今日の臨床サポート

敗血症

著者: 片岡惇1) 練馬光が丘病院 総合救急診療科 集中治療部門

著者: 則末泰博2) 東京ベイ・浦安市川医療センター 救急集中治療科 集中治療部門

監修: 志賀隆 国際医療福祉大学 医学部救急医学/国際医療福祉大学病院 救急医療部

著者校正/監修レビュー済:2021/06/30
参考ガイドライン:
  1. 日本集中治療医学会/日本救急医学会:日本版敗血症診療ガイドライン2020 The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020(J-SSCG)
  1. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.
患者向け説明資料

概要・推奨   

  1. 敗血症は「致死的な臓器障害を伴う感染症」(SOFAスコアが2点以上上昇している場合)、敗血症性ショックは「平均血圧65mmHg以上を維持するために昇圧薬が必要な低血圧+血清乳酸値>2mmol/L」と定義される(Sepsis-3)(推奨度1)。
  1. 敗血症は死亡率が高く、早期認識し、早期介入をすることが重要である。感染症では、全身状態の時系列評価を繰り返し、qSOFAをモニタリングし、qSOFA≧2点では敗血症を考慮し集中治療管理を念頭に置く(推奨度1)。
  1. qSOFA
  1. 閲覧にはご契約が必要
  1. 閲覧にはご契約が必要 となりま
  1. 閲覧にはご契約
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
  1. 閲覧に
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご 契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要と なります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
  1. 閲覧にはご契約が必要と
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要と
閲覧にはご契
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
片岡惇 : 未申告[2021年]
則末泰博 : 特に申告事項無し[2021年]
監修:志賀隆 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 2021年2月に出版された日本版敗血症診療ガイドライン2020の内容を踏まえて改訂を行った。
  1. 前回改訂時から現在までに新たに発表されたエビデンスについて追記した。
  1. 新たな項目として、PICS /ICU-AWについて追加した。

病態、疫学、診察

疾患(疫学・病態)のまとめ  
  1. 敗血症は感染によって生じる全身の炎症反応である[1][2]
  1. 敗血症では、種々のサイトカインをはじめとする多量のケミカルメディエーターが産生され、多彩な病状を示す。
  1. 1991年の会議で、感染によってSIRS(systemic inflammatory response syndrome)と診断された場合に敗血症と、敗血症に伴って臓器不全を来した場合を重症敗血症と定義されてきたが[1][2]、2016年には従来の重症敗血症を敗血症と定義する提案(Sepsis-3)がなされた[3][4][5]
  1. 同様に、敗血症のうち、適切な輸液を行っても、昇圧薬が必要な場合を敗血症性ショックと定義されてきたが[1][2]、2016年のSepsis-3では平均血圧65mmHg以上を維持するために昇圧薬が必要な低血圧+血清乳酸値>2mmol/Lとより厳しい条件での提案がなされた[4][5]
  1. 国際ガイドラインSurviving sepsis campaign guideline 2016[6][7]、および本邦の敗血症ガイドラインでも[8]、Sepsis-3の定義を用いることとしている。
  1. 現在でも敗血症の頻度は高く、ICUでの死亡の最大の原因である。日本救急医学会の重症敗血症/敗血症性ショック患者を前向きに登録したsepsis registryでは、28日死亡率23.1%(144/624)、病院死亡率29.5%(184/624)であったと報告されている[9]
  1. 敗血症患者数は増加しているが、死亡率は、特に「敗血症バンドル」を遵守した場合には、低下することが示されている[10]
  1. 敗血症、敗血症性ショックになるに従い、また、SIRSの陽性項目数が増加するに従い、死亡率が増加することが示されている[11]
 
  1. SIRS、sepsisの世界的な最初の定義(推奨度1)。(参考文献:[1][2]
  1. それまで統一されていなかった敗血症の定義や診断基準が、初めて国際的に定められた内容。
  1. 感染によってSIRS(systemic inflammatory response syndrome)と診断された場合に敗血症sepsisと、敗血症に伴って臓器不全を来した場合を重症敗血症severe sepsis、敗血症のうち、適切な輸液を行っても、昇圧薬が必要な場合を敗血症性ショックと定義された。
  1. 追記:記載の参考文献は同じ内容。
 
  1. Sepsis-3の提唱(推奨度1)。(参考文献:[3][4][5]
  1. 下記文献はsepsisとseptic shockを定義するための、大規模データベースを用いた研究。
  1. JAMA. 2016 May 24-31;315(20):2237.[3]
  1. JAMA. 2016 Feb 23;315(8):775-87.[4]
 
  1. Surviving sepsis campaign guidelines 2016(推奨度1)。(参考文献:[6][7]
  1. 世界的な視点からの敗血症診療ガイドライン。4年ごとに改訂されている。
  1. 追記:記載の参考文献は同じ内容。
 
  1. 日本版敗血症診療ガイドライン 2020年版(推奨度1)。(参考文献:[8]
  1. 本邦の敗血症診療ガイドライン。
  1. 追記:記載の参考文献は同じ内容。
 
  1. 敗血症バンドルの遵守と予後の関係(the IMPreSS study)(推奨度1)。(参考文献:[10]
  1. 世界62カ国618病院での、重症敗血症、敗血症性ショック患者を対象に、敗血症バンドルを守っているか、守っていないかで、院内死亡率を比較検討した、前向き観察研究。3時間バンドルを守っていた群(20% vs 31%, p<0.001)、6時間バンドルを守っていた群(22% vs 32%, p<0.001)の方が、有意に院内死亡率が低かった。
  1. 追記:この研究時の敗血症バンドルは2012年版で現在とは異なる[12]
  1. 3時間バンドル:
  1. 乳酸値を測定する
  1. 抗菌薬投与前に血液培養を採取する
  1. 広域抗菌薬を投与する
  1. 低血圧、もしくは乳酸値4mmol/L以上であれば、30mL/kgの晶質液を投与する
  1. 6時間バンドル:
  1. 初期蘇生輸液で平均血圧65mmHgを維持できない場合は昇圧薬を投与する
  1. 敗血症性ショック、もしくは最初の乳酸値が4mmol/L以上の場合は、CVPとScvO2を測定する
  1. 乳酸値が上昇していた場合は再測定する
問診、診察のポイント  
  1. 感染症状の有無を確認する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

まずは15日間無料トライアル
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

著者: R C Bone, R A Balk, F B Cerra, R P Dellinger, A M Fein, W A Knaus, R M Schein, W J Sibbald
雑誌名: Chest. 1992 Jun;101(6):1644-55.
Abstract/Text An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.

PMID 1303622  Chest. 1992 Jun;101(6):1644-55.
著者:
雑誌名: Crit Care Med. 1992 Jun;20(6):864-74.
Abstract/Text OBJECTIVE: To define the terms "sepsis" and "organ failure" in a precise manner.
DATA SOURCES: Review of the medical literature and the use of expert testimony at a consensus conference.
SETTING: American College of Chest Physicians (ACCP) headquarters in Northbrook, IL.
PARTICIPANTS: Leadership members of ACCP/Society of Critical Care Medicine (SCCM).
RESULTS: An ACCP/SCCM Consensus Conference was held in August of 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic variables by which a patient could be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods were recommended when dealing with septic patients as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended.
CONCLUSION: The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.

PMID 1597042  Crit Care Med. 1992 Jun;20(6):864-74.
著者: Christopher W Seymour, Vincent X Liu, Theodore J Iwashyna, Frank M Brunkhorst, Thomas D Rea, André Scherag, Gordon Rubenfeld, Jeremy M Kahn, Manu Shankar-Hari, Mervyn Singer, Clifford S Deutschman, Gabriel J Escobar, Derek C Angus
雑誌名: JAMA. 2016 Feb 23;315(8):762-74. doi: 10.1001/jama.2016.0288.
Abstract/Text IMPORTANCE: The Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown.
OBJECTIVE: To evaluate the validity of clinical criteria to identify patients with suspected infection who are at risk of sepsis.
DESIGN, SETTINGS, AND POPULATION: Among 1.3 million electronic health record encounters from January 1, 2010, to December 31, 2012, at 12 hospitals in southwestern Pennsylvania, we identified those with suspected infection in whom to compare criteria. Confirmatory analyses were performed in 4 data sets of 706,399 out-of-hospital and hospital encounters at 165 US and non-US hospitals ranging from January 1, 2008, until December 31, 2013.
EXPOSURES: Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, systemic inflammatory response syndrome (SIRS) criteria, Logistic Organ Dysfunction System (LODS) score, and a new model derived using multivariable logistic regression in a split sample, the quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA) score (range, 0-3 points, with 1 point each for systolic hypotension [≤100 mm Hg], tachypnea [≥22/min], or altered mentation).
MAIN OUTCOMES AND MEASURES: For construct validity, pairwise agreement was assessed. For predictive validity, the discrimination for outcomes (primary: in-hospital mortality; secondary: in-hospital mortality or intensive care unit [ICU] length of stay ≥3 days) more common in sepsis than uncomplicated infection was determined. Results were expressed as the fold change in outcome over deciles of baseline risk of death and area under the receiver operating characteristic curve (AUROC).
RESULTS: In the primary cohort, 148,907 encounters had suspected infection (n = 74,453 derivation; n = 74,454 validation), of whom 6347 (4%) died. Among ICU encounters in the validation cohort (n = 7932 with suspected infection, of whom 1289 [16%] died), the predictive validity for in-hospital mortality was lower for SIRS (AUROC = 0.64; 95% CI, 0.62-0.66) and qSOFA (AUROC = 0.66; 95% CI, 0.64-0.68) vs SOFA (AUROC = 0.74; 95% CI, 0.73-0.76; P < .001 for both) or LODS (AUROC = 0.75; 95% CI, 0.73-0.76; P < .001 for both). Among non-ICU encounters in the validation cohort (n = 66 522 with suspected infection, of whom 1886 [3%] died), qSOFA had predictive validity (AUROC = 0.81; 95% CI, 0.80-0.82) that was greater than SOFA (AUROC = 0.79; 95% CI, 0.78-0.80; P < .001) and SIRS (AUROC = 0.76; 95% CI, 0.75-0.77; P < .001). Relative to qSOFA scores lower than 2, encounters with qSOFA scores of 2 or higher had a 3- to 14-fold increase in hospital mortality across baseline risk deciles. Findings were similar in external data sets and for the secondary outcome.
CONCLUSIONS AND RELEVANCE: Among ICU encounters with suspected infection, the predictive validity for in-hospital mortality of SOFA was not significantly different than the more complex LODS but was statistically greater than SIRS and qSOFA, supporting its use in clinical criteria for sepsis. Among encounters with suspected infection outside of the ICU, the predictive validity for in-hospital mortality of qSOFA was statistically greater than SOFA and SIRS, supporting its use as a prompt to consider possible sepsis.

PMID 26903335  JAMA. 2016 Feb 23;315(8):762-74. doi: 10.1001/jama.2016・・・
著者: Manu Shankar-Hari, Gary S Phillips, Mitchell L Levy, Christopher W Seymour, Vincent X Liu, Clifford S Deutschman, Derek C Angus, Gordon D Rubenfeld, Mervyn Singer, Sepsis Definitions Task Force
雑誌名: JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289.
Abstract/Text IMPORTANCE: Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition.
OBJECTIVE: To develop a new definition and clinical criteria for identifying septic shock in adults.
DESIGN, SETTING, AND PARTICIPANTS: The Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force (19 participants) to revise current sepsis/septic shock definitions. Three sets of studies were conducted: (1) a systematic review and meta-analysis of observational studies in adults published between January 1, 1992, and December 25, 2015, to determine clinical criteria currently reported to identify septic shock and inform the Delphi process; (2) a Delphi study among the task force comprising 3 surveys and discussions of results from the systematic review, surveys, and cohort studies to achieve consensus on a new septic shock definition and clinical criteria; and (3) cohort studies to test variables identified by the Delphi process using Surviving Sepsis Campaign (SSC) (2005-2010; n = 28,150), University of Pittsburgh Medical Center (UPMC) (2010-2012; n = 1,309,025), and Kaiser Permanente Northern California (KPNC) (2009-2013; n = 1,847,165) electronic health record (EHR) data sets.
MAIN OUTCOMES AND MEASURES: Evidence for and agreement on septic shock definitions and criteria.
RESULTS: The systematic review identified 44 studies reporting septic shock outcomes (total of 166,479 patients) from a total of 92 sepsis epidemiology studies reporting different cutoffs and combinations for blood pressure (BP), fluid resuscitation, vasopressors, serum lactate level, and base deficit to identify septic shock. The septic shock-associated crude mortality was 46.5% (95% CI, 42.7%-50.3%), with significant between-study statistical heterogeneity (I2 = 99.5%; τ2 = 182.5; P < .001). The Delphi process identified hypotension, serum lactate level, and vasopressor therapy as variables to test using cohort studies. Based on these 3 variables alone or in combination, 6 patient groups were generated. Examination of the SSC database demonstrated that the patient group requiring vasopressors to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L (18 mg/dL) after fluid resuscitation had a significantly higher mortality (42.3% [95% CI, 41.2%-43.3%]) in risk-adjusted comparisons with the other 5 groups derived using either serum lactate level greater than 2 mmol/L alone or combinations of hypotension, vasopressors, and serum lactate level 2 mmol/L or lower. These findings were validated in the UPMC and KPNC data sets.
CONCLUSIONS AND RELEVANCE: Based on a consensus process using results from a systematic review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.

