講義 救急・集中治療領域における免疫学的考察と臨床研究の重要性

講義　救急・集中治療領域における免疫学的考察と臨床研究の重要性

 

名古屋大学大学院医学系研究科 救急・集中治療医学分野

松田直之

 

はじめに

　免疫（immunity）は，異物に対する生体の防御機能であり，ローマ共和制時代の元老院議員の課税や罰則の法的免除を意味するimmunitasを語源とする^1）。生体の免疫反応は，大きく2つに分類され，生まれながらに既に獲得している自然免疫（innate immunity）や天然免疫（native immunity），そして微生物や癌などの異物により刺激されて防御能力を獲得する適応免疫（adaptive immunity）の2つのパターンが知られている。

　このような免疫は，白血球系細胞と上皮細胞などの協調と調和の中で行われる。自然免疫では，好中球，マクロファージ，ナチュラルキラー細胞（NK細胞）などの食細胞と補体が重要な役割を担う。これらの食細胞には，異物を認識するToll-like受容体やスカベンジャー受容体などの細胞内情報伝達系が存在する。一方，適応免疫は，Bリンパ球とBリンパ球が産生する抗体が中心的役割を担う。抗体は，ウイルスや毒素などの異物の暴露から2〜4日遅れて，Bリンパ球より産生される。

　虚血，細胞死，感染，異物などの生体侵襲は，交感神経と副交感神経の自律神経バランス，炎症性サイトカインと抗炎症性サイトカインのサイトカインバランス，ホルモン分泌変化において，免疫担当細胞に細胞数および機能変化をもたらす。外傷，crash症候群，環境異常症の管理においては虚血と壊死の側面から，感染症学については異物に対する観点から，ミトコンドリア細胞死とともに生体侵襲を捉え，基礎研究では創薬基盤形成を目標とし，臨床研究の側面からはこれらの管理学を発展させる必要がある。本稿は，生体侵襲の与える免疫機構への影響を総論としてまとめ，適時，内容をアップグレードさせることで，救急・集中治療医がその専門性をより一層に高めるために，生体侵襲と免疫の関係についての理解を深めることを目的とする。

 

１．自然免疫と細胞性免疫

　生体が展開する免疫反応は，発生面では自然免疫と適応免疫，機能面では細胞性免疫と体液性免疫の大きく2つに分類される。これらに関与する免疫担当細胞は，骨髄の造血幹細胞（hematopoietic stem cell：HSC）^2）に由来し，HSCの分化したものである（図1）。細胞性免疫は，主に好中球，マクロファージ，樹状細胞が担当する。液性免疫は，Bリンパ球の抗体産生が重要であり，ウイルスなどの異物に対する中和と排除をもたらす。

　細胞性免疫として貪食能力を持つ細胞は，食細胞（phagocyte）と呼ばれる。食細胞は，好中球，マクロファージ，樹状細胞である。好中球は，ヒト成人の末梢血で40~70％（約65%）を占め，ヒトの自然免疫における中心を担う。マクロファージは，単球が分化したものであり，組織に移行する中で，ミクログリア（脳），肺胞マクロファージ（肺），クッパー細胞（肝臓），メサンギウム細胞（腎臓），破骨細胞（骨），ランゲルハンス細胞（皮膚），類上皮細胞，巨細胞などとして機能する。また，樹状細胞は，末梢に存在する時期の未成熟な状態では微生物や異物を取り込む働きを持ち，末梢で勉強すると成熟型樹状細胞として組織からリンパ組織へ移動し，さらに長い樹状突起を伸し，二次リンパ組織内でTリンパ球と結合し，Tリンパ球を活性化させる。Tリンパ球を活性化させる際に，樹状細胞の役割は大きい。このような食細胞において，異物との関わりを外傷管理や手術管理で考えることは重要であり，食細胞機能がどのように修飾されるかの評価は診療において重要である。

　組織における上皮系細胞，血管内皮細胞，そして，免疫担当細胞として好中球，マクロファージ，幼若型樹状細胞のような食細胞は，Toll-like受容体^3-5）やスカベンジャー受容体^6-8）を発現し，自然免疫や死細胞の除去に寄与している。スカベンジャー受容体は，異物や死細胞の貪食を行うものであり，炎症期における重要な役割を担う。スカベンジャー受容体^6-8）は，表1にように直接に結合する自然免疫型受容体と補体や抗体によってオプソニン化された粒子に反応するオプソニン受容体に区分されている。

　一方，好塩基球，好酸球，肥満細胞は，消化管，呼吸器，尿管の粘膜上皮における生体防御に関与している。これらの好塩基球，好酸球，肥満細胞は，直接に異物を認識できるが，貪食能はなく，細胞質内の顆粒分子を細胞外に放出することで，異物を除去する。寄生虫などの大きな異物に対して効力を持つ。

 

２．適応免疫と体液性免疫

　適応免疫と体液性免疫に関与するリンパ球は，血液中では総白血球数の20~40%（約30%）であり，骨髄で成熟するBリンパ球と，胸腺で成熟するTリンパ球^9-11）に分類される。リンパ球数が減少する病態は，低栄養と交感神経緊張であり，ウイルス感染症やエイズでも低下する。リンパ球のうち，液性免疫として抗体を産生するのはBリンパ球である。Tリンパ球は，細胞傷害性T細胞（cytotoxic T cell，キラーT細胞）とヘルパーT細胞（helper T cell）の2つに分類され，細胞傷害性T細胞は，ウイルスやレジオネラなどの細胞内寄生微生物を傷害させる。ヘルパーT細胞は，B細胞の抗原産生を活性化させる補助的な作用を持ち，さらに好塩基球，好酸球，肥満細胞の活性化に関与する。また，リンパ球の中には，細胞膜上に抗原特異的受容体を発現させていないナチュラルキラー細胞（NK細胞）^{12, 13）}が存在する。ヘルパーT細胞やNK細胞は，異物を認識する際に，主要組織適合遺伝子複合体（major histocompatibility complex：MHC）を用いる特徴がある。

 

３. MHC分子の発現と機能

　ヒトのMHCは，MHCクラスⅠ分子^{14, 15）}とMHCクラスⅡ分子^{16 ,17）}として2つのクラスターに分類されており，これらは遺伝子領域6p21.3で転写される。このゲノム領域は，免疫に関与する多くの分子を産生する領域であり，免疫応答の中心をなす領域である。翻訳後のMHCは，α鎖，β鎖および結合するペプチドの３量体であり，MHCクラスⅠ分子のβ鎖はβ2ミクログロブリンである。結合できるペプチド長は，MHCクラスⅠ分子でアミノ残基8~10個，MHCクラスⅡ分子で10~20個である。MHCはそれぞれ，細胞傷害性T細胞とヘルパーT細胞の機能において重要な役割を担う。

　MHCクラスⅠ分子^{14, 15）}は，細胞傷害性T細胞だけではなく，ほぼすべての細胞に存在しており，細胞質内でプロテアーゼにより消化されたベプチドと結合し，細胞膜上へ輸送する機能を持つ（図２）。一方，MHCクラスⅡ分子^{16 ,17）}は，B細胞，マクロファージ，樹状細胞，NK細胞に高密度で発現しており，エンドソームで分解されて産生されたペプチドを細胞膜上に運搬し，ヘルパーT細胞による補助作用を強化する働きをする。例えば，B細胞では，抗体を細胞膜表面に膜型受容体として持つため，ここに結合した抗原をエンドサイトーシスとして細胞内へ運搬し，リソソームでペプチドに分解されるとMHCクラスⅡ分子により細胞膜上に運搬され，結合したヘルパーT細胞がB細胞の形質細胞への分化を誘導し，抗体産生を高める（図3）。また，マクロファージではMHCクラスⅡ分子を発現しており，マクロファージに内で消化されたペプチドをマクロファージの細胞膜上に発現させ，ヘルパーT細胞との連動によりマクロファージを活性化させる（図4）。このように，MHCクラスⅡ分子は，細胞内のペプチドを細胞膜上に運搬し，細胞膜上に発現させ，B細胞，マクロファージ，樹状細胞， NK細胞の機能を高める作用を担う。　

　また，MHCには，CD4やCD8などの共同受容体（co-receptor）が存在し，胸腺におけるT細胞の分化を補助している。CD8は，MHCクラスⅠ分子の共同受容体であり，細胞傷害性T細胞の異物に対する認識を高める。一方，CD4は，MHCクラスⅡ分子の共同受容体であり，マクロファージ，樹状細胞，およびB細胞の異物認識を高める。

 

４．補体の活性化と機能

　補体^{18 ,19）}は，自然免疫として細胞貪食に関与するほか，抗原のオプソニン化，標的細胞への細胞膜傷害性分子複合体（membrane attack complex）^18-20）の活性化，抗体産生促進などを主作用とする。この補体系は，約30種類の血清蛋白と膜蛋白で構成されている。C1～C9の補体蛋白， B因子，D因子，マンノース結合レクチン関連セリンプロテアーゼMASP（-1, -2, -3），プロペルジンなどが代表的分子である（表２）。補体の活性化は，①抗原・抗体複合体による古典的経路，② 病原菌細胞膜に結合した抗体による第２経路，③ マンノース結合レクチンやリガンド結合型フィコリンなどによるレクチン経路の3つの経路（図5）が知られており，補体受容体（表3）を介した反応として説明できる。補体欠損による病態としては，感染症罹患率の増加が知られているほか，C1，C2, C4の欠損により古典的経路やレクチン経路が障害されると全身性エリテマトーデスの発症が高まることが知られている。

