| <!DOCTYPE html> |
| <html lang="en-US"> |
| <head> |
| <meta charset="UTF-8"> |
| <title>07a5063c-af33-499a-9fe6-703afe32ad5c</title> |
| <meta name="viewport" content="width=device-width, initial-scale=1"> |
| <link rel="stylesheet" href="https://cdn.mathpix.com/fonts/cmu.css"/> |
| <style>html,body { |
| width: 100%; |
| height: 100%; |
| } |
| *, *::before,*::after { |
| box-sizing: border-box; |
| } |
| body { |
| margin: 0; |
| color: #1E2029; |
| font-size: 14px; |
| line-height: normal; |
| } |
| hr { |
| box-sizing: content-box; |
| height: 0; |
| overflow: visible; |
| } |
| h1, h2, h3, h4, h5, h6 { |
| margin-top: 0; |
| margin-bottom: 0.5em; |
| color: rgba(0, 0, 0, 0.85); |
| font-weight: 500; |
| } |
| p { |
| margin-top: 0; |
| margin-bottom: 1em; |
| } |
| ol, ul, dl { |
| margin-top: 0; |
| margin-bottom: 1em; |
| } |
| ol ol, ul ul, ol ul, ul ol { |
| margin-bottom: 0; |
| } |
| dt { |
| font-weight: 500; |
| } |
| dd { |
| margin-bottom: 0.5em; |
| margin-left: 0; |
| } |
| blockquote { |
| margin: 0 0 1em; |
| } |
| dfn { |
| font-style: italic; |
| } |
| b, strong { |
| font-weight: bolder; |
| } |
| small { |
| font-size: 80%; |
| } |
| sub, sup { |
| position: relative; |
| font-size: 75%; |
| line-height: 0; |
| vertical-align: baseline; |
| } |
| sub { |
| bottom: -0.25em; |
| } |
| sup { |
| top: -0.5em; |
| } |
| a { |
| color: #0B93ff; |
| text-decoration: none; |
| background-color: transparent; |
| outline: none; |
| cursor: pointer; |
| transition: color 0.3s; |
| } |
| a:hover { |
| color: #33aaff; |
| } |
| a:active { |
| color: #0070d9; |
| } |
| a:active, a:hover { |
| text-decoration: none; |
| outline: 0; |
| } |
| a[disabled] { |
| color: rgba(0, 0, 0, 0.25); |
| cursor: not-allowed; |
| pointer-events: none; |
| } |
| pre, code, kbd, samp { |
| font-size: 1em; |
| } |
| pre { |
| margin-top: 0; |
| margin-bottom: 1em; |
| overflow: auto; |
| } |
| figure { |
| margin: 0 0 1em; |
| } |
| img { |
| vertical-align: middle; |
| border-style: none; |
| } |
| svg:not(:root) { |
| overflow: hidden; |
| } |
| table { |
| border-collapse: collapse; |
| } |
| caption { |
| padding-top: 0.75em; |
| padding-bottom: 0.3em; |
| color: rgba(0, 0, 0, 0.45); |
| text-align: left; |
| caption-side: bottom; |
| } |
| th { |
| text-align: inherit; |
| } |
| mjx-container[jax="SVG"] { |
| direction: ltr; |
| } |
| |
| mjx-container[jax="SVG"] > svg { |
| overflow: visible; |
| min-height: 1px; |
| min-width: 1px; |
| } |
| |
| mjx-container[jax="SVG"] > svg a { |
| fill: blue; |
| stroke: blue; |
| } |
| |
| mjx-container[jax="SVG"][display="true"] { |
| display: block; |
| text-align: center; |
| margin: 1em 0; |
| } |
| |
| mjx-container[jax="SVG"][display="true"][width="full"] { |
| display: flex; |
| } |
| |
| mjx-container[jax="SVG"][justify="left"] { |
| text-align: left; |
| } |
| |
| mjx-container[jax="SVG"][justify="right"] { |
| text-align: right; |
| } |
| |
| g[data-mml-node="merror"] > g { |
| fill: red; |
| stroke: red; |
| } |
| |
| g[data-mml-node="merror"] > rect[data-background] { |
| fill: yellow; |
| stroke: none; |
| } |
| |
| g[data-mml-node="mtable"] > line[data-line], svg[data-table] > g > line[data-line] { |
| stroke-width: 70px; |
| fill: none; |
| } |
| |
| g[data-mml-node="mtable"] > rect[data-frame], svg[data-table] > g > rect[data-frame] { |
| stroke-width: 70px; |
| fill: none; |
| } |
| |
| g[data-mml-node="mtable"] > .mjx-dashed, svg[data-table] > g > .mjx-dashed { |
| stroke-dasharray: 140; |
| } |
| |
| g[data-mml-node="mtable"] > .mjx-dotted, svg[data-table] > g > .mjx-dotted { |
| stroke-linecap: round; |
| stroke-dasharray: 0,140; |
| } |
| |
| g[data-mml-node="mtable"] > g > svg { |
| overflow: visible; |
| } |
| |
| [jax="SVG"] mjx-tool { |
| display: inline-block; |
| position: relative; |
| width: 0; |
| height: 0; |
| } |
| |
| [jax="SVG"] mjx-tool > mjx-tip { |
| position: absolute; |
| top: 0; |
| left: 0; |
| } |
| |
| mjx-tool > mjx-tip { |
| display: inline-block; |
| padding: .2em; |
| border: 1px solid #888; |
| font-size: 70%; |
| background-color: #F8F8F8; |
| color: black; |
| box-shadow: 2px 2px 5px #AAAAAA; |
| } |
| |
| g[data-mml-node="maction"][data-toggle] { |
| cursor: pointer; |
| } |
| |
| mjx-status { |
| display: block; |
| position: fixed; |
| left: 1em; |
| bottom: 1em; |
| min-width: 25%; |
