lower versus higher hemoglobin threshold for transfusion ... · among patients with septic shock,...

慈恵ICU勉強会 2014/11/11 松井宏樹

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 nejm.org 1

original article

Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock

Lars B. Holst, M.D., Nicolai Haase, M.D., Ph.D., Jørn Wetterslev, M.D., Ph.D., Jan Wernerman, M.D., Ph.D., Anne B. Guttormsen, M.D., Ph.D.,

Sari Karlsson, M.D., Ph.D., Pär I. Johansson, M.D., Ph.D., Anders Åneman, M.D., Ph.D., Marianne L. Vang, M.D., Robert Winding, M.D.,

Lars Nebrich, M.D., Helle L. Nibro, M.D., Ph.D., Bodil S. Rasmussen, M.D., Ph.D., Johnny R.M. Lauridsen, M.D., Jane S. Nielsen, M.D., Anders Oldner, M.D., Ph.D.,

Ville Pettilä, M.D., Ph.D., Maria B. Cronhjort, M.D., Lasse H. Andersen, M.D., Ulf G. Pedersen M.D., Nanna Reiter, M.D., Jørgen Wiis, M.D.,

Jonathan O. White, M.D., Lene Russell, M.D., Klaus J. Thornberg, M.D., Peter B. Hjortrup, M.D., Rasmus G. Müller, M.D., Morten H. Møller, M.D., Ph.D.,

Morten Steensen, M.D., Inga Tjäder, M.D., Ph.D., Kristina Kilsand, R.N., Suzanne Odeberg-Wernerman, M.D., Ph.D., Brit Sjøbø, R.N.,

Helle Bundgaard, M.D., Ph.D., Maria A. Thyø, M.D., David Lodahl, M.D., Rikke Mærkedahl, M.D., Carsten Albeck, M.D., Dorte Illum, M.D., Mary Kruse, M.D.,

Per Winkel, M.D., D.M.Sci., and Anders Perner, M.D., Ph.D., for the TRISS Trial Group* and the Scandinavian Critical Care Trials Group

From the Department of Intensive Care (L.B.H., N.H., L.H.A., U.G.P., N.R., J. Wiis, J.O.W., L.R., K.J.T., P.B.H., R.G.M., M.H.M., M.S., A.P.), Copenhagen Trial Unit, Center for Clinical Intervention Research (J. Wet-terslev, P.W.), and Section for Transfu-sion Medicine (P.I.J.), Rigshospitalet and University of Copenhagen, Copenhagen, Randers Hospital, Randers (M.L.V., H.B., M.A.T.), Herning Hospital, Herning (R.W., D.L., R.M.), Hvidovre Hospital, Hvidovre (L.N., C.A.), Aarhus University Hospital, Aarhus (H.L.N., D.I.), Aalborg University Hospital, Aalborg (B.S.R.), Holbæk Hospi-tal, Holbæk (J.R.M.L.), Kolding Hospital, Kolding (J.S.N.), and Hjørring Hospital, Hjørring (M.K.) — all in Denmark; Karo-linska University Hospital, Huddinge, Stock-holm (J. Wernerman, I.T., K.K., S.O.-W.), Karolinska University Hospital, Solna (A.O.), and Södersjukhuset, Stockholm (M.B.C.) — all in Sweden; Haukeland University Hospital and University of Bergen, Bergen, Norway (A.B.G., B.S.); Tampere Univer-sity Hospital, Tampere (S.K.), and Hel-sinki University Hospital and University of Helsinki, Helsinki (V.P.) — all in Finland; and Liverpool Hospital, Sydney (A.Å.). Address reprint requests to Dr. Perner at the Department of Intensive Care, Rigshos-pitalet, Blegdamsvej 9, DK-2100 Copen-hagen, Denmark, or at [email protected].

* Members of the Transfusion Require-ments in Septic Shock (TRISS) TrialGroup are listed in the SupplementaryAppendix, available at NEJM.org.

This article was published on October 1, 2014, at NEJM.org.DOI: 10.1056/NEJMoa1406617Copyright © 2014 Massachusetts Medical Society.

A BS TR AC T

BACKGROUNDBlood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established.METHODSIn this multicenter, parallel-group trial, we randomly assigned patients in the inten-sive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome mea-sure was death by 90 days after randomization.RESULTSWe analyzed data from 998 of 1005 patients (99.3%) who underwent randomiza-tion. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P = 0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups.CONCLUSIONSAmong patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Stra-tegic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.)

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N Engl J Med. 2014 Oct 9;371(15):1381-‐91

もくじ

•  これまでの流れと背景 •  Introduc1on •  Methods •  Results •  Discussion •  Editorial •  まとめ •  批判的吟味

これまでの流れと背景

•  15年前、カナダの研究グループが『TRICC』というトライアルを発表。 Hb<7g/dlで輸血を開始すべきという基盤を作った。（7g/dl vs 10g/dlで比較）

30日以内の生存率カプラン・マイヤー曲線p=0.10

7g/dl 10g/dl

30日死亡率

18.7％ 23.3％ P=0.10

414

·

Februar y 11, 1999

The New England Journal of Medicine

gan-failure scores of 7 were assigned to all patientswho died within 30 days after admission to the in-tensive care unit, the number of patients with mul-tiorgan failure was substantially increased in bothgroups, and the results were marginally better in therestrictive-strategy group (20.6 percent vs. 26.0 per-cent, P=0.07). Similarly, when all patients who diedwere given a multiple-organ-dysfunction score of24, the total scores (P=0.03) and the changes in thescores from base line (P=0.04) were significantlylower in the restrictive-strategy group (Table 2).

Cardiac events, primarily pulmonary edema andmyocardial infarction, were more frequent in the lib-eral-strategy group than in the restrictive-strategygroup during the stay in the intensive care unit(P<0.01) (Table 3). However, there were no signifi-cant differences in the rates of cardiac events (41 per-cent in the restrictive-strategy group and 44 percentin the liberal-strategy group, P=0.86), infectiouscomplications (3 percent and 4 percent, respectively;P=1.00), or multiorgan failure (37 percent and 32percent, respectively; P=0.59) in the 48 hours pre-ceding death among the patients who died (Table 4).