 

５. T細胞の活性化

　T細胞は，胸腺内で成熟し，血液，二次リンパ組織，輸出リンパ管を循環しており，二次リンパ組織において成熟樹状細胞のMHC複合体と結合することによってエフェクターT細胞として活性化する。まず，胸腺においてT細胞は，Runx^21）とTh-POX^22）の２つの転写因子の関与により，CD8とCD４の発現制御が行われていることが確認されている。Runx^21）は，T細胞においてCD８を発現させ，細胞傷害性T細胞としての分化をもたらす。一方，Th-POX^22）は，T細胞にCD4を発現させ，ヘルパーT細胞としての分化をもたらす。このような過程において，成熟樹状細胞はナイーブT細胞に対してIL−２受容体α鎖（CD25）とIL-2の転写を高め，T細胞の成熟と活性化に関与する。T細胞におけるIL-2産生に関与する転写活性因子としては，① NFAT（nuclear factor of activated T cell），② NF−κB（nuclear factor-κB），③ AP-1（activator protein-1），④ Oct1の４つの関与が知られている。

　このような状況において，CD4陽性ヘルパーT細胞は，Th1，Th17，Th2，Tregに分化する細胞内情報伝達シグナルを持つ（図6）。 Th1細胞は，IFN-γを産生し，マクロファージ，NK細胞，細胞傷害性T細胞の病原体排除機能を増強させる。Th17細胞は，IL-17を産生する細胞であり，IL-17RA/RC受容体の存在する好中球の活性化に関与する。一方，Th2細胞は，IL-４産生を特徴とし，好酸球，好塩基球，肥満細胞などの上皮系バリア機能を誘導する。Tregは，胸腺で誘導される内在性Treg（natural Treg：nTreg）と末梢で分化誘導される誘導性Treg（inducible Treg：iTregs）に分類されており， nTregは CD4⁺ CD25^high であるT細胞として，FoxP3転写因子活性により誘導される。Tregは，IL-10およびTGF-βを産生することで細胞傷害性T細胞などの攻撃性を抑制するが，炎症回復期の線維芽細胞などの増殖にも関与している。

 

６．生体侵襲におけるDANPSとPAMPS

　生体の細胞傷害や微生物との反応においては細胞性免疫が働くが，産生される炎症性サイトカインや炎症性分子により炎症という別な表現形が現れる。これらの反応は， damage-associated molecular patterns（DAMPs）と総称され，微生物との反応においてはpathogen-associated molecular patterns（PAMPs）と呼称され^{5, 23)}，このような2012年レベルのテクニカルタームの出現により，多くの言葉を説明に用いずに共通概念を描くことができるようになった。現在，2016年の段階では，虚血，細胞死，ミトコンドリア死などに伴い生体内で増加する内因性分子の受容体反応も解明されてきている。Toll-like受容体，nucleotide-binding oligomerization domain（NOD）， NOD-like receptors （NLRs），AIM2-like receptors（ALRs），retinoic acid-inducible gene-Ⅰ（RIG-Ⅰ）like receptors（RLRs），C型レクチン受容体などは，主要なDAMPs受容体であり，細胞性免疫と炎症を考える上で重要である。 Toll-like受容体⁵⁾は，PAMPs受容体としてのみではなく，DAMPs受容体としての機能も持つ（表4）。

 

７．免疫能に対する生体侵襲の考察

　生体侵襲については，私は2000年より，①虚血，②細胞死（壊死），③感染，④異物の4つとして，生体への侵襲の入力を説明してきた。結果としては，交感神経・副交感神経の活性バランス，サイトカイン産生，ホルモン分泌の表情（現れ方）の観察が重要である。外傷や手術などにおいては，直接的な組織傷害，虚血再灌流，組織乾燥などの影響により，DAMPs産生に伴うDAMPs受容体反応^{5, 23)}として炎症が高まるばかりか，食細胞機能が変化する。外傷侵襲は，Th1/Th2バランスを低下させることが知られており^{24, 25）}，細胞性免疫低下として好中球やマクロファージなどの食細胞機能が低下し，DAMPsの組織内クリアランスの低下や，微生物や腫瘍細胞などに対する防御能が低下する可能性に注意する。さらに，DAMPsの蓄積は，組織・上皮系細胞の炎症性シグナルとして，急性肺傷害，急性腎傷害，播種性血管内凝固などの多臓器不全の誘引となる可能性を持つ^5）。

　このような状態の集中治療管理では，プロポフォール^{26, 27）}やデクスメデトミジン^28）などを鎮静剤として用いるが，これらはTh2有意に傾いたTh1/Th2バランスをTh1方向に改善させる傾向がある。鎮痛薬として使用されるモルヒネやフェンタニールは，オピオイドμ受容体を介してCD4陽性ヘルパーT細胞数を低下させ，CD8陽性細胞傷害性T細胞を増加させることが知られている^29-31）。手術領域では，ASA physical status class 3あるいはclass 4の肺小細胞癌に対する24症例の前向き研究^-32）として，硬膜外麻酔やフェンタニールによる術中・術後の疼痛管理で，術後１日におけるTh1/Th2バランスを術前と同等に維持できるという結論である。　

　生体侵襲期において交感神経活性を抑制することの意義は，血行動態の安定化や酸素需要の適正化に加えて，①コルチゾルの分泌抑制，②白血球系細胞の機能維持にある。生体侵襲による交感神経緊張は，代謝性アシドーシスの呼吸性代償，つまり過換気応答などの影響も受け，青斑核などからのノルエピネフリンの放出を介して視床下部からのCRH（corticotropin-releasing hormone）および下垂体前葉からのACTH（adrenocorticotropic hormone）の分泌を高め，副腎皮質からのコルチゾル分泌を高める。これらは，食細胞機能を低下させる可能性や多能性分化細胞の機能不全を導く可能性がある。血漿コルチゾルは，2~18μg/dLレベルの日内変動で維持されているが，生体侵襲により反応性にコルチゾルが高い状態では，免疫抑制状態となることを確認できる。フェンタニール^33），バルビタールやプロポフォール^34），ミダゾラム^35）やエトミデート^36）などは，下垂体前葉からのACTH放出や副腎皮質からのコルチゾル分泌を抑制する。アドレナリンα₂作動薬デクスメデトミジンも，副腎皮質束状帯におけるコルチゾル産生を抑制する^37）。

　生体侵襲の緩和を目的とする「集中治療管理」などにおいては，このような静脈麻酔薬濃度と免疫細胞機能との関連に洞察が必要である。さらに，好中球やリンパ球にはアドレナリン受容体が存在し，高濃度カテコラミン暴露により，好中球やリンパ球は細胞死を起こす^{38, 39）}。出血により虚血が生じる場合には，ミトコンドリア機能が変化し，あるいはミトコンドリア死により，DANPs反応として細胞性免疫が低下する。白血球除去の不確実な輸血によっては，輸血後10日でも細胞傷害性T細胞が減少することが報告されており^40），輸血後に腫瘍免疫やウイルス免疫が低下する可能性についても洞察が必要である。

 

おわりに

　生体侵襲における免疫管理は，早期退院および長期予後改善のために今後より一層に不可欠な急性期管理における学術となる。T細胞におけるT細胞受容体機能，B細胞の抗体産生機能，補体への作用，好中球などの食細胞機能，スカベンジャー受容体機能などを，自律神経，サイトカイン，およびホルモンの各バランスの観点より時系列で的確に評価していくことが必要である。急性期管理病態学を研鑽する中で，救急・集中治療の重要性として，免疫の研究を推進しなければならない。

 

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図と表の解説

 

表１．スカベンジャー受容体の区分と作動分子

　スカベンジャー受容体は，マンノース受容体やDectin-1のような然免疫型受容体と，CR3などのような補体やCD64のようなT細胞受容体などの抗体によって反応するオプソニン受容体に区分されている。

 

表２．補体の種類と機能

 

表３．補体受容体の種類と機能

 

表４．Toll-like受容体におけるPAMPsとDAMPsリガンド

 Toll-like受容体（TLR）は，単球，マクロファージ，樹状細胞，好中球，繊維芽細胞，内皮細胞，上皮細胞などのAlert細胞^5）で炎症性分子の産生に関与する炎症性受容体であるとともに，免疫細胞で発現しているタイプI膜貫通型パターン認識受容体ファミリーの１つである。ヒトでは10種類のサブタイプ，マウスでは12種類のサブタイプが同定されている。TLRsは，細菌・カビ・原生生物・ウイルスなどの微生物の蛋白・核酸・脂質，炭水化物に保存されている病原関連分子パターン（pathogen-associated molecular patterns：PAMPs）を認識し，自然免疫や獲得免疫のトリガーとなるばかりではなく，damage-associated molecular patterns（DAMPs）として生体内分子の危機トリガーとして機能している。

 

図1. 造血細胞の分化

 