PMID 26903336  JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016・・・
著者: Mervyn Singer, Clifford S Deutschman, Christopher Warren Seymour, Manu Shankar-Hari, Djillali Annane, Michael Bauer, Rinaldo Bellomo, Gordon R Bernard, Jean-Daniel Chiche, Craig M Coopersmith, Richard S Hotchkiss, Mitchell M Levy, John C Marshall, Greg S Martin, Steven M Opal, Gordon D Rubenfeld, Tom van der Poll, Jean-Louis Vincent, Derek C Angus
雑誌名: JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
Abstract/Text IMPORTANCE: Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
OBJECTIVE: To evaluate and, as needed, update definitions for sepsis and septic shock.
PROCESS: A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment).
KEY FINDINGS FROM EVIDENCE SYNTHESIS: Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant.
RECOMMENDATIONS: Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.
CONCLUSIONS AND RELEVANCE: These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.

PMID 26903338  JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016・・・
著者: Andrew Rhodes, Laura E Evans, Waleed Alhazzani, Mitchell M Levy, Massimo Antonelli, Ricard Ferrer, Anand Kumar, Jonathan E Sevransky, Charles L Sprung, Mark E Nunnally, Bram Rochwerg, Gordon D Rubenfeld, Derek C Angus, Djillali Annane, Richard J Beale, Geoffrey J Bellinghan, Gordon R Bernard, Jean-Daniel Chiche, Craig Coopersmith, Daniel P De Backer, Craig J French, Seitaro Fujishima, Herwig Gerlach, Jorge Luis Hidalgo, Steven M Hollenberg, Alan E Jones, Dilip R Karnad, Ruth M Kleinpell, Younsuck Koh, Thiago Costa Lisboa, Flavia R Machado, John J Marini, John C Marshall, John E Mazuski, Lauralyn A McIntyre, Anthony S McLean, Sangeeta Mehta, Rui P Moreno, John Myburgh, Paolo Navalesi, Osamu Nishida, Tiffany M Osborn, Anders Perner, Colleen M Plunkett, Marco Ranieri, Christa A Schorr, Maureen A Seckel, Christopher W Seymour, Lisa Shieh, Khalid A Shukri, Steven Q Simpson, Mervyn Singer, B Taylor Thompson, Sean R Townsend, Thomas Van der Poll, Jean-Louis Vincent, W Joost Wiersinga, Janice L Zimmerman, R Phillip Dellinger
雑誌名: Crit Care Med. 2017 Mar;45(3):486-552. doi: 10.1097/CCM.0000000000002255.
Abstract/Text OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012."
DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development.
METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable.
RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions.
CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

PMID 28098591  Crit Care Med. 2017 Mar;45(3):486-552. doi: 10.1097/CCM・・・
著者: Andrew Rhodes, Laura E Evans, Waleed Alhazzani, Mitchell M Levy, Massimo Antonelli, Ricard Ferrer, Anand Kumar, Jonathan E Sevransky, Charles L Sprung, Mark E Nunnally, Bram Rochwerg, Gordon D Rubenfeld, Derek C Angus, Djillali Annane, Richard J Beale, Geoffrey J Bellinghan, Gordon R Bernard, Jean-Daniel Chiche, Craig Coopersmith, Daniel P De Backer, Craig J French, Seitaro Fujishima, Herwig Gerlach, Jorge Luis Hidalgo, Steven M Hollenberg, Alan E Jones, Dilip R Karnad, Ruth M Kleinpell, Younsuk Koh, Thiago Costa Lisboa, Flavia R Machado, John J Marini, John C Marshall, John E Mazuski, Lauralyn A McIntyre, Anthony S McLean, Sangeeta Mehta, Rui P Moreno, John Myburgh, Paolo Navalesi, Osamu Nishida, Tiffany M Osborn, Anders Perner, Colleen M Plunkett, Marco Ranieri, Christa A Schorr, Maureen A Seckel, Christopher W Seymour, Lisa Shieh, Khalid A Shukri, Steven Q Simpson, Mervyn Singer, B Taylor Thompson, Sean R Townsend, Thomas Van der Poll, Jean-Louis Vincent, W Joost Wiersinga, Janice L Zimmerman, R Phillip Dellinger
雑誌名: Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. Epub 2017 Jan 18.
Abstract/Text OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012".
DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development.
METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable.
RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions.
CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

PMID 28101605  Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.100・・・
著者: Andrew Rhodes, Gary Phillips, Richard Beale, Maurizio Cecconi, Jean Daniel Chiche, Daniel De Backer, Jigeeshu Divatia, Bin Du, Laura Evans, Ricard Ferrer, Massimo Girardis, Despoina Koulenti, Flavia Machado, Steven Q Simpson, Cheng Cheng Tan, Xavier Wittebole, Mitchell Levy
雑誌名: Intensive Care Med. 2015 Sep;41(9):1620-8. doi: 10.1007/s00134-015-3906-y. Epub 2015 Jun 25.
Abstract/Text INTRODUCTION: Despite evidence demonstrating the value of performance initiatives, marked differences remain between hospitals in the delivery of care for patients with sepsis. The aims of this study were to improve our understanding of how compliance with the 3-h and 6-h Surviving Sepsis Campaign (SSC) bundles are used in different geographic areas, and how this relates to outcome.
METHODS: This was a global, prospective, observational, quality improvement study of compliance with the SSC bundles in patients with either severe sepsis or septic shock.
RESULTS: A total of 1794 patients from 62 countries were enrolled in the study with either severe sepsis or septic shock. Overall compliance with all the 3-h bundle metrics was 19%. This was associated with lower hospital mortality than non-compliance (20 vs. 31%, p < 0.001). Overall compliance with all the 6-h bundle metrics was 36%. This was associated with lower hospital mortality than non-compliance (22 vs. 32%, p < 0.001). After adjusting the crude mortality differences for ICU admission, sepsis status (severe sepsis or septic shock), location of diagnosis, APACHE II score and country, compliance remained independently associated with improvements in hospital mortality for both the 3-h bundle (OR = 0.64 (95% CI 0.47-0.87), p = 0.004)) and 6-h bundle (OR = 0.71 (95% CI 0.56-0.90), p = 0.005)).
DISCUSSION: Compliance with all of the evidence-based bundle metrics was not high. Patients whose care included compliance with all of these metrics had a 40% reduction in the odds of dying in hospital with the 3-h bundle and 36% for the 6-h bundle.

PMID 26109396  Intensive Care Med. 2015 Sep;41(9):1620-8. doi: 10.1007・・・
著者: Kirsi-Maija Kaukonen, Michael Bailey, David Pilcher, D Jamie Cooper, Rinaldo Bellomo
雑誌名: N Engl J Med. 2015 Apr 23;372(17):1629-38. doi: 10.1056/NEJMoa1415236. Epub 2015 Mar 17.
Abstract/Text BACKGROUND: The consensus definition of severe sepsis requires suspected or proven infection, organ failure, and signs that meet two or more criteria for the systemic inflammatory response syndrome (SIRS). We aimed to test the sensitivity, face validity, and construct validity of this approach.
METHODS: We studied data from patients from 172 intensive care units in Australia and New Zealand from 2000 through 2013. We identified patients with infection and organ failure and categorized them according to whether they had signs meeting two or more SIRS criteria (SIRS-positive severe sepsis) or less than two SIRS criteria (SIRS-negative severe sepsis). We compared their characteristics and outcomes and assessed them for the presence of a step increase in the risk of death at a threshold of two SIRS criteria.
RESULTS: Of 1,171,797 patients, a total of 109,663 had infection and organ failure. Among these, 96,385 patients (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%) had SIRS-negative severe sepsis. Over a period of 14 years, these groups had similar characteristics and changes in mortality (SIRS-positive group: from 36.1% [829 of 2296 patients] to 18.3% [2037 of 11,119], P<0.001; SIRS-negative group: from 27.7% [100 of 361] to 9.3% [122 of 1315], P<0.001). Moreover, this pattern remained similar after adjustment for baseline characteristics (odds ratio in the SIRS-positive group, 0.96; 95% confidence interval [CI], 0.96 to 0.97; odds ratio in the SIRS-negative group, 0.96; 95% CI, 0.94 to 0.98; P=0.12 for between-group difference). In the adjusted analysis, mortality increased linearly with each additional SIRS criterion (odds ratio for each additional criterion, 1.13; 95% CI, 1.11 to 1.15; P<0.001) without any transitional increase in risk at a threshold of two SIRS criteria.
CONCLUSIONS: The need for two or more SIRS criteria to define severe sepsis excluded one in eight otherwise similar patients with infection, organ failure, and substantial mortality and failed to define a transition point in the risk of death. (Funded by the Australian and New Zealand Intensive Care Research Centre.).

PMID 25776936  N Engl J Med. 2015 Apr 23;372(17):1629-38. doi: 10.1056・・・
著者: R Phillip Dellinger, Mitchell M Levy, Andrew Rhodes, Djillali Annane, Herwig Gerlach, Steven M Opal, Jonathan E Sevransky, Charles L Sprung, Ivor S Douglas, Roman Jaeschke, Tiffany M Osborn, Mark E Nunnally, Sean R Townsend, Konrad Reinhart, Ruth M Kleinpell, Derek C Angus, Clifford S Deutschman, Flavia R Machado, Gordon D Rubenfeld, Steven A Webb, Richard J Beale, Jean-Louis Vincent, Rui Moreno, Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup
雑誌名: Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af.
Abstract/Text OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008.
DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development.
METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Some recommendations were ungraded (UG). Recommendations were classified into three groups: 1) those directly targeting severe sepsis; 2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and 3) pediatric considerations.
RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 hr of recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 hrs of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1C); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients) (1C); fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥ 65 mm Hg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO2/FIO2 ratio of ≤ 100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 hrs) for patients with early ARDS and a Pao2/Fio2 < 150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL, targeting an upper blood glucose ≤ 180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hrs after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 hrs of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5 to 10 mins (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C).
CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

PMID 23353941  Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM・・・
著者: Christina Wacker, Anna Prkno, Frank M Brunkhorst, Peter Schlattmann
雑誌名: Lancet Infect Dis. 2013 May;13(5):426-35. doi: 10.1016/S1473-3099(12)70323-7. Epub 2013 Feb 1.
Abstract/Text BACKGROUND: Procalcitonin is a promising marker for identification of bacterial infections. We assessed the accuracy and clinical value of procalcitonin for diagnosis of sepsis in critically ill patients.
METHODS: We searched Medline, Embase, ISI Web of Knowledge, the Cochrane Library, Scopus, BioMed Central, and Science Direct, from inception to Feb 21, 2012, and reference lists of identified primary studies. We included articles written in English, German, or French that investigated procalcitonin for differentiation of septic patients--those with sepsis, severe sepsis, or septic shock--from those with a systemic inflammatory response syndrome of non-infectious origin. Studies of healthy people, patients without probable infection, and children younger than 28 days were excluded. Two independent investigators extracted patient and study characteristics; discrepancies were resolved by consensus. We calculated individual and pooled sensitivities and specificities. We used I(2) to test heterogeneity and investigated the source of heterogeneity by metaregression.
FINDINGS: Our search returned 3487 reports, of which 30 fulfilled the inclusion criteria, accounting for 3244 patients. Bivariate analysis yielded a mean sensitivity of 0 · 77 (95% CI 0 · 72-0 · 81) and specificity of 0 · 79 (95% CI 0 · 74-0 · 84). The area under the receiver operating characteristic curve was 0 · 85 (95% CI 0 · 81-0 · 88). The studies had substantial heterogeneity (I(2)=96%, 95% CI 94-99). None of the subgroups investigated--population, admission category, assay used, severity of disease, and description and masking of the reference standard--could account for the heterogeneity.
INTERPRETATION: Procalcitonin is a helpful biomarker for early diagnosis of sepsis in critically ill patients. Nevertheless, the results of the test must be interpreted carefully in the context of medical history, physical examination, and microbiological assessment.
FUNDING: Ministry of Education and Research, the Deutsche Forschungsgemeinschaft, Thuringian Ministry for Education, Science and Culture, the Thuringian Foundation for Technology, Innovation and Research, and the German Sepsis Society.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23375419  Lancet Infect Dis. 2013 May;13(5):426-35. doi: 10.1016/・・・
著者: Xin Zhang, Dan Liu, You-Ning Liu, Rui Wang, Li-Xin Xie
雑誌名: Crit Care. 2015 Sep 11;19:323. doi: 10.1186/s13054-015-1032-4. Epub 2015 Sep 11.
Abstract/Text INTRODUCTION: The early diagnosis of sepsis remains a challenge. Recently, soluble cluster of differentiation 14 subtype (sCD14-ST), also known as presepsin, has been identified as a potential biomarker of sepsis. We performed a meta-analysis to assess the diagnostic accuracy of presepsin for sepsis in patients with systemic inflammation.
METHODS: We systematically searched the PubMed, Embase, Web of Knowledge and Cochrane databases. Studies were included if they assessed the diagnostic accuracy of presepsin for sepsis in adult patients with systemic inflammatory response syndrome (SIRS). Furthermore, a 2 × 2 contingency table was constructed based on these results. Two authors independently judged the studies and extracted the data. The diagnostic accuracy of presepsin in sepsis was calculated using a bivariate meta-analysis model. The Q-test and I (2) index were used to test the heterogeneity.
RESULTS: Eight studies involving a total of 1,815 patients were included in the present study. The pooled sensitivity, specificity, diagnostic odds ratio, positive likelihood ratio and negative likelihood ratio were 0.86 (95% CI: 0.79-0.91), 0.78 (95% CI: 0.68-0.85), 22 (95% CI: 10-48), 3.8 (95% CI: 2.6-5.7), and 0.18 (95% CI: 0.11-0.28), respectively. The area under the summary receiver operator characteristic curve was 0.89 (95% CI: 0.86-0.92). Meta-regression analysis revealed that consecutive patient selection, sample size and setting significantly accounted for the heterogeneity of sensitivity.
CONCLUSIONS: Our findings suggest that presepsin exhibits very good diagnostic accuracy (AUC=0.89) for the diagnosis for sepsis. Nevertheless, an overall assessment of all the clinical indexes for sepsis diagnosis and continual re-evaluation of presepsin during the course of the disease are needed.