Subgroup Analyses

When the patients were analyzed according to age(<55 years vs. »55 years) and APACHE II score(«20 vs. >20), there were no significant differencesin base-line characteristics. In the restrictive-strategygroup, 173 patients were younger than 55 years, 207patients had an APACHE II score of 20 or less, 151patients had cardiac disease, 100 had a traumatic in-jury, and 114 had a severe infection or septic shock.In the liberal-strategy group, 161 patients wereyounger than 55 years, 217 had an APACHE IIscore of 20 or less, 175 had cardiac disease, 100 hada traumatic injury, and 104 had a severe infection orseptic shock. All outcomes in the two transfusion-strategy groups were similar for the patients whowere older than 55 years and for those with anAPACHE II score of more than 20 (P>0.36). How-ever, 30-day mortality was significantly lower in therestrictive-strategy group than in the liberal-strategygroup among the patients with an APACHE II scoreof 20 or less (8.7 percent vs. 16.1 percent; 95 per-cent confidence interval for the absolute difference,1.0 to 13.6 percent; P=0.03) and among the pa-tients who were less than 55 years of age (5.7 per-cent vs. 13.0 percent; 95 percent confidence interval,1.1 to 13.5 percent; P=0.02). There were no signif-icant differences in 30-day mortality between treat-ment groups in the subgroup of patients with a pri-mary or secondary diagnosis of cardiac disease (20.5percent in the restrictive-strategy group and 22.9percent in the liberal-strategy group; 95 percentconfidence interval for the difference, ¡6.7 to 11.3percent; P=0.69), in the subgroup of patients withsevere infections and septic shock (22.8 percent and

Figure 2. Kaplan–Meier Estimates of Survival in the 30 Days af-ter Admission to the Intensive Care Unit in the Restrictive-Strat-egy and Liberal-Strategy Groups.Panel A shows the survival curves for all patients in the studygroups. Panel B shows the survival curves in the subgroup ofpatients with an APACHE II score of 20 or less. Panel C showsthe survival curves in the subgroup of patients who wereyounger than 55 years.

50

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The New England Journal of Medicine Downloaded from nejm.org on November 3, 2014. For personal use only. No other uses without permission.


10g/dl

7g/dl

Hébert PC, et al. A mulHcenter, randomized, controlled clinical trial of transfusion requirements in criHcal care. N Engl J Med 1999; 340:409-‐17.

これまでの流れと背景

•  敗血症患者でも、Hbが低下し赤血球輸血が

必要となる場面が多い。しかしHb濃度がいくつになったら輸血を開始

するのが良いか、という「しきい値」は未だに

定められていない。

Introduc1on

•  2012年“Surviving Sepsis Campaign”では、、、

•  としているが、根拠は少なく、臨床医はこれに従わずに輸血を行っていることが多い。

治療を開始し、初の6時間はHt>30％を保つこと。その後はHbが7g/dlを下回らないように輸血を行い、 Hb 7〜9g/dlを目標値とすること。

Introduc1on

•  2014年に発表されたProCESSという論文でも、高いHbを目標として輸血することへ疑問を投げかけている。（2014.5.13勉強会）

Protocol-based Care for Early Septic Shock

n engl j med 370;18 nejm.org may 1, 2014 1691

pendix). Similarly, in a post hoc analysis, there was no evidence of a treatment effect within ranges of values for the APACHE II score, serum lactate level, or time from meeting the criteria for shock to randomization (Table S7 in the Sup-plementary Appendix).

Discussion

In our study, adherence to the two experimental protocols was high, and, as expected, protocol-based care, as compared with usual care, result-ed in increased use of central venous catheteriza-tion, intravenous fluids, vasoactive agents, and blood transfusions. The two protocol-based re-suscitation approaches led to a small but tran-sient improvement in blood pressure by the end of the resuscitation period but a higher require-ment for intensive care and renal-replacement therapy. There were no significant differences in mortality, either overall or in a number of pre-specified and post hoc subgroups.

Our results differ from those of Rivers et al.4; however, our study was not a direct replication of that study, and there are probably several fac-tors that contribute to the differences. Although the two trials used similar inclusion criteria, the enrolled populations differed. The study cohorts were similar with respect to many demographic and clinical characteristics, including the sever-ity of illness (Table S8 in the Supplementary Appendix), but the cohort in the study by Rivers et al. was slightly older, had higher rates of pre-existing heart and liver disease, and had a higher initial serum lactate level. Although we modified the minimum fluid bolus required to establish the presence of refractory hypotension, the mean volume of the bolus that was administered fell within the range used in the study by Rivers et al. (20 to 30 ml per kilogram). The mean initial Scvo2 reported by Rivers et al. was 49%, which was lower than that in the ProCESS trial. How-ever, early central venous catheterization was considered to be part of usual care in that trial, allowing Scvo2 readings to be made before ad-ministration of the initial fluid bolus, the re-sponse to which was required to establish re-fractory hypotension. In contrast, for patients randomly assigned to the protocol-based EGDT group in our study, we measured Scvo2 only after the initial fluid bolus had been administered, making a direct comparison problematic. None-

theless, the cohort in the study by Rivers et al. may have had, on average, more severe or persis-tent shock than the patients in our cohort. How-ever, we were unable to show a benefit even when we restricted the analyses to the sickest third of our patients — those with the highest serum lactate levels and those with the highest APACHE II scores.

Both trials used the same EGDT protocol

Protocol-based EGDT Protocol-based standard therapy

Usual care

90

days

Mor

talit

y (%

)

50

40

30

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00 10 20 30 40 50 60

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B Cumulative Mortality to 1 Yr

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No. at RiskProtocol-based EGDTProtocol-based standard therapyUsual care

439446456

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No. at RiskProtocol-based EGDTProtocol-based standard therapyUsual care

439446456

289308285

217212211

194196199

175179181

156158164

145142139

Figure 2. Cumulative Mortality.