| padding: .2em .4em; |
| border: 1px solid #888; |
| font-size: 90%; |
| background-color: #F8F8F8; |
| color: black; |
| } |
| |
| foreignObject[data-mjx-xml] { |
| font-family: initial; |
| line-height: normal; |
| overflow: visible; |
| } |
| |
| mjx-container[jax="SVG"] path[data-c], mjx-container[jax="SVG"] use[data-c] { |
| stroke-width: 3; |
| } |
| #setText > div { |
| justify-content: inherit; |
| margin-top: 0; |
| margin-bottom: 1em; |
| |
| |
| } |
| #setText div:last-child { |
| margin-bottom: 0 !important; |
| } |
| #setText > br, #preview-content br { |
| line-height: 1.2; |
| } |
| #preview-content > div { |
| margin-top: 0; |
| margin-bottom: 1em; |
| |
| } |
| .proof > div, |
| #preview-content .proof > div, #setText .proof > div, |
| .theorem > div, |
| #preview-content .theorem > div, #setText .theorem > div { |
| margin-top: 1rem; |
| } |
| mjx-container { |
| text-indent: 0; |
| overflow-y: hidden; |
| overflow-x: auto; |
| padding-top: 1px; |
| padding-bottom: 1px; |
| |
| } |
| .math-inline mjx-container { |
| display: inline-block !important; |
| page-break-inside: avoid; |
| max-width: 100%; |
| padding: 0; |
| line-height: 0; |
| } |
| .math-inline[data-overflow="visible"] mjx-container { |
| overflow: visible; |
| } |
| .math-inline mjx-container mjx-assistive-mml { |
| max-width: 100%; |
| } |
| .math-block { |
| align-items: center; |
| page-break-after: auto; |
| page-break-inside: avoid; |
| margin: 0; |
| display: block; |
| } |
| .math-inline { |
| display: inline-flex; |
| max-width: 100%; |
| } |
| .math-block[data-width="full"] { |
| overflow-x: auto; |
| display: flex; |
| } |
| .math-block[data-width="full"] mjx-container[jax=SVG][display=true] { |
| display: flex; |
| flex: 1 1; |
| justify-content: center; |
| } |
| svg .math-inline { |
| display: initial; |
| max-width: initial; |
| } |
| svg .math-inline mjx-container { |
| max-width: initial; |
| } |
| svg mjx-container { |
| overflow: visible; |
| padding: 0; |
| } |
| svg .math-block[data-width="full"] { |
| overflow: visible; |
| } |
| .math-block, .math-inline { |
| --mmd-highlight-color: rgba(0, 147, 255, 0.25); |
| --mmd-highlight-text-color: #1e2029; |
| } |
| .math-block[data-highlight-color] mjx-container[jax="SVG"] > svg { |
| background-color: var(--mmd-highlight-color); |
| } |
| .math-block[data-highlight-text-color] mjx-container[jax="SVG"] > svg { |
| color: var(--mmd-highlight-text-color); |
| } |
| .math-inline[data-highlight-color] mjx-container[jax="SVG"] { |
| background-color: var(--mmd-highlight-color); |
| } |
| .math-inline[data-highlight-text-color] mjx-container[jax="SVG"] { |
| color: var(--mmd-highlight-text-color); |
| } |
| .math-block p { |
| flex-shrink: 1; |
| } |
| .math-block mjx-container { |
| margin: 0 !important; |
| } |
| .math-error { |
| background-color: yellow; |
| color: red; |
| } |
| #preview-content img, #setText img { |
| max-width: 100%; |
| } |
| #preview-content blockquote, #setText blockquote { |
| page-break-inside: avoid; |
| color: #666; |
| margin: 0 0 1em 0; |
| padding-left: 3em; |
| border-left: .5em solid #eee; |
| } |
| #preview-content pre, #setText pre { |
| border: none; |
| padding: 0; |
| overflow: auto; |
| font-size: 85%; |
| line-height: 1.45; |
| border-radius: 6px; |
| box-sizing: border-box; |
| background: #f8f8fa; |
| } |
| #preview-content pre code, #setText pre code { |
| padding: 1rem; |
| display: block; |
| overflow-x: auto; |
| line-height: 24px; |
| } |
| #preview-content table, #setText table { |
| display: table; |
| overflow: auto; |
| max-width: 100%; |
| border-collapse: collapse; |
| page-break-inside: avoid; |
| margin-bottom: 1em; |
| } |
| #preview-content table th, #setText table th { |
| text-align: center; |
| font-weight: bold; |
| } |
| #preview-content table td, #setText table td, |
| #preview-content table th, #setText table th { |
| border: 1px solid #dfe2e5; |
| padding: 6px 13px; |
| } |
| #preview-content table tr, #setText table tr { |
| background-color: #fff; |
| border-top: 1px solid #c6cbd1; |
| } |
| #preview-content table tr:nth-child(2n), #setText table tr:nth-child(2n) { |
| background-color: #f6f8fa; |
| } |
| .main-title, |
| #preview-content .main-title, #setText .main-title { |
| text-align: center; |
| line-height: 1.2; |
| margin: 0 auto 1em auto; |
| } |
