特別講演

敗血症治療における当院の早期治療介入の意義~当院のrTMの治療効果を含め~
中山晴雄1, 2, 3)1) 東邦大学医療センター大橋病院 脳神経外科 2) 東邦大学医療センター大橋病院 院内感染対策室
3) 東邦大学医療センター大橋病院 教育支援管理部

第7回東京East救急医療研究会
2020. 11. 25 @ webinar, Japan

第7回東京East救急医療研究会

COI開示
筆頭演者氏名： 中山晴雄

演題発表に関連し開示すべきCOI関係にある企業などはありません．

注意事項
本講演内において紹介する「ART-123（リコンビナント・トロンボモジュ
リン︓rTM）」の海外臨床試験データ*は、「敗⾎症患者」を対象としており、本邦で承認されている効能・効果「汎発性⾎管内⾎液凝固症（DIC）」とは異なります。
⼀⽅で「⽇本版敗⾎症性ガイドライン2020 CQ15-5」における敗⾎症性DICに対するrTM投与検討時のエビデンスとして採⽤されています。
本講演内におけるrTM海外臨床試験データは、rTMが敗⾎症性DICに対して使⽤されることを⽬的として紹介するものであり、適応外使⽤を推奨する
ものではありません。
* ART-123海外第Ⅱ相臨床試験︓後期第Ⅱ相試験
Vincent JL,et al Crit Care Med 2013 Sep;41(9):2069-79* ART-123海外第Ⅲ相臨床試験︓SCARLET試験
Vincent JL,et al JAMA.2019 May 28;321(20):1993-2002

36.4% 28日 死亡率37.6%
院内 死亡率ICU 死亡率
日本集中治療医学会第1回Sepsis Registry 調査
松田直之ほか. 日集中医誌 2013; 20: 329-334.

30.8%

Sepsis is an emergency
1. 早期の感染対策
2. 適切な循環管理敗血症診療ガイドラインの流れ
SSCG2016
Special Article

SSCG2012

Surviving Sepsis Campaign: International
Guidelines for Management of Sepsis and Septic
Shock: 2016
Andrew Rhodes, MB BS, MD(Res) (Co-chair)1; Laura E. Evans, MD, MSc, FCCM (Co-chair)2;Waleed Alhazzani, MD, MSc, FRCPC (methodology chair)3; Mitchell M. Levy, MD, MCCM4;
Massimo Antonelli, MD5; Ricard Ferrer, MD, PhD6; Anand Kumar, MD, FCCM7;
Jonathan E. Sevransky, MD, FCCM8; Charles L. Sprung, MD, JD, MCCM9; Mark E. Nunnally, MD, FCCM2;
Bram Rochwerg, MD, MSc (Epi)3; Gordon D. Rubenfeld, MD (conflict of interest chair)10;
Derek C. Angus, MD, MPH, MCCM11; Djillali Annane, MD12; Richard J. Beale, MD, MB BS13;
Geoffrey J. Bellinghan, MRCP14; Gordon R. Bernard, MD15; Jean-Daniel Chiche, MD16;
Craig Coopersmith, MD, FACS, FCCM8; Daniel P. De Backer, MD, PhD17; Craig J. French, MB BS18;
Seitaro Fujishima, MD19; Herwig Gerlach, MBA, MD, PhD20; Jorge Luis Hidalgo, MD, MACP, MCCM21;
Steven M. Hollenberg, MD, FCCM22; Alan E. Jones, MD23; Dilip R. Karnad, MD, FACP24;
Ruth M. Kleinpell, PhD, RN-CS, FCCM25; Younsuck Koh, MD, PhD, FCCM26; Thiago Costa Lisboa, MD27;
Flavia R. Machado, MD, PhD28; John J. Marini, MD29; John C. Marshall, MD, FRCSC30;John E. Mazuski, MD, PhD, FCCM31; Lauralyn A. McIntyre, MD, MSc, FRCPC32;
Anthony S. McLean, MB ChB, MD, FRACP, FJFICM33; Sangeeta Mehta, MD34; Rui P. Moreno, MD, PhD35;
John Myburgh, MB ChB, MD, PhD, FANZCA, FCICM, FAICD36; Paolo Navalesi, MD37;
Osamu Nishida, MD, PhD38; Tiffany M. Osborn, MD, MPH, FCCM31; Anders Perner, MD39;
Colleen M. Plunkett25; Marco Ranieri, MD40; Christa A. Schorr, MSN, RN, FCCM22;
Maureen A. Seckel, CCRN, CNS, MSN, FCCM41; Christopher W. Seymour, MD42; Lisa Shieh, MD, PhD43;
Khalid A. Shukri, MD44; Steven Q. Simpson, MD45; Mervyn Singer, MD46; B. Taylor Thompson, MD47;
Sean R. Townsend, MD48; Thomas Van der Poll, MD49; Jean-Louis Vincent, MD, PhD, FCCM50;
W. Joost Wiersinga, MD, PhD51, Janice L. Zimmerman, MD, MACP, MCCM52;
R. Phillip Dellinger, MD, MCCM22*See also p. 553.
St. George’s Hospital London, England, United Kingdom.
2
New York University School of Medicine New York, NY.
3
McMaster University Hamilton, Ontario, Canada.
4
Brown University School of Medicine Providence, RI.
5
Instituto di Anestesiologia e Rianimazione, Università Cattolica del Sacro
Cuore, Rome, Italy.
6
Vall d’Hebron University Hospital Barcelona, Spain.
7
University of Manitoba Winnipeg, Manitoba, Canada.
1