Panel A shows cumulative in-hospital mortality, truncated at 60 days, and Panel B cumulative mortality up to 1 year after randomization.

The New England Journal of Medicine Downloaded from nejm.org on November 3, 2014. For personal use only. No other uses without permission.


Introduc1on

The ProCESS InvesHgators. A randomized trial of protocol-‐based care for early sepHc shock. N Engl J Med 2014;370:1683-‐ 93.

Protocol-‐based EGDT群 vs. protocol-‐based standard therapy群 vs. usual care群で 60日死亡率を比較

ProCESS$RCT$

11$

Figure,S6.,Processes,of,care,during,the,6h,resuscitation,intervention.,

$

Panel$A$–$time$(minutes)$until$a$central$venous$catheter$is$placed.$Panel$B$–$time$(minutes)$until$a$central$venous$catheter$for$oximetric$monitoring$is$placed.$Central$venous$catheterization$defined$as$use$of$oximetric$catheter$or$multiple$serial$ScvO2$measures.$Panel$C$–$$Intravenous$fluid$volume$by$hour$(mean$+$SD).$Panel$D$–$use$of$resuscitation$interventions.$ScvO2$–$central$venous$oxygen$saturation;$PRBC$–$packed$red$blood$cell;$EGDT$–$early$goalHdirected$therapy..$PPvalues$represent$comparisons$across$the$3$arms.$&,

$ ,

ProCESS$RCT$

11$

Figure,S6.,Processes,of,care,during,the,6h,resuscitation,intervention.,

$

Panel$A$–$time$(minutes)$until$a$central$venous$catheter$is$placed.$Panel$B$–$time$(minutes)$until$a$central$venous$catheter$for$oximetric$monitoring$is$placed.$Central$venous$catheterization$defined$as$use$of$oximetric$catheter$or$multiple$serial$ScvO2$measures.$Panel$C$–$$Intravenous$fluid$volume$by$hour$(mean$+$SD).$Panel$D$–$use$of$resuscitation$interventions.$ScvO2$–$central$venous$oxygen$saturation;$PRBC$–$packed$red$blood$cell;$EGDT$–$early$goalHdirected$therapy..$PPvalues$represent$comparisons$across$the$3$arms.$&,

$ ,

輸血

→死亡率に有意な差は認められなかった。

ProCESS



original article

Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock

Lars B. Holst, M.D., Nicolai Haase, M.D., Ph.D., Jørn Wetterslev, M.D., Ph.D., Jan Wernerman, M.D., Ph.D., Anne B. Guttormsen, M.D., Ph.D.,

Sari Karlsson, M.D., Ph.D., Pär I. Johansson, M.D., Ph.D., Anders Åneman, M.D., Ph.D., Marianne L. Vang, M.D., Robert Winding, M.D.,

Lars Nebrich, M.D., Helle L. Nibro, M.D., Ph.D., Bodil S. Rasmussen, M.D., Ph.D., Johnny R.M. Lauridsen, M.D., Jane S. Nielsen, M.D., Anders Oldner, M.D., Ph.D.,

Ville Pettilä, M.D., Ph.D., Maria B. Cronhjort, M.D., Lasse H. Andersen, M.D., Ulf G. Pedersen M.D., Nanna Reiter, M.D., Jørgen Wiis, M.D.,

Jonathan O. White, M.D., Lene Russell, M.D., Klaus J. Thornberg, M.D., Peter B. Hjortrup, M.D., Rasmus G. Müller, M.D., Morten H. Møller, M.D., Ph.D.,

Morten Steensen, M.D., Inga Tjäder, M.D., Ph.D., Kristina Kilsand, R.N., Suzanne Odeberg-Wernerman, M.D., Ph.D., Brit Sjøbø, R.N.,

Helle Bundgaard, M.D., Ph.D., Maria A. Thyø, M.D., David Lodahl, M.D., Rikke Mærkedahl, M.D., Carsten Albeck, M.D., Dorte Illum, M.D., Mary Kruse, M.D.,

Per Winkel, M.D., D.M.Sci., and Anders Perner, M.D., Ph.D., for the TRISS Trial Group* and the Scandinavian Critical Care Trials Group

From the Department of Intensive Care (L.B.H., N.H., L.H.A., U.G.P., N.R., J. Wiis, J.O.W., L.R., K.J.T., P.B.H., R.G.M., M.H.M., M.S., A.P.), Copenhagen Trial Unit, Center for Clinical Intervention Research (J. Wet-terslev, P.W.), and Section for Transfu-sion Medicine (P.I.J.), Rigshospitalet and University of Copenhagen, Copenhagen, Randers Hospital, Randers (M.L.V., H.B., M.A.T.), Herning Hospital, Herning (R.W., D.L., R.M.), Hvidovre Hospital, Hvidovre (L.N., C.A.), Aarhus University Hospital, Aarhus (H.L.N., D.I.), Aalborg University Hospital, Aalborg (B.S.R.), Holbæk Hospi-tal, Holbæk (J.R.M.L.), Kolding Hospital, Kolding (J.S.N.), and Hjørring Hospital, Hjørring (M.K.) — all in Denmark; Karo-linska University Hospital, Huddinge, Stock-holm (J. Wernerman, I.T., K.K., S.O.-W.), Karolinska University Hospital, Solna (A.O.), and Södersjukhuset, Stockholm (M.B.C.) — all in Sweden; Haukeland University Hospital and University of Bergen, Bergen, Norway (A.B.G., B.S.); Tampere Univer-sity Hospital, Tampere (S.K.), and Hel-sinki University Hospital and University of Helsinki, Helsinki (V.P.) — all in Finland; and Liverpool Hospital, Sydney (A.Å.). Address reprint requests to Dr. Perner at the Department of Intensive Care, Rigshos-pitalet, Blegdamsvej 9, DK-2100 Copen-hagen, Denmark, or at [email protected].

* Members of the Transfusion Require-ments in Septic Shock (TRISS) TrialGroup are listed in the SupplementaryAppendix, available at NEJM.org.

This article was published on October 1, 2014, at NEJM.org.DOI: 10.1056/NEJMoa1406617Copyright © 2014 Massachusetts Medical Society.

A BS TR AC T

BACKGROUNDBlood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established.METHODSIn this multicenter, parallel-group trial, we randomly assigned patients in the inten-sive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome mea-sure was death by 90 days after randomization.RESULTSWe analyzed data from 998 of 1005 patients (99.3%) who underwent randomiza-tion. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P = 0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups.CONCLUSIONSAmong patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Stra-tegic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.)



N Engl J Med. 2014 Oct 9;371(15):1381-‐91

Introduc1on

今までの研究では、輸血が死亡率を上昇させるという報告がある。一方で、死亡率を改善させるという研究もある。

今回、敗血症性ショックでICU入室した患者に対し、輸血を低閾値で行う群 vs. 高閾値で行う群で比較を行った。

Methods •  患者：デンマーク、スウェーデン、ノルウェー、フィンランド

の32のICUから集められた。

•  デザイン：他施設並行群間試験

•  期間：2011年12月〜2013年12月

•  ランダム化：コンピュータを使ってランダム化

•  盲検化：部分盲検化

•  対象：18歳以上の敗血症性ショックの診断基準を満たすICU入室患者、Hb<9g/dlの者。

Methods

•  介入：18歳以上の敗血症性ショックの診断基準を満たすICU入室患者に対し、

低閾値群高閾値群

Hb<7g/dlで輸血を行う Hb<9g/dlで輸血を行う

•  Hb濃度は輸血が1単位終わったところ、または新たな輸血が始まるところで測定する。

•  介入はICUにいる間ずっと行う（ただし大90日まで）。 •  致死的な出血や虚血を起こした場合、ECMOを使用しなければいけない場合

には医師の判断で自由に輸血を行える。 •  「ICUでの輸血」以外のすべての介入を、医師の判断で行える。

Methods

Primary endpoint 1．90日以内の死亡率

Secondary endpoint 1．昇圧剤の使用、人工呼吸器の使用、腎代替療法の有無。

＊それぞれ5日目、14日目、28日目に判定

2．重篤な副作用の出現数 3．虚血性イベントの発生数

＊AMI、腸管虚血、脳虚血、肢虚血

4．昇圧剤、人工呼吸器、腎代替療法を行わなかった比率

Methods •  2つの先行研究*から高閾値群の死亡率45％とした。 TRICCの結果に基づき、低閾値群の90日死亡率の方が9%低いと予測し、検出力80%、有意水準5%で計算した。 ⇛1000人の患者が集められた。

*①Carlsen S, Perner A, East Danish Sep1c Shock Cohort Inves1gators. Acta Anaesthesiol Scand 2011;55:394-‐400. 　②Smith SH, Perner A. Higher vs. lower fluid volume for sep1c shock. Crit Care 2012;16:R76.

サンプルサイズ

Methods

•  Primary outcome：ITTで解析。ロジスティック回帰分析で2群の平均を比較。

•  2群の比較にカイ二乗検定、比率・順序に関してウィルコクソン符号順位検定を行った。

（Primary outcomeに関してはPer-‐protocolでも検討してその結果をITTと比較した。）

Results

Hemoglobin Threshold for Tr ansfusion in Septic Shock


solution when the blood concentration of hemo-globin had decreased to the assigned transfusion threshold (≤7 g per deciliter [lower threshold] or ≤9 g per deciliter [higher threshold]). These lev-els of hemoglobin have frequently been used as thresholds for transfusion in patients with septic

shock.15 Hemoglobin concentrations were reas-sessed within 3 hours after termination of the transfusion or before the initiation of another transfusion. The intervention period was the en-tire ICU stay, to a maximum of 90 days after ran-domization.

1005 Underwent randomization

5 Were excluded after randomization1 Underwent randomization in error4 Withdrew consent

1224 Patients were assessed for eligibility

219 Were excluded3 Declined transfusion4 Had previous adverse reaction

to transfusion137 Received blood transfusion in ICU

20 Had acute coronary syndrome16 Had life-threatening bleeding

3 Had acute burn injury17 Withdrew from active therapy34 Were excluded because consent could

not be obtained

503 Were assigned to the lowerhemoglobin threshold

497 Were assigned to the higherhemoglobin threshold

38 Discontinued the study29 Were withdrawn at

patient’s or surrogate’srequest

9 Were withdrawn atphysician’s request

1 Withdrew consent for theuse of data

24 Discontinued the study18 Were withdrawn at

patient’s or surrogate’srequest

6 Were withdrawn atphysician’s request

1 Withdrew consent for theuse of data

502 (99.8%) Were included in all analysesof mortality

488 (97.0%) Were included in all analysesof outcomes

496 (99.8%) Were included in all analysesof mortality

489 (98.4%) Were included in all analysesof outcomes

Figure 1. Assessment, Randomization, and Follow-up.

Patients were excluded if they had undergone randomization in this study previously, if there were medical reasons, if they had received a blood transfusion during the current intensive care unit (ICU) admission, if there was a docu-mented wish not to receive a transfusion, or if informed consent could not be obtained. A total of 15 patients met two exclusion criteria. One patient was excluded immediately after randomization when it was determined that an inclusion criterion had not been met, and 4 were excluded because consent was withdrawn during the trial. Thereafter, 5 additional patients underwent randomization in order for the study to obtain the full sample. All the patients who with-drew from the trial at their own request or at a surrogate’s request allowed the use of their data, but 14 patients or surrogates in the lower-threshold group (hemoglobin level, ≤7 g per deciliter) and 7 in the higher-threshold group (hemoglobin level, ≤9 g per deciliter) did not want further data registered except for mortality data, which were obtained from national registries. The process data (hemoglobin assessments and numbers of transfusions and temporary protocol suspensions and protocol violations) and some of the secondary-outcome data for these patients are missing.



患者振り分け

低閾値群　502人高閾値群　496人

1224人が適合 ↓

219人が除外（輸血拒否、ランダム化の前に輸血）

↓ 1005人がランダム化

↓ 5人が除外（エラー、同意を辞退）

↓ 同様に38人、24人が研究から外れた

終的に 502人 vs. 496人

Results Character Baseline　


n engl j med nejm.org6

tic shock who were in the ICU, we observed no significant differences in mortality at 90 days, in the numbers of patients with ischemic events or with severe adverse reactions, in the use of life support, or in the numbers of days alive and out of the hospital between the group of patients who underwent transfusion at a lower hemoglo-bin threshold and the group of those who under-went transfusion at a higher hemoglobin thresh-old. Similar results were observed in subgroups of patients with chronic cardiovascular disease, with older age, or with greater disease severity. The patients in the lower-threshold group re-

ceived 50% fewer units of blood than those in the higher-threshold group, and 36% of the patients in the lower-threshold group did not undergo transfusion in the ICU, as compared with 1% of the patients in the higher-threshold group.

Our results are consistent with those ob-tained in the TRICC trial, which assessed a lower versus higher hemoglobin threshold for blood transfusion in a broad population of adult patients in the ICU.9 In that trial, there were no significant differences in mortality at 30 days in the full trial population (the primary outcome) or among patients 55 years of age or older or

Table 1. Characteristics of the Trial Patients at Baseline.*

Characteristic

Lower Hemoglobin Threshold (N = 502)

Higher Hemoglobin Threshold(N = 496)

Age — yr

Median 67 67

Interquartile range 57–73 58–75

Male sex — no. (%) 272 (54.2) 259 (52.2)

Chronic cardiovascular disease — no. (%)† 75 (14.9) 66 (13.3)

Chronic lung disease — no. (%)‡ 111 (22.1) 102 (20.6)

Hematologic cancer — no. (%) 39 (7.8) 36 (7.3)

Admission to a university hospital — no. (%) 323 (64.3) 324 (65.3)

Surgery during index hospitalization — no. (%)

Emergency 191 (38.0) 217 (43.8)

Elective 59 (11.8) 53 (10.7)

Source of ICU admittance — no. (%)

Emergency department 90 (17.9) 79 (15.9)

General ward 268 (53.4) 257 (51.8)

Operating or recovery room 113 (22.5) 121 (24.4)

Other ICU 31 (6.2) 39 (7.9)

Source of sepsis — no. (%)§

Lungs 267 (53.2) 259 (52.2)

Abdomen 206 (41.0) 198 (39.9)

Urinary tract 58 (11.6) 61 (12.3)

Soft tissue 59 (11.8) 59 (11.9)

Other 50 (10.0) 47 (9.5)

Positive culture from blood or sterile site 188 (37.5) 160 (32.3)

Interval from ICU admission to randomization — hr

Median 23 20


SAPS II¶

Median 51 52






Table 1. (Continued.)

Characteristic



SOFA score∥

Median 10 10


Renal-replacement therapy — no. (%)** 68 (13.5) 53 (10.7)

Mechanical ventilation — no. (%)†† 345 (68.7) 350 (70.6)

* None of the differences between the two groups were significant (P≥0.05). Additional details regarding baseline char-acteristics are provided in Table S1 in the Supplementary Appendix. The lower hemoglobin threshold was defined as a hemoglobin level of 7 g per deciliter or less, and the higher hemoglobin threshold as a hemoglobin level of 9 g per deciliter or less. ICU denotes intensive care unit.

† Patients were considered to have chronic cardiovascular disease if they had any history of myocardial infarction, sta-ble or unstable angina pectoris, chronic heart failure (defined as New York Heart Association class III or IV), cerebral infarction or transitory cerebral ischemia, previous treatment with nitrates, percutaneous coronary intervention, coro-nary-artery bypass grafting, or noncoronary vascular interventions.

‡ Patients were considered to have chronic lung disease if they had any history of chronic obstructive pulmonary dis-ease, asthma or other chronic lung disease, or any treatment with a drug indicated for chronic lung disease.

§ Some patients had more than one source of infection. Other sources of sepsis included a vascular catheter, meningi-tis, or endocarditis or were unclear.

¶ The Simplified Acute Physiology Score (SAPS) II25 was assessed in the 24 hours before randomization. The SAPS II is calculated from 17 variables and ranges from 0 to 163, with higher scores indicating higher severity of disease. One or two of the 17 variables were missing for 77 patients in the higher-threshold group and for 99 in the lower-threshold group, so their values were not included here.

∥ The Sepsis-Related Organ Failure Assessment (SOFA)26 score was assessed in the 24 hours before randomization. The SOFA grades organ failure, with subscores ranging from 0 to 4 for each of six organ systems (cerebral, circula-tion, pulmonary, hepatic, renal, and coagulation). The aggregated score ranges from 0 to 24, with higher scores indi-cating more severe organ failure. One variable was missing for 51 patients in the higher-threshold group and for 64 in the lower-threshold group, so their values were not included here.

** Renal-replacement therapy was defined as therapy for acute or chronic kidney failure at randomization.†† Mechanical ventilation was defined as invasive or noninvasive ventilation in the 24 hours before randomization.

Bloo

d H

emog

lobi

n (g

/dl)

11

9

10

8

7

6

0Base-line

28272625242322212019181716151413121110987654321

Days since Randomization

Lower hemoglobin threshold

Higher hemoglobin threshold

Figure 2. Blood Hemoglobin Levels in Patients in the ICU at Baseline and after Randomization.

The graphs show the median daily lowest levels of blood hemoglobin in the lower-threshold group and the higher-threshold group. Baseline values were the lowest blood hemoglobin level measured in the 24 hours before random-ization. Day 1 was defined as the time of randomization to the end of that day and lasted a median of 15 hours in the lower-threshold group and 14 hours in the higher-threshold group. The I bars indicate the 25th and 75th percentiles.




n engl j med nejm.org6

tic shock who were in the ICU, we observed no significant differences in mortality at 90 days, in the numbers of patients with ischemic events or with severe adverse reactions, in the use of life support, or in the numbers of days alive and out of the hospital between the group of patients who underwent transfusion at a lower hemoglo-bin threshold and the group of those who under-went transfusion at a higher hemoglobin thresh-old. Similar results were observed in subgroups of patients with chronic cardiovascular disease, with older age, or with greater disease severity. The patients in the lower-threshold group re-

ceived 50% fewer units of blood than those in the higher-threshold group, and 36% of the patients in the lower-threshold group did not undergo transfusion in the ICU, as compared with 1% of the patients in the higher-threshold group.

Our results are consistent with those ob-tained in the TRICC trial, which assessed a lower versus higher hemoglobin threshold for blood transfusion in a broad population of adult patients in the ICU.9 In that trial, there were no significant differences in mortality at 30 days in the full trial population (the primary outcome) or among patients 55 years of age or older or

Table 1. Characteristics of the Trial Patients at Baseline.*

Characteristic



Age — yr

Median 67 67


Male sex — no. (%) 272 (54.2) 259 (52.2)

Chronic cardiovascular disease — no. (%)† 75 (14.9) 66 (13.3)

Chronic lung disease — no. (%)‡ 111 (22.1) 102 (20.6)

Hematologic cancer — no. (%) 39 (7.8) 36 (7.3)

Admission to a university hospital — no. (%) 323 (64.3) 324 (65.3)

Surgery during index hospitalization — no. (%)

Emergency 191 (38.0) 217 (43.8)

Elective 59 (11.8) 53 (10.7)

Source of ICU admittance — no. (%)

Emergency department 90 (17.9) 79 (15.9)

General ward 268 (53.4) 257 (51.8)

Operating or recovery room 113 (22.5) 121 (24.4)

Other ICU 31 (6.2) 39 (7.9)

Source of sepsis — no. (%)§

Lungs 267 (53.2) 259 (52.2)

Abdomen 206 (41.0) 198 (39.9)

Urinary tract 58 (11.6) 61 (12.3)

Soft tissue 59 (11.8) 59 (11.9)

Other 50 (10.0) 47 (9.5)

Positive culture from blood or sterile site 188 (37.5) 160 (32.3)

Interval from ICU admission to randomization — hr

Median 23 20


SAPS II¶

Median 51 52




Baselineは類似

Results



Table 1. (Continued.)

Characteristic



SOFA score∥

Median 10 10


Renal-replacement therapy — no. (%)** 68 (13.5) 53 (10.7)

Mechanical ventilation — no. (%)†† 345 (68.7) 350 (70.6)

* None of the differences between the two groups were significant (P≥0.05). Additional details regarding baseline char-acteristics are provided in Table S1 in the Supplementary Appendix. The lower hemoglobin threshold was defined as a hemoglobin level of 7 g per deciliter or less, and the higher hemoglobin threshold as a hemoglobin level of 9 g per deciliter or less. ICU denotes intensive care unit.

† Patients were considered to have chronic cardiovascular disease if they had any history of myocardial infarction, sta-ble or unstable angina pectoris, chronic heart failure (defined as New York Heart Association class III or IV), cerebral infarction or transitory cerebral ischemia, previous treatment with nitrates, percutaneous coronary intervention, coro-nary-artery bypass grafting, or noncoronary vascular interventions.

‡ Patients were considered to have chronic lung disease if they had any history of chronic obstructive pulmonary dis-ease, asthma or other chronic lung disease, or any treatment with a drug indicated for chronic lung disease.

§ Some patients had more than one source of infection. Other sources of sepsis included a vascular catheter, meningi-tis, or endocarditis or were unclear.

¶ The Simplified Acute Physiology Score (SAPS) II25 was assessed in the 24 hours before randomization. The SAPS II is calculated from 17 variables and ranges from 0 to 163, with higher scores indicating higher severity of disease. One or two of the 17 variables were missing for 77 patients in the higher-threshold group and for 99 in the lower-threshold group, so their values were not included here.

∥ The Sepsis-Related Organ Failure Assessment (SOFA)26 score was assessed in the 24 hours before randomization. The SOFA grades organ failure, with subscores ranging from 0 to 4 for each of six organ systems (cerebral, circula-tion, pulmonary, hepatic, renal, and coagulation). The aggregated score ranges from 0 to 24, with higher scores indi-cating more severe organ failure. One variable was missing for 51 patients in the higher-threshold group and for 64 in the lower-threshold group, so their values were not included here.

** Renal-replacement therapy was defined as therapy for acute or chronic kidney failure at randomization.†† Mechanical ventilation was defined as invasive or noninvasive ventilation in the 24 hours before randomization.

Bloo

d H

emog

lobi

n (g

/dl)

11

9

10

8

7

6

0Base-line

28272625242322212019181716151413121110987654321




Figure 2. Blood Hemoglobin Levels in Patients in the ICU at Baseline and after Randomization.

The graphs show the median daily lowest levels of blood hemoglobin in the lower-threshold group and the higher-threshold group. Baseline values were the lowest blood hemoglobin level measured in the 24 hours before random-ization. Day 1 was defined as the time of randomization to the end of that day and lasted a median of 15 hours in the lower-threshold group and 14 hours in the higher-threshold group. The I bars indicate the 25th and 75th percentiles.



•  ベースラインの低Hb値の平均は、両群ともに8.4g/dl。 •  ランダム化後の低Hb値は下図のようになった。

ベースライン 8.4g/dl

低閾値群

高閾値群

Results

低閾値群高閾値群 p

総赤血球輸血回数 1545回 3088回 <0.001 平均赤血球輸血単位数 1単位 4単位 <0.001

輸血を受けなかった患者数 176人（36.1%） 6人(1.2%) <0.001 出血の合併 147人（30％） 148人（30％）

FFP 113人（23％） 127人（26％）

PC 79人（16％） 96人（20％）

Albumin 306人（63％） 303人（62％）

HES製剤 16人（3％） 15人（3％）

輸血回数、出血の合併、輸血の種類など

Results •  Primary outcome：90日後の死亡率

低閾値群高閾値群相対危険度（95％CI）

p値

90日後死亡率

43.0％（216人）

45.0％（223人）

0.94 （0.78-‐1.09）

0.44

Results Hemoglobin Threshold for Tr ansfusion in Septic Shock


B Relative Risk of the Primary Outcome

A Time to Death

Prob

abili

ty o

f Sur

viva

l

1.0

0.8

0.6

0.4

0.2

0.00 10 30 50 7020 40 60 80 90


P=0.41

No. at RiskLower hemoglobin thresholdHigher hemoglobin threshold

502496

334321

306287

286273



0.7 1.0 2.01.5

HigherHemoglobinThreshold

Better

LowerHemoglobinThreshold

Better

Age>70 yr≤70 yr

Chronic cardiovasculardisease

YesNo

SAPS II at baseline>53≤53

All patients


HigherHemoglobinThreshold Relative Risk (95% CI)Subgroup

0.98 (0.79–1.18)

0.94 (0.78–1.09)1.10 (0.91–1.30)0.83 (0.64–1.04)

0.90 (0.75–1.06)1.08 (0.75–1.40)

0.5

0.94 (0.75–1.14)

P Valuefor Hetero-

geneity

93/173123/329

42/75174/427

112/207104/295216/502

98/185125/311

33/66190/430

139/226 84/270223/496

0.85

0.25

0.06

no. of events/no. of patients in subgroup

Figure 3. Time to Death and Relative Risk of Death at 90 Days.Panel A shows the survival curves, with data censored at 90 days, in the two intervention groups in the intention-to-treat population. Kaplan–Meier analysis showed that the survival time did not differ significantly between the two groups (P = 0.41 by Cox regression analysis, with adjustment for the stratification variables). Panel B shows the relative risks (black boxes) with 95% confidence intervals (horizontal lines) for the primary outcome measure of death by day 90 in the lower-threshold group, as compared with the higher-threshold group, among all the patients and in the three pre-specified subgroups, as assessed by means of logistic-regression analysis, with adjustment for the stratification vari-ables. The size of each black box is proportional to the size of the corresponding subgroup. Chronic cardiovascular disease was defined as any history of myocardial infarction, any history of stable or unstable angina pectoris, previous treatment with nitrates, percutaneous coronary intervention, coronary-artery bypass grafting or noncoronary vascular interventions, any history of chronic heart failure (defined as New York Heart Association class III or IV), or any history of cerebral infarction or transitory cerebral ischemia. The Simplified Acute Physiology Score (SAPS) II25 is calculated from 17 baseline variables; scores range from 0 to 163, with higher scores indicating higher severity of disease. A total of 1 or 2 of the 17 variables were missing for 77 patients in the higher-threshold group and for 99 in the lower-threshold group. In this analysis, these missing variables were considered to be within the normal range, thereby not contributing to the composite SAPS II of these patients.



90日以内の生存曲線（カプラン・マイヤー曲線）。両群で生存率に大きな差はない。P=0.41

　　低閾値群

　　高閾値群

Primary outcome

Results



B Relative Risk of the Primary Outcome

A Time to Death

Prob

abili

ty o

f Sur

viva

l

1.0

0.8

0.6

0.4

0.2

0.00 10 30 50 7020 40 60 80 90


P=0.41

No. at RiskLower hemoglobin thresholdHigher hemoglobin threshold

502496

334321

306287

286273



0.7 1.0 2.01.5

HigherHemoglobinThreshold

Better


Better

Age>70 yr≤70 yr

Chronic cardiovasculardisease

YesNo

SAPS II at baseline>53≤53

All patients


HigherHemoglobinThreshold Relative Risk (95% CI)Subgroup

0.98 (0.79–1.18)

0.94 (0.78–1.09)1.10 (0.91–1.30)0.83 (0.64–1.04)

0.90 (0.75–1.06)1.08 (0.75–1.40)

0.5

0.94 (0.75–1.14)

P Valuefor Hetero-

geneity

93/173123/329

42/75174/427

112/207104/295216/502

98/185125/311

33/66190/430

139/226 84/270223/496

0.85

0.25

0.06

no. of events/no. of patients in subgroup

Figure 3. Time to Death and Relative Risk of Death at 90 Days.Panel A shows the survival curves, with data censored at 90 days, in the two intervention groups in the intention-to-treat population. Kaplan–Meier analysis showed that the survival time did not differ significantly between the two groups (P = 0.41 by Cox regression analysis, with adjustment for the stratification variables). Panel B shows the relative risks (black boxes) with 95% confidence intervals (horizontal lines) for the primary outcome measure of death by day 90 in the lower-threshold group, as compared with the higher-threshold group, among all the patients and in the three pre-specified subgroups, as assessed by means of logistic-regression analysis, with adjustment for the stratification vari-ables. The size of each black box is proportional to the size of the corresponding subgroup. Chronic cardiovascular disease was defined as any history of myocardial infarction, any history of stable or unstable angina pectoris, previous treatment with nitrates, percutaneous coronary intervention, coronary-artery bypass grafting or noncoronary vascular interventions, any history of chronic heart failure (defined as New York Heart Association class III or IV), or any history of cerebral infarction or transitory cerebral ischemia. The Simplified Acute Physiology Score (SAPS) II25 is calculated from 17 baseline variables; scores range from 0 to 163, with higher scores indicating higher severity of disease. A total of 1 or 2 of the 17 variables were missing for 77 patients in the higher-threshold group and for 99 in the lower-threshold group. In this analysis, these missing variables were considered to be within the normal range, thereby not contributing to the composite SAPS II of these patients.