| .author, |
| #preview-content .author, #setText .author { |
| text-align: center; |
| margin: 0 auto; |
| display: flex; |
| justify-content: center; |
| flex-wrap: wrap; |
| } |
| .author p, |
| #preview-content .author p, #setText .author p { |
| min-width: 30%; |
| max-width: 50%; |
| padding: 0 7px; |
| } |
| .author > p > span, |
| #preview-content .author > p > span, #setText .author > p > span { |
| display: block; |
| text-align: center; |
| } |
| .section-title, |
| #preview-content .section-title, #setText .section-title { |
| margin-top: 1.5em; |
| } |
| .abstract, |
| #preview-content .abstract, #setText .abstract { |
| text-align: justify; |
| margin-bottom: 1em; |
| } |
| .abstract p, |
| #preview-content .abstract p, #setText .abstract p { |
| margin-bottom: 0; |
| } |
| #preview-content sup, #setText sup { |
| top: -.5em; |
| position: relative; |
| font-size: 75%; |
| line-height: 0; |
| vertical-align: baseline; |
| } |
| .text-url, |
| #preview-content .text-url, #setText .text-url { |
| color: #0B93ff; |
| cursor: text; |
| pointer-events: none; |
| } |
| .text-url a:hover, |
| #preview-content .text-url a:hover, #setText .text-url a:hover { |
| color: #0B93ff; |
| } |
| mark, |
| #preview-content mark, #setText mark { |
| background-color: #feffe6; |
| } |
| span[data-underline-type] mark, |
| #preview-content span[data-underline-type] mark, |
| #setText span[data-underline-type] mark { |
| background: inherit; |
| background-color: #feffe6; |
| padding-top: 0; |
| padding-bottom: 0; |
| } |
| *[data-has-dotfill] { |
| position: relative; |
| overflow: hidden; |
| } |
| *[data-has-dotfill] .dotfill::after { |
| position: absolute; |
| padding-left: .25ch; |
| content: " . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . "; |
| text-align: right; |
| } |
| .smiles, |
| #preview-content .smiles, #setText .smiles { |
| text-align: center; |
| } |
| div.svg-container, |
| #preview-content > div.svg-container, |
| #setText > div.svg-container { |
| display: flex; |
| justify-content: center; |
| } |
| @media print { |
| #preview { |
| font-size: 10pt !important; |
| } |
| .math-block svg, .math-inline svg { |
| shape-rendering: crispEdges; |
| margin-top: 1px; |
| } |
| #preview-content img, #setText img { |
| display: block; |
| } |
| #preview-content .figure_img img, #setText .figure_img img { |
| display: inline; |
| } |
| #preview-content h1, #preview-content h2, #preview-content h3, |
| #preview-content h4, #preview-content h5, #preview-content h6, |
| #setText h1, #setText h2, #setText h3, |
| #setText h4, #setText h5, #setText h6 { |
| page-break-inside: avoid; |
| position: relative; |
| border: 2px solid transparent; |
| } |
| #preview-content h1::after, #preview-content h2::after, #preview-content h3::after, |
| #preview-content h4::after, #preview-content h5::after, #preview-content h6::after, |
| #setText h1::after, #setText h2::after, #setText h3::after, |
| #setText h4::after, #setText h5::after, #setText h6::after { |
| content: ""; |
| display: block; |
| height: 100px; |
| margin-bottom: -100px; |
| position: relative; |
| } |
| } |
| #preview-content code, #setText code { |
| font-family: Inconsolata; |
| font-size: inherit; |
| display: initial; |
| background: #f8f8fa; |
| } |
| #preview-content .mmd-highlight code, #setText .mmd-highlight code, |
| #preview-content pre.mmd-highlight code, #setText pre.mmd-highlight code { |
| background-color: transparent; |
| } |
| #preview-content pre code, #setText pre code { |
| font-family: 'DM Mono', Inconsolata, monospace; |
| color: #333; |
| font-size: 15px; |
| } |
| .hljs-comment, .hljs-quote, |
| #preview-content .hljs-comment, #setText .hljs-comment, |
| #preview-content .hljs-quote, #setText .hljs-quote { |
| color: #998; |
| font-style: italic; |
| } |
| .hljs-command, |
| #preview-content .hljs-command, #setText .hljs-command { |
| color: #005cc5; |
| } |
| .hljs-keyword, .hljs-selector-tag, .hljs-subst, |
| #preview-content .hljs-keyword, #setText .hljs-keyword, |
| #preview-content .hljs-selector-tag, #setText .hljs-selector-tag, |
| #preview-content .hljs-subst, #setText .hljs-subst { |
| color: #d73a49; |
| font-weight: bold; |
| } |
| .hljs-number, .hljs-literal, .hljs-variable, |
| .hljs-template-variable, .hljs-tag .hljs-attr, |
| #preview-content .hljs-number, #setText .hljs-number, |