PMID 26357898  Crit Care. 2015 Sep 11;19:323. doi: 10.1186/s13054-015-・・・
著者: J L Vincent, A de Mendonça, F Cantraine, R Moreno, J Takala, P M Suter, C L Sprung, F Colardyn, S Blecher
雑誌名: Crit Care Med. 1998 Nov;26(11):1793-800.
Abstract/Text OBJECTIVE: To evaluate the use of the Sequential Organ Failure Assessment (SOFA) score in assessing the incidence and severity of organ dysfunction in critically ill patients.
DESIGN: Prospective, multicenter study.
SETTING: Forty intensive care units (ICUs) in 16 countries.
PATIENTS: Patients admitted to the ICU in May 1995 (n = 1,449), excluding patients who underwent uncomplicated elective surgery with an ICU length of stay <48 hrs.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: The main outcome measures included incidence of dysfunction/failure of different organs and the relationship of this dysfunction with outcome. In this cohort of patients, the median length of ICU stay was 5 days, and the ICU mortality rate was 22%. Multiple organ dysfunction and high SOFA scores for any individual organ were associated with increased mortality. The presence of infection on admission (28.7% of patients) was associated with higher SOFA scores for each organ. The evaluation of a subgroup of 544 patients who stayed in the ICU for at least 1 wk showed that survivors and nonsurvivors followed a different course. This subgroup had greater respiratory, cardiovascular, and neurologic scores than the other patients. In this subgroup, the total SOFA score increased in 44% of the nonsurvivors but in only 20% of the survivors (p < .001). Conversely, the total SOFA score decreased in 33% of the survivors compared with 21% of the nonsurvivors (p < .001).
CONCLUSIONS: The SOFA score is a simple, but effective method to describe organ dysfunction/failure in critically ill patients. Regular, repeated scoring enables patient condition and disease development to be monitored and better understood. The SOFA score may enable comparison between patients that would benefit clinical trials.

PMID 9824069  Crit Care Med. 1998 Nov;26(11):1793-800.
著者: Mitchell M Levy, Laura E Evans, Andrew Rhodes
雑誌名: Crit Care Med. 2018 Jun;46(6):997-1000. doi: 10.1097/CCM.0000000000003119.
Abstract/Text
PMID 29767636  Crit Care Med. 2018 Jun;46(6):997-1000. doi: 10.1097/CC・・・
著者: Mitchell M Levy, Laura E Evans, Andrew Rhodes
雑誌名: Intensive Care Med. 2018 Jun;44(6):925-928. doi: 10.1007/s00134-018-5085-0. Epub 2018 Apr 19.
Abstract/Text
PMID 29675566  Intensive Care Med. 2018 Jun;44(6):925-928. doi: 10.100・・・
著者: E Rivers, B Nguyen, S Havstad, J Ressler, A Muzzin, B Knoblich, E Peterson, M Tomlanovich, Early Goal-Directed Therapy Collaborative Group
雑誌名: N Engl J Med. 2001 Nov 8;345(19):1368-77. doi: 10.1056/NEJMoa010307.
Abstract/Text BACKGROUND: Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit.
METHODS: We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups.
RESULTS: Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P = 0.009). During the interval from 7 to 72 hours, the patients assigned to early goal-directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs. 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs. 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs. 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs. 7.36+/-0.12) than the patients assigned to standard therapy (P < or = 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs. 15.9+/-6.4, P < 0.001).
CONCLUSIONS: Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.

PMID 11794169  N Engl J Med. 2001 Nov 8;345(19):1368-77. doi: 10.1056/・・・
著者: ProCESS Investigators, Donald M Yealy, John A Kellum, David T Huang, Amber E Barnato, Lisa A Weissfeld, Francis Pike, Thomas Terndrup, Henry E Wang, Peter C Hou, Frank LoVecchio, Michael R Filbin, Nathan I Shapiro, Derek C Angus
雑誌名: N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18.
Abstract/Text BACKGROUND: In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.
METHODS: In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support.
RESULTS: We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support.
CONCLUSIONS: In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.).

PMID 24635773  N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/・・・
著者: ARISE Investigators, ANZICS Clinical Trials Group, Sandra L Peake, Anthony Delaney, Michael Bailey, Rinaldo Bellomo, Peter A Cameron, D James Cooper, Alisa M Higgins, Anna Holdgate, Belinda D Howe, Steven A R Webb, Patricia Williams
雑誌名: N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.1056/NEJMoa1404380. Epub 2014 Oct 1.
Abstract/Text BACKGROUND: Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain.
METHODS: In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization.
RESULTS: Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (±SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964±1415 ml vs. 1713±1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P<0.001 for all comparisons). At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, -0.3 percentage points; 95% confidence interval, -4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay.
CONCLUSIONS: In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. (Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ARISE ClinicalTrials.gov number, NCT00975793.).

PMID 25272316  N Engl J Med. 2014 Oct 16;371(16):1496-506. doi: 10.105・・・
著者: Paul R Mouncey, Tiffany M Osborn, G Sarah Power, David A Harrison, M Zia Sadique, Richard D Grieve, Rahi Jahan, Sheila E Harvey, Derek Bell, Julian F Bion, Timothy J Coats, Mervyn Singer, J Duncan Young, Kathryn M Rowan, ProMISe Trial Investigators
雑誌名: N Engl J Med. 2015 Apr 2;372(14):1301-11. doi: 10.1056/NEJMoa1500896. Epub 2015 Mar 17.
Abstract/Text BACKGROUND: Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains.
METHODS: We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days.
RESULTS: We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%.
CONCLUSIONS: In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).

PMID 25776532  N Engl J Med. 2015 Apr 2;372(14):1301-11. doi: 10.1056/・・・
著者: W A Knaus, E A Draper, D P Wagner, J E Zimmerman
雑誌名: Crit Care Med. 1985 Oct;13(10):818-29.
Abstract/Text This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.

PMID 3928249  Crit Care Med. 1985 Oct;13(10):818-29.
著者: Alan E Jones, Nathan I Shapiro, Stephen Trzeciak, Ryan C Arnold, Heather A Claremont, Jeffrey A Kline, Emergency Medicine Shock Research Network (EMShockNet) Investigators
雑誌名: JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010.158.
Abstract/Text CONTEXT: Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department.
OBJECTIVE: To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation (ScvO2) as goals of early sepsis resuscitation.
DESIGN, SETTING, AND PATIENTS: Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals.
INTERVENTIONS: We randomly assigned patients to 1 of 2 resuscitation protocols. The ScvO2 group was resuscitated to normalize central venous pressure, mean arterial pressure, and ScvO2 of at least 70%; and the lactate clearance group was resuscitated to normalize central venous pressure, mean arterial pressure, and lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to 6 hours. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment.
MAIN OUTCOME MEASURE: The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at Delta equal to -10%.
RESULTS: Of the 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographic, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalization. Thirty-four patients (23%) in the ScvO2 group died while in the hospital (95% confidence interval [CI], 17%-30%) compared with 25 (17%; 95% CI, 11%-24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined -10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, -3% to 15%). There were no differences in treatment-related adverse events between the groups.
CONCLUSION: Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00372502.

PMID 20179283  JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010・・・
著者: Matthew W Semler, Wesley H Self, Jonathan P Wanderer, Jesse M Ehrenfeld, Li Wang, Daniel W Byrne, Joanna L Stollings, Avinash B Kumar, Christopher G Hughes, Antonio Hernandez, Oscar D Guillamondegui, Addison K May, Liza Weavind, Jonathan D Casey, Edward D Siew, Andrew D Shaw, Gordon R Bernard, Todd W Rice, SMART Investigators and the Pragmatic Critical Care Research Group
雑誌名: N Engl J Med. 2018 Mar 1;378(9):829-839. doi: 10.1056/NEJMoa1711584. Epub 2018 Feb 27.
Abstract/Text BACKGROUND: Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes.
METHODS: In a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days - a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) - all censored at hospital discharge or 30 days, whichever occurred first.
RESULTS: Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60).
CONCLUSIONS: Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779 .).

PMID 29485925  N Engl J Med. 2018 Mar 1;378(9):829-839. doi: 10.1056/N・・・
著者: SAFE Study Investigators, Australian and New Zealand Intensive Care Society Clinical Trials Group, Australian Red Cross Blood Service, George Institute for International Health, John Myburgh, D James Cooper, Simon Finfer, Rinaldo Bellomo, Robyn Norton, Nicole Bishop, Sing Kai Lo, Shirley Vallance
雑誌名: N Engl J Med. 2007 Aug 30;357(9):874-84. doi: 10.1056/NEJMoa067514.
Abstract/Text BACKGROUND: The Saline versus Albumin Fluid Evaluation study suggested that patients with traumatic brain injury resuscitated with albumin had a higher mortality rate than those resuscitated with saline. We conducted a post hoc follow-up study of patients with traumatic brain injury who were enrolled in the study.
METHODS: For patients with traumatic brain injury (i.e., a history of trauma, evidence of head trauma on a computed tomographic [CT] scan, and a score of < or =13 on the Glasgow Coma Scale [GCS]), we recorded baseline characteristics from case-report forms, clinical records, and CT scans and determined vital status and functional neurologic outcomes 24 months after randomization.
RESULTS: We followed 460 patients, of whom 231 (50.2%) received albumin and 229 (49.8%) received saline. The subgroup of patients with GCS scores of 3 to 8 were classified as having severe brain injury (160 [69.3%] in the albumin group and 158 [69.0%] in the saline group). Demographic characteristics and indexes of severity of brain injury were similar at baseline. At 24 months, 71 of 214 patients in the albumin group (33.2%) had died, as compared with 42 of 206 in the saline group (20.4%) (relative risk, 1.63; 95% confidence interval [CI], 1.17 to 2.26; P=0.003). Among patients with severe brain injury, 61 of 146 patients in the albumin group (41.8%) died, as compared with 32 of 144 in the saline group (22.2%) (relative risk, 1.88; 95% CI, 1.31 to 2.70; P<0.001); among patients with GCS scores of 9 to 12, death occurred in 8 of 50 patients in the albumin group (16.0%) and 8 of 37 in the saline group (21.6%) (relative risk, 0.74; 95% CI, 0.31 to 1.79; P=0.50).
CONCLUSIONS: In this post hoc study of critically ill patients with traumatic brain injury, fluid resuscitation with albumin was associated with higher mortality rates than was resuscitation with saline. (Current Controlled Trials number, ISRCTN76588266 [controlled-trials.com].).

Copyright 2007 Massachusetts Medical Society.
PMID 17761591  N Engl J Med. 2007 Aug 30;357(9):874-84. doi: 10.1056/N・・・
著者: Frank M Brunkhorst, Christoph Engel, Frank Bloos, Andreas Meier-Hellmann, Max Ragaller, Norbert Weiler, Onnen Moerer, Matthias Gruendling, Michael Oppert, Stefan Grond, Derk Olthoff, Ulrich Jaschinski, Stefan John, Rolf Rossaint, Tobias Welte, Martin Schaefer, Peter Kern, Evelyn Kuhnt, Michael Kiehntopf, Christiane Hartog, Charles Natanson, Markus Loeffler, Konrad Reinhart, German Competence Network Sepsis (SepNet)
雑誌名: N Engl J Med. 2008 Jan 10;358(2):125-39. doi: 10.1056/NEJMoa070716.
Abstract/Text BACKGROUND: The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids.
METHODS: In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points.
RESULTS: The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate.
CONCLUSIONS: The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

2008 Massachusetts Medical Society
PMID 18184958  N Engl J Med. 2008 Jan 10;358(2):125-39. doi: 10.1056/N・・・
著者: Anders Perner, Nicolai Haase, Anne B Guttormsen, Jyrki Tenhunen, Gudmundur Klemenzson, Anders Åneman, Kristian R Madsen, Morten H Møller, Jeanie M Elkjær, Lone M Poulsen, Asger Bendtsen, Robert Winding, Morten Steensen, Pawel Berezowicz, Peter Søe-Jensen, Morten Bestle, Kristian Strand, Jørgen Wiis, Jonathan O White, Klaus J Thornberg, Lars Quist, Jonas Nielsen, Lasse H Andersen, Lars B Holst, Katrin Thormar, Anne-Lene Kjældgaard, Maria L Fabritius, Frederik Mondrup, Frank C Pott, Thea P Møller, Per Winkel, Jørn Wetterslev, 6S Trial Group, Scandinavian Critical Care Trials Group
雑誌名: N Engl J Med. 2012 Jul 12;367(2):124-34. doi: 10.1056/NEJMoa1204242. Epub 2012 Jun 27.
Abstract/Text BACKGROUND: Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.
METHODS: In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization.
RESULTS: Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.
CONCLUSIONS: Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer's acetate. (Funded by the Danish Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.).

PMID 22738085  N Engl J Med. 2012 Jul 12;367(2):124-34. doi: 10.1056/N・・・
著者: John A Myburgh, Simon Finfer, Rinaldo Bellomo, Laurent Billot, Alan Cass, David Gattas, Parisa Glass, Jeffrey Lipman, Bette Liu, Colin McArthur, Shay McGuinness, Dorrilyn Rajbhandari, Colman B Taylor, Steven A R Webb, CHEST Investigators, Australian and New Zealand Intensive Care Society Clinical Trials Group
雑誌名: N Engl J Med. 2012 Nov 15;367(20):1901-11. doi: 10.1056/NEJMoa1209759. Epub 2012 Oct 17.
Abstract/Text BACKGROUND: The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported.
METHODS: We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy.
RESULTS: A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001).
CONCLUSIONS: In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).