図2. 寄生細胞に対する細胞傷害性T細胞の作用

　サイトメガロウイルスやレジオネラなどに感染された細胞では，CD８陽性の細胞傷害性T細胞の機能が期待される。寄生細胞では，寄生異物の断片分子や断片小胞がMHCクラスⅠ分子により細胞膜に運搬される。T細胞受容体（TCR）は，αおよびβのヘテロ２量体であり，CD3複合体と会合して，T細胞膜上に存在する。さらに，細胞傷害性T細胞では，TCRと細胞内異物・MHCクラスⅠ分子複合体との接着と認識に，CD8がco-receptorとして補助的に作用する。

 

図3. B細胞に対するヘルパーT細胞の作用

　B細胞は細胞膜上に抗体として膜型グログリンを発現することができ，膜型グロブリンを介して，結合した抗原を細胞内に取り込み，エンドソームでペプチドに断片化する。この抗原断片は，細胞質内でMHCクラスⅡ分子に補綴され，細胞膜上に運搬され，ヘルパーT細胞により認識される。ヘルパーT細胞には，T細胞受容体が存在し，CD4をco-receptorとして，B細胞の活性化を施し，この異物に対して特異的な抗体を産生する形質細胞やメモリー細胞（memory cell）への分化を促進させる。このようなB細胞分化において，抗体記憶に対する生体侵襲の影響の研究は不十分である。

 

図4. マクロファージに対するヘルパーT細胞の作用

　マクロファージ，好中球，未成熟樹状細胞は，食細胞として微生物などの異物を貪食する。主に組織に存在するマクロファージは，肺胞マクロファージ，クッパー細胞などのように，呼称を変えて呼ばれる。マクロファージは，貪食した分子をプロテアーゼでペプチドレベルに断片化する。この分解断片は，細胞質内でMHCクラスⅡ分子に補綴され，マクロファージの細胞膜上に運搬され，ヘルパーT細胞により認識される。ヘルパーT細胞のマクロファージの作用は，IFN-γを放出するTh1とIL-4およびIL-13の分泌を行うTh2細胞で異なる。Th1細胞は，IFN-γを介してマクロファージの貪食能と殺傷能をM1マクロファージとして高める。一方，Th2細胞は，IL-4とIL-13を介してM2マクロファージとしてマクロファージにIL-10やTGF-βなどの増殖性サイトカインの分泌をもたらす。M2マクロファージは，M1タイプの活性化マクロファージとは異なり，真菌認識を行うDectin-1，好酸球や好塩基球を誘導するCCL17，CCL18，CCL22などのケモカイン，そして線維芽細胞を増殖させるTGF-β，コラーゲン合成のために必要なプロリン産生を高めるアルギニン分解酵素アルギナーゼなどを産生する特徴があり，Th2有意のヘルパーT細胞バランスにより，炎症期に随伴した線維化期が遷延する危険性がある。

 

図5. 補体活性化の3つの経路

 　補体の活性化は，①抗原・抗体複合体による古典的経路，② 病原菌細胞膜に結合した抗体による第２経路，③ マンノース結合レクチンやリガンド結合型フィコリンなどによるレクチン経路の3つの経路が知られており，C3bによるC5b産生が重要な役割を担う。C3bはC3変換酵素により，C5と会合するとC５をC5aとC5bに分解できる。C5aは，C3aとともに，炎症性ペプチドとして作用する。一方，C5bは，C6，C7，C8細胞膜傷害性分子複合体（membrane attack complex）を形成し，さらにC9を細胞膜内に貫入させ，微生物膜に10 nmレベルの小孔を形成する。このような補体を介した小孔形成は，サイトメガロウイルス，コロナウイルス，ヘルペスウイルスのようなエンベロープを持つウイルス，ブドウ球菌などの厚いペプチドグリカン層を持つグラム陽性菌の除去に有効と考えられる。

 

図6. ヘルパーT細胞の分化

　ヘルパーT細胞は，T細胞受容体とCD4により，マクロファージ，B細胞，幼若型樹状細胞に結合し，これらの機能を修飾する。その作用は，分化形体により差異があり，転写因子活性とサイトカイン受容体シグナルにより，Th1，Th17，Th2などに分化し，産生し，放出するサイトカインを変える。

臨床研究 輸血 Cardiac Surgery Hb 7.5 g/dL vs 9.0 g/dL

Liberal or restrictive transfusion after cardiac surgery.
Murphy GJ, Pike K, Rogers CA, Wordsworth S, Stokes EA, Angelini GD, Reeves BC; TITRe2 Investigators. Collaborators (79)
N Engl J Med. 2015 Mar 12;372(11):997-1008. doi: 10.1056/NEJMoa1403612.

＜松田直之 コメント＞
日本では，白血球除去製剤として赤血球製剤（MAP製剤）が使用できます。
特に，心機能低下症例では，酸素需給の適正化のために，Hb 10g/dLレベルのHb濃度を維持することが大切と考えます。

BACKGROUND:
Whether a restrictive threshold for hemoglobin level in red-cell transfusions, as compared with a liberal threshold, reduces postoperative morbidity and health care costs after cardiac surgery is uncertain.
METHODS:
We conducted a multicenter, parallel-group trial in which patients older than 16 years of age who were undergoing nonemergency cardiac surgery were recruited from 17 centers in the United Kingdom. Patients with a postoperative hemoglobin level of less than 9 g per deciliter were randomly assigned to a restrictive transfusion threshold (hemoglobin level <7.5 g per deciliter) or a liberal transfusion threshold (hemoglobin level <9 g per deciliter). The primary outcome was a serious infection (sepsis or wound infection) or an ischemic event (permanent stroke [confirmation on brain imaging and deficit in motor, sensory, or coordination functions], myocardial infarction, infarction of the gut, or acute kidney injury) within 3 months after randomization. Health care costs, excluding the index surgery, were estimated from the day of surgery to 3 months after surgery.
<font size="3">RESULTS:
A total of 2007 patients underwent randomization; 4 participants withdrew, leaving 1000 in the restrictive-threshold group and 1003 in the liberal-threshold group. Transfusion rates after randomization were 53.4% and 92.2% in the two groups, respectively. The primary outcome occurred in 35.1% of the patients in the restrictive-threshold group and 33.0% of the patients in the liberal-threshold group (odds ratio, 1.11; 95% confidence interval [CI], 0.91 to 1.34; P=0.30); there was no indication of heterogeneity according to subgroup. There were more deaths in the restrictive-threshold group than in the liberal-threshold group (4.2% vs. 2.6%; hazard ratio, 1.64; 95% CI, 1.00 to 2.67; P=0.045). Serious postoperative complications, excluding primary-outcome events, occurred in 35.7% of participants in the restrictive-threshold group and 34.2% of participants in the liberal-threshold group. Total costs did not differ significantly between the groups.
CONCLUSIONS:
A restrictive transfusion threshold after cardiac surgery was not superior to a liberal threshold with respect to morbidity or health care costs. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN70923932.).





参考資料

Transfusion Indication Threshold Reduction (TITRe2) randomized controlled trial in cardiac surgery: statistical analysis plan.
Pike K, Nash RL, Murphy GJ, Reeves BC, Rogers CA.
Trials. 2015 Dec;16(1):564. doi: 10.1

Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis.
Holst LB, Petersen MW, Haase N, Perner A, Wetterslev J.
BMJ. 2015 Mar 24;350:h1354. doi: 10.1136/bmj.h1354.

論文紹介 Ultrafiltration in decompensated heart failure with cardiorenal syndrome

N Engl J Med. 2012 Dec 13;367(24):2296-304.
ある程度の腎機能が維持されていれば、限外濾過は薬物療法より優れてはいない？！

Ultrafiltration in decompensated heart failure with cardiorenal syndrome.
Bart BA, Goldsmith SR, Lee KL, Givertz MM, O'Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, LeWinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E; Heart Failure Clinical Research Network.

BACKGROUND:
Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function.
METHODS:
We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days.
RESULTS:
Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03).
CONCLUSIONS:
In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events.

公表 Acute Respiratory Distress Syndrome Berlin Definition

ARDSの新定義 Berlin Definition 2012が公表されました。



Acute Respiratory Distress Syndrome Berlin Definition
The ARDS Definition Task Force
JAMA. 2012;307(23):doi:10.1001/jama.2012.5669

The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm HgPaO2/FIO2 300 mmHg), moderate (100mmHgPaO2/FIO2 200mmHg), and severe (PaO2/ FIO2 100mmHg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (40 mL/cm H2O), positive endexpiratory pressure (10 cm H2O), and corrected expired volume per minute (10 L/min). The draft Berlin Definition was empirically evaluated using patient level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%;95%CI, 24%-30%; 32%;95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P.001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P.001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P.001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.

「亀なのに空を飛ぶ」 Berlin Definition 2012

文献紹介 統合失調症患者さんの自律神経障害

Autonomic modulation in healthy first-degree relatives of patients with major depressive disorder.
Berger S, Schulz S, Kletta C, Voss A, Bär KJ.
Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(7):1723-8.