| #preview-content .hljs-literal, #setText .hljs-literal, |
| #preview-content .hljs-variable, #setText .hljs-variable, |
| #preview-content .hljs-template-variable, #setText .hljs-template-variable, |
| #preview-content .hljs-tag .hljs-attr, #setText .hljs-tag .hljs-attr { |
| color: #005cc5; |
| } |
| .hljs-string, .hljs-doctag, |
| #preview-content .hljs-string, #setText .hljs-string, |
| #preview-content .hljs-doctag, #setText .hljs-doctag { |
| color: #24292e; |
| } |
| .hljs-title, .hljs-section, .hljs-selector-id, |
| #preview-content .hljs-title, #setText .hljs-title, |
| #preview-content .hljs-section, #setText .hljs-section, |
| #preview-content .hljs-selector-id, #setText .hljs-selector-id { |
| color: #6f42c1; |
| font-weight: bold; |
| } |
| .hljs-subst, |
| #preview-content .hljs-subst, #setText .hljs-subst { |
| font-weight: normal; |
| } |
| .hljs-type, .hljs-class .hljs-title, |
| #preview-content .hljs-type, #setText .hljs-type, |
| #preview-content .hljs-class .hljs-title, #setText .hljs-class .hljs-title { |
| color: #458; |
| font-weight: bold; |
| } |
| .hljs-tag, .hljs-name, .hljs-attribute, |
| #preview-content .hljs-tag, #setText .hljs-tag, |
| #preview-content .hljs-name, #setText .hljs-name, |
| #preview-content .hljs-attribute, #setText .hljs-attribute { |
| color: #000080; |
| font-weight: normal; |
| } |
| .hljs-regexp, .hljs-link, |
| #preview-content .hljs-regexp, #setText .hljs-regexp, |
| #preview-content .hljs-link, #setText .hljs-link { |
| color: #009926; |
| } |
| .hljs-symbol, .hljs-bullet, |
| #preview-content .hljs-symbol, #setText .hljs-symbol, |
| #preview-content .hljs-bullet, #setText .hljs-bullet { |
| color: #990073; |
| } |
| .hljs-built_in, .hljs-builtin-name, |
| #preview-content .hljs-built_in, #setText .hljs-built_in, |
| #preview-content .hljs-builtin-name, #setText .hljs-builtin-name { |
| color: #24292e; |
| } |
| .hljs-meta, |
| #preview-content .hljs-meta, #setText .hljs-meta { |
| color: #999; |
| font-weight: bold; |
| } |
| .hljs-meta-keyword, |
| #preview-content .hljs-meta-keyword, #setText .hljs-meta-keyword { |
| color: #d73a49; |
| } |
| .hljs-meta-string, |
| #preview-content .hljs-meta-string, #setText .hljs-meta-string { |
| color: #032f62; |
| } |
| .hljs-deletion, |
| #preview-content .hljs-deletion, #setText .hljs-deletion { |
| background: #fdd; |
| } |
| .hljs-addition, |
| #preview-content .hljs-addition, #setText .hljs-addition { |
| background: #dfd; |
| } |
| .hljs-emphasis, |
| #preview-content .hljs-emphasis, #setText .hljs-emphasis { |
| font-style: italic; |
| } |
| .hljs-strong, |
| #preview-content .hljs-strong, #setText .hljs-strong { |
| font-weight: bold; |
| } |
| .table_tabular, |
| #preview-content .table_tabular, #setText .table_tabular { |
| overflow-x: auto; |
| padding: 0 2px 0.5em 2px; |
| } |
| .tabular, |
| #preview-content .tabular, #setText .tabular { |
| display: inline-table !important; |
| width: auto; |
| table-layout: auto; |
| border-collapse: collapse; |
| border-spacing: 0; |
| margin: 0 0 1em; |
| font-size: inherit; |
| height: fit-content; |
| } |
| .tabular th, |
| #preview-content .tabular th, #setText .tabular th { |
| border: none !important; |
| padding: 6px 13px; |
| background-color: transparent; |
| font-weight: bold; |
| } |
| .tabular tr, |
| #preview-content .tabular tr, #setText .tabular tr { |
| border-top: none !important; |
| border-bottom: none !important; |
| background-color: transparent; |
| } |
| .tabular td, |
| #preview-content .tabular td, #setText .tabular td { |
| border-style: none !important; |
| background-color: #fff; |
| border-color: #000 !important; |
| word-break: keep-all; |
| padding: 0.1em 0.5em !important; |
| } |
| .tabular td > p, |
| #preview-content .tabular td > p, #setText .tabular td > p { |
| margin-bottom: 0; |
| margin-top: 0; |
| } |
| .tabular td._empty, |
| #preview-content .tabular td._empty, #setText .tabular td._empty { |
| height: 1.3em; |
| } |
| .tabular td .f, |
| #preview-content .tabular td .f, #setText .tabular td .f { |
| opacity: 0; |
| } |
| #preview-content .sub-table table, #setText .sub-table table { |
| margin-bottom: 0; |
| } |
| html[data-theme="dark"] .tabular tr, |
| html[data-theme="dark"] #preview-content .tabular tr, html[data-theme="dark"] #setText .tabular tr, |