PMID 23075127  N Engl J Med. 2012 Nov 15;367(20):1901-11. doi: 10.1056・・・
著者: John H Boyd, Jason Forbes, Taka-aki Nakada, Keith R Walley, James A Russell
雑誌名: Crit Care Med. 2011 Feb;39(2):259-65. doi: 10.1097/CCM.0b013e3181feeb15.
Abstract/Text OBJECTIVE: To determine whether central venous pressure and fluid balance after resuscitation for septic shock are associated with mortality.
DESIGN: We conducted a retrospective review of the use of intravenous fluids during the first 4 days of care.
SETTING: Multicenter randomized controlled trial.
PATIENTS: The Vasopressin in Septic Shock Trial (VASST) study enrolled 778 patients who had septic shock and who were receiving a minimum of 5 μg of norepinephrine per minute.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Based on net fluid balance, we determined whether one's fluid balance quartile was correlated with 28-day mortality. We also analyzed whether fluid balance was predictive of central venous pressure and furthermore whether a guideline-recommended central venous pressure of 8-12 mm Hg yielded a mortality advantage. At enrollment, which occurred on average 12 hrs after presentation, the average fluid balance was +4.2 L. By day 4, the cumulative average fluid balance was +11 L. After correcting for age and Acute Physiology and Chronic Health Evaluation II score, a more positive fluid balance at both at 12 hrs and day 4 correlated significantly with increased mortality. Central venous pressure was correlated with fluid balance at 12 hrs, whereas on days 1-4, there was no significant correlation. At 12 hrs, patients with central venous pressure <8 mm Hg had the lowest mortality rate followed by those with central venous pressure 8-12 mm Hg. The highest mortality rate was observed in those with central venous pressure >12 mm Hg. Contrary to the overall effect, patients whose central venous pressure was <8 mm Hg had improved survival with a more positive fluid balance.
CONCLUSIONS: A more positive fluid balance both early in resuscitation and cumulatively over 4 days is associated with an increased risk of mortality in septic shock. Central venous pressure may be used to gauge fluid balance ≤ 12 hrs into septic shock but becomes an unreliable marker of fluid balance thereafter. Optimal survival in the VASST study occurred with a positive fluid balance of approximately 3 L at 12 hrs.

PMID 20975548  Crit Care Med. 2011 Feb;39(2):259-65. doi: 10.1097/CCM.・・・
著者: Xiaobo Yang, Bin Du
雑誌名: Crit Care. 2014 Nov 27;18(6):650. doi: 10.1186/s13054-014-0650-6. Epub 2014 Nov 27.
Abstract/Text INTRODUCTION: Fluid resuscitation is crucial in managing hemodynamically unstable patients. The last decade witnessed the use of pulse pressure variation (PPV) to predict fluid responsiveness. However, as far as we know, no systematic review and meta-analysis has been carried out to evaluate the value of PPV in predicting fluid responsiveness specifically upon patients admitted into intensive care units.
METHODS: We searched MEDLINE and EMBASE and included clinical trials that evaluated the association between PPV and fluid responsiveness after fluid challenge in mechanically ventilated patients in intensive care units. Data were synthesized using an exact binomial rendition of the bivariate mixed-effects regression model modified for synthesis of diagnostic test data.
RESULT: Twenty-two studies with 807 mechanically ventilated patients with tidal volume more than 8 ml/kg and without spontaneous breathing and cardiac arrhythmia were included, and 465 were responders (58%). The pooled sensitivity was 0.88 (95% confidence interval (CI) 0.81 to 0.92) and pooled specificity was 0.89 (95% CI 0.84 to 0.92). A summary receiver operating characteristic curve yielded an area under the curve of 0.94 (95% CI 0.91 to 0.95). A significant threshold effect was identified.
CONCLUSIONS: PPV predicts fluid responsiveness accurately in mechanically ventilated patients with relative large tidal volume and without spontaneous breathing and cardiac arrhythmia.

PMID 25427970  Crit Care. 2014 Nov 27;18(6):650. doi: 10.1186/s13054-0・・・
著者: Zhongheng Zhang, Xiao Xu, Sheng Ye, Lei Xu
雑誌名: Ultrasound Med Biol. 2014 May;40(5):845-53. doi: 10.1016/j.ultrasmedbio.2013.12.010. Epub 2014 Feb 2.
Abstract/Text Respiratory variation in the inferior vena cava (ΔIVC) has been extensively studied with respect to its value in predicting fluid responsiveness, but the results are conflicting. This systematic review was aimed at investigating the diagnostic accuracy of ΔIVC in predicting fluid responsiveness. Databases including Medline, Embase, Scopus and Web of Knowledge were searched from inception to May 2013. Studies exploring the diagnostic performance of ΔIVC in predicting fluid responsiveness were included. To allow for more between- and within-study variance, a hierarchical summary receiver operating characteristic model was used to pool the results. Subgroup analyses were performed for patients on mechanical ventilation, spontaneously breathing patients and those challenged with colloids and crystalloids. A total of 8 studies involving 235 patients were eligible for analysis. Cutoff values of ΔIVC varied across studies, ranging from 12% to 40%. The pooled sensitivity and specificity in the overall population were 0.76 (95% confidence interval [CI]: 0.61-0.86) and 0.86 (95% CI: 0.69-0.95), respectively. The pooled diagnostic odds ratio (DOR) was 20.2 (95% CI: 6.1-67.1). The diagnostic performance of ΔIVC appeared to be better in patients on mechanical ventilation than in spontaneously breathing patients (DOR: 30.8 vs. 13.2). The pooled area under the receiver operating characteristic curve was 0.84 (95% CI: 0.79-0.89). Our study indicates that ΔIVC measured with point-of-care ultrasonography is of great value in predicting fluid responsiveness, particularly in patients on controlled mechanical ventilation and those resuscitated with colloids.

Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.
PMID 24495437  Ultrasound Med Biol. 2014 May;40(5):845-53. doi: 10.101・・・
著者: Thomas G V Cherpanath, Alexander Hirsch, Bart F Geerts, Wim K Lagrand, Mariska M Leeflang, Marcus J Schultz, A B Johan Groeneveld
雑誌名: Crit Care Med. 2016 May;44(5):981-91. doi: 10.1097/CCM.0000000000001556.
Abstract/Text OBJECTIVE: Passive leg raising creates a reversible increase in venous return allowing for the prediction of fluid responsiveness. However, the amount of venous return may vary in various clinical settings potentially affecting the diagnostic performance of passive leg raising. Therefore we performed a systematic meta-analysis determining the diagnostic performance of passive leg raising in different clinical settings with exploration of patient characteristics, measurement techniques, and outcome variables.
DATA SOURCES: PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and citation tracking of relevant articles.
STUDY SELECTION: Clinical trials were selected when passive leg raising was performed in combination with a fluid challenge as gold standard to define fluid responders and non-responders.
DATA EXTRACTION: Trials were included if data were reported allowing the extraction of sensitivity, specificity, and area under the receiver operating characteristic curve.
DATA SYNTHESIS: Twenty-three studies with a total of 1,013 patients and 1,034 fluid challenges were included. The analysis demonstrated a pooled sensitivity of 86% (95% CI, 79-92), pooled specificity of 92% (95% CI, 88-96), and a summary area under the receiver operating characteristic curve of 0.95 (95% CI, 0.92-0.98). Mode of ventilation, type of fluid used, passive leg raising starting position, and measurement technique did not affect the diagnostic performance of passive leg raising. The use of changes in pulse pressure on passive leg raising showed a lower diagnostic performance when compared with passive leg raising-induced changes in flow variables, such as cardiac output or its direct derivatives (sensitivity of 58% [95% CI, 44-70] and specificity of 83% [95% CI, 68-92] vs sensitivity of 85% [95% CI, 78-90] and specificity of 92% [95% CI, 87-94], respectively; p < 0.001).
CONCLUSIONS: Passive leg raising retains a high diagnostic performance in various clinical settings and patient groups. The predictive value of a change in pulse pressure on passive leg raising is inferior to a passive leg raising-induced change in a flow variable.

PMID 26741579  Crit Care Med. 2016 May;44(5):981-91. doi: 10.1097/CCM.・・・
著者: Pietro Caironi, Gianni Tognoni, Serge Masson, Roberto Fumagalli, Antonio Pesenti, Marilena Romero, Caterina Fanizza, Luisa Caspani, Stefano Faenza, Giacomo Grasselli, Gaetano Iapichino, Massimo Antonelli, Vieri Parrini, Gilberto Fiore, Roberto Latini, Luciano Gattinoni, ALBIOS Study Investigators
雑誌名: N Engl J Med. 2014 Apr 10;370(15):1412-21. doi: 10.1056/NEJMoa1305727. Epub 2014 Mar 18.
Abstract/Text BACKGROUND: Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established.
METHODS: In this multicenter, open-label trial, we randomly assigned 1818 patients with severe sepsis, in 100 intensive care units (ICUs), to receive either 20% albumin and crystalloid solution or crystalloid solution alone. In the albumin group, the target serum albumin concentration was 30 g per liter or more until discharge from the ICU or 28 days after randomization. The primary outcome was death from any cause at 28 days. Secondary outcomes were death from any cause at 90 days, the number of patients with organ dysfunction and the degree of dysfunction, and length of stay in the ICU and the hospital.
RESULTS: During the first 7 days, patients in the albumin group, as compared with those in the crystalloid group, had a higher mean arterial pressure (P=0.03) and lower net fluid balance (P<0.001). The total daily amount of administered fluid did not differ significantly between the two groups (P=0.10). At 28 days, 285 of 895 patients (31.8%) in the albumin group and 288 of 900 (32.0%) in the crystalloid group had died (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%) in the albumin group and 389 of 893 (43.6%) in the crystalloid group had died (relative risk, 0.94; 95% CI, 0.85 to 1.05; P=0.29). No significant differences in other secondary outcomes were observed between the two groups.
CONCLUSIONS: In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days. (Funded by the Italian Medicines Agency; ALBIOS ClinicalTrials.gov number, NCT00707122.).

PMID 24635772  N Engl J Med. 2014 Apr 10;370(15):1412-21. doi: 10.1056・・・
著者: François Lamontagne, Alvin Richards-Belle, Karen Thomas, David A Harrison, M Zia Sadique, Richard D Grieve, Julie Camsooksai, Robert Darnell, Anthony C Gordon, Doreen Henry, Nicholas Hudson, Alexina J Mason, Michelle Saull, Chris Whitman, J Duncan Young, Kathryn M Rowan, Paul R Mouncey, 65 trial investigators
雑誌名: JAMA. 2020 Feb 12;. doi: 10.1001/jama.2020.0930. Epub 2020 Feb 12.
Abstract/Text Importance: Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.
Objective: To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.
Design, Setting, and Participants: A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.
Interventions: Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307).
Main Outcome and Measures: The primary clinical outcome was all-cause mortality at 90 days.
Results: Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, -5.0; 95% CI, -7.8 to -2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, -8.7 mg; 95% CI, -12.8 to -4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, -2.85%; 95% CI, -6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33 [2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]).
Conclusions and Relevance: Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study.
Trial Registration: isrctn.org Identifier: ISRCTN10580502.

PMID 32049269  JAMA. 2020 Feb 12;. doi: 10.1001/jama.2020.0930. Epub 2・・・
著者: James A Russell, Keith R Walley, Joel Singer, Anthony C Gordon, Paul C Hébert, D James Cooper, Cheryl L Holmes, Sangeeta Mehta, John T Granton, Michelle M Storms, Deborah J Cook, Jeffrey J Presneill, Dieter Ayers, VASST Investigators
雑誌名: N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/NEJMoa067373.
Abstract/Text BACKGROUND: Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors.
METHODS: In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 microg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 microg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions.
RESULTS: A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P=1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P=0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P=0.76). A test for heterogeneity between these two study strata was not significant (P=0.10).
CONCLUSIONS: Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors. (Current Controlled Trials number, ISRCTN94845869 [controlled-trials.com].).

Copyright 2008 Massachusetts Medical Society.
PMID 18305265  N Engl J Med. 2008 Feb 28;358(9):877-87. doi: 10.1056/N・・・
著者: Anthony C Gordon, Alexina J Mason, Neeraja Thirunavukkarasu, Gavin D Perkins, Maurizio Cecconi, Magda Cepkova, David G Pogson, Hollmann D Aya, Aisha Anjum, Gregory J Frazier, Shalini Santhakumaran, Deborah Ashby, Stephen J Brett, VANISH Investigators
雑誌名: JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485.
Abstract/Text IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative.
OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock.
DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock.
INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103).
MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes.
RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]).
CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191.

