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機械的陽圧換気(人工呼吸)に関連する呼吸器有害事象の防止に関する研究

中橋, 奨 北海道大学

2022.03.24

概要

【背景と目的】
機械的陽圧換気(人工呼吸)は、重症患者管理の根幹を成す一方、無気肺、人工呼吸器関連肺炎(VAP)、人工呼吸器関連肺傷害(VALI)等の呼吸器合併症(ventilator-associated event :VAE)を好発する。VAE は患者予後に悪影響を及ぼすが、予防策は未整備のままであり、何れの施設においても実践可能な予防の基本戦略が求められている。VAE 予防の為の患者管理要件を解明すべく、ICU の臨床データを用いて分析的研究を行った(検討Ⅰ)。VAE の中でも重篤な好中球性炎症が進行する VALI は極めて注意が必要である。VALI は呼吸促迫症候群(ARDS)に合併する一般的な VAE であるが、VALI/ARDS の好中球性炎症 に対する治療法はなく救命は困難を極め、その対策は喫緊の課題である。VALI の好中球活 性化関連メディエーターを標的とした研究はいずれも失敗に終わっている。そこで炎症性メ ディエーター放出の引き金となる人工呼吸の「機械的伸展刺激」に着眼、肺メカニクス改善 作用を有するprone position の適用によってこの制御を目指す動物実験を行った。(検討Ⅱ)。

【対象と方法】
(検討Ⅰ)ICU の人工呼吸患者を対象とした VAE 発生リスクの網羅的探索を電子カルテ情報を用いて実施した。独立リスク因子の解析は Cox 比例ハザードモデルを用い、多変量解析を行った。防止策確立が目標であるから、調査変数は患者因子のみならず呼吸管理・ケア内容(鎮静深度、筋弛緩薬、気管切開、人工呼吸器設定等)に主眼を置いた。VAE が患者転帰に及ぼす影響を検討する為、VAE と死亡、人工呼吸期間及び退院時日常生活動作(ADL)との関係の分析を行った。さらに VAE 発生に関わる患者管理要因として早期リハビリテーション/理学療法に着眼し、この実施の有無と VAE 発生との連関の解析を行った。
(検討Ⅱ)麻酔・筋弛緩及び気管切開下にて家兎を人工呼吸管理した。肺胞洗浄及び高圧・高容量の侵襲的換気で VALI/ARDS を惹起し、この VALI/ARDS モデル家兎を 3 群(コントロール群 / supine position 群 / prone position 群、各群 n=5)に分けた。その後、低 1回換気(6mL/kg)を用いた人工呼吸を 7 時間実施し、実験プロトコルの最後に dynamic 2-deoxy-2-[(18)F] fluoro-D-glucose (18F-FDG) PET と dynamic CT を撮像した。コントロール群は病態惹起直後に撮像し、これをベースラインと位置付けた。撮像した PET 及び CT 画像を解析し、前者からは肺局所の好中球性炎症(18F-FDG uptake rate)を、後者からは(ア)肺局所の含気(aeration)及び伸展刺激(total and dynamic strain)と(イ)肺胞拡張の均一性(inhomogeneity)を定量化し、群間の直接比較を基に prone position の効果を検証した。効果機序探索の為、18F-FDG uptake rate 進展、position、機械的伸展刺激、inhomogeneity との関連性の統計学的分析を加えた。

【結果と考察】
(検討Ⅰ)VAE 発生に関係する呼吸管理法関連項目の網羅的探索の結果、以下のリスク因子を同定した:①集中治療専門医の患者管理への参画の有無、②人工呼吸器設定パラメーターである駆動圧、③ICU 滞在期間中の体重増加、④浮腫の有無、⑤早期リハビリテーション/理学療法の介入の有無。③及び④は“過剰輸液”の代替標と解釈した。ARDS の予後予測因子である駆動圧が、ARDS のみならず人工呼吸患者全般に重要であるとの結果を得た。VAE は、死亡ハザード比(2.6)が有意に高く、且つ人工呼吸期間延長、退院時 ADL低下とも関連する事を確認した。
欧米では多くの研究が進む中、本邦の VAE は解明が進んでおらず、本結果はその先駆けとなるものである。VAE のリスク因子は患者要因に着目した先行報告が多かったが、本研究は呼吸管理要因を同定し得た予防策に繋がる成果である。患者予後に悪影響を及ぼす VAE発症には、疾患重症度等のみならず ICU における呼吸管理の質と方法が寄与する事を証明した。
(検討Ⅱ)VALI/ARDS 肺の人工呼吸管理における prone position の適用が、7 時間後の 18F-FDG uptake rate を遅延させる事を確認した。Prone position の VALI 関連好中球性炎症の進展抑制作用を、in vivo real time imaging で明らかにした点は重要であり、prone position と肺局所の好中球性炎症の関連を示す知見と考えられる。
PET 画像から prone position と supine position 間で 18F-FDG uptake rate 差が生じた肺領域は ventral region である事が判明した。同部を CT 画像で分析すると、supine positionでは高含気で total 及び dynamic strain が大きく(機械的伸展刺激が大)、且つ inhomogeneity が顕著であった。Prone position では同部の含気と total 及び dynamic strain は抑制されており(機械的伸展刺激が小)、且つ inhomogeneity が少ない事から、両群間の特徴の相違が明らかとなった。Ventral region は、ベースライン炎症が比較的高い事を確認した。PET と CT の結果を重ね合わせると、prone position の局所炎症遅延の機序には、a) ベースラインの炎症(元々の炎症程度)・b) inhomogeneity・c) 機械的伸展刺激の 3 要素が関係すると示唆された。この関連の統計学的検討から、a)×c)及び b)×c)間の交互作用を立証出来た。この結果は、元々高炎症の部位、或いは高 inhomogeneity の部位に対し、機械的伸展刺激が重畳負荷されると、同部の好中球活性が誘導され炎症が増大する事を示している。Prone position が、局所の b) inhomogeneity と c) 機械的伸展刺激を共に緩和・改善させる事は CT 解析より明らかであった為、a)×c)及び b)×c)の交互作用を減じる事によって ventral region(元々高炎症で inhomogeneity が大である炎症進展リスクの高い領域)の好中球性炎症進展を遅延させたと考察した。

【結論】
人工呼吸に関連した呼吸器系有害事象である VAE に対する研究を行った。日常防止策として、適切な体液管理の下、適切な呼吸器設定が肝要であり、駆動圧は低く抑える事が鍵である。同時に早期リハビリテーション/理学療法を進める事も重要である。ARDS への VALI対策は、prone position の適用によって肺胞拡張の inhomogeneity を是正し、肺局所への機械的伸展刺激を緩和する事で VALI 関連肺好中球性炎症の遅延を誘導できる可能性が示唆された。

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