Copyright © 2017 by the Society of Critical Care Medicine and theEuropean Society of Intensive Care Medicine
DOI: 10.1097/CCM.0000000000002255

486

www.ccmjournal.org

2008

Emory University Hospital Atlanta, GA.

8
9

2012

SSCG2008

Hadassah Hebrew University Medical Center Jerusalem, Israel.

Sunnybrook Health Sciences Centre Toronto, Ontario, Canada.

10

University of Pittsburgh Critical Care Medicine CRISMA Laboratory
Pittsburgh, PA.

11

Hospital Raymond Poincare Garches, France.

12Saint Thomas Hospital London, England, United Kingdom.

13

University College London Hospitals London, England, United Kingdom.

14

Vanderbilt University Medical Center Nashville, TN.

15

Service de Reanimation Medicale Paris, France.

16

CHIREC Hospitals Braine L’Alleud, Belgium.

17

2016

日本版敗血症診療GL

Western Hospital Victoria, Australia.

18

March 2017 • Volume 45 • Number 3

Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

2007
日本版敗血症診療2006

SSCG2004

The Japanese Guidelines for the Management of Sepsis

日本集中治療医学会 Sepsis Registry 委員会

日本集中治療医学会
Sepsis Registry 委員会
2004

SSCG; Surviving Sepsis Campaign Guidelines

敗血症の新定義

感染に対する宿主生体反応の調整不全で、生命を脅かす臓器障害•感染症に起因する全身症状を伴った症候; 2001
•感染による全身性炎症反応症候群（SIRS）; 1991

敗血症の新定義と診断基準

感染に対する宿主生体反応の調整不全で、生命を脅かす臓器障害•感染症が疑われ、SOFAスコアが2点以上増加したもの

敗血症性ショックの新定義と診断基準

敗血症の部分集合であり、実質的に死亡率を上昇させる重度の循環・細胞・代謝の異常を呈するもの• 十分な輸液負荷にもかかわらず、平均動脈圧65mmHg 以上を維持するために血管作動薬を必要とし、かつ血清乳酸値が2 mmol/Lを超えるもの

敗血症の新定義

臓器障害

感染

SIRS

qSOFAスコア

呼吸回数 22回/分 以上
精神状態の変化
収縮期血圧 100 mmHg 以下

https://s3-ap-northeast-1.amazonaws.com/s3-kangoroo.com/upload/images/saito/nikkei/0509-zu2.png

英国早期警告スコア（National Early Warning Score：NEWS）

http://www.covidien.co.jp/medtronic_rms/vol_93?article=01

英国早期警告スコア（National Early Warning Score：NEWS）

http://www.covidien.co.jp/medtronic_rms/vol_93?article=01

英国早期警告スコア（National Early Warning Score：NEWS）

Powerful sign & tool

http://www.covidien.co.jp/medtronic_rms/vol_93?article=01

英国早期警告スコア（National Early Warning Score：NEWS）

SPO2 ≠ 呼吸の観察

http://www.covidien.co.jp/medtronic_rms/vol_93?article=01

英国早期警告スコア（National Early Warning Score：NEWS）

SPO2 = 酸素化の指標

http://www.covidien.co.jp/medtronic_rms/vol_93?article=01

英国早期警告スコア（National Early Warning Score：NEWS）

呼吸数 ≠ 呼吸の観察

http://www.covidien.co.jp/medtronic_rms/vol_93?article=01

英国早期警告スコア（National Early Warning Score：NEWS）

呼吸数 = 全身状態の指標

http://www.covidien.co.jp/medtronic_rms/vol_93?article=01

英国早期警告スコア(NEWS)への対応

低リスク: 周囲に報告・相談, 観察強化
高度リスク: ICUへ移動
http://www.covidien.co.jp/medtronic_rms/vol_93?article=01

Sepsis is an emergency
1. 早期の感染対策
2. 適切な循環管理初期蘇生開始の判断
委員会報告

日集中医誌 2013;20:124-73.