PMID 27483065  JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.・・・
著者: William F McIntyre, Kevin J Um, Waleed Alhazzani, Alexandra P Lengyel, Ludhmila Hajjar, Anthony C Gordon, François Lamontagne, Jeff S Healey, Richard P Whitlock, Emilie P Belley-Côté
雑誌名: JAMA. 2018 May 8;319(18):1889-1900. doi: 10.1001/jama.2018.4528.
Abstract/Text Importance: Vasopressin is an alternative to catecholamine vasopressors for patients with distributive shock-a condition due to excessive vasodilation, most frequently from severe infection. Blood pressure support with a noncatecholamine vasopressor may reduce stimulation of adrenergic receptors and decrease myocardial oxygen demand. Atrial fibrillation is common with catecholamines and is associated with adverse events, including mortality and increased length of stay (LOS).
Objectives: To determine whether treatment with vasopressin + catecholamine vasopressors compared with catecholamine vasopressors alone was associated with reductions in the risk of adverse events.
Data Sources: MEDLINE, EMBASE, and CENTRAL were searched from inception to February 2018. Experts were asked and meta-registries searched to identify ongoing trials.
Study Selection: Pairs of reviewers identified randomized clinical trials comparing vasopressin in combination with catecholamine vasopressors to catecholamines alone for patients with distributive shock.
Data Extraction and Synthesis: Two reviewers abstracted data independently. A random-effects model was used to combine data.
Main Outcomes and Measures: The primary outcome was atrial fibrillation. Other outcomes included mortality, requirement for renal replacement therapy (RRT), myocardial injury, ventricular arrhythmia, stroke, and LOS in the intensive care unit and hospital. Measures of association are reported as risk ratios (RRs) for clinical outcomes and mean differences for LOS.
Results: Twenty-three randomized clinical trials were identified (3088 patients; mean age, 61.1 years [14.2]; women, 45.3%). High-quality evidence supported a lower risk of atrial fibrillation associated with vasopressin treatment (RR, 0.77 [95% CI, 0.67 to 0.88]; risk difference [RD], -0.06 [95% CI, -0.13 to 0.01]). For mortality, the overall RR estimate was 0.89 (95% CI, 0.82 to 0.97; RD, -0.04 [95% CI, -0.07 to 0.00]); however, when limited to trials at low risk of bias, the RR estimate was 0.96 (95% CI, 0.84 to 1.11). The overall RR estimate for RRT was 0.74 (95% CI, 0.51 to 1.08; RD, -0.07 [95% CI, -0.12 to -0.01]). However, in an analysis limited to trials at low risk of bias, RR was 0.70 (95% CI, 0.53 to 0.92, P for interaction = .77). There were no significant differences in the pooled risks for other outcomes.
Conclusions and Relevance: In this systematic review and meta-analysis, the addition of vasopressin to catecholamine vasopressors compared with catecholamines alone was associated with a lower risk of atrial fibrillation. Findings for secondary outcomes varied.

PMID 29801010  JAMA. 2018 May 8;319(18):1889-1900. doi: 10.1001/jama.2・・・
著者: Daniel De Backer, Patrick Biston, Jacques Devriendt, Christian Madl, Didier Chochrad, Cesar Aldecoa, Alexandre Brasseur, Pierre Defrance, Philippe Gottignies, Jean-Louis Vincent, SOAP II Investigators
雑誌名: N Engl J Med. 2010 Mar 4;362(9):779-89. doi: 10.1056/NEJMoa0907118.
Abstract/Text BACKGROUND: Both dopamine and norepinephrine are recommended as first-line vasopressor agents in the treatment of shock. There is a continuing controversy about whether one agent is superior to the other.
METHODS: In this multicenter, randomized trial, we assigned patients with shock to receive either dopamine or norepinephrine as first-line vasopressor therapy to restore and maintain blood pressure. When blood pressure could not be maintained with a dose of 20 microg per kilogram of body weight per minute for dopamine or a dose of 0.19 microg per kilogram per minute for norepinephrine, open-label norepinephrine, epinephrine, or vasopressin could be added. The primary outcome was the rate of death at 28 days after randomization; secondary end points included the number of days without need for organ support and the occurrence of adverse events.
RESULTS: The trial included 1679 patients, of whom 858 were assigned to dopamine and 821 to norepinephrine. The baseline characteristics of the groups were similar. There was no significant between-group difference in the rate of death at 28 days (52.5% in the dopamine group and 48.5% in the norepinephrine group; odds ratio with dopamine, 1.17; 95% confidence interval, 0.97 to 1.42; P=0.10). However, there were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine (207 events [24.1%] vs. 102 events [12.4%], P<0.001). A subgroup analysis showed that dopamine, as compared with norepinephrine, was associated with an increased rate of death at 28 days among the 280 patients with cardiogenic shock but not among the 1044 patients with septic shock or the 263 with hypovolemic shock (P=0.03 for cardiogenic shock, P=0.19 for septic shock, and P=0.84 for hypovolemic shock, in Kaplan-Meier analyses).
CONCLUSIONS: Although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events. (ClinicalTrials.gov number, NCT00314704.)

2010 Massachusetts Medical Society
PMID 20200382  N Engl J Med. 2010 Mar 4;362(9):779-89. doi: 10.1056/NE・・・
著者: R Bellomo, M Chapman, S Finfer, K Hickling, J Myburgh
雑誌名: Lancet. 2000 Dec 23-30;356(9248):2139-43.
Abstract/Text BACKGROUND: Low-dose dopamine is commonly administered to critically ill patients in the belief that it reduces the risk of renal failure by increasing renal blood flow. However, these effects have not been established in a large randomised controlled trial, and use of dopamine remains controversial. We have done a multicentre, randomised, double-blind, placebo-controlled study of low-dose dopamine in patients with at least two criteria for the systemic inflammatory response syndrome and clinical evidence of early renal dysfunction (oliguria or increase in serum creatinine concentration).
METHODS: 328 patients admitted to 23 participating intensive-care units (ICUs) were randomly assigned a continuous intravenous infusion of low-dose dopamine (2 microg kg(-1) min(-1)) or placebo administered through a central venous catheter while in the ICU. The primary endpoint was the peak serum creatinine concentration during the infusion. Analyses excluded four patients with major protocol violations.
FINDINGS: The groups assigned dopamine (n=161) and placebo (n=163) were similar in terms of baseline characteristics, renal function, and duration of trial infusion. There was no difference between the dopamine and placebo groups in peak serum creatinine concentration during treatment (245 [SD 144] vs 249 [147] micromol/L; p=0.93), in the increase from baseline to highest value during treatment (62 [107] vs 66 [108] micromol/L; p=0.82), or in the numbers of patients whose serum creatinine concentration exceeded 300 micromol/L (56 vs 56; p=0.92) or who required renal replacement therapy (35 vs 40; p=0.55). Durations of ICU stay (13 [14] vs 14 [15] days; p=0.67) and of hospital stay (29 [27] vs 33 [39] days; p=0.29) were also similar. There were 69 deaths in the dopamine group and 66 in the placebo group.
INTERPRETATION: Administration of low-dose dopamine by continuous intravenous infusion to critically ill patients at risk of renal failure does not confer clinically significant protection from renal dysfunction.

PMID 11191541  Lancet. 2000 Dec 23-30;356(9248):2139-43.
著者: Nicolas Bréchot, David Hajage, Antoine Kimmoun, Julien Demiselle, Cara Agerstrand, Santiago Montero, Matthieu Schmidt, Charles-Edouard Luyt, Guillaume Lebreton, Guillaume Hékimian, Erwan Flecher, Elie Zogheib, Bruno Levy, Arthur S Slutsky, Daniel Brodie, Pierre Asfar, Alain Combes, International ECMO Network
雑誌名: Lancet. 2020 Aug 22;396(10250):545-552. doi: 10.1016/S0140-6736(20)30733-9.
Abstract/Text BACKGROUND: Patients with sepsis-induced cardiomyopathy with cardiogenic shock have a high mortality. This study assessed venoarterial extracorporeal membrane oxygenation (VA-ECMO) support for sepsis-induced cardiogenic shock refractory to conventional treatments.
METHODS: In this retrospective, multicentre, international cohort study, we compared outcomes of 82 patients (aged ≥18 years) with septic shock who received VA-ECMO at five academic ECMO centres, with 130 controls (not receiving ECMO) obtained from three large databases of septic shock. All patients had severe myocardial dysfunction (cardiac index 3 L/min per m2 or less or left ventricular ejection fraction [LVEF] 35% or less) and severe haemodynamic compromise (inotrope score at least 75 μg/kg per min or lactic acidaemia at least 4 mmol/L) at time of inclusion. The primary endpoint was survival at 90 days. A propensity score-weighted analysis was done to control for confounders.
FINDINGS: At baseline, patients treated with VA-ECMO had more severe myocardial dysfunction (mean cardiac index 1·5 L/min per m2vs 2·2 L/min per m2, LVEF 17% vs 27%), more severe haemodynamic impairment (inotrope score 279 μg/kg per min vs 145 μg/kg per min, lactataemia 8·9 mmol/L vs 6·5 mmol/L), and more severe organ failure (Sequential Organ Failure Assessment score 17 vs 13) than did controls, with p<0·0001 for each comparison. Survival at 90 days for patients treated with VA-ECMO was significantly higher than for controls (60% vs 25%, risk ratio [RR] for mortality 0·54, 95% CI [0·40-0·70]; p<0·0001). After propensity score weighting, ECMO remained associated with improved survival (51% vs 14%, adjusted RR for mortality 0·57, 95% CI [0·35-0·93]; p=0·0029). Lactate and catecholamine clearance were also significantly enhanced in patients treated with ECMO. Among the 49 survivors treated with ECMO, 32 who had been treated at the largest centre reported satisfactory Short Form-36 evaluated health-related quality of life at 1-year follow-up.
INTERPRETATION: Patients with severe sepsis-induced cardiogenic shock treated with VA-ECMO had a large and significant improvement in survival compared with controls not receiving ECMO. However, despite the careful propensity-weighted analysis, we cannot rule out unmeasured confounders.
FUNDING: None.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32828186  Lancet. 2020 Aug 22;396(10250):545-552. doi: 10.1016/S0・・・
著者: Pierre Asfar, Ferhat Meziani, Jean-François Hamel, Fabien Grelon, Bruno Megarbane, Nadia Anguel, Jean-Paul Mira, Pierre-François Dequin, Soizic Gergaud, Nicolas Weiss, François Legay, Yves Le Tulzo, Marie Conrad, René Robert, Frédéric Gonzalez, Christophe Guitton, Fabienne Tamion, Jean-Marie Tonnelier, Pierre Guezennec, Thierry Van Der Linden, Antoine Vieillard-Baron, Eric Mariotte, Gaël Pradel, Olivier Lesieur, Jean-Damien Ricard, Fabien Hervé, Damien du Cheyron, Claude Guerin, Alain Mercat, Jean-Louis Teboul, Peter Radermacher, SEPSISPAM Investigators
雑誌名: N Engl J Med. 2014 Apr 24;370(17):1583-93. doi: 10.1056/NEJMoa1312173. Epub 2014 Mar 18.
Abstract/Text BACKGROUND: The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.
METHODS: In a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28.
RESULTS: At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality.
CONCLUSIONS: Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.).

PMID 24635770  N Engl J Med. 2014 Apr 24;370(17):1583-93. doi: 10.1056・・・
著者: Jean-Pierre Frat, Arnaud W Thille, Alain Mercat, Christophe Girault, Stéphanie Ragot, Sébastien Perbet, Gwénael Prat, Thierry Boulain, Elise Morawiec, Alice Cottereau, Jérôme Devaquet, Saad Nseir, Keyvan Razazi, Jean-Paul Mira, Laurent Argaud, Jean-Charles Chakarian, Jean-Damien Ricard, Xavier Wittebole, Stéphanie Chevalier, Alexandre Herbland, Muriel Fartoukh, Jean-Michel Constantin, Jean-Marie Tonnelier, Marc Pierrot, Armelle Mathonnet, Gaëtan Béduneau, Céline Delétage-Métreau, Jean-Christophe M Richard, Laurent Brochard, René Robert, FLORALI Study Group, REVA Network
雑誌名: N Engl J Med. 2015 Jun 4;372(23):2185-96. doi: 10.1056/NEJMoa1503326. Epub 2015 May 17.
Abstract/Text BACKGROUND: Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia.
METHODS: We performed a multicenter, open-label trial in which we randomly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy, standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation. The primary outcome was the proportion of patients intubated at day 28; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28.
RESULTS: A total of 310 patients were included in the analyses. The intubation rate (primary outcome) was 38% (40 of 106 patients) in the high-flow-oxygen group, 47% (44 of 94) in the standard group, and 50% (55 of 110) in the noninvasive-ventilation group (P=0.18 for all comparisons). The number of ventilator-free days at day 28 was significantly higher in the high-flow-oxygen group (24±8 days, vs. 22±10 in the standard-oxygen group and 19±12 in the noninvasive-ventilation group; P=0.02 for all comparisons). The hazard ratio for death at 90 days was 2.01 (95% confidence interval [CI], 1.01 to 3.99) with standard oxygen versus high-flow oxygen (P=0.046) and 2.50 (95% CI, 1.31 to 4.78) with noninvasive ventilation versus high-flow oxygen (P=0.006).
CONCLUSIONS: In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates. There was a significant difference in favor of high-flow oxygen in 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique Interrégional 2010 of the French Ministry of Health; FLORALI ClinicalTrials.gov number, NCT01320384.).