| html[data-theme="dark"] .tabular td, |
| html[data-theme="dark"] #preview-content .tabular td, html[data-theme="dark"] #setText .tabular td { |
| background-color: #202226; |
| border-color: #fff !important; |
| } |
| .figure_img, |
| #preview-content .figure_img, #setText .figure_img { |
| margin-bottom: 0.5em; |
| overflow-x: auto; |
| } |
| div.figure_img img, |
| #preview-content div.figure_img img, #setText div.figure_img img { |
| display: inline; |
| margin: 0; |
| } |
| ol.enumerate, ul.itemize, |
| #preview-content ol.enumerate, #setText ol.enumerate, |
| #preview-content ul.itemize, #setText ul.itemize { |
| padding-inline-start: 40px; |
| margin: 0 0 1em 0; |
| } |
| li > ol.enumerate, li > ul.itemize, |
| #preview-content li > ol.enumerate, #setText li > ol.enumerate, |
| #preview-content li > ul.itemize, #setText li > ul.itemize { |
| margin: 0; |
| } |
| ul.itemize > li, |
| #preview-content ul.itemize > li, #setText ul.itemize > li { |
| position: relative; |
| min-height: 1.4em; |
| margin-bottom: 0; |
| } |
| .enumerate > .li_enumerate, |
| #preview-content .enumerate > .li_enumerate, #setText .enumerate > .li_enumerate { |
| margin-bottom: 0; |
| } |
| .itemize > li > span.li_level, .li_enumerate.not_number > span.li_level, |
| #preview-content .itemize > li > span.li_level, #setText .itemize > li > span.li_level, |
| #preview-content .li_enumerate.not_number > span.li_level, #setText .li_enumerate.not_number > span.li_level { |
| position: absolute; |
| right: 100%; |
| white-space: nowrap; |
| width: max-content; |
| display: flex; |
| justify-content: flex-end; |
| padding-right: 10px; |
| box-sizing: border-box; |
| } |
| .li_enumerate.not_number, |
| #preview-content .li_enumerate.not_number, #setText .li_enumerate.not_number { |
| position: relative; |
| display: inline-block; |
| list-style-type: none; |
| min-height: 1.4em; |
| } |
| .itemize > li > span.li_level .math-inline, |
| .enumerate > li > span.li_level .math-inline, |
| #preview-content .itemize > li > span.li_level .math-inline, |
| #setText .itemize > li > span.li_level .math-inline, |
| #preview-content .enumerate > li > span.li_level .math-inline, |
| #setText .enumerate > li > span.li_level .math-inline { |
| display: inline-block; |
| } |
| #preview { |
| font-family: 'CMU Serif', 'Georgia', Helvetica, Arial, sans-serif; |
| font-size: 17px; |
| visibility: visible; |
| word-break: break-word; |
| padding: 2.5em; |
| max-width: 800px; |
| margin: auto; |
| box-sizing: content-box; |
| } |
| #preview h1, #preview h2, #preview h3, #preview h4, #preview h5, #preview strong { |
| font-family: 'CMU Serif Bold', 'Georgia', Helvetica, Arial, sans-serif; |
| } |
| #preview i, #preview em { |
| font-family: 'CMU Serif Italic', 'Georgia', Helvetica, Arial, sans-serif; |
| } |
| .mmd-menu { |
| max-width: 320px; |
| position: absolute; |
| background-color: white; |
| color: black; |
| width: auto; |
| padding: 5px 0; |
| border: 1px solid #E5E6EB; |
| margin: 0; |
| cursor: default; |
| font: menu; |
| text-align: left; |
| text-indent: 0; |
| text-transform: none; |
| line-height: normal; |
| letter-spacing: normal; |
| word-spacing: normal; |
| word-wrap: normal; |
| white-space: nowrap; |
| float: none; |
| z-index: 201; |
| border-radius: 5px; |
| -webkit-border-radius: 5px; |
| -moz-border-radius: 5px; |
| -khtml-border-radius: 5px; |
| box-shadow: 0 10px 20px #808080; |
| -webkit-box-shadow: 0 10px 20px #808080; |
| -moz-box-shadow: 0 10px 20px #808080; |
| -khtml-box-shadow: 0 10px 20px #808080; |
| } |
| .mmd-menu:focus { outline: none; } |
| .mmd-menu.mmd-menu-sm { |
| max-width: 100vw; |
| padding-bottom: 34px; |
| border-radius: 0; |
| -webkit-border-radius: 0; |
| -moz-border-radius: 0; |
| -khtml-border-radius: 0; |
| } |
| .mmd-menu-item-icon { |
| color: #1E2029; |
| margin-left: auto; |
| align-items: center; |
| display: none; |
| flex-shrink: 0; |
| } |
| .mmd-menu-item { |
| padding: 8px 1.25rem; |
| display: flex; |
| background: transparent; |
| height: 52px; |
| max-height: 52px; |
| } |
| .mmd-menu-item:focus { outline: none; } |
| .mmd-menu-item.active { |
| background-color: #e1e0e5; |
| } |
| .mmd-menu-item.active .mmd-menu-item-icon { |
| display: flex; |
| } |
| .mmd-menu-item-container { |
| overflow: hidden; |
| } |
| .mmd-menu-item-title { |
| color: #1E2029; |