BACKGROUND:
Cardiac mortality is known to be increased in patients with major depression. Several studies have reported an imbalance within the autonomic nervous system (ANS) of patients with major depressive disorder (MDD) as one putative cause. Since a heritability of autonomic modulation was demonstrated in healthy subjects, we aimed to investigate autonomic modulation in first-degree relatives of patients with MDD to find potential autonomic imbalances.
METHODS:
We included 30 patients with MDD, 30 of their first-degree relatives (siblings or offspring) and 30 matched healthy controls in our study. We obtained a high resolution electrocardiogram and beat to beat blood pressure measurements for 30 min at rest. Linear and nonlinear parameters of heart rate variability (HRV) and baroreflex sensitivity (BRS) were calculated.
RESULTS:
Parameters of HRV and BRS did not differ significantly between relatives and controls. We found significant differences between patients and controls for some HRV and BRS parameters confirming results of previous studies.
DISCUSSION:
Findings of our study suggest that an imbalance of autonomic function is related to patients with depression and not to first-degree relatives. Thus, a genetic background for autonomic dysfunction is rather unlikely.

参考文献 Heart rate variabilityについて
Bar KJ, Letzsch A, Jochum T,Wagner G, GreinerW, Sauer H. Loss of efferent vagal activity in acute schizophrenia. J Psychiatr Res. 2005;39:519–527.

Bar KJ, Boettger MK, Koschke M, et al. Non-linear complexity measures of heart rate variability in acute schizophrenia. Clin Neurophysiol. 2007;118:2009–2015.

Okada T, Toichi M, Sakihama M. Influences of an anticholinergic antiparkinsonian drug, parkinsonism, and psychotic symptoms on cardiac autonomic function in schizophrenia. J Clin Psychopharmacol. 2003;23:441–447.

Toichi M, Kubota Y, Murai T, et al. The influence of psychotic states on the autonomic nervous system in schizophrenia. Int J Psychophysiol. 1999;31:147–154.

Voss A, Busjahn A, Wessel N, et al. Familial and genetic influences on heart rate variability. J Electrocardiol. 1996;29:154–160.

Malik M. Heart rate variability: standards of measurement, physiological interpretation and clinical use, Task force of the European Society of cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996;93:1043–1065.

Baumert M, Baier V, Haueisen J, et al. Forecasting of life threatening arrhythmias using the compression entropy of heart rate. Methods Inf Med. 2004;43:202–206.

参考文献 Blood Pressure variabilityについて
Bar KJ, Boettger MK, Voss A. Differences between heart rate　and blood pressure variability in schizophrenia. Biomed Tech (Berl). 2006;51:237–239.

文献 JAMA ヘリコプター広域搬送の有効性について

Association between helicopter vs ground emergency medical services and survival for adults with major trauma.
Galvagno SM Jr, Haut ER, Zafar SN, Millin MG, Efron DT, Koenig GJ Jr, Baker SP, Bowman SM, Pronovost PJ, Haider AH.
JAMA. 2012 Apr 18;307(15):1602-10.

Abstract
CONTEXT:
Helicopter emergency medical services and their possible effect on outcomes for traumatically injured patients remain a subject of debate. Because helicopter services are a limited and expensive resource, a methodologically rigorous investigation of its effectiveness compared with ground emergency medical services is warranted.
OBJECTIVE:
To assess the association between the use of helicopter vs ground services and survival among adults with serious traumatic injuries.
DESIGN, SETTING, AND PARTICIPANTS:
Retrospective cohort study involving 223,475 patients older than 15 years, having an injury severity score higher than 15, and sustaining blunt or penetrating trauma that required transport to US level I or II trauma centers and whose data were recorded in the 2007-2009 versions of the American College of Surgeons National Trauma Data Bank.
INTERVENTIONS:
Transport by helicopter or ground emergency services to level I or level II trauma centers.
MAIN OUTCOME MEASURES:
Survival to hospital discharge and discharge disposition.
RESULTS:
A total of 61,909 patients were transported by helicopter and 161,566 patients were transported by ground. Overall, 7813 patients (12.6%) transported by helicopter died compared with 17,775 patients (11%) transported by ground services. Before propensity score matching, patients transported by helicopter to level I and level II trauma centers had higher Injury Severity Scores. In the propensity score-matched multivariable regression model, for patients transported to level I trauma centers, helicopter transport was associated with an improved odds of survival compared with ground transport (odds ratio [OR], 1.16; 95% CI, 1.14-1.17; P

　

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EM-ICU内Pro&Con 肝性脳症に対する栄養や分枝鎖アミノ酸の位置付け

名大ICUでも急性肝不全の治療が増えてきておりますが，
より良き急性期治療を目指して，討論を交えたカンファレンスを行っております。
木曜日の全症例カンファレンスの後にPro & Cons討論（演者選定）も行われます。
分枝鎖アミノ酸？　経腸栄養推進松田の観点など，参考として下さい。

参考文献

Three targets of branched-chain amino acid supplementation in the treatment of liver disease.
Holecek M.
Nutrition. 2010 May;26(5):482-90. Epub 2010 Jan 13. Review.

Protein intake in renal and hepatic disease.
Ambühl PM.
Int J Vitam Nutr Res. 2011 Mar;81(2-3):162-72. Review.

Branched-chain amino acids in liver disease: new aspects of long known phenomena.
Plauth M, Schütz T.
Curr Opin Clin Nutr Metab Care. 2011 Jan;14(1):61-6. Review.

Branched-chain amino acid metabolism in heart disease: an epiphenomenon or a real culprit?
Huang Y, Zhou M, Sun H, Wang Y.
Cardiovasc Res. 2011 May 1;90(2):220-3. Review.

Nutraceutical approach for preventing obesity-related colorectal and liver carcinogenesis.
Shimizu M, Kubota M, Tanaka T, Moriwaki H.
Int J Mol Sci. 2012;13(1):579-95. Epub 2012 Jan 5.

Nutrition in hepatic encephalopathy.
Chadalavada R, Sappati Biyyani RS, Maxwell J, Mullen K.
Nutr Clin Pract. 2010 Jun;25(3):257-64. Review.

Branched chain amino acids supplemented with L-acetylcarnitine versus BCAA treatment in hepatic coma: a randomized and controlled double blind study.
Malaguarnera M, Risino C, Cammalleri L, Malaguarnera L, Astuto M, Vecchio I, Rampello L.
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Dejong CH, van de Poll MC, Soeters PB, Jalan R, Olde Damink SW.
J Nutr. 2007 Jun;137(6 Suppl 1):1579S-1585S; discussion 1597S-1598S. Review.

など

JC文献 ARDSにおける治療薬

2012年4月12日　救急・ICU　Journal Clubの1つの討議内容　杤久保順平先生担当

Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004477.
Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome.
Adhikari N, Burns KE, Meade MO.
Source
Critical Care Medicine and Medicine, Sunnybrook and Women's College Health Centre, 2075 Bayview Avenue, B7.04a, Toronto, M4N 3M5, Ontario, Canada. neill.adhikari@sw.ca
Abstract
BACKGROUND:
Multiple pharmacologic treatments have been studied for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).
OBJECTIVES:
Our objective was to determine the effects of pharmacologic treatments on clinical outcomes in adults with ALI or ARDS.
SEARCH STRATEGY:
We searched OVID versions of CENTRAL (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to week 2, January 2004), EMBASE (1980 to week 4, 2004), CINAHL (1982 to week 2, January 2004), and HEALTHSTAR (1995 to December 2003); proceedings from four conferences (1994 to 2003); and bibliographies of review articles and included studies.
SELECTION CRITERIA:
Randomized controlled trials of pharmacologic treatments compared to no therapy or placebo for established ALI or ARDS in adults admitted to an intensive care unit, with measurement of early mortality (primary outcome), late mortality, duration of mechanical ventilation, ventilator-free days to day 28, or adverse events. We excluded trials of nitric oxide, partial liquid ventilation, fluid and nutritional interventions, oxygen, and trials in other populations reporting outcomes in subgroups of patients with ALI or ARDS.
DATA COLLECTION AND ANALYSIS:
Two reviewers independently screened titles and abstracts, rated studies for inclusion, extracted data and assessed methodologic quality of included studies. Disagreements were resolved by consensus in consultation with a third reviewer. For each pharmacologic therapy, we quantitatively pooled the results of studies using random effects models where permitted by the available data. We contacted study authors when clarification of the primary outcome was required.
MAIN RESULTS:
Thirty three trials randomizing 3272 patients met our inclusion criteria. Pooling of results showed no effect on early mortality of prostaglandin E1 (seven trials randomizing 697 patients; relative risk [RR] 0.95, 95% confidence interval [CI] 0.77 to 1.17), N-acetylcysteine (five trials randomizing 239 patients; RR 0.89, 95% CI 0.65 to 1.21), early high-dose corticosteroids (two trials randomizing 187 patients; RR 1.12, 95% CI 0.72 to 1.74), or surfactant (nine trials randomizing 1441 patients; RR 0.93, 95% CI 0.77 to 1.12). Two interventions were beneficial in single small trials; corticosteroids given for late phase ARDS reduced hospital mortality (24 patients; RR 0.20, 95% CI 0.05 to 0.81), and pentoxifylline reduced one-month mortality (RR 0.67, 95% CI 0.47 to 0.95) in 30 patients with metastatic cancer and ARDS. Individual trials of nine additional interventions failed to show a beneficial effect on prespecified outcomes.
REVIEWERS' CONCLUSIONS:
Effective pharmacotherapy for ALI and ARDS is extremely limited, with insufficient evidence to support any specific intervention.