PMID 25981908  N Engl J Med. 2015 Jun 4;372(23):2185-96. doi: 10.1056/・・・
著者: Loic Barrot, Pierre Asfar, Frederic Mauny, Hadrien Winiszewski, Florent Montini, Julio Badie, Jean-Pierre Quenot, Sebastien Pili-Floury, Belaid Bouhemad, Guillaume Louis, Bertrand Souweine, Olivier Collange, Julien Pottecher, Bruno Levy, Marc Puyraveau, Lucie Vettoretti, Jean-Michel Constantin, Gilles Capellier, LOCO2 Investigators and REVA Research Network
雑誌名: N Engl J Med. 2020 Mar 12;382(11):999-1008. doi: 10.1056/NEJMoa1916431.
Abstract/Text BACKGROUND: In patients with acute respiratory distress syndrome (ARDS), the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network recommends a target partial pressure of arterial oxygen (Pao2) between 55 and 80 mm Hg. Prospective validation of this range in patients with ARDS is lacking. We hypothesized that targeting the lower limit of this range would improve outcomes in patients with ARDS.
METHODS: In this multicenter, randomized trial, we assigned patients with ARDS to receive either conservative oxygen therapy (target Pao2, 55 to 70 mm Hg; oxygen saturation as measured by pulse oximetry [Spo2], 88 to 92%) or liberal oxygen therapy (target Pao2, 90 to 105 mm Hg; Spo2, ≥96%) for 7 days. The same mechanical-ventilation strategies were used in both groups. The primary outcome was death from any cause at 28 days.
RESULTS: After the enrollment of 205 patients, the trial was prematurely stopped by the data and safety monitoring board because of safety concerns and a low likelihood of a significant difference between the two groups in the primary outcome. Four patients who did not meet the eligibility criteria were excluded. At day 28, a total of 34 of 99 patients (34.3%) in the conservative-oxygen group and 27 of 102 patients (26.5%) in the liberal-oxygen group had died (difference, 7.8 percentage points; 95% confidence interval [CI], -4.8 to 20.6). At day 90, 44.4% of the patients in the conservative-oxygen group and 30.4% of the patients in the liberal-oxygen group had died (difference, 14.0 percentage points; 95% CI, 0.7 to 27.2). Five mesenteric ischemic events occurred in the conservative-oxygen group.
CONCLUSIONS: Among patients with ARDS, early exposure to a conservative-oxygenation strategy with a Pao2 between 55 and 70 mm Hg did not increase survival at 28 days. (Funded by the French Ministry of Health; LOCO2 ClinicalTrials.gov number, NCT02713451.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32160661  N Engl J Med. 2020 Mar 12;382(11):999-1008. doi: 10.105・・・
著者:
雑誌名: N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/NEJM200005043421801.
Abstract/Text BACKGROUND: Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients.
METHODS: Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less. The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28.
RESULTS: The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [+/-SD], 12+/-11 vs. 10+/-11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight (P<0.001), respectively, and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water (P<0.001), respectively.
CONCLUSIONS: In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.

PMID 10793162  N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/N・・・
著者: Matthias Briel, Maureen Meade, Alain Mercat, Roy G Brower, Daniel Talmor, Stephen D Walter, Arthur S Slutsky, Eleanor Pullenayegum, Qi Zhou, Deborah Cook, Laurent Brochard, Jean-Christophe M Richard, Francois Lamontagne, Neera Bhatnagar, Thomas E Stewart, Gordon Guyatt
雑誌名: JAMA. 2010 Mar 3;303(9):865-73. doi: 10.1001/jama.2010.218.
Abstract/Text CONTEXT: Trials comparing higher vs lower levels of positive end-expiratory pressure (PEEP) in adults with acute lung injury or acute respiratory distress syndrome (ARDS) have been underpowered to detect small but potentially important effects on mortality or to explore subgroup differences.
OBJECTIVES: To evaluate the association of higher vs lower PEEP with patient-important outcomes in adults with acute lung injury or ARDS who are receiving ventilation with low tidal volumes and to investigate whether these associations differ across prespecified subgroups.
DATA SOURCES: Search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (1996-January 2010) plus a hand search of conference proceedings (2004-January 2010).
STUDY SELECTION: Two reviewers independently screened articles to identify studies randomly assigning adults with acute lung injury or ARDS to treatment with higher vs lower PEEP (with low tidal volume ventilation) and also reporting mortality.
DATA EXTRACTION: Data from 2299 individual patients in 3 trials were analyzed using uniform outcome definitions. Prespecified effect modifiers were tested using multivariable hierarchical regression, adjusting for important prognostic factors and clustering effects.
RESULTS: There were 374 hospital deaths in 1136 patients (32.9%) assigned to treatment with higher PEEP and 409 hospital deaths in 1163 patients (35.2%) assigned to lower PEEP (adjusted relative risk [RR], 0.94; 95% confidence interval [CI], 0.86-1.04; P = .25). Treatment effects varied with the presence or absence of ARDS, defined by a value of 200 mm Hg or less for the ratio of partial pressure of oxygen to fraction of inspired oxygen concentration (P = .02 for interaction). In patients with ARDS (n = 1892), there were 324 hospital deaths (34.1%) in the higher PEEP group and 368 (39.1%) in the lower PEEP group (adjusted RR, 0.90; 95% CI, 0.81-1.00; P = .049); in patients without ARDS (n = 404), there were 50 hospital deaths (27.2%) in the higher PEEP group and 44 (19.4%) in the lower PEEP group (adjusted RR, 1.37; 95% CI, 0.98-1.92; P = .07). Rates of pneumothorax and vasopressor use were similar.
CONCLUSIONS: Treatment with higher vs lower levels of PEEP was not associated with improved hospital survival. However, higher levels were associated with improved survival among the subgroup of patients with ARDS.

PMID 20197533  JAMA. 2010 Mar 3;303(9):865-73. doi: 10.1001/jama.2010.・・・
著者: Claude Guérin, Jean Reignier, Jean-Christophe Richard, Pascal Beuret, Arnaud Gacouin, Thierry Boulain, Emmanuelle Mercier, Michel Badet, Alain Mercat, Olivier Baudin, Marc Clavel, Delphine Chatellier, Samir Jaber, Sylvène Rosselli, Jordi Mancebo, Michel Sirodot, Gilles Hilbert, Christian Bengler, Jack Richecoeur, Marc Gainnier, Frédérique Bayle, Gael Bourdin, Véronique Leray, Raphaele Girard, Loredana Baboi, Louis Ayzac, PROSEVA Study Group
雑誌名: N Engl J Med. 2013 Jun 6;368(23):2159-68. doi: 10.1056/NEJMoa1214103. Epub 2013 May 20.
Abstract/Text BACKGROUND: Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS.
METHODS: In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg, with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion.
RESULTS: A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group.
CONCLUSIONS: In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique National 2006 and 2010 of the French Ministry of Health; PROSEVA ClinicalTrials.gov number, NCT00527813.).

PMID 23688302  N Engl J Med. 2013 Jun 6;368(23):2159-68. doi: 10.1056/・・・
著者: Laurent Papazian, Jean-Marie Forel, Arnaud Gacouin, Christine Penot-Ragon, Gilles Perrin, Anderson Loundou, Samir Jaber, Jean-Michel Arnal, Didier Perez, Jean-Marie Seghboyan, Jean-Michel Constantin, Pierre Courant, Jean-Yves Lefrant, Claude Guérin, Gwenaël Prat, Sophie Morange, Antoine Roch, ACURASYS Study Investigators
雑誌名: N Engl J Med. 2010 Sep 16;363(12):1107-16. doi: 10.1056/NEJMoa1005372.
Abstract/Text BACKGROUND: In patients undergoing mechanical ventilation for the acute respiratory distress syndrome (ARDS), neuromuscular blocking agents may improve oxygenation and decrease ventilator-induced lung injury but may also cause muscle weakness. We evaluated clinical outcomes after 2 days of therapy with neuromuscular blocking agents in patients with early, severe ARDS.
METHODS: In this multicenter, double-blind trial, 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS within the previous 48 hours were randomly assigned to receive, for 48 hours, either cisatracurium besylate (178 patients) or placebo (162 patients). Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FIO2) of less than 150, with a positive end-expiratory pressure of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day in-hospital mortality rate), adjusted for predefined covariates and baseline differences between groups with the use of a Cox model.
RESULTS: The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P=0.04), after adjustment for both the baseline PaO2:FIO2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P=0.08). Mortality at 28 days was 23.7% (95% CI, 18.1 to 30.5) with cisatracurium and 33.3% (95% CI, 26.5 to 40.9) with placebo (P=0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups.
CONCLUSIONS: In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. (Funded by Assistance Publique-Hôpitaux de Marseille and the Programme Hospitalier de Recherche Clinique Régional 2004-26 of the French Ministry of Health; ClinicalTrials.gov number, NCT00299650.)

PMID 20843245  N Engl J Med. 2010 Sep 16;363(12):1107-16. doi: 10.1056・・・
著者: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Herbert P Wiedemann, Arthur P Wheeler, Gordon R Bernard, B Taylor Thompson, Douglas Hayden, Ben deBoisblanc, Alfred F Connors, R Duncan Hite, Andrea L Harabin
雑誌名: N Engl J Med. 2006 Jun 15;354(24):2564-75. doi: 10.1056/NEJMoa062200. Epub 2006 May 21.
Abstract/Text BACKGROUND: Optimal fluid management in patients with acute lung injury is unknown. Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary-organ perfusion.
METHODS: In a randomized study, we compared a conservative and a liberal strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology.
RESULTS: The rate of death at 60 days was 25.5 percent in the conservative-strategy group and 28.4 percent in the liberal-strategy group (P=0.30; 95 percent confidence interval for the difference, -2.6 to 8.4 percent). The mean (+/-SE) cumulative fluid balance during the first seven days was -136+/-491 ml in the conservative-strategy group and 6992+/-502 ml in the liberal-strategy group (P<0.001). As compared with the liberal strategy, the conservative strategy improved the oxygenation index ([mean airway pressure x the ratio of the fraction of inspired oxygen to the partial pressure of arterial oxygen]x100) and the lung injury score and increased the number of ventilator-free days (14.6+/-0.5 vs. 12.1+/-0.5, P<0.001) and days not spent in the intensive care unit (13.4+/-0.4 vs. 11.2+/-0.4, P<0.001) during the first 28 days but did not increase the incidence or prevalence of shock during the study or the use of dialysis during the first 60 days (10 percent vs. 14 percent, P=0.06).
CONCLUSIONS: Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures. These results support the use of a conservative strategy of fluid management in patients with acute lung injury. (ClinicalTrials.gov number, NCT00281268 [ClinicalTrials.gov].).

Copyright 2006 Massachusetts Medical Society.
PMID 16714767  N Engl J Med. 2006 Jun 15;354(24):2564-75. doi: 10.1056・・・
著者: Juliana Barr, Gilles L Fraser, Kathleen Puntillo, E Wesley Ely, Céline Gélinas, Joseph F Dasta, Judy E Davidson, John W Devlin, John P Kress, Aaron M Joffe, Douglas B Coursin, Daniel L Herr, Avery Tung, Bryce R H Robinson, Dorrie K Fontaine, Michael A Ramsay, Richard R Riker, Curtis N Sessler, Brenda Pun, Yoanna Skrobik, Roman Jaeschke, American College of Critical Care Medicine
雑誌名: Crit Care Med. 2013 Jan;41(1):263-306. doi: 10.1097/CCM.0b013e3182783b72.
Abstract/Text OBJECTIVE: To revise the "Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult" published in Critical Care Medicine in 2002.
METHODS: The American College of Critical Care Medicine assembled a 20-person, multidisciplinary, multi-institutional task force with expertise in guideline development, pain, agitation and sedation, delirium management, and associated outcomes in adult critically ill patients. The task force, divided into four subcommittees, collaborated over 6 yr in person, via teleconferences, and via electronic communication. Subcommittees were responsible for developing relevant clinical questions, using the Grading of Recommendations Assessment, Development and Evaluation method (http://www.gradeworkinggroup.org) to review, evaluate, and summarize the literature, and to develop clinical statements (descriptive) and recommendations (actionable). With the help of a professional librarian and Refworks database software, they developed a Web-based electronic database of over 19,000 references extracted from eight clinical search engines, related to pain and analgesia, agitation and sedation, delirium, and related clinical outcomes in adult ICU patients. The group also used psychometric analyses to evaluate and compare pain, agitation/sedation, and delirium assessment tools. All task force members were allowed to review the literature supporting each statement and recommendation and provided feedback to the subcommittees. Group consensus was achieved for all statements and recommendations using the nominal group technique and the modified Delphi method, with anonymous voting by all task force members using E-Survey (http://www.esurvey.com). All voting was completed in December 2010. Relevant studies published after this date and prior to publication of these guidelines were referenced in the text. The quality of evidence for each statement and recommendation was ranked as high (A), moderate (B), or low/very low (C). The strength of recommendations was ranked as strong (1) or weak (2), and either in favor of (+) or against (-) an intervention. A strong recommendation (either for or against) indicated that the intervention's desirable effects either clearly outweighed its undesirable effects (risks, burdens, and costs) or it did not. For all strong recommendations, the phrase "We recommend …" is used throughout. A weak recommendation, either for or against an intervention, indicated that the trade-off between desirable and undesirable effects was less clear. For all weak recommendations, the phrase "We suggest …" is used throughout. In the absence of sufficient evidence, or when group consensus could not be achieved, no recommendation (0) was made. Consensus based on expert opinion was not used as a substitute for a lack of evidence. A consistent method for addressing potential conflict of interest was followed if task force members were coauthors of related research. The development of this guideline was independent of any industry funding.
CONCLUSION: These guidelines provide a roadmap for developing integrated, evidence-based, and patient-centered protocols for preventing and treating pain, agitation, and delirium in critically ill patients.

PMID 23269131  Crit Care Med. 2013 Jan;41(1):263-306. doi: 10.1097/CCM・・・
著者: NICE-SUGAR Study Investigators, Simon Finfer, Dean R Chittock, Steve Yu-Shuo Su, Deborah Blair, Denise Foster, Vinay Dhingra, Rinaldo Bellomo, Deborah Cook, Peter Dodek, William R Henderson, Paul C Hébert, Stephane Heritier, Daren K Heyland, Colin McArthur, Ellen McDonald, Imogen Mitchell, John A Myburgh, Robyn Norton, Julie Potter, Bruce G Robinson, Juan J Ronco
雑誌名: N Engl J Med. 2009 Mar 26;360(13):1283-97. doi: 10.1056/NEJMoa0810625. Epub 2009 Mar 24.
Abstract/Text BACKGROUND: The optimal target range for blood glucose in critically ill patients remains unclear.
METHODS: Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). We defined the primary end point as death from any cause within 90 days after randomization.
RESULTS: Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39).
CONCLUSIONS: In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987.)