| white-space: nowrap; |
| text-overflow: ellipsis; |
| overflow: hidden; |
| font-size: 14px; |
| line-height: 20px; |
| } |
| .mmd-menu-item-value { |
| color: #7d829c; |
| white-space: nowrap; |
| text-overflow: ellipsis; |
| overflow: hidden; |
| font-size: 12px; |
| line-height: 16px; |
| } |
| html[data-theme="dark"] .mmd-menu-item-title { |
| color: #ebefe7; |
| } |
| html[data-theme="dark"] .mmd-menu-item.active .mmd-menu-item-title { |
| color: #1E2029; |
| } |
| html[data-theme="dark"] .mmd-menu { |
| background-color: #33363a; |
| } |
| .mmd-context-menu-overlay { |
| background: rgba(0, 0, 0, 0.56); |
| } |
| .ClipboardButton { |
| padding: 0; |
| margin: 0.5rem; |
| display: inline-block; |
| cursor: pointer; |
| color: rgb(36, 41, 47); |
| background: rgb(246, 248, 250); |
| border-radius: 6px; |
| border: 1px solid rgba(31, 35, 40, 0.15); |
| box-shadow: rgba(31, 35, 40, 0.04) 0 1px 0 0, rgba(255, 255, 255, 0.25) 0 1px 0 0 inset; |
| position: relative; |
| } |
| .ClipboardButton:hover { |
| background-color: rgb(243, 244, 246); |
| border-color: rgba(31, 35, 40, 0.15); |
| transition-duration: .1s; |
| } |
| td .mmd-clipboard-copy-container { |
| line-height: 0; |
| } |
| td .ClipboardButton { |
| margin: 1px; |
| line-height: 0; |
| } |
| td .ClipboardButton .mmd-clipboard-icon { |
| margin: 1px !important; |
| transform: scale(0.6); |
| } |
| .mmd-clipboard-icon { |
| fill: currentColor; |
| vertical-align: text-bottom; |
| } |
| .mmd-clipboard-copy-icon { |
| color: rgb(101, 109, 118); |
| } |
| .mmd-clipboard-check-icon { |
| color: rgb(26, 127, 55); |
| } |
| .mmd-tooltipped-no-delay:hover::before, |
| .mmd-tooltipped-no-delay:hover::after { |
| animation-delay: 0s; |
| } |
| .mmd-tooltipped:hover::before, |
| .mmd-tooltipped:hover::after { |
| display: inline-block; |
| text-decoration: none; |
| animation-name: tooltip-appear; |
| animation-duration: .1s; |
| animation-fill-mode: forwards; |
| animation-timing-function: ease-in; |
| animation-delay: .4s; |
| } |
| .mmd-tooltipped-w::before { |
| top: 50%; |
| bottom: 50%; |
| left: -7px; |
| margin-top: -6px; |
| border-left-color: rgb(36, 41, 47); |
| } |
| .mmd-tooltipped::before { |
| position: absolute; |
| z-index: 1000001; |
| display: none; |
| width: 0; |
| height: 0; |
| color: rgb(36, 41, 47); |
| pointer-events: none; |
| content: ""; |
| border: 6px solid transparent; |
| opacity: 0; |
| } |
| .mmd-tooltipped-w::after { |
| right: 100%; |
| bottom: 50%; |
| margin-right: 6px; |
| transform: translateY(50%); |
| } |
| .mmd-tooltipped::after { |
| position: absolute; |
| z-index: 1000000; |
| display: none; |
| padding: 0.5em 0.75em; |
| font: normal normal 11px/1.5 'CMU Serif', 'Georgia', Helvetica, Arial, sans-serif; |
| -webkit-font-smoothing: subpixel-antialiased; |
| color: white; |
| text-align: center; |
| text-decoration: none; |
| text-shadow: none; |
| text-transform: none; |
| letter-spacing: normal; |
| word-wrap: break-word; |
| white-space: pre; |
| pointer-events: none; |
| content: attr(aria-label); |
| background: rgb(36, 41, 47); |
| border-radius: 6px; |
| opacity: 0; |
| }</style> |
| </head> |
| <body> |
| <div id="preview" class="preview scrollEditor"> |
| <div id="container-ruller" /> |
| <div id="preview-content"> |
| <h1 type="title" class="main-title" id="early-goal-directed-therapy-using-a-physiological-holistic-view%3A-the-andromeda-shock-a-randomized-controlled-trial"> |
| Early goal-directed therapy using a physiological holistic view: the ANDROMEDA-SHOCK-a randomized controlled trial </h1> |
| <div><div class="author"> |
| <p><span>Glenn Hernández <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.686ex" height="1.928ex" role="img" focusable="false" viewBox="0 -852.2 745.2 852.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="msup"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="TeXAtom" transform="translate(533,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mo"><path data-c="2217" d="M229 286Q216 420 216 436Q216 454 240 464Q241 464 245 464T251 465Q263 464 273 456T283 436Q283 419 277 356T270 286L328 328Q384 369 389 372T399 375Q412 375 423 365T435 338Q435 325 425 315Q420 312 357 282T289 250L355 219L425 184Q434 175 434 161Q434 146 425 136T401 125Q393 125 383 131T328 171L270 213Q283 79 283 63Q283 53 276 44T250 35Q231 35 224 44T216 63Q216 80 222 143T229 213L171 171Q115 130 110 127Q106 124 100 124Q87 124 76 134T64 161Q64 166 64 169T67 175T72 181T81 188T94 195T113 204T138 215T170 230T210 250L74 315Q65 324 65 338Q65 353 74 363T98 374Q106 374 116 368T171 328L229 286Z"></path></g></g></g></g></g></g></g></svg></mjx-container></span>, Alexandre Biasi Cavalcanti <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span>, Gustavo Ospina-Tascón <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.885ex" role="img" focusable="false" viewBox="0 -833.2 436.6 833.