グルタチオン前駆体としてのNACについて
1.
[N-acetylcysteine (NAC) inhibited pulmonary fibrosis in acute respiratory distress syndrome (ARDS)].
Li XF, Ouyang B, Wu JF, Chen J, Guan XD.
Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2011 Oct;23(10):599-601. Chinese.
PMID: 22242225 [PubMed - in process]
Related citations

2.
From neurogenic pulmonary edema to fat embolism syndrome: a brief review of experimental and clinical investigations of acute lung injury and acute respiratory distress syndrome.
Chen HI.
Chin J Physiol. 2009 Nov 30;52(5 Suppl):339-44. Review.
PMID: 20359124 [PubMed - indexed for MEDLINE]
Related citations

3.
N-acetylcysteine improves group B streptococcus clearance in a rat model of chronic ethanol ingestion.
Tang SM, Gabelaia L, Gauthier TW, Brown LA.
Alcohol Clin Exp Res. 2009 Jul;33(7):1197-201. Epub 2009 Apr 9.
PMID: 19389194 [PubMed - indexed for MEDLINE] Free PMC Article
Related citations

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Attenuation of pulmonary inflammation after exposure to blast overpressure by N-acetylcysteine amide.
Chavko M, Adeeb S, Ahlers ST, McCarron RM.
Shock. 2009 Sep;32(3):325-31.

集中治療 論文紹介＜鎮静＞ Dexmedetomidine vs Midazolam or Propofol

Dexmedetomidine vs Midazolam or Propofol for Sedation During Prolonged Mechanical Ventilation: Two Randomized Controlled Trials
Stephan M. Jakob, Esko Ruokonen, R. Michael Grounds, Toni Sarapohja, Chris Garratt, Stuart J. Pocock, J. Raymond Bratty, Jukka Takala , for the Dexmedetomidine for Long-Term Sedation Investigators

ABSTRACT

Context Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α2-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.

Objective To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care.

Design, Setting, and Patients Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251).

Interventions Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials.

Main Outcome Measures For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223).

Results Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001).

Conclusions Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine.

重要事項 Lilly Announces Withdrawal of Xigris® Following Recent Clinical Trial Results

播種性血管内凝固症候群（DIC）を合併した重症敗血症治療の治療に，活性化プロテインCの効力はないとして，
Xigris®の販売の中止が，Eli Lilly and Company より宣言されました。
これは，PROWESS-SHOCK TRIAL: A PROTOCOL OVERVIEW AND PERSPECTIVESの結果を受けたものです。
対照群の治療成績が極めて良くなっています（24.2%）が，当教室もよりDICの病態をも解明する必然が出てきました。
現在，若手の世界連携で動いているVAHGの活動の中で，血管内皮細胞炎症性DICの本質を解明し，新規創薬を提唱する必然が出てきました。

NDIANAPOLIS, Oct. 25, 2011 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) announces withdrawal of its Xigris® [drotrecogin alfa (activated)] product in all markets following results of the PROWESS-SHOCK study, which showed the study did not meet the primary endpoint of a statistically significant reduction in 28-day all-cause mortality in patients with septic shock. The company is working with regulatory agencies on this withdrawal, and is in the process of notifying health care professionals and clinical trial investigators.
"While there were no new safety findings, the study failed to demonstrate that Xigris improved patient survival and thus calls into question the benefit-risk profile of Xigris and its continued use," said Timothy Garnett, M.D., Lilly's Senior Vice President and Chief Medical Officer. "Patients currently receiving treatment with Xigris should have treatment discontinued, and Xigris treatment should not be initiated for new patients."
"We believe the original Xigris approval was appropriate and these recent results were quite unexpected," Garnett added. "A contributing factor to these study results could be advances in the standard of care for treating severe sepsis over the past 10 years."
Xigris was approved in the United States by the Food and Drug Administration (FDA) in November 2001, and was licensed in the European Union in 2002. The PROWESS-SHOCK study was initiated in March of 2008 as a condition for continued market authorization in Europe. Lilly committed to conduct a new placebo-controlled clinical trial to help refine appropriate patient identification for treatment with Xigris and to confirm the benefit-risk profile of the product.
BioCritica, Inc. has sales and marketing rights for Xigris in the United States and Puerto Rico, and Lilly sells and markets Xigris in other countries.
Patients, physicians, pharmacists, or other healthcare professionals with additional questions about Xigris should contact The Lilly Answer Center at 1-800-LillyRx or visit www.Lilly.com.
About Severe Sepsis
Sepsis is a common and deadly disease(1). Severe sepsis can develop as a complication after common illnesses such as pneumonia and bacterial infections, and is characterized by an overwhelming systemic response to infection which can rapidly lead to organ failure and ultimately death.
About Xigris
Xigris (drotrecogin alfa [activated]) is a recombinant form of human Activated Protein C. It is administered by intravenous infusion. Based on the results of the PROWESS study the U.S. Food and Drug Administration approved Xigris in November 2001 for the reduction of mortality in adult patients with severe sepsis who have a high risk of death (e.g., as determined by APACHE II). Xigris is not indicated in adult patients with severe sepsis and a lower risk of death (e.g., APACHE II score <25). Xigris is not indicated in pediatric patients. In 2002, the EMA licensed Xigris for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care.


SHOCK, Vol. 34, Supplement 1, pp. 48Y53, 2010
PROWESS-SHOCK TRIAL: A PROTOCOL OVERVIEW AND PERSPECTIVES

Elie´zer Silva,* Luiz Francisco Poli de Figueiredo,† and Fernando Colombari*
*Intensive Care Unit, Hospital Israelita Albert Einstein; and †Faculdade de Medicina,
Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil

ABSTRACT―Sepsis remains a challenge for intensive care physicians, as it keeps up with high mortality rate in spite of the
high costs associated with its treatment. Several studies indicate that the infusion of Drotrecogin-alpha activated (DrotAA)
reduce mortality in patients at high risk of death when administered early and secured the appropriate initial treatment of
sepsis as recommended by Surviving Sepsis Campaign. Europe and United States of America differ regarding the criteria of
high risk of death in sepsis, two or more organ dysfunctions and Acute Physiology and Chronic Health Evaluation 25 or
more, respectively. In addition to varied definitions of high risk of death for inclusion of patients in sepsis studies, the
possibility of bleeding related to drug use and intrinsic limitations related to study design led the Company to develop a new
randomized, multinational, placebo-controlled, double-blind study to assess the effectiveness of drug in patients with septic
shock in adults.

文献 Legionella 肺炎と保健所届出の義務

レジオネラ菌は，1976年に米国ペンシルベニア州米国在郷軍人会大会において，参加者や周辺住民221人が原因不明の肺炎にかかり，34人が死亡したことで有名となった菌であり，在郷軍人 (legionnaire) にちなんで Legionella pneumophila と名づけられた。レジオネラ菌は鞭毛を持つちびちびぽつぽつとした大きさ2 - 5µmレベルの桿菌で，アカントアメーバなどのアメーバ類に寄生して増殖する。アカントアメーバは24時間風呂などの浴槽表面に生着しやすく，ここに寄生したレジオネラは37~41℃で繁殖しやすい。
　レジオネラ菌は糖を利用しないため，通常の細菌検査用培地では生育しない。このため，レジオネラ菌の培養には，エネルギー源として利用できるセリン，スレオニンなどの必須アミノ酸を加える必要がある。診断には，尿中レジオネラ抗原の検出，喀痰のヒメネス染色を用いる。レジオネラは肺浸潤において，肺胞上皮細胞や線維芽細胞に細胞内寄生する特徴がある。このため，宿主細胞に浸透することのできる抗菌薬として，ニューキノロン，エリスロマイシン，リファンピシンなどの抗菌薬が推奨されている。現在，低心機能状態でレジオネラ肺炎を併発している患者の治療を行っている。レジオネラ症は4類感染症に定められており，病原体診断や血清学的診断によりレジオネラ症を診断した医師は，直ちに最寄りの保健所に届け出る義務があるほど，劇症化して死に至る可能性のある菌種である。現在ポリクリにきている学生さんは，以下の論文も読んでみて下さい。


文献1. Int J Gen Med. 2011 Jan 6;4:15-9.　PCRによるレジオネラ症の血清診断

Community-acquired pneumonia due to Legionella pneumophila, the utility of PCR, and a review of the antibiotics used.

Zarogoulidis P, Alexandropoulou I, Romanidou G, Konstasntinidis TG, Terzi E, Saridou S, Stefanis A, Zarogoulidis K, Constantinidis TC.