2009 Massachusetts Medical Society
PMID 19318384  N Engl J Med. 2009 Mar 26;360(13):1283-97. doi: 10.1056・・・
著者: Jean Reignier, Julie Boisramé-Helms, Laurent Brisard, Jean-Baptiste Lascarrou, Ali Ait Hssain, Nadia Anguel, Laurent Argaud, Karim Asehnoune, Pierre Asfar, Frédéric Bellec, Vlad Botoc, Anne Bretagnol, Hoang-Nam Bui, Emmanuel Canet, Daniel Da Silva, Michael Darmon, Vincent Das, Jérôme Devaquet, Michel Djibre, Frédérique Ganster, Maité Garrouste-Orgeas, Stéphane Gaudry, Olivier Gontier, Claude Guérin, Bertrand Guidet, Christophe Guitton, Jean-Etienne Herbrecht, Jean-Claude Lacherade, Philippe Letocart, Frédéric Martino, Virginie Maxime, Emmanuelle Mercier, Jean-Paul Mira, Saad Nseir, Gael Piton, Jean-Pierre Quenot, Jack Richecoeur, Jean-Philippe Rigaud, René Robert, Nathalie Rolin, Carole Schwebel, Michel Sirodot, François Tinturier, Didier Thévenin, Bruno Giraudeau, Amélie Le Gouge, NUTRIREA-2 Trial Investigators, Clinical Research in Intensive Care and Sepsis (CRICS) group
雑誌名: Lancet. 2018 Jan 13;391(10116):133-143. doi: 10.1016/S0140-6736(17)32146-3. Epub 2017 Nov 8.
Abstract/Text BACKGROUND: Whether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition.
METHODS: In this randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20-25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate <2 mmol/L). The primary endpoint was mortality on day 28 after randomisation in the intention-to-treat-population. This study is registered with ClinicalTrials.gov, number NCT01802099.
FINDINGS: After the second interim analysis, the independent Data Safety and Monitoring Board deemed that completing patient enrolment was unlikely to significantly change the results of the trial and recommended stopping patient recruitment. Between March 22, 2013, and June 30, 2015, 2410 patients were enrolled and randomly assigned; 1202 to the enteral group and 1208 to the parenteral group. By day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died (absolute difference estimate 2·0%; [95% CI -1·9 to 5·8]; p=0·33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0·89 [95% CI 0·72-1·09]; p=0·25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1·89 [1·62-2·20]; p<0·0001), diarrhoea (432 [36%] vs 393 [33%]; 1·20 [1·05-1·37]; p=0·009), bowel ischaemia (19 [2%] vs five [<1%]; 3·84 [1·43-10·3]; p=0·007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3·7 [1·03-13·2; p=0·04).
INTERPRETATION: In critically ill adults with shock, early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition.
FUNDING: La Roche-sur-Yon Departmental Hospital and French Ministry of Health.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29128300  Lancet. 2018 Jan 13;391(10116):133-143. doi: 10.1016/S0・・・
著者: Jonathan E Sevransky, Richard E Rothman, David N Hager, Gordon R Bernard, Samuel M Brown, Timothy G Buchman, Laurence W Busse, Craig M Coopersmith, Christine DeWilde, E Wesley Ely, Lindsay M Eyzaguirre, Alpha A Fowler, David F Gaieski, Michelle N Gong, Alex Hall, Jeremiah S Hinson, Michael H Hooper, Gabor D Kelen, Akram Khan, Mark A Levine, Roger J Lewis, Chris J Lindsell, Jessica S Marlin, Anna McGlothlin, Brooks L Moore, Katherine L Nugent, Samuel Nwosu, Carmen C Polito, Todd W Rice, Erin P Ricketts, Caroline C Rudolph, Fred Sanfilippo, Kert Viele, Greg S Martin, David W Wright, VICTAS Investigators
雑誌名: JAMA. 2021 Feb 23;325(8):742-750. doi: 10.1001/jama.2020.24505.
Abstract/Text Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis.
Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis.
Design, Setting, and Participants: Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020.
Interventions: Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone.
Main Outcomes and Measures: The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality.
Results: Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group.
Conclusions and Relevance: Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference.
Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

PMID 33620405  JAMA. 2021 Feb 23;325(8):742-750. doi: 10.1001/jama.202・・・
著者: Balasubramanian Venkatesh, Simon Finfer, Jeremy Cohen, Dorrilyn Rajbhandari, Yaseen Arabi, Rinaldo Bellomo, Laurent Billot, Maryam Correa, Parisa Glass, Meg Harward, Christopher Joyce, Qiang Li, Colin McArthur, Anders Perner, Andrew Rhodes, Kelly Thompson, Steve Webb, John Myburgh, ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group
雑誌名: N Engl J Med. 2018 Mar 1;378(9):797-808. doi: 10.1056/NEJMoa1705835. Epub 2018 Jan 19.
Abstract/Text BACKGROUND: Whether hydrocortisone reduces mortality among patients with septic shock is unclear.
METHODS: We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days.
RESULTS: From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia.
CONCLUSIONS: Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).

PMID 29347874  N Engl J Med. 2018 Mar 1;378(9):797-808. doi: 10.1056/N・・・
著者: Djillali Annane, Alain Renault, Christian Brun-Buisson, Bruno Megarbane, Jean-Pierre Quenot, Shidasp Siami, Alain Cariou, Xavier Forceville, Carole Schwebel, Claude Martin, Jean-François Timsit, Benoît Misset, Mohamed Ali Benali, Gwenhael Colin, Bertrand Souweine, Karim Asehnoune, Emmanuelle Mercier, Loïc Chimot, Claire Charpentier, Bruno François, Thierry Boulain, Franck Petitpas, Jean-Michel Constantin, Gilles Dhonneur, François Baudin, Alain Combes, Julien Bohé, Jean-François Loriferne, Roland Amathieu, Fabrice Cook, Michel Slama, Olivier Leroy, Gilles Capellier, Auguste Dargent, Tarik Hissem, Virginie Maxime, Eric Bellissant, CRICS-TRIGGERSEP Network
雑誌名: N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/NEJMoa1705716.
Abstract/Text BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock.
METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group).
RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group.
CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

PMID 29490185  N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/N・・・
著者: Didier Keh, Evelyn Trips, Gernot Marx, Stefan P Wirtz, Emad Abduljawwad, Sven Bercker, Holger Bogatsch, Josef Briegel, Christoph Engel, Herwig Gerlach, Anton Goldmann, Sven-Olaf Kuhn, Lars Hüter, Andreas Meier-Hellmann, Axel Nierhaus, Stefan Kluge, Josefa Lehmke, Markus Loeffler, Michael Oppert, Kerstin Resener, Dirk Schädler, Tobias Schuerholz, Philipp Simon, Norbert Weiler, Andreas Weyland, Konrad Reinhart, Frank M Brunkhorst, SepNet–Critical Care Trials Group
雑誌名: JAMA. 2016 Nov 1;316(17):1775-1785. doi: 10.1001/jama.2016.14799.
Abstract/Text Importance: Adjunctive hydrocortisone therapy is suggested by the Surviving Sepsis Campaign in refractory septic shock only. The efficacy of hydrocortisone in patients with severe sepsis without shock remains controversial.
Objective: To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock.
Design, Setting, and Participants: Double-blind, randomized clinical trial conducted from January 13, 2009, to August 27, 2013, with a follow-up of 180 days until February 23, 2014. The trial was performed in 34 intermediate or intensive care units of university and community hospitals in Germany, and it included 380 adult patients with severe sepsis who were not in septic shock.
Interventions: Patients were randomly allocated 1:1 either to receive a continuous infusion of 200 mg of hydrocortisone for 5 days followed by dose tapering until day 11 (n = 190) or to receive placebo (n = 190).
Main Outcomes and Measures: The primary outcome was development of septic shock within 14 days. Secondary outcomes were time until septic shock, mortality in the intensive care unit or hospital, survival up to 180 days, and assessment of secondary infections, weaning failure, muscle weakness, and hyperglycemia (blood glucose level >150 mg/dL [to convert to millimoles per liter, multiply by 0.0555]).
Results: The intention-to-treat population consisted of 353 patients (64.9% male; mean [SD] age, 65.0 [14.4] years). Septic shock occurred in 36 of 170 patients (21.2%) in the hydrocortisone group and 39 of 170 patients (22.9%) in the placebo group (difference, -1.8%; 95% CI, -10.7% to 7.2%; P = .70). No significant differences were observed between the hydrocortisone and placebo groups for time until septic shock; mortality in the intensive care unit or in the hospital; or mortality at 28 days (15 of 171 patients [8.8%] vs 14 of 170 patients [8.2%], respectively; difference, 0.5%; 95% CI, -5.6% to 6.7%; P = .86), 90 days (34 of 171 patients [19.9%] vs 28 of 168 patients [16.7%]; difference, 3.2%; 95% CI, -5.1% to 11.4%; P = .44), and 180 days (45 of 168 patients [26.8%] vs 37 of 167 patients [22.2%], respectively; difference, 4.6%; 95% CI, -4.6% to 13.7%; P = .32). In the hydrocortisone vs placebo groups, 21.5% vs 16.9% had secondary infections, 8.6% vs 8.5% had weaning failure, 30.7% vs 23.8% had muscle weakness, and 90.9% vs 81.5% had hyperglycemia.
Conclusions and Relevance: Among adults with severe sepsis not in septic shock, use of hydrocortisone compared with placebo did not reduce the risk of septic shock within 14 days. These findings do not support the use of hydrocortisone in these patients.
Trial Registration: clinicaltrials.gov Identifier: NCT00670254.

PMID 27695824  JAMA. 2016 Nov 1;316(17):1775-1785. doi: 10.1001/jama.2・・・
著者: Lars B Holst, Nicolai Haase, Jørn Wetterslev, Jan Wernerman, Anne B Guttormsen, Sari Karlsson, Pär I Johansson, Anders Aneman, Marianne L Vang, Robert Winding, Lars Nebrich, Helle L Nibro, Bodil S Rasmussen, Johnny R M Lauridsen, Jane S Nielsen, Anders Oldner, Ville Pettilä, Maria B Cronhjort, Lasse H Andersen, Ulf G Pedersen, Nanna Reiter, Jørgen Wiis, Jonathan O White, Lene Russell, Klaus J Thornberg, Peter B Hjortrup, Rasmus G Müller, Morten H Møller, Morten Steensen, Inga Tjäder, Kristina Kilsand, Suzanne Odeberg-Wernerman, Brit Sjøbø, Helle Bundgaard, Maria A Thyø, David Lodahl, Rikke Mærkedahl, Carsten Albeck, Dorte Illum, Mary Kruse, Per Winkel, Anders Perner, TRISS Trial Group, Scandinavian Critical Care Trials Group
雑誌名: N Engl J Med. 2014 Oct 9;371(15):1381-91. doi: 10.1056/NEJMoa1406617. Epub 2014 Oct 1.
Abstract/Text BACKGROUND: Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established.
METHODS: In this multicenter, parallel-group trial, we randomly assigned patients in the intensive 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 measure was death by 90 days after randomization.
RESULTS: We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. 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.
CONCLUSIONS: Among 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 Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.).

PMID 25270275  N Engl J Med. 2014 Oct 9;371(15):1381-91. doi: 10.1056/・・・
著者: Stéphane Gaudry, David Hajage, Fréderique Schortgen, Laurent Martin-Lefevre, Bertrand Pons, Eric Boulet, Alexandre Boyer, Guillaume Chevrel, Nicolas Lerolle, Dorothée Carpentier, Nicolas de Prost, Alexandre Lautrette, Anne Bretagnol, Julien Mayaux, Saad Nseir, Bruno Megarbane, Marina Thirion, Jean-Marie Forel, Julien Maizel, Hodane Yonis, Philippe Markowicz, Guillaume Thiery, Florence Tubach, Jean-Damien Ricard, Didier Dreyfuss, AKIKI Study Group
雑誌名: N Engl J Med. 2016 Jul 14;375(2):122-33. doi: 10.1056/NEJMoa1603017. Epub 2016 May 15.
Abstract/Text BACKGROUND: The timing of renal-replacement therapy in critically ill patients who have acute kidney injury but no potentially life-threatening complication directly related to renal failure is a subject of debate.
METHODS: In this multicenter randomized trial, we assigned patients with severe acute kidney injury (Kidney Disease: Improving Global Outcomes [KDIGO] classification, stage 3 [stages range from 1 to 3, with higher stages indicating more severe kidney injury]) who required mechanical ventilation, catecholamine infusion, or both and did not have a potentially life-threatening complication directly related to renal failure to either an early or a delayed strategy of renal-replacement therapy. With the early strategy, renal-replacement therapy was started immediately after randomization. With the delayed strategy, renal-replacement therapy was initiated if at least one of the following criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, blood urea nitrogen level higher than 112 mg per deciliter, or oliguria for more than 72 hours after randomization. The primary outcome was overall survival at day 60.
RESULTS: A total of 620 patients underwent randomization. The Kaplan-Meier estimates of mortality at day 60 did not differ significantly between the early and delayed strategies; 150 deaths occurred among 311 patients in the early-strategy group (48.5%; 95% confidence interval [CI], 42.6 to 53.8), and 153 deaths occurred among 308 patients in the delayed-strategy group (49.7%, 95% CI, 43.8 to 55.0; P=0.79). A total of 151 patients (49%) in the delayed-strategy group did not receive renal-replacement therapy. The rate of catheter-related bloodstream infections was higher in the early-strategy group than in the delayed-strategy group (10% vs. 5%, P=0.03). Diuresis, a marker of improved kidney function, occurred earlier in the delayed-strategy group (P<0.001).
CONCLUSIONS: In a trial involving critically ill patients with severe acute kidney injury, we found no significant difference with regard to mortality between an early and a delayed strategy for the initiation of renal-replacement therapy. A delayed strategy averted the need for renal-replacement therapy in an appreciable number of patients. (Funded by the French Ministry of Health; ClinicalTrials.gov number, NCT01932190.).