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></g></g></svg></mjx-container></span>, Fernando Godinho Zampieri <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span>, Arnaldo Dubin <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 436.6 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g></g></g></g></g></svg></mjx-container></span>, F. Javier Hurtado <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g></g></g></g></g></svg></mjx-container></span>, Gilberto Friedman <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z"></path></g></g></g></g></g></svg></mjx-container></span>, Ricardo Castro <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span>, Leyla Alegría <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span>, Maurizio Cecconi <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.903ex" role="img" focusable="false" viewBox="0 -841 436.6 841"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path></g></g></g></g></g></svg></mjx-container></span>, Jean-Louis Teboul <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path></g></g></g></g></g></svg></mjx-container></span> and Jan Bakker <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="6.321ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 2794 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mo" transform="translate(500,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path></g><g data-mml-node="mo" transform="translate(1278,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(1556,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(2556,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(2834,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span> The ANDROMEDA-SHOCK Study Investigators</span></p> |
| </div></div> |
| <div class="abstract" style="width: 80%; margin: 0 auto 1em auto; font-size: .9em;"> |
| <h4 id="abstract_head" class="abstract_head" style="text-align: center;"> |
| Abstract</h4> |
| <p style="text-indent: 1em;">Background: Septic shock is a highly lethal condition. Early recognition of tissue hypoperfusion and its reversion are key factors for limiting progression to multiple organ dysfunction and death. Lactate-targeted resuscitation is the gold-standard under current guidelines, although it has several pitfalls including that non-hypoxic sources of lactate might predominate in an unknown proportion of patients. Peripheral perfusion-targeted resuscitation might provide a real-time response to increases in flow that could lead to a more timely decision to stop resuscitation, thus avoiding fluid overload and the risks of over-resuscitation. This article reports the rationale, study design and analysis plan of the ANDROMEDA-SHOCK Study. Methods: ANDROMEDA-SHOCK is a randomized controlled trial which aims to determine if a peripheral perfusiontargeted resuscitation is associated with lower 28-day mortality compared to a lactate-targeted resuscitation in patients with septic shock with less than 4 h of diagnosis. Both groups will be treated with the same sequential approach during the 8-hour study period pursuing normalization of capillary refill time versus normalization or a decrease of more than 20% of lactate every 2 h . The common protocol starts with fluid responsiveness assessment and fluid loading in responders, followed by a vasopressor and an inodilator test if necessary. The primary outcome is 28-day mortality, and the secondary outcomes are: free days of mechanical ventilation, renal replacement therapy and vasopressor support during the first 28 days after randomization; multiple organ dysfunction during the first 72 h after randomization; intensive care unit and hospital lengths of stay; and all-cause mortality at 90-day. A sample size of 422 patients was calculated to detect a 15% absolute reduction in mortality in the peripheral perfusion group with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Conclusions: If peripheral perfusion-targeted resuscitation improves 28-day mortality, this could lead to simplified algorithms, assessing almost in real-time the reperfusion process, and pursuing more physiologically sound objectives. At the end, it might prevent the risk of over-resuscitation and lead to a better utilization of intensive care unit resources.</p> |
