Hydrocortisone plus Fludrocortisone for Adults with Septic Shock
Djillali Annane, M.Dら
N Engl J Med 2018; 378:809-818
In brief, corticosteroids improve cardiovascular function by restoring effective blood volume through increased mineralocorticoid activity and by increasing systemic vascular resistance, an effect that is partly related to endothelial glucocorticoid receptors. This might explain why in our trial there was less need for vasopressors with hydrocortisone plus fludrocortisone than with placebo. Corticosteroids attenuate inflammation in various organs in both animals and humans with sepsis, an effect partly related to inhibition of nuclear factor κB (NF-κB). In our trial, hydrocortisone-plus-fludrocortisone therapy accelerated the resolution of organ failure in adults with septic shock.
There are two main differences between trials that showed a survival benefit from corticosteroid therapy (APROCCHSS and Ger-Inf-05) and those that did not (CORTICUS and HYPRESS).
First, in the APROCCHSS and Ger-Inf-05 trials, fludrocortisone was added to hydrocortisone to provide additional mineralocorticoid potency. It was administered enterally in the absence of an intravenous formulation of this drug. The rationale for adding mineralocorticoid treatment is that an experimental sepsis study showed marked NF-κB–mediated down-regulation of vascular mineralocorticoid receptors. Treatment with aldosterone, a mineralocorticoid-receptor agonist, restored α1-adrenoceptor expression, improved contractile response to phenylephrine, and improved survival in mice with endotoxic shock. In a recent pharmacokinetic study involving adults with septic shock, enteral administration of 50 μg of fludrocortisone resulted in plasma concentrations of the drug that exerted significant mineralocorticoid effects, with some interindividual variability.
Second, the APROCCHSS and Ger-Inf-05 trials focused on patients with septic shock whose condition did not improve after initial resuscitation according to the 6-hour bundle of care outlined in the Surviving Sepsis Campaign guidelines.
Hence, the Ger-Inf-05 and APROCCHSS trials independently showed a survival benefit with hydrocortisone plus fludrocortisone in adults with septic shock and persistent vasopressor dependency and organ failures.
「ざっくり」言うと・・
ステロイドの効果を肯定する研究 (APROCCHSS and Ger-Inf-05)で、鉱質コルチコイド作用は心血管系の機能を改善。、血管内皮の糖質コルチコイド受容体に働き血管抵抗を維持（昇圧剤の必要性↓）、臓器の炎症を↓。
なぜステロイドの効果を否定する研究(CORTICUS and HYPRESS)との違いが・・
第1：フルドロコルチゾンで鉱質コルチコイド作用。ネズミではフェニレフリンの効果↑。
第2：効果を肯定する研究のほうが重症（他の手段が駄目な）患者群を扱う。
フルドロコルチゾン - Wikipedia
フルドロコルチゾン(英: fludrocortisone)とは合成コルチコステロイドの一つであり、中等度の糖質コルチコイド作用とそれ以上の鉱質コルチコイド作用を有する。 アメリカ合衆国での商品名はFlorinef、日本での商品名はフロリネフ（ブリストル製薬）である。
フェニレフリン - Wikipedia
フェニレフリン（英:phenylephrine）とはアドレナリン作動薬の1つ。商品名はネオシネジン
フェニレフリンはα1受容体を選択的に活性化することにより血圧を上昇させる一方で、心臓・気管・末梢血管のβ受容体にはほとんど作用しない。カテコールアミンと異なりカテコール-O-メチル基転移酵素（COMT）による代謝を受けないため経口投与が可能で作用時間は長い。
Djillali Annane, M.Dら
N Engl J Med 2018; 378:809-818
In brief, corticosteroids improve cardiovascular function by restoring effective blood volume through increased mineralocorticoid activity and by increasing systemic vascular resistance, an effect that is partly related to endothelial glucocorticoid receptors. This might explain why in our trial there was less need for vasopressors with hydrocortisone plus fludrocortisone than with placebo. Corticosteroids attenuate inflammation in various organs in both animals and humans with sepsis, an effect partly related to inhibition of nuclear factor κB (NF-κB). In our trial, hydrocortisone-plus-fludrocortisone therapy accelerated the resolution of organ failure in adults with septic shock.
There are two main differences between trials that showed a survival benefit from corticosteroid therapy (APROCCHSS and Ger-Inf-05) and those that did not (CORTICUS and HYPRESS).
First, in the APROCCHSS and Ger-Inf-05 trials, fludrocortisone was added to hydrocortisone to provide additional mineralocorticoid potency. It was administered enterally in the absence of an intravenous formulation of this drug. The rationale for adding mineralocorticoid treatment is that an experimental sepsis study showed marked NF-κB–mediated down-regulation of vascular mineralocorticoid receptors. Treatment with aldosterone, a mineralocorticoid-receptor agonist, restored α1-adrenoceptor expression, improved contractile response to phenylephrine, and improved survival in mice with endotoxic shock. In a recent pharmacokinetic study involving adults with septic shock, enteral administration of 50 μg of fludrocortisone resulted in plasma concentrations of the drug that exerted significant mineralocorticoid effects, with some interindividual variability.
Second, the APROCCHSS and Ger-Inf-05 trials focused on patients with septic shock whose condition did not improve after initial resuscitation according to the 6-hour bundle of care outlined in the Surviving Sepsis Campaign guidelines.
Hence, the Ger-Inf-05 and APROCCHSS trials independently showed a survival benefit with hydrocortisone plus fludrocortisone in adults with septic shock and persistent vasopressor dependency and organ failures.
「ざっくり」言うと・・
ステロイドの効果を肯定する研究 (APROCCHSS and Ger-Inf-05)で、鉱質コルチコイド作用は心血管系の機能を改善。、血管内皮の糖質コルチコイド受容体に働き血管抵抗を維持（昇圧剤の必要性↓）、臓器の炎症を↓。
なぜステロイドの効果を否定する研究(CORTICUS and HYPRESS)との違いが・・
第1：フルドロコルチゾンで鉱質コルチコイド作用。ネズミではフェニレフリンの効果↑。
第2：効果を肯定する研究のほうが重症（他の手段が駄目な）患者群を扱う。
フルドロコルチゾン - Wikipedia
フルドロコルチゾン(英: fludrocortisone)とは合成コルチコステロイドの一つであり、中等度の糖質コルチコイド作用とそれ以上の鉱質コルチコイド作用を有する。 アメリカ合衆国での商品名はFlorinef、日本での商品名はフロリネフ（ブリストル製薬）である。
フェニレフリン - Wikipedia
フェニレフリン（英:phenylephrine）とはアドレナリン作動薬の1つ。商品名はネオシネジン
フェニレフリンはα1受容体を選択的に活性化することにより血圧を上昇させる一方で、心臓・気管・末梢血管のβ受容体にはほとんど作用しない。カテコールアミンと異なりカテコール-O-メチル基転移酵素（COMT）による代謝を受けないため経口投与が可能で作用時間は長い。