PMID 27181456  N Engl J Med. 2016 Jul 14;375(2):122-33. doi: 10.1056/N・・・
著者: Saber D Barbar, Raphaël Clere-Jehl, Abderrahmane Bourredjem, Romain Hernu, Florent Montini, Rémi Bruyère, Christine Lebert, Julien Bohé, Julio Badie, Jean-Pierre Eraldi, Jean-Philippe Rigaud, Bruno Levy, Shidasp Siami, Guillaume Louis, Lila Bouadma, Jean-Michel Constantin, Emmanuelle Mercier, Kada Klouche, Damien du Cheyron, Gaël Piton, Djillali Annane, Samir Jaber, Thierry van der Linden, Gilles Blasco, Jean-Paul Mira, Carole Schwebel, Loïc Chimot, Philippe Guiot, Mai-Anh Nay, Ferhat Meziani, Julie Helms, Claire Roger, Benjamin Louart, Remi Trusson, Auguste Dargent, Christine Binquet, Jean-Pierre Quenot, IDEAL-ICU Trial Investigators and the CRICS TRIGGERSEP Network
雑誌名: N Engl J Med. 2018 Oct 11;379(15):1431-1442. doi: 10.1056/NEJMoa1803213.
Abstract/Text BACKGROUND: Acute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal-replacement therapy is the standard of care for severe acute kidney injury, the ideal time for initiation remains controversial.
METHODS: In a multicenter, randomized, controlled trial, we assigned patients with early-stage septic shock who had severe acute kidney injury at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification system but without life-threatening complications related to acute kidney injury to receive renal-replacement therapy either within 12 hours after documentation of failure-stage acute kidney injury (early strategy) or after a delay of 48 hours if renal recovery had not occurred (delayed strategy). The failure stage of the RIFLE classification system is characterized by a serum creatinine level 3 times the baseline level (or ≥4 mg per deciliter with a rapid increase of ≥0.5 mg per deciliter), urine output less than 0.3 ml per kilogram of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome was death at 90 days.
RESULTS: The trial was stopped early for futility after the second planned interim analysis. A total of 488 patients underwent randomization; there were no significant between-group differences in the characteristics at baseline. Among the 477 patients for whom follow-up data at 90 days were available, 58% of the patients in the early-strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of the patients in the delayed-strategy group (41 patients).
CONCLUSIONS: Among patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy. (Funded by the French Ministry of Health; IDEAL-ICU ClinicalTrials.gov number, NCT01682590 .).

PMID 30304656  N Engl J Med. 2018 Oct 11;379(15):1431-1442. doi: 10.10・・・
著者: STARRT-AKI Investigators, Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group, United Kingdom Critical Care Research Group, Canadian Nephrology Trials Network, Irish Critical Care Trials Group, Sean M Bagshaw, Ron Wald, Neill K J Adhikari, Rinaldo Bellomo, Bruno R da Costa, Didier Dreyfuss, Bin Du, Martin P Gallagher, Stéphane Gaudry, Eric A Hoste, François Lamontagne, Michael Joannidis, Giovanni Landoni, Kathleen D Liu, Daniel F McAuley, Shay P McGuinness, Javier A Neyra, Alistair D Nichol, Marlies Ostermann, Paul M Palevsky, Ville Pettilä, Jean-Pierre Quenot, Haibo Qiu, Bram Rochwerg, Antoine G Schneider, Orla M Smith, Fernando Thomé, Kevin E Thorpe, Suvi Vaara, Matthew Weir, Amanda Y Wang, Paul Young, Alexander Zarbock
雑誌名: N Engl J Med. 2020 Jul 16;383(3):240-251. doi: 10.1056/NEJMoa2000741.
Abstract/Text BACKGROUND: Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain.
METHODS: We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury. Patients were randomly assigned to receive an accelerated strategy of renal-replacement therapy (in which therapy was initiated within 12 hours after the patient had met eligibility criteria) or a standard strategy (in which renal-replacement therapy was discouraged unless conventional indications developed or acute kidney injury persisted for >72 hours). The primary outcome was death from any cause at 90 days.
RESULTS: Of the 3019 patients who had undergone randomization, 2927 (97.0%) were included in the modified intention-to-treat analysis (1465 in the accelerated-strategy group and 1462 in the standard-strategy group). Of these patients, renal-replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and in 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 643 patients (43.9%) in the accelerated-strategy group and in 639 (43.7%) in the standard-strategy group (relative risk, 1.00; 95% confidence interval [CI], 0.93 to 1.09; P = 0.92). Among survivors at 90 days, continued dependence on renal-replacement therapy was confirmed in 85 of 814 patients (10.4%) in the accelerated-strategy group and in 49 of 815 patients (6.0%) in the standard-strategy group (relative risk, 1.74; 95% CI, 1.24 to 2.43). Adverse events occurred in 346 of 1503 patients (23.0%) in the accelerated-strategy group and in 245 of 1489 patients (16.5%) in the standard-strategy group (P<0.001).
CONCLUSIONS: Among critically ill patients with acute kidney injury, an accelerated renal-replacement strategy was not associated with a lower risk of death at 90 days than a standard strategy. (Funded by the Canadian Institutes of Health Research and others; STARRT-AKI ClinicalTrials.gov number, NCT02568722.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32668114  N Engl J Med. 2020 Jul 16;383(3):240-251. doi: 10.1056/・・・
著者: Dinna N Cruz, Massimo Antonelli, Roberto Fumagalli, Francesca Foltran, Nicola Brienza, Abele Donati, Vincenzo Malcangi, Flavia Petrini, Giada Volta, Franco M Bobbio Pallavicini, Federica Rottoli, Francesco Giunta, Claudio Ronco
雑誌名: JAMA. 2009 Jun 17;301(23):2445-52. doi: 10.1001/jama.2009.856.
Abstract/Text CONTEXT: Polymyxin B fiber column is a medical device designed to reduce blood endotoxin levels in sepsis. Gram-negative-induced abdominal sepsis is likely associated with high circulating endotoxin. Reducing circulating endotoxin levels with polymyxin B hemoperfusion could potentially improve patient clinical outcomes.
OBJECTIVE: To determine whether polymyxin B hemoperfusion added to conventional medical therapy improves clinical outcomes (mean arterial pressure [MAP], vasopressor requirement, oxygenation, organ dysfunction) and mortality compared with conventional therapy alone.
DESIGN, SETTING, AND PATIENTS: A prospective, multicenter, randomized controlled trial (Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis [EUPHAS]) conducted at 10 Italian tertiary care intensive care units between December 2004 and December 2007. Sixty-four patients were enrolled with severe sepsis or septic shock who underwent emergency surgery for intra-abdominal infection.
INTERVENTION: Patients were randomized to either conventional therapy (n=30) or conventional therapy plus 2 sessions of polymyxin B hemoperfusion (n=34).
MAIN OUTCOME MEASURES: Primary outcome was change in MAP and vasopressor requirement, and secondary outcomes were PaO(2)/FIO(2) (fraction of inspired oxygen) ratio, change in organ dysfunction measured using Sequential Organ Failure Assessment (SOFA) scores, and 28-day mortality.
RESULTS: MAP increased (76 to 84 mm Hg; P = .001) and vasopressor requirement decreased (inotropic score, 29.9 to 6.8; P < .001) at 72 hours in the polymyxin B group but not in the conventional therapy group (MAP, 74 to 77 mm Hg; P = .37; inotropic score, 28.6 to 22.4; P = .14). The PaO(2)/FIO(2) ratio increased slightly (235 to 264; P = .049) in the polymyxin B group but not in the conventional therapy group (217 to 228; P = .79). SOFA scores improved in the polymyxin B group but not in the conventional therapy group (change in SOFA, -3.4 vs -0.1; P < .001), and 28-day mortality was 32% (11/34 patients) in the polymyxin B group and 53% (16/30 patients) in the conventional therapy group (unadjusted hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.20-0.94; adjusted HR, 0.36; 95% CI, 0.16-0.80).
CONCLUSION: In this preliminary study, polymyxin B hemoperfusion added to conventional therapy significantly improved hemodynamics and organ dysfunction and reduced 28-day mortality in a targeted population with severe sepsis and/or septic shock from intra-abdominal gram-negative infections.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00629382.

PMID 19531784  JAMA. 2009 Jun 17;301(23):2445-52. doi: 10.1001/jama.20・・・
著者: R Phillip Dellinger, Sean M Bagshaw, Massimo Antonelli, Debra M Foster, David J Klein, John C Marshall, Paul M Palevsky, Lawrence S Weisberg, Christa A Schorr, Stephen Trzeciak, Paul M Walker, EUPHRATES Trial Investigators
雑誌名: JAMA. 2018 Oct 9;320(14):1455-1463. doi: 10.1001/jama.2018.14618.
Abstract/Text Importance: Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity using polymyxin B hemoperfusion may improve clinical outcomes.
Objective: To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity.
Design, Setting, and Participants: Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017.
Interventions: Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients).
Main Outcomes and Measures: The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9.
Results: Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, -5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, -10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group).
Conclusions and Relevance: Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days.
Trial Registration: ClinicalTrials.gov Identifier: NCT01046669.

PMID 30304428  JAMA. 2018 Oct 9;320(14):1455-1463. doi: 10.1001/jama.2・・・
著者: Jean-Louis Vincent, Bruno Francois, Igor Zabolotskikh, Mradul Kumar Daga, Jean-Baptiste Lascarrou, Mikhail Y Kirov, Ville Pettilä, Xavier Wittebole, Ferhat Meziani, Emmanuelle Mercier, Suzana M Lobo, Philip S Barie, Mark Crowther, Charles T Esmon, Jawed Fareed, Satoshi Gando, Kenneth J Gorelick, Marcel Levi, Jean-Paul Mira, Steven M Opal, Joseph Parrillo, James A Russell, Hidehiko Saito, Kazuhisa Tsuruta, Takumi Sakai, David Fineberg, SCARLET Trial Group
雑誌名: JAMA. 2019 May 28;321(20):1993-2002. doi: 10.1001/jama.2019.5358.
Abstract/Text Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy.
Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy.
Design, Setting, and Participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019.
Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days.
Main Outcome and Measures: The primary end point was 28-day all-cause mortality.
Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group.
Conclusions and Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality.
Trial Registration: ClinicalTrials.gov Identifier: NCT01598831.

PMID 31104069  JAMA. 2019 May 28;321(20):1993-2002. doi: 10.1001/jama.・・・
著者: Dale M Needham, Judy Davidson, Henry Cohen, Ramona O Hopkins, Craig Weinert, Hannah Wunsch, Christine Zawistowski, Anita Bemis-Dougherty, Susan C Berney, O Joseph Bienvenu, Susan L Brady, Martin B Brodsky, Linda Denehy, Doug Elliott, Carl Flatley, Andrea L Harabin, Christina Jones, Deborah Louis, Wendy Meltzer, Sean R Muldoon, Jeffrey B Palmer, Christiane Perme, Marla Robinson, David M Schmidt, Elizabeth Scruth, Gayle R Spill, C Porter Storey, Marta Render, John Votto, Maurene A Harvey
雑誌名: Crit Care Med. 2012 Feb;40(2):502-9. doi: 10.1097/CCM.0b013e318232da75.
Abstract/Text BACKGROUND: Millions of patients are discharged from intensive care units annually. These intensive care survivors and their families frequently report a wide range of impairments in their health status which may last for months and years after hospital discharge.
OBJECTIVES: To report on a 2-day Society of Critical Care Medicine conference aimed at improving the long-term outcomes after critical illness for patients and their families.
PARTICIPANTS: Thirty-one invited stakeholders participated in the conference. Stakeholders represented key professional organizations and groups, predominantly from North America, which are involved in the care of intensive care survivors after hospital discharge.
DESIGN: Invited experts and Society of Critical Care Medicine members presented a summary of existing data regarding the potential long-term physical, cognitive and mental health problems after intensive care and the results from studies of postintensive care unit interventions to address these problems. Stakeholders provided reactions, perspectives, concerns and strategies aimed at improving care and mitigating these long-term health problems.
MEASUREMENTS AND MAIN RESULTS: Three major themes emerged from the conference regarding: (1) raising awareness and education, (2) understanding and addressing barriers to practice, and (3) identifying research gaps and resources. Postintensive care syndrome was agreed upon as the recommended term to describe new or worsening problems in physical, cognitive, or mental health status arising after a critical illness and persisting beyond acute care hospitalization. The term could be applied to either a survivor or family member.
CONCLUSIONS: Improving care for intensive care survivors and their families requires collaboration between practitioners and researchers in both the inpatient and outpatient settings. Strategies were developed to address the major themes arising from the conference to improve outcomes for survivors and families.

PMID 21946660  Crit Care Med. 2012 Feb;40(2):502-9. doi: 10.1097/CCM.0・・・

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから