyses.
time (7 days) and9.2
group
effects.
Albumin
Crystalloids
✤ 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)
Net Fluid Balance (ml)
4000
3000
2000
1000
0
surements to
including day
net fluid balan
albumin and c
daily net fluid
between the t
cluding 20% a
ucts, such as
platelets; and
excreted fluid
other fluid los
with continuo
as feces, aspir
and insensible
balance was c
tion to day 1,
study groups.
cates the med
interquartile r
centile range.
comparison p
analysis of var
time (7 days)
ly assigned to
loid solution
alone (908) f
patient enrol
the interval
the clinical cr
ization: 6 ho
versus more t
of 8 patients
(2 patients in
drawal of co
and 1 in the
domization e
Appendix).
After follo
were available
the albumin
The
n e w e ng l a n d j o u r na l
The findings in our trial may appear to contradict those of the predefined subgroup analysis
from the SAFE study,5 which suggested a survival advantage with an albumin-based strategy
during severe sepsis. The plausibility of this hypothesis was supported by the significant hemodynamic advantages observed23 and by further
investigations showing that the correction of
hypoalbuminemia reduced the severity of organ
サンプルサイズは十分か
of
m e dic i n e
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 mortality than that seen with other fluid regimens.24
Our results confirm that administration of
albumin produces small but significant hemodynamic advantages. A significantly greater proportion of patients in the albumin group than in
Table 2. Outcomes.
Crystalloid Group
Relative Risk
(95% CI)
P Value
285/895 (31.8)
288/900 (32.0)
1.00 (0.87–1.14)
0.94
365/888 (41.1)
389/893 (43.6)
0.94 (0.85–1.05)
0.29
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)
6.00
5.62
4.00–8.50
3.92–8.28
1.20
1.42
0.46–2.31
0.60–2.50
2.00
2.00
1.56–2.48
1.57–2.50
0.83
0.75
0.14–2.14
0.07–2.00
0.64
0.50
0.00–1.62
0.00–1.59
0.28
0.20
0.00–1.00
0.00–0.92
9
9
4–18
4–17
20
20
10–36
9–38
Outcome
Albumin Group
Primary outcome: death at 28 days — no./total no. (%)
Secondary outcomes
Death at 90 days — no./total no. (%)
New organ failures — no./total no. (%)*
✤ 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
SOFA score†
Median
Interquartile range
Cardiovascular
Median
Interquartile range
Respiratory
Median
Interquartile range
Renal
Interquartile range
Coagulation
Median
Interquartile range
なった可能性がある
—
0.23
—
0.03
—
0.63
—
0.15
—
0.04
—
0.02
—
0.42
—
0.65
SOFA subscore†
Median
め研究がUnderpowerと
0.99
Liver
Median
Interquartile range
Length of stay — days
In ICU
Median
Interquartile range
In hospital‡
Median
Interquartile range
RRR、ARR、NNTはそれぞれいくらか
32.0％
31.8％
0.63％
0.2％
500
28日死亡率には有意差は認めなかった
SECONDARY/TERTIARY OUTCOMEの評価
The
n e w e ng l a n d j o u r na l
1.0
0.9
✤90日死亡率も有意に改善
Probability of Survival
0.8
することはできなかった
0.7
Albumin
0.6
Crystalloids
0.5
0.4
0.3
P=0.39
(41.1％ vs 43.6％、p = 0.29)
0.0
0
10
20
30
40
50
60
70
80
90
535
521
529
511
523
504
Days since Randomization
No. at Risk
Albumin
Crystalloids
903
907
733
729
647
652
597
598
567
676
556
551
545
538
Figure 2. Probability of Survival from Randomization through Day 90.
The graph shows the Kaplan–Meier estimates for the probability of survival 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.
of data from the 1121 patients with septic shock
of
edly lower
study, sinc
minemia a
lar volume.
days was lo
increasing
derpowered
of the patien
of severe se
In concl
to crystallo
compared
patients wi
the ICU did
or 90 days,
variables. T
was seen in
of patients
confirmati
Supported b
Disclosure f
the full text of
We thank
Davide Chium
Chiara, M.D.,
Mauro Paniga
M.D., Alberto
the residency
Emma Vecla, F
Scientifico (IR
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
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
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
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
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

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