•  Sub-‐group解析 –  年齢、慢性心疾患の有無、SAPS IIでSub-‐group解析を行ってみたが、

明らかな有意差は見いだせなかった。

年齢

慢性心疾患

SAPS II　ベースライン

7g/dlの方がベター

9g/dlの方がベター

Results

低閾値群高閾値群相対危険度（95％CI）

P値

生命維持の使用

5日目 278/432(64.4) 267/429(62.2) 1.04 (0.93-‐1.14)

0.47

14日目 140/380(36.8) 135/367(36.8) 0.99 (0.81-‐1.19)

0.95

28日目 53/330(16.1) 64/332(19.9) 0.77 (0.54-‐1.09)

0.14

ICUにおける虚血性イベントの発生

35/488(7.2) 39/489(8.0) 0.90 (0.58-‐1.39)

0.64

重篤な副作用 0/488 1/489（0.2） 1.00 昇圧剤なしの平均期間 73 75 0.93

人工呼吸器なしの平均期間 65 67 0.49 腎代替療法なしの平均期間 85 83 0.54

Secondary outcome

*重篤な副作用：溶血反応

Discussion

•  輸血開始の低閾値群、高閾値群で90日死亡率に有意差は見られなかった。

•  輸血は低閾値群では50％少なくすんだ。また輸血を全く受けずにすんだ患者も低閾値群で多い。（36%対1%）

•  これは1999年TRICCトライアルで得られた結果（低 vs. 高閾値群で30日死亡率に有意差なし）を支持する内容である。

Discussion

今回の研究の強み →バイアスの可能性が低いこと。 •  ランダム化が隠されている、統計学者（筆者）は

盲検化されている。 •  患者が大学病院、市中病院いずれからも集めら

れており、患者の偏りが少ない。 •  プロトコールが実践的である。 •  患者のベースラインが、これまでの研究と類似し

ている。

Discussion

今回の研究のLimita1onは、

•  調査員、臨床医、患者はいずれも、どちらのグループに属しているか盲検化されていない。

•  虚血イベントの発生などのサブグループ解析を行うには、検出力が不十分である。

•  心筋虚血の有無を調査しておらず、見逃した可能性がある。

•  プロトコールに反してしまった症例がいくつかある（輸血のトライアルではこれらをなくすのは困難）

Editorial

•  2012年に著者らも輸血の閾値について、19のRCTを集め、6264人の患者を調査した。今回の結果と同様、低い閾値で輸血を開始しても明らかな有害事象は認められなかった。

•  敗血症性ショックを含む1341人の患者を調査した “ProCESSトライアル”や、1600人の患者を調査した “ARISEトライアル”では、通常の輸血とEGDTでの輸血を比較している。 2つの研究ではEGDT群で2倍の輸血が必要であったにも関わらず、90日死亡率に差はなかった。

Carson Jl et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell trans-‐ fusion. Cochrane Database Syst Rev 2012;4

The ProCESS InvesHgators. A randomized trial of protocol-‐based sepHc shock. N Engl J Med 2014;370:1683-‐ 93. The ARISE InvesHgators. Goal-‐directed resuscitaHon for paHents with early sepHc shock.N Engl J Med.

Editorial •  重症敗血症を含む、全ての重症患者に対する輸血の開始基準は今後

“Hb<7g/dl”でほぼ間違いないと考えられる。

•  新しい知見が増えてきたので、敗血症に対する種々のガイドラインも早急にアップデートする必要があるのでは。

•  “Surviving Sepsis Campaign 2012”でもHb<7g/dlでの輸血開始を推奨。ただし「組織灌流が改善し、心筋虚血や重篤な低酸素血症、急性出血、虚血性心疾患などの特殊な状況でなければ、、、」という前置きがつくために、臨床医は結果的に多めの輸血を行ってしまうことが報告されている。

•  開始基準Hb<7g/dlを標準化するために、この余計な前置きをなくしてしまうのはどうであろうか。

•  ただし急性冠症候群の患者に対する輸血開始のエビデンスはまだ十分ではないため、高めの閾値（例えば9g/dl-‐10g/dl）で輸血を開始する方が良いかもしれない。

まとめ

敗血症性ショックの患者において、輸血の開始基準をHb<7g/dl（低閾値）とHb<9g/dl（高閾値）で比較すると、、、

•  Hb<7g/dlで開始する方が輸血量は少なくてすむ。 •  両群で90日死亡率、生命維持の使用、生存率に

有意差はない。 •  両群で虚血性イベントの発生、輸血の重篤な合

併症についても、その数に有意差はない。

批判的吟味

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敗血症性ショックの患者に7g/dlと9g/dlを基準に輸血を行うと、90日死亡率に差はあるか。

32のICUから集められた、他施設群間比較試験。輸血以外の介入は自由に行なえ、実践的な研究デザイン。

批判的吟味

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コンピュータによるランダム割付。

患者、臨床医、調査員は盲検化されていない。統計学者は盲検化されている。

批判的吟味

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Page 3 2003/07/21

1000人中5人の脱落者。ITTで分析が行われた。Per-‐protocolでも解析し、その結果をITTのものと比較した。

輸血以外の治療に関しては、臨床の判断に任せられた。

先行研究からサンプルサイズを計算。今回の研究の死亡率と先行研究に大きなズレはなかった。ただし、死亡率やや高すぎるか。

批判的吟味

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Page 3 2003/07/21

患者数(%) 生存曲線の比較

敗血症性ショックの患者に対する輸血の基準は、7g/dlでも9g/dl でも90日死亡率に差はない。

RR(95％CI）：0.94 (0.78-‐1.09), p=0.44 結果は正確と言えそうである。

批判的吟味

Page 4 2003/07/21

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当施設より術後患者が少ない点は異なるが、その他大きな差異はない。

90日死亡率、院外死亡率、生命維持の使用について検討されていた。

今までの研究結果とも矛盾しない結果であり、実臨床に適応できると考える。

lower versus higher hemoglobin threshold for transfusion ... · among patients with septic shock,...

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