Source
Regional Laboratory of Public Health, East Macedonia-Thrace, Komotini, Greece. pzarog@hotmail.com

Abstract
INTRODUCTION:
There are at least 40 types of Legionella bacteria, half of which are capable of producing disease in humans. The Legionella pneumophila bacterium, the root cause of Legionnaires' disease, causes 90% of legionellosis cases.
CASE PRESENTATION:
We describe the case of a 60-year-old woman with a history of diabetes mellitus and arterial hypertension who was admitted to our hospital with fever and symptoms of respiratory infection, diarrhea, and acute renal failure. We used real-time polymerase chain reaction (PCR) to detect L. pneumophila DNA in peripheral blood and serum samples and urine antigen from a patient with pneumonia. Legionella DNA was detected in all two sample species when first collected.
CONCLUSION:
Since Legionella is a cause of 2% to 15% of all community-acquired pneumonias that require hospitalization, legionellosis should be taken into account in an atypical pulmonary infection and not be forgotten. Moreover, real-time PCR should be considered a useful diagnostic method.

L. pneumophila with a real-time polymerase chain reaction (PCR) kit (Aqua Screen L. pneumophila-detection kit for real-time PCR; Minerva Biolabs, Minerva, OH)を用いたレジオネラ検出。

文献2. Aust Fam Physician. 2008 Oct;37(10):812-5.　レジオネラは下痢を合併しやすい

Could it be Legionella?

Darby J, Buising K.

Source
Infectious Diseases Unit, St Vincent's Hospital, Fitzroy, Victoria. jonathan.darby@svhm.org.au

Abstract
BACKGROUND:
Community acquired pneumonia is a common condition presenting to general practitioners and emergency departments across Australia. Legionella is one of many pathogens responsible for community acquired pneumonia. Cases of Legionella may occur sporadically or as part of an outbreak.
OBJECTIVE:
This article describes the clinical manifestations of Legionella infection and provides clinicians with an approach to its diagnosis and management.
DISCUSSION:
Legionella infection is typically associated with community acquired pneumonia, which can be severe. Features pointing to Legionella as a cause of pneumonia include the presence of gastrointestinal symptoms, especially diarrhoea; neurological symptoms, especially confusion; fever up to 40 degrees C; hyponatraemia; and hepatic dysfunction. However, none of these is required to make the diagnosis. Sometimes nonrespiratory symptoms can predominate. Diagnosis requires the use of special tests specific for Legionella, the most clinically useful being urinary antigen tests and serology. Recommended treatments include macrolide therapy or doxycycline.

文献 特発性肺線維症 Cochrane Database Syst Rev. 2010 Sep 8;(9):CD003134.

Non-steroid agents for idiopathic pulmonary fibrosis

Spagnolo P, Del Giovane C, Luppi F, Cerri S, Balduzzi S, Walters EH, D'Amico R, Richeldi L.

Source
Center for Rare Lung Disease, University of Modena and Reggio Emilia, Modena Italy and Respiratory Disease Section, Department of Oncology, Hematology and Respiratory Disease, University of Modena and Reggio Emilia, Modena, Italy.

Abstract
BACKGROUND:
Idiopathic pulmonary fibrosis is a chronic progressive lung disease with poor outcome and no effective treatment to date. This is an update of a Cochrane Review first published in 2003.
OBJECTIVES:
To assess the efficacy of non-steroid agents in adults with idiopathic pulmonary fibrosis.
SEARCH STRATEGY:
We searched the Cochrane Airways Group Register (30 March 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2010), Ovid MEDLINE to March week 5, 2010, EMBASE to week 13, 2010 and PubMed to April 2010, with additional handsearching, including abstracts of international conferences. We also contacted pharmaceutical companies and researchers in the field.
SELECTION CRITERIA:
Randomised studies comparing non-steroid drugs with placebo or steroids in adults with idiopathic pulmonary fibrosis.
DATA COLLECTION AND ANALYSIS:
Two authors independently assessed trial quality, extracted data and assessed risk of bias. We contacted pharmaceutical companies to obtain missing information, if any. We combined survival outcomes using Peto odds ratios or hazard ratios (HR).
MAIN RESULTS:
Fifteen trials involving 10 different drugs were included. Two trials enrolling 1156 patients compared interferon gamma-1beta with placebo: interferon gamma-1beta did not significantly improve survival (HR 0.88, 95% CI 0.47 to 1.64; P = 0.68). Four trials involving 1155 patients compared pirfenidone with placebo. Three trials, conducted in 1046 patients, provided data on progression-free survival: pirfenidone significantly reduced the risk of disease progression by 30% (HR 0.70, 95% CI 0.56 to 0.88, P = 0.002). Data on the effect of pirfenidone on pulmonary function could only be assessed for two studies analysing 314 patients. Forced vital capacity or vital capacity was significantly improved by pirfenidone (mean difference 0.08 L, 95% CI 0.03 to 0.13, P = 0.0006).
AUTHORS' CONCLUSIONS:
Based on available data, partly still unpublished, pirfenidone appears to improve progression-free survival and, to a lesser extent, pulmonary function in patients with idiopathic pulmonary fibrosis. More data are needed on overall survival and quality of life on treatment. From the studies in this review, interferon gamma-1beta has not been shown to affect survival. Other agents evaluated in single studies either failed to provide evidence for a benefit or need to be assessed in larger randomised controlled trials.

論文 拒食症のRefeeding症候群の集中治療管理

Anorexia Nervosaの急性期管理は，救急・集中治療で対応するとよいのでしょう。
NICEガイドラインなども参照すると良いと思います。
より学術的に対応する必要があります。

文献1　Anorexia Nervosa
Nature. 2011 Aug 31.

Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.

Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG, Kutalik Z, Martinet D, Shen Y, Valsesia A, Beckmann ND, Thorleifsson G, Belfiore M, Bouquillon S, Campion D, de Leeuw N, de Vries BB, Esko T, Fernandez BA, Fernández-Aranda F, Fernández-Real JM, Gratacòs M, Guilmatre A, Hoyer J, Jarvelin MR, Frank Kooy R, Kurg A, Le Caignec C, Männik K, Platt OS, Sanlaville D, Van Haelst MM, Villatoro Gomez S, Walha F, Wu BL, Yu Y, Aboura A, Addor MC, Alembik Y, Antonarakis SE, Arveiler B, Barth M, Bednarek N, Béna F, Bergmann S, Beri M, Bernardini L, Blaumeiser B, Bonneau D, Bottani A, Boute O, Brunner HG, Cailley D, Callier P, Chiesa J, Chrast J, Coin L, Coutton C, Cuisset JM, Cuvellier JC, David A, de Freminville B, Delobel B, Delrue MA, Demeer B, Descamps D, Didelot G, Dieterich K, Disciglio V, Doco-Fenzy M, Drunat S, Duban-Bedu B, Dubourg C, El-Sayed Moustafa JS, Elliott P, Faas BH, Faivre L, Faudet A, Fellmann F, Ferrarini A, Fisher R, Flori E, Forer L, Gaillard D, Gerard M, Gieger C, Gimelli S, Gimelli G, Grabe HJ, Guichet A, Guillin O, Hartikainen AL, Heron D, Hippolyte L, Holder M, Homuth G, Isidor B, Jaillard S, Jaros Z, Jiménez-Murcia S, Joly Helas G, Jonveaux P, Kaksonen S, Keren B, Kloss-Brandstätter A, Knoers NV, Koolen DA, Kroisel PM, Kronenberg F, Labalme A, Landais E, Lapi E, Layet V, Legallic S, Leheup B, Leube B, Lewis S, Lucas J, Macdermot KD, Magnusson P, Marshall C, Mathieu-Dramard M, McCarthy MI, Meitinger T, Antonietta Mencarelli M, Merla G, Moerman A, Mooser V, Morice-Picard F, Mucciolo M, Nauck M, Coumba Ndiaye N, Nordgren A, Pasquier L, Petit F, Pfundt R, Plessis G, Rajcan-Separovic E, Paolo Ramelli G, Rauch A, Ravazzolo R, Reis A, Renieri A, Richart C, Ried JS, Rieubland C, Roberts W, Roetzer KM, Rooryck C, Rossi M, Saemundsen E, Satre V, Schurmann C, Sigurdsson E, Stavropoulos DJ, Stefansson H, Tengström C, Thorsteinsdóttir U, Tinahones FJ, Touraine R, Vallée L, van Binsbergen E, Van der Aa N, Vincent-Delorme C, Visvikis-Siest S, Vollenweider P, Völzke H, Vulto-van Silfhout AT, Waeber G, Wallgren-Pettersson C, Witwicki RM, Zwolinksi S, Andrieux J, Estivill X, Gusella JF, Gustafsson O, Metspalu A, Scherer SW, Stefansson K, Blakemore AI, Beckmann JS, Froguel P.

Abstract
Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.


文献2　Anorexia Nervosa
Eur Psychiatry. 2011 Aug 29.

Repetitive transcranial magnetic stimulation in anorexia nervosa: A pilot study.
Van den Eynde F, Guillaume S, Broadbent H, Campbell IC, Schmidt U.

Source
King's College London, Institute of Psychiatry, Section of Eating Disorders, De Crespigny Park, London, SE5 8AF, United Kingdom.
Abstract
The search for new treatments to improve outcome in people with anorexia nervosa continues. This pilot study investigated whether one session of high frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the left dorsolateral prefrontal cortex reduces eating disorder related symptoms following exposure to visual and real food stimuli. Safety and tolerability were also assessed. Ten right-handed people with anorexia nervosa underwent one session of rTMS. Subjective experiences related to the eating disorder (e.g. urge to restrict, feeling full etc.) were assessed before and after rTMS. Non-parametric repeated measures tests were used. rTMS was safe and well-tolerated, and resulted in reduced levels of feeling full, feeling fat and feeling anxious. Thus, rTMS may reduce core symptoms of anorexia nervosa. Future research should establish the therapeutic potential of rTMS in anorexia nervosa. PMID: 21880470

文献3 Anorexia Nervosa
J Am Acad Child Adolesc Psychiatry. 2011 Sep;50(9):915-24.