日本版敗血症診療ガイドライン

The Japanese Guidelines for the Management of Sepsis
日本集中治療医学会 Sepsis Registry 委員会†
要約：本ガイドラインは，2007 年 3 月に発足した日本集中治療医学会 Sepsis Registry 委員会
が作成した敗血症診療ガイドラインである。本ガイドラインは，欧米で作成された Surviving
Sepsis Campaign guidelines（SSCG）で取り上げられていないわが国独自の治療法や，日本と欧米で見解の相違のある治療法を主に取り上げ，原則としてエビデンスに基づいて作成された。その作成方法は SSCG2008 に準じているが，わが国独自の治療法に関しては日本語文献も参考にするとともに，同委員会が日本集中治療医学会認定施設を対象に行った 2 回の Sepsis
Registry 調査の結果を参考にした。本ガイドラインはわが国初の敗血症に関する独自のガイ
ドラインであり，臨床現場で適切に活用されることが期待される。

血圧低下にこだわらず, 代謝性アシドーシ
目
Ⅰ．はじめにⅡ．方法
Ⅲ．診断と感染症に対する治療
1. 敗血症の定義と診断
2. 感染症の診断
3. 抗菌薬治療

次4. 画像診断
Ⅳ．全身管理と補助療法
5. 初期蘇生と循環作動薬
6. 人工呼吸管理
7. 血糖コントロール
8. 栄養管理

9. ステロイド
10. DIC 対策
11. 急性血液浄化療法
12. 免疫グロブリン
13. タンパク分解酵素阻害薬
Ⅴ．おわりにスの進行, 血中乳酸値の上昇を認めた場合
委員長： 織田 成人（千葉大学大学院医学研究院救急集中治療医学）
委 員： 相引 眞幸（愛媛大学大学院医学系研究科救急侵襲制御医学）
池田 寿昭（東京医科大学八王子医療センター特定集中治療部）
今泉均（札幌医科大学医学部救急・集中治療医学講座）
遠藤 重厚（岩手医科大学医学部救急医学）落合 亮一（東邦大学医学部麻酔科学第一講座）
小谷 穣治（兵庫医科大学救急・災害医学講座）
志馬 伸朗（京都府立医科大学附属病院集中治療部）
西田修（藤田保健衛生大学医学部麻酔・侵襲制御医学）
野口 隆之（大分大学医学部麻酔科学教室）
松田 直之（名古屋大学大学院医学系研究科救急・集中治療
医学分野）
アドバイザー：
平澤 博之（千葉大学名誉教授）
ガイドライン作成ワーキンググループメンバー
秋富 慎司（岩手医科大学医学部救急医学）
安宅 一晃（大阪市立総合医療センター集中治療部）
井上 茂亮（東海大学医学部外科学系救命救急医学）
氏家 良人（岡山大学大学院医歯薬学総合研究科救急医学）
江木 盛時（岡山大学病院集中治療部）
垣花 泰之（鹿児島大学大学院医歯学総合研究科救急・集中治療医学分野）後藤 孝治（大分大学医学部麻酔科学講座・集中治療部）
坂本 照夫（久留米大学医学部救急医学）佐々木淳一（慶応義塾大学医学部救急医学）
貞広 智仁（千葉大学大学院医学研究院救急集中治療医学）佐藤 挌夫（京都大学医学部初期診療・救急医学）

ガイドライン発行日 2012 年 11 月 6 日
受付日 2012 年 11 月 12 日
採択日 2012 年 11 月 12 日

柴田 純平（藤田保健衛生大学医学部麻酔・侵襲制御医学）
鈴木泰（岩手医科大学医学部救急医学）巽博臣（札幌医科大学医学部救急・集中治療医学講座）
中永士師明（秋田大学医学部救急医学）中村 智之（藤田保健衛生大学医学部麻酔・侵襲制御医学）
仲村 将高（千葉大学大学院医学研究院救急集中治療医学）
布宮伸（自治医科大学大学院医学研究科集中治療医学）
長谷川隆一（公立陶生病院救急部）
林淑朗（Royal Brisbane and Women’s Hospital,
Department of Intensive Care Medicine
The University of Queensland, UQ Centre
for Clinical Research）
藤島清太郎（慶應義塾大学医学部救急医学）
升田 好樹（札幌医科大学医学部救急・集中治療医学講座）
松田 兼一（山梨大学医学部救急集中治療医学）
真弓 俊彦（一宮市立市民病院救命救急センター）
山直也（札幌医科大学放射線医学講座）に, 初期蘇生を 開始する(1A)†著者連絡先：一般社団法人日本集中治療医学会（〒 113-0033 東京都文京区本郷 3-32-6 ハイヴ本郷 3F）− 124 −CNS Drugs Volume 27, Issue 9, September 2013

Gu et al. Critical Care 2014, 18:570
http://ccforum.com/content/18/5/570

RESEARCH

初期蘇生開始の判断

Open Access

The effect of goal-directed therapy on mortality
in patients with sepsis - earlier is better:a meta-analysis of randomized controlled trials
Wan-Jie Gu1, Fei Wang2, Jan Bakker3, Lu Tang2 and Jing-Chen Liu1*
Abstract
Introduction: The Surviving Sepsis Campaign guidelines recommend goal-directed therapy (GDT) for the early
resuscitation of patients with sepsis. However, the findings of the ProCESS (Protocolized Care for Early Septic Shock) trial
showed no benefit from GDT for reducing mortality rates in early septic shock. We performed a meta-analysis tointegrate these findings with existing literature on this topic and evaluate the effect of GDT on mortality due to sepsis.
Methods: We searched the PubMed, Embase and CENTRAL (Cochrane Central Register of Controlled Trials) databases
and reference lists of extracted articles. Randomized controlled trials comparing GDT with standard therapy or usual
care in patients with sepsis were included. The prespecified primary outcome was overall mortality.
Results: In total, 13 trials involving 2,525 adult patients were included. GDT significantly reduced overall mortality in the
random-effects model (relative risk (RR), 0.83; 95% confidence interval (CI), 0.71 to 0.96; P =0.01; I2 = 56%). Predefined
subgroup analysis according to the timing of GDT for resuscitation suggested that a mortality benefit was seen only inthe subgroup of early GDT within the first 6 hours (seven trials; RR, 0.77; 95% CI, 0.67 to 0.89; P =0.0004; I2 = 40%), but
not in the subgroup with late or unclear timing of GDT (six trials; RR, 0.92; 95% CI, 0.69 to 1.24; P =0.59; I2 = 56%). GDT
was significantly associated with the use of dobutamine (five trials; RR, 2.71; 95% CI, 1.20 to 6.10; P =0.02).
Conclusions: The results of the present meta-analysis suggest that GDT significantly reduces overall mortality inpatients with sepsis, especially when initiated early. However, owing to the variable quality of the studies, strong anddefinitive recommendations cannot be made.

Introduction

initiation of the therapeutic measures, together with

Cite this article as: Sepsis
Gu etisal.:
The effectoftogoal-directedmortalityin patientstargets.
with sepsis(hemodynamic)
The Surviving
Sepsisa systemic
response
infection, which therapy
may pro- onspecificgress to severe sepsis and septic shock [1]. Severe sepsis Campaign guidelines recommend GDT for the early reearlier is better: a meta-analysisof randomized
controlled
trials.
Critical9,Care2014 18:570.
CNS Drugs
Volume27, Issue
September2013
and septic shock represent global problems with a higheconomic burden. In the United States, more thansuscitation of patients with sepsis [1], which is basedlargely upon the results of the Rivers et al. trial, in whichGu et al. Critical Care 2014, 18:570
http://ccforum.com/content/18/5/570

RESEARCH

初期蘇生開始の判断

Open Access

The effect of goal-directed therapy on mortality
in patients with sepsis - earlier is better:a meta-analysis of randomized controlled trials
Wan-Jie Gu1, Fei Wang2, Jan Bakker3, Lu Tang2 and Jing-Chen Liu1*
Abstract

目標達成だけでは予後の改善はなく,Introduction: The Surviving Sepsis Campaign guidelines recommend goal-directed therapy (GDT) for the early
resuscitation of patients with sepsis. However, the findings of the ProCESS (Protocolized Care for Early Septic Shock) trial
showed no benefit from GDT for reducing mortality rates in early septic shock. We performed a meta-analysis tointegrate these findings with existing literature on this topic and evaluate the effect of GDT on mortality due to sepsis.

早期(6時間以内)に達成した場合にのみ
Methods: We searched the PubMed, Embase and CENTRAL (Cochrane Central Register of Controlled Trials) databases
and reference lists of extracted articles. Randomized controlled trials comparing GDT with standard therapy or usual
care in patients with sepsis were included. The prespecified primary outcome was overall mortality.

Results: In total, 13 trials involving 2,525 adult patients were included. GDT significantly reduced overall mortality in the
random-effects model (relative risk (RR), 0.83; 95% confidence interval (CI), 0.71 to 0.96; P =0.01; I2 = 56%). Predefined
subgroup analysis according to the timing of GDT for resuscitation suggested that a mortality benefit was seen only inthe subgroup of early GDT within the first 6 hours (seven trials; RR, 0.77; 95% CI, 0.67 to 0.89; P =0.0004; I2 = 40%), but
not in the subgroup with late or unclear timing of GDT (six trials; RR, 0.92; 95% CI, 0.69 to 1.24; P =0.59; I2 = 56%). GDT
was significantly associated with the use of dobutamine (five trials; RR, 2.71; 95% CI, 1.20 to 6.10; P =0.02).

死亡率を低下させる

Conclusions: The results of the present meta-analysis suggest that GDT significantly reduces overall mortality inpatients with sepsis, especially when initiated early. However, owing to the variable quality of the studies, strong anddefinitive recommendations cannot be made.

Introduction

initiation of the therapeutic measures, together with

Cite this article as: Sepsis
Gu etisal.:
The effectoftogoal-directedmortalityin patientstargets.
with sepsis(hemodynamic)
The Surviving
Sepsisa systemic
response
infection, which therapy
may pro- onspecificgress to severe sepsis and septic shock [1]. Severe sepsis Campaign guidelines recommend GDT for the early reearlier is better: a meta-analysisof randomized
controlled
trials.
Critical9,Care2014 18:570.
CNS Drugs
Volume27, Issue
September2013
and septic shock represent global problems with a higheconomic burden. In the United States, more thansuscitation of patients with sepsis [1], which is basedlargely upon the results of the Rivers et al. trial, in which

Early Goal-Directed Therapy（EGDT）

CNS Drugs Volume 27, Issue 9, September 2013

ProCESS, ARISE, ProMISe の比較
31施設

全体
895 例
EGDT群 439 例
ST群
456 例

51施設

1,600例
796例
804例
N Engl J Med. 2014 May 1;370(18):1683-93,
N Engl J Med. 2014 Oct 16;371(16):1496-506,
N Engl J Med. 2015 Apr 2;372(14):1301-11.

56施設

1,260例
630例
630例

初期蘇生開始の判断

常にスピード感を持って初期蘇生・循環作動薬を使いこなすことが重要.
血管内容量減少を評価した後に細胞外補充液を30mL/kg以上投与する.
日本救急医学会雑誌 28巻S1
S1-S232(2017.02)
CNS Page
Drugs Volume27, Issue 9, September 2013

Early Goal-Directed Therapy（EGDT）

EGDTから
Early Lactate-Guided Therapyへ
目標達成を来院後6時間以内に目指す

CNS Drugs Volume 27, Issue 9, September 2013

Early Lactate-Guided Therapy
Early Lactate-Guided Therapy in Intensive Care
Unit Patients
A Multicenter, Open-Label, Randomized Controlled Trial
Tim C. Jansen1, Jasper van Bommel1, F. Jeanette Schoonderbeek3, Steven J. Sleeswijk Visser4,
Johan M. van der Klooster5, Alex P. Lima1, Sten P. Willemsen2, and Jan Bakker1, for the LACTATE study group*1
Department of Intensive Care, Erasmus MC University Medical Centre, Rotterdam, The Netherlands; 2Department of Biostatistics, University
Medical Centre Rotterdam, Rotterdam, The Netherlands; 3Department of Intensive Care, Ikazia Hospital, Rotterdam, The Netherlands; 4Department
of Intensive Care, Reinier de Graaf Hospital, Delft, The Netherlands; and 5Department of Intensive Care, St. Franciscus Gasthuis, Rotterdam,
The Netherlands

Rationale: It is unknown whether lactate monitoring aimed to decrease levels during initial treatment in critically ill patients improves
outcome.
Objectives: To assess the effect of lactate monitoring and resuscitation directed at decreasing lactate levels in intensive care unit (ICU)
patients admitted with a lactate level of greater than or equal to 3.0
mEq/L.
Methods: Patients were randomly allocated to two groups. In thelactate group, treatment was guided by lactate levels with theobjective to decrease lactate by 20% or more per 2 hours forthe initial 8 hours of ICU stay. In the control group, the treatment
team had no knowledge of lactate levels (except for the admission
value) during this period. The primary outcome measure washospital mortality.
Measurements and Main Results: The lactate group received more
fluids and vasodilators. However, there were no significant differences in lactate levels between the groups. In the intention-to-treat
population (348 patients), hospital mortality in the control groupwas 43.5% (77/177) compared with 33.9% (58/171) in the lactategroup (P 5 0.067). When adjusted for predefined risk factors,
hospital mortality was lower in the lactate group (hazard ratio,
0.61; 95% confidence interval, 0.43–0.87; P 5 0.006). In the lactategroup, Sequential Organ Failure Assessment scores were lower
between 9 and 72 hours, inotropes could be stopped earlier, andpatients could be weaned from mechanical ventilation and discharged from the ICU earlier.
Conclusions: In patients with hyperlactatemia on ICU admission,lactate-guided therapy significantly reduced hospital mortality
when adjusting for predefined risk factors. As this was consistent
with important secondary endpoints, this study suggests that initiallactate monitoring has clinical benefit.
Clinical trial registered with www.clinicaltrials.gov (NCT00270673).
Keywords: lactate; shock; central venous oxygenation; early goal
directed therapy; oxygen delivery(Received in original form December 23, 2010; accepted in final form May 11, 2010)

AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject

Increased blood lactate levels have been associated withsignificant morbidity and mortality. Nevertheless, it isunknown whether monitoring of lactate aimed to decreaselevels during initial treatment in critically ill patients
improves outcome.
What This Study Adds to the Field

In patients with hyperlactatemia on ICU admission, lactatemonitoring followed by targeted treatment significantly
reduced ICU length of stay. In addition, ICU and hospitalmortality were reduced when adjusting for predefined risk
factors. This study suggests that initial treatment aimed at
reducing lactate levels has clinical benefit.