A double-blind, placebo-controlled study of risperidone for the treatment of adolescents and young adults with anorexia nervosa: a pilot study.
Hagman J, Gralla J, Sigel E, Ellert S, Dodge M, Gardner R, O'Lonergan T, Frank G, Wamboldt MZ.

Source
University of Colorado School of Medicine and Children's Hospital Colorado.

Abstract
OBJECTIVE:
The purpose of this double-blind, placebo-controlled exploratory pilot study was to evaluate the safety and efficacy of risperidone for the treatment of anorexia nervosa.
METHOD:
Forty female subjects 12 to 21 years of age (mean, 16 years) with primary anorexia nervosa in an eating disorders program were randomized to receive risperidone (n = 18) or placebo (n = 22). Subjects completed the Eating Disorder Inventory 2, Color-A-Person Test, Body Image Software, and Multidimensional Anxiety Scale for Children at baseline and regular intervals. Weight, laboratory values, and electrocardiograms were monitored. Study medication was started at 0.5 mg daily and titrated upward weekly in 0.5-mg increments to a maximum dose of 4 mg until the subject reached a study endpoint.
RESULTS:
The mean dose for the risperidone group was 2.5 mg and for the placebo group was 3 mg for a mean duration of 9 weeks. Subjects taking risperidone had a significant decrease on the Eating Disorder Inventory 2 Drive for Thinness subscale over the first 7 weeks (effect size, 0.88; p = .002), but this difference was not sustained to the end of the study (p = .13). The Eating Disorder Inventory 2 Interpersonal Distrust subscale decreased significantly more in subjects taking risperidone (effect size, 0.60; p = .03). Subjects taking risperidone had increased prolactin levels (week 7; p = .001). There were no significant differences between groups at baseline or the end of the study for the other rating scales, change in weight, or laboratory measurements.
CONCLUSIONS:
This study does not demonstrate a benefit for the addition of risperidone in adolescents with anorexia nervosa during the weight-restoration phase of care. Clinical trial registration information-A Double-Blind, Placebo-Controlled Study of Risperidone for the Treatment of Anorexia Nervosa, http://www.clinicaltrials.gov, NCT00140426.

文献4　Anorexia Nervosa
Nutrition. 2011 Aug 24.
Ghrelin and anorexia nervosa: A psychosomatic perspective.
Ogiso K, Asakawa A, Amitani H, Inui A.

Source
Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan.
Abstract
Anorexia nervosa (AN) is a serious medical illness associated with gastrointestinal, metabolic, and psychological complications, and there are no effective pharmacologic treatments for the condition. Recent studies have suggested that the regulatory peptides, including ghrelin, are involved in the pathologic feeding behavior of AN. Previous studies have indicated that plasma total ghrelin and acyl ghrelin levels in patients with AN are higher than in controls, and the ratio of des-acyl ghrelin to acyl ghrelin in AN tend to be higher than in controls. In addition, ghrelin has been reported to stimulate appetite and food intake in various diseases, including chronic heart failure, chronic obstructive pulmonary disease, and cancer. Because it is speculated that difficulties in resolving the underlying psychological condition preclude reversal of the pathologic feeding behavior in AN, ghrelin is expected to be applied in a clinical setting as a new treatment. In this review, we describe the role of ghrelin in the pathophysiology and potential treatment of AN along the gut-brain axis.


文献5　Anorexia Nervosa
Pharmacol Rev. 2009 Dec;61(4):430-81.
Ghrelin gene products and the regulation of food intake and gut motility.
Chen CY, Asakawa A, Fujimiya M, Lee SD, Inui A.

Source
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Japan.

Abstract
A breakthrough using "reverse pharmacology" identified and characterized acyl ghrelin from the stomach as the endogenous cognate ligand for the growth hormone (GH) secretagogue receptor (GHS-R) 1a. The unique post-translational modification of O-n-octanoylation at serine 3 is the first in peptide discovery history and is essential for GH-releasing ability. Des-acyl ghrelin, lacking O-n-octanoylation at serine 3, is also produced in the stomach and remains the major molecular form secreted into the circulation. The third ghrelin gene product, obestatin, a novel 23-amino acid peptide identified from rat stomach, was found by comparative genomic analysis. Three ghrelin gene products actively participate in modulating appetite, adipogenesis, gut motility, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. Knockdown or knockout of acyl ghrelin and/or GHS-R1a, and overexpression of des-acyl ghrelin show benefits in the therapy of obesity and metabolic syndrome. By contrast, agonism of acyl ghrelin and/or GHS-R1a could combat human anorexia-cachexia, including anorexia nervosa, chronic heart failure, chronic obstructive pulmonary disease, liver cirrhosis, chronic kidney disease, burn, and postsurgery recovery, as well as restore gut dysmotility, such as diabetic or neurogenic gastroparesis, and postoperative ileus. The ghrelin acyl-modifying enzyme, ghrelin O-Acyltransferase (GOAT), which attaches octanoate to serine-3 of ghrelin, has been identified and characterized also from the stomach. To date, ghrelin is the only protein to be octanylated, and inhibition of GOAT may have effects only on the stomach and is unlikely to affect the synthesis of other proteins. GOAT may provide a critical molecular target in developing novel therapeutics for obesity and type 2 diabetes.


文献6　Anorexia Nervosa
Eur Eat Disord Rev. 2011 Jul 21.

Association of Candidate Genes with Phenotypic Traits Relevant to Anorexia Nervosa.
Root TL, Szatkiewicz JP, Jonassaint CR, Thornton LM, Pinheiro AP, Strober M, Bloss C, Berrettini W, Schork NJ, Kaye WH, Bergen AW, Magistretti P, Brandt H, Crawford S, Crow S, Fichter MM, Goldman D, Halmi KA, Johnson C, Kaplan AS, Keel PK, Klump KL, La Via M, Mitchell JE, Rotondo A, Treasure J, Woodside DB, Bulik CM.

Source
Johns Hopkins University School of Medicine, Division of General Internal Medicine, Baltimore MD.

Abstract
This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein, we investigate alternative phenotypes associated with AN. In 1762 females, using regression analyses, we examined the following: (i) lowest illness-related attained body mass index; (ii) age at menarche; (iii) drive for thinness; (iv) body dissatisfaction; (v) trait anxiety; (vi) concern over mistakes; and (vii) the anticipatory worry and pessimism versus uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes. Copyright © 2011 John Wiley & Sons, Ltd and Eating Disorders Association.


文献7　Anorexia Nervosa
Pharmacogenomics. 2008 Oct;9(10):1487-520.
Genetic susceptibility to eating disorders: associated polymorphisms and pharmacogenetic suggestions.
Monteleone P, Maj M.

Source
Department of Psychiatry, University of Naples SUN, Largo Madonna delle Grazie, 80138 Naples, Italy. monteri@tin.it

Abstract
Anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) are characterized by abnormal eating behaviors often resulting in dramatic physical consequences for the patients. The etiology of eating disorders (EDs) is currently unknown; however, a strong genetic contribution is likely to be involved. To date, the majority of genetic studies have focused on candidate genes, and polymorphic variants of genes coding for substances likely to be involved in the etiopathogenesis of EDs have been assessed for association with AN, BN, BED and/or ED-related phenotypic traits. Results have been generally inconsistent and cannot be considered conclusive because of several methodological flaws and differences, such as small sample sizes, ethnic heterogeneity of studied populations, lack of statistical correction for multiple testing, adoption of different diagnostic criteria and population stratification. Although, at present, no convincing evidence for associations of candidate genes with EDs has been provided, the 5-HT(2A) receptor gene and the BDNF gene seem to be promising candidates for genetic influences on AN, since polymorphic variants of these genes have been found quite consistently, although not specifically, linked to AN restricting subtype in large sample studies. Moreover, pharmacogenetic investigations have suggested a possible role of some gene polymorphisms in predicting the response to treatment with selective serotonin reuptake inhibitors in BN, but results are still preliminary. The heterogeneity of ED phenotypes is believed to represent the most relevant variable responsible for contradictory and not conclusive results. Future studies should focus on more homogeneous subgroups, either relying on specific ED traits or identifying endophenotypes. This will be useful also for prevention and treatment of EDs.


文献8　Anorexia Nervosa
Whitelaw M, Gilbertson H, Lam PY, Sawyer SM. J Adolesc Health 2010;46:577-82.
Does aggressive refeeding in hospitalized adolescents with anorexia nervosa result in increased hypophosphatemia?

Department of Nutrition and Food Services, Royal Children's Hospital, Victoria, Australia. melissa.whitelaw@rch.org.au


Abstract
PURPOSE:
Concerns about refeeding syndrome have led to relatively conservative nutritional rehabilitation in malnourished inpatients with anorexia nervosa (AN), which delays weight gain. Compared to other programs, we aggressively refed hospitalized adolescents. We sought to determine the incidence of hypophosphatemia (HP) in 12-18-year-old inpatients in order to inform nutritional guidelines in this group.

METHODS:
A 1-year retrospective chart review was undertaken of 46 admissions (29 adolescents) with AN admitted to the adolescent ward of a tertiary children's hospital. Data collected over the initial 2 weeks included number of past admissions, nutritional intake, weight, height, body mass index, and weight change at 2 weeks. Serum phosphorus levels and oral phosphate supplementation was recorded.

RESULTS:
The mean (SD) age was 15.7 years (1.4). The mean (SD) ideal body weight was 72.9% (9.1). Sixty-one percent of admissions were commenced on 1,900 kcal (8,000 kJ), and 28% on 2,200 kcal (9,300 kJ). Four patients were deemed at high risk of refeeding syndrome; of these patients, three were commenced on rehydration therapy and one on 1,400 kcal (6,000 kJ). All patients were graded up to 2,700 kcal (11,400 kJ) with further increments of 300 kcal (1,260 kJ) as required. Thirty-seven percent developed mild HP; no patient developed moderate or severe HP. Percent ideal body weight at admission was significantly associated with the subsequent development of HP (p = .007).

CONCLUSIONS:
These data support more aggressive approaches to nutritional rehabilitation for hospitalized adolescents with AN compared to current recommendations and practice.

文献9　Anorexia Nervosa
Lakartidningen. 2005 Sep 5-11;102(36):2464-7.
[Somatic complications of anorexia nervosa in children and adolescents. Prognosis is good if the patient achieves normal weight within a couple of years].
[Article in Swedish]
Ejderhamn J, Borgström B, Wentz E.
Source
Anorexicentrum, AB Mando, Huddinge, Sweden. jan.ejderhamn@neurotec.ki.se
Abstract
This article presents an overview of somatic complications in anorexia nervosa in children and adolescents. Cardiovascular-, gastrointestinal-, and endocrine- complications are often observed as a consequence of starvation in anorexia nervosa, Prolongation of QT interval can cause fatal arrhythmias. Checking levels of serum electrolytes, phosphate and magnesium daily during initial phase of refeeding is necessary to avoid the Refeeding syndrome. The activity of the thyroid gland and the gonads is depressed. The patients will remain or return to a prepubertal status with poor growth and low levels of sex hormones. This, in addition to low IGF-I, low adrenal androgens and lack of energy, may result in subnormal development of bone density. If anorexia nervosa starts early in life and continues for many years there will not be a full recovery, resulting in osteoporosis and a decrease of final height. The other complications however have a good prognosis when food intake is normalised.

文献10　Anorexia Nervosa
Arch Gen Psychiatry. 2011 Jul;68(7):724-31.
Mortality rates in patients with anorexia nervosa and other eating disorders: a meta-analysis of 36 studies.
Arcelus J, Mitchell AJ, Wales J, Nielsen S.

Source
Loughborough University Centre for Research into Eating Disorders, Loughborough University England. J.Arcelus@lboro.ac.uk
Abstract
CONTEXT:
Morbidity and mortality rates in patients with eating disorders are thought to be high, but exact rates remain to be clarified.
OBJECTIVE:
To systematically compile and analyze the mortality rates in individuals with anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS).
DATA SOURCES:
A systematic literature search, appraisal, and meta-analysis were conducted of the MEDLINE/PubMed, PsycINFO, and Embase databases and 4 full-text collections (ie, ScienceDirect, Ingenta Select, Ovid, and Wiley-Blackwell Interscience).
STUDY SELECTION:
English-language, peer-reviewed articles published between January 1, 1966, and September 30, 2010, that reported mortality rates in patients with eating disorders.
DATA EXTRACTION:
Primary data were extracted as raw numbers or confidence intervals and corrected for years of observation and sample size (ie, person-years of observation). Weighted proportion meta-analysis was used to adjust for study size using the DerSimonian-Laird model to allow for heterogeneity inclusion in the analysis.
DATA SYNTHESIS:
From 143 potentially relevant articles, we found 36 quantitative studies with sufficient data for extraction. The studies reported outcomes of AN during 166 642 person-years, BN during 32 798 person-years, and EDNOS during 22 644 person-years. The weighted mortality rates (ie, deaths per 1000 person-years) were 5.1 for AN, 1.7 for BN, and 3.3 for EDNOS. The standardized mortality ratios were 5.86 for AN, 1.93 for BN, and 1.92 for EDNOS. One in 5 individuals with AN who died had committed suicide.
CONCLUSIONS:
Individuals with eating disorders have significantly elevated mortality rates, with the highest rates occurring in those with AN. The mortality rates for BN and EDNOS are similar. The study found age at assessment to be a significant predictor of mortality for patients with AN. Further research is needed to identify predictors of mortality in patients with BN and EDNOS.

文献11　Anorexia Nervosa
Proc Nutr Soc. 2009 Aug;68(3):281-8.
Feeding size 0: the challenges of anorexia nervosa. Managing anorexia from a dietitian's perspective.
Cockfield A, Philpot U.

Source
The Retreat, York, UK. ACockfield@theretreatyork.org.uk

Abstract
Anorexia nervosa has the highest mortality rate of any psychiatric condition and its management is complex and multi-faceted, requiring a multidisciplinary team approach. Dietitians are an important part of the multidisciplinary team, offering objective nutritional advice with the aim of helping the patient to develop an improved relationship with food. Refeeding patients with a low body weight requires careful management; nonetheless, refeeding the low-weight patient with anorexia presents many additional complications, largely of a psychological nature. Treatment plans need to consider psychological, physical, behavioural and psycho-social factors relating to anorexia nervosa. Currently, there is no consistent approach and a paucity of evidence to support best practice for weight restoration in this group of patients. Tube feeding is utilised at varying BMI in anorexia nervosa, mainly in an inpatient setting. However, its use should be seen as a last resort and limited to a life-saving intervention. Weight restoration is best managed by an experienced dietitian within a specialist eating disorders team, using normal foods. This approach is ideal for nutrition rehabilitation, promoting skills for eating and normal behaviour and providing a longer-term solution by challenging unhelpful coping strategies from the onset. Dietitians have a unique mix of skills and knowledge in numerous areas including nutrition, physiology, psychology, sociology and behaviour change, which can be applied to support patients with thoughts and behaviours around food, weight and appetite. Further research is required into the effectiveness of dietetic interventions in eating disorders in order to establish an evidence base for best practice.



松任谷さんぐらいの元気で行きましょう。
救急・集中治療の皆さんは，病院内をニコニコと元気よく歩きましょう！

論文紹介 敗血症性ショックにおけるバソプレシン VASST初編

Vasopressin versus norepinephrine infusion in patients with septic shock.

Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators.

N Engl J Med 2008 28;358:877-87.


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.

論文紹介 敗血症性ショックにおけるバソプレシン （VASST続編）

Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock.

Russell JA, Walley KR, Gordon AC, Cooper DJ, Hébert PC, Singer J, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ; Dieter Ayers for the Vasopressin and Septic Shock Trial Investigators.
St Paul's Hospital, iCAPTURE Centre, Canada.

Crit Care Med 2009;37:811-8.


OBJECTIVE: Vasopressin and corticosteroids are often added to support cardiovascular dysfunction in patients who have septic shock that is nonresponsive to fluid resuscitation and norepinephrine infusion. However, it is unknown whether vasopressin treatment interacts with corticosteroid treatment. DESIGN: Post hoc substudy of a multicenter randomized blinded controlled trial of vasopressin vs. norepinephrine in septic shock. SETTING: Twenty-seven Intensive Care Units in Canada, Australia, and the United States. PATIENTS:: Seven hundred and seventy-nine patients who had septic shock and were ongoing hypotension requiring at least 5 microg/min of norepinephrine infusion for 6 hours. INTERVENTIONS: Patients were randomized to blinded vasopressin (0.01-0.03 units/min) or norepinephrine (5-15 microg/min) infusion added to open-label vasopressors. Corticosteroids were given according to clinical judgment at any time in the 28-day postrandomization period. MEASUREMENTS: The primary end point was 28-day mortality. We tested for interaction between vasopressin treatment and corticosteroid treatment using logistic regression. Secondary end points were organ dysfunction, use of open-label vasopressors and vasopressin levels. MAIN RESULTS: There was a statistically significant interaction between vasopressin infusion and corticosteroid treatment (p = 0.008). In patients who had septic shock and were also treated with corticosteroids, vasopressin, compared to norepinephrine, was associated with significantly decreased mortality (35.9% vs. 44.7%, respectively, p = 0.03). In contrast, in patients who did not receive corticosteroids, vasopressin was associated with increased mortality compared with norepinephrine (33.7% vs. 21.3%, respectively, p = 0.06). In patients who received vasopressin infusion, use of corticosteroids significantly increased plasma vasopressin levels by 33% at 6 hours (p = 0.006) to 67% at 24 hours (p = 0.025) compared with patients who did not receive corticosteroids. CONCLUSIONS: There is a statistically significant interaction between vasopressin and corticosteroids. The combination of low-dose vasopressin and corticosteroids was associated with decreased mortality and organ dysfunction compared with norepinephrine and corticosteroids.