Increased blood lactate levels have been associated withsignificant morbidity and mortality ever since their first description in 1843 by Scherer (1). Many studies have emphasized
the prognostic importance of either a single lactate level (2) orlimited lactate reduction during treatment (3–5). Interestingly,
the prognostic value of lactate levels seems to be independent
from the underlying critical illness (6) or the presence of shockor organ failure (7).
Despite this strong and already long-lasting predictive powerof lactate levels, little evidence exists on what interventions
would benefit patients with increased lactate levels or a failure
to reduce lactate (8). Earlier studies have shown that improving
lactate metabolism by the administration of dichloroacetate
decreases lactate levels but does not result in improved outcome
in critically ill patients (9, 10). This could indicate that the
detrimental outcome associated with increased lactate levels ordelayed reduction is more likely related to the underlying cause
than to the hyperlactatemia itself.
Both experimental (11) and clinical studies (12, 13) haveemphasized tissue hypoxia, characterized by supply-dependent

Am J Respir Crit Care Med.
2010
Sep
15;182(6):752-61
CNS Drugs
Volume27, Issue
9, September 2013
Supported by Pulsion Medical Systems AG (Munich, Germany), which provided
the CeVOX central venous oximetry monitors and catheters, and by Roche
Diagnostics (Mannheim, Germany), which provided Accutrend hand-held lactate
analyzers. Sponsors have not been involved in the design of the study and have
had no access to the data, nor were they involved in the analysis of the data orcontent of this article.

Early Lactate-Guided Therapy
Early Lactate-Guided Therapy in Intensive Care
Unit Patients
A Multicenter, Open-Label, Randomized Controlled Trial
Tim C. Jansen1, Jasper van Bommel1, F. Jeanette Schoonderbeek3, Steven J. Sleeswijk Visser4,
Johan M. van der Klooster5, Alex P. Lima1, Sten P. Willemsen2, and Jan Bakker1, for the LACTATE study group*1
Department of Intensive Care, Erasmus MC University Medical Centre, Rotterdam, The Netherlands; 2Department of Biostatistics, University
Medical Centre Rotterdam, Rotterdam, The Netherlands; 3Department of Intensive Care, Ikazia Hospital, Rotterdam, The Netherlands; 4Department
of Intensive Care, Reinier de Graaf Hospital, Delft, The Netherlands; and 5Department of Intensive Care, St. Franciscus Gasthuis, Rotterdam,
The Netherlands

LACTATE study

Rationale: It is unknown whether lactate monitoring aimed to decrease levels during initial treatment in critically ill patients improves
outcome.
Objectives: To assess the effect of lactate monitoring and resuscitation directed at decreasing lactate levels in intensive care unit (ICU)
patients admitted with a lactate level of greater than or equal to 3.0
mEq/L.
Methods: Patients were randomly allocated to two groups. In thelactate group, treatment was guided by lactate levels with theobjective to decrease lactate by 20% or more per 2 hours forthe initial 8 hours of ICU stay. In the control group, the treatment
team had no knowledge of lactate levels (except for the admission
value) during this period. The primary outcome measure washospital mortality.
Measurements and Main Results: The lactate group received more
fluids and vasodilators. However, there were no significant differences in lactate levels between the groups. In the intention-to-treat
population (348 patients), hospital mortality in the control groupwas 43.5% (77/177) compared with 33.9% (58/171) in the lactategroup (P 5 0.067). When adjusted for predefined risk factors,
hospital mortality was lower in the lactate group (hazard ratio,
0.61; 95% confidence interval, 0.43–0.87; P 5 0.006). In the lactategroup, Sequential Organ Failure Assessment scores were lower
between 9 and 72 hours, inotropes could be stopped earlier, andpatients could be weaned from mechanical ventilation and discharged from the ICU earlier.
Conclusions: In patients with hyperlactatemia on ICU admission,lactate-guided therapy significantly reduced hospital mortality
when adjusting for predefined risk factors. As this was consistent
with important secondary endpoints, this study suggests that initiallactate monitoring has clinical benefit.
Clinical trial registered with www.clinicaltrials.gov (NCT00270673).

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

Increased blood lactate levels have been associated withsignificant morbidity and mortality. Nevertheless, it isunknown whether monitoring of lactate aimed to decreaselevels during initial treatment in critically ill patients
improves outcome.

死亡リスクを39%減少

Keywords: lactate; shock; central venous oxygenation; early goal
directed therapy; oxygen delivery(Received in original form December 23, 2010; accepted in final form May 11, 2010)

What This Study Adds to the Field

In patients with hyperlactatemia on ICU admission, lactatemonitoring followed by targeted treatment significantly
reduced ICU length of stay. In addition, ICU and hospitalmortality were reduced when adjusting for predefined risk
factors. This study suggests that initial treatment aimed at
reducing lactate levels has clinical benefit.

Increased blood lactate levels have been associated withsignificant morbidity and mortality ever since their first description in 1843 by Scherer (1). Many studies have emphasized
the prognostic importance of either a single lactate level (2) orlimited lactate reduction during treatment (3–5). Interestingly,
the prognostic value of lactate levels seems to be independent
from the underlying critical illness (6) or the presence of shockor organ failure (7).
Despite this strong and already long-lasting predictive powerof lactate levels, little evidence exists on what interventions
would benefit patients with increased lactate levels or a failure
to reduce lactate (8). Earlier studies have shown that improving
lactate metabolism by the administration of dichloroacetate
decreases lactate levels but does not result in improved outcome
in critically ill patients (9, 10). This could indicate that the
detrimental outcome associated with increased lactate levels ordelayed reduction is more likely related to the underlying cause
than to the hyperlactatemia itself.
Both experimental (11) and clinical studies (12, 13) haveemphasized tissue hypoxia, characterized by supply-dependent

Am J Respir Crit Care Med.
2010
Sep
15;182(6):752-61
CNS Drugs
Volume27, Issue
9, September 2013
Supported by Pulsion Medical Systems AG (Munich, Germany), which provided
the CeVOX central venous oximetry monitors and catheters, and by Roche
Diagnostics (Mannheim, Germany), which provided Accutrend hand-held lactate
analyzers. Sponsors have not been involved in the design of the study and have
had no access to the data, nor were they involved in the analysis of the data orcontent of this article.

敗血症の初期蘇生の指標に乳酸値を用いるか？

敗血症の初期蘇生には,乳酸値を用いた経時的な評価を行うことを推奨する.

日本救急医学会雑誌 28巻S1
S1-S232(2017.02)
CNS Page
Drugs Volume27, Issue 9, September 2013

Sepsis is an emergency
1. 早期の感染対策
2. 適切な循環管理初期抗菌薬投与開始のタイミング

CNS Drugs Volume 27, Issue 9, September 2013
Crit Care Med. 2006 Jun;34(6):1589-96.

敗血症の原因微生物
MRSA

Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
MSSA

Enterobacter cloacase
Others
日本集中治療医学会第1回Sepsis Registry 調査
松田直之ほか. 日集中医誌 2013; 20: 329-334.

No. (%)
41 (15.4)
36 (13.5)
28 (10.5)
28 (10.5)
24 (9.0)
20 (7.5)
89 (33.4)
266 (100)

早期介入で術後敗血症は減少する!!

Crit Care Med 2004; 32: 916-921

早期介入で術後敗血症は減少する!!

18(1.6%) vs 4(0.3%)
P = 0.0044

Crit Care Med 2004; 32: 916-921

DICの合併は敗血症の予後を左右する
(%)

死
亡
率

血栓と循環 2015; 23: 111–115.

Discussion

DICは治療すべきなのか？

Nat Rev Immunol 2013; 13: 34-45.

敗血症性DICにATIIIは有功か？

JSEPTIC-DIC study

JSEPTIC-DIC study'#(!
*AT&"$+

20111201312
本邦の最新かつ大規模後ろ向き研究
DIC 1784

AT

 vs. control
Propensity%)

Shock. 2016 Dec;46(6):623-631.

Shock 2016; 46 (6): 623-631.

CNS Drugs Volume 27, Issue 9, September 2013

敗血症性DICにATIIIは有功か？
P(対象): 敗血症性DIC患者
1,784人JSEPTIC-DIC study'

I(介入): ATIII 投与患者
#(!
*AT&"$+
715人 (461人)

20111201312
C(対照): ATIII 非投与患者
DIC 1784

1,069人 (461人)
O(アウトカム):主要評価項
AT vs. control

目：院内全死亡率，生存期
Propensity%

間，重篤な有害事象として)
収集された主要な出血
Shock. 2016 Dec;46(6):623-631.

Shock 2016; 46 (6): 623-631.

CNS Drugs Volume 27, Issue 9, September 2013

RRT

敗血症性DICにATIIIは有功か？
院内全死亡率: 有意差なし



(IPTW解析以外)
生存期間: 有意差なし
重篤な有害事象として収集された主要な出血:輸血を有する出血が増加,
輸血量が全種類で増加



Shock 2016; 46 (6)Shock. 2016 Dec;46(6):623-631.

CNS Drugs Volume 27, Issue 9, September 2013

敗血症性DICにrTMは有功か？
研究名：SCARLET trial
デザイン：国際多施設共同二重盲検無作為化プラセ
ボ対照並行群間比較試験（Phase Ⅲ）
参加国・地域：北米、南米、欧州、アジア・オセア
ニア（日本を除く）

SCARLET: Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin

CNS Drugs Volume 27, Issue 9, September 2013

敗血症性DICにrTMは有功か？
(%)
35
30

28日死亡率28日以内の有害事象

28日以内の有害事象（頭蓋内出血、生命に関わる出血、担当医が重篤と判定した出血イベントで、赤血球濃厚液
1,440mL［典型的には6単位］以上を2日で輸血した場合）

29.4
25

26.8

20
15
10
5

5.8

4

0
rTM 群

Control 群

CNS Drugs Volume 27, Issue 9, September 2013
rTM 群（106/395例)，Control
群（119/405例)

CQ Wg15. DIC診断と治療
76. 敗血症性DICはどのように診断を行うか？
77. 敗血症性DICが疑われる症例で除外診断を行うか？
78. 敗血症性DICにアンチトロンビンの補充を行うか？
79. 敗血症性DICにヘパリン，ヘパリン類の投与を行うか？
80. 敗血症性DICにrTM投与を行うか？

81. 敗血症性DICにタンパク分解酵素阻害薬の投与を行うか？

日本版敗血症診療ガイドライン2020特別委員会

CQ Wg15. DIC診断と治療
Answer：76. 敗血症性DICはどのように診断を行うか？
敗血症性DIC患者に対してリコンビナント・トロンボモジュリン製剤を投与することを弱く推奨する.
77. 敗血症性DICが疑われる症例で除外診断を行うか？
(GRADE
2C エビデンスの確実性＝低)78. 敗血症性DICにアンチトロンビンの補充を行うか？
79. 敗血症性DICにヘパリン，ヘパリン類の投与を行うか？
80. 敗血症性DICにrTM投与を行うか？

81. 敗血症性DICにタンパク分解酵素阻害薬の投与を行うか？

日本版敗血症診療ガイドライン2020特別委員会

CQ Wg15. DIC診断と治療
76. 敗血症性DICはどのように診断を行うか？

P(対象): 敗血症性DIC患者(成人)
77. 敗血症性DICが疑われる症例で除外診断を行うか？
I(介入): rTM 投与患者

78. 敗血症性DICにアンチトロンビンの補充を行うか？
C(対照): rTM 非投与患者/
79. 敗血症性DICにヘパリン，ヘパリン類の投与を行うか？
プラセボ投与患者

80. 敗血症性DICにrTM投与を行うか？ O(アウトカム):主要評価項
目：死亡率，出血性合併症

81. 敗血症性DICにタンパク分解酵素阻害薬の投与を行うか？
発生率, DIC離脱率

日本版敗血症診療ガイドライン2020特別委員会

CQ Wg15. DIC診断と治療
76. 敗血症性DICはどのように診断を行うか？

死亡率: 41人減少/1,000人

77. 敗血症性DICが疑われる症例で除外診断を行うか？

出血性合併症発生率: 12人増加/1,000人
78. 敗血症性DICにアンチトロンビンの補充を行うか？

29名の正味の利益

79. 敗血症性DICにヘパリン，ヘパリン類の投与を行うか？

死亡率減少の相対的価値は, 出血の増加に

80. 敗血症性DICにrTM投与を行うか？
比べて一般的に高く, これを考慮しても81. 敗血症性DICにタンパク分解酵素阻害薬の投与を行うか？
利益が害を上回っている可能性が高い

日本版敗血症診療ガイドライン2020特別委員会

CQ Wg15. DIC診断と治療
Answer：76. 敗血症性DICはどのように診断を行うか？
敗血症性DIC患者に対してリコンビナント・トロンボモジュリン製剤を投与することを弱く推奨する.
77. 敗血症性DICが疑われる症例で除外診断を行うか？
(GRADE
2C エビデンスの確実性＝低)78. 敗血症性DICにアンチトロンビンの補充を行うか？
79. 敗血症性DICにヘパリン，ヘパリン類の投与を行うか？
80. 敗血症性DICにrTM投与を行うか？

81. 敗血症性DICにタンパク分解酵素阻害薬の投与を行うか？

日本版敗血症診療ガイドライン2020特別委員会

敗血症性ショックの新定義と診断基準
Take Home Message

Sepsis is an emergency
1. 早期の感染対策
2. 適切な循環管理
ご清聴ありがとうございました。