| <p style="text-indent: 1em;">Trial registration <a href="http://ClinicalTrials.gov" target="_blank" rel="noopener" style="display: inline-block">ClinicalTrials.gov</a> Identifier: NCT03078712 (registered retrospectively March 13th, 2017)</p> |
| </div> |
| <div>Keywords: Septic shock, Resuscitation, Peripheral perfusion, Lactate, Fluid responsiveness</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="background"> |
| Background</h2> |
| <div>Septic shock is a potentially lethal condition associated with a mortality risk of up to <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="9.175ex" height="1.882ex" role="img" focusable="false" viewBox="0 -750 4055.4 832"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1222.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(2222.4,0)"><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(3222.4,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> [1, 2]. Early recognition of tissue hypoperfusion and its reversion are key factors for limiting progression to multiple organ dysfunction and death [1-6].</div> |
| <div>Hyperlactatemia has been traditionally considered as a hallmark of ongoing tissue hypoxia and anaerobic metabolism [7, 8]. A recent study targeting a decrease in lactate levels as a resuscitation goal in critically ill patients showed a significant improvement in organ failure and outcomes associated with this endpoint [9]. Therefore, normalization of lactate levels has been recommended as a resuscitation target by current guidelines [10]. However, other non-hypoperfusion-related causes of hyperlactatemia might predominate in an unknown number of patients [11, 12]. In that setting, sustained efforts to increase cardiac output (CO) with fluids or vasoactive drugs could lead to detrimental effects of over-resuscitation [13, 14]. In addition, lactate exhibits a biphasic recovery rate even after a successful resuscitation [15], introducing an important confounder for practitioners.</div> |
| <div>Monitoring peripheral perfusion is particularly attractive because of its easy clinical accessibility and more importantly, because it could reflect the adequacy of intraabdominal visceral organ perfusion [16, 17]. The skin territory lacks auto-regulatory flow control, and therefore, sympathetic activation impairs skin perfusion during circulatory dysfunction [17], a phenomenon that could be evaluated by peripheral perfusion assessment. A robust body of evidence confirms that abnormal peripheral perfusion after initial resuscitation is associated with increased morbidity and mortality [18-23], whereby it could be used as a potential resuscitation goal [24]. In fact, the presence of a cold clammy skin, mottling or prolonged capillary refill time (CRT) has been suggested as indicators to initiate fluid resuscitation in patients with septic shock [17]. Interestingly, CRT was the first parameter to be normalized in patients surviving from septic shock and predicted lactate normalization at 24 h [18]. A recent pilot study suggests that targeting peripheral perfusion during septic shock resuscitation is safe and associated with less fluid administration and organ dysfunctions [25]. Therefore, the excellent prognosis associated with CRT recovery, its rapid-response time to fluid loading, its relative simplicity, its availability in resourcelimited settings and its capacity to change in parallel with perfusion of physiologically relevant territories such as the hepatosplanchnic region [16] constitute strong reasons to evaluate the usefulness of CRT to guide resuscitation in septic shock patients.</div> |
| <div>Consequently, we decided to conduct a randomized controlled trial (RCT) comparing peripheral<br> |
| perfusion-targeted resuscitation (PPTR) versus lactatetargeted resuscitation (LTR) in patients with septic shock, hypothesizing that resuscitation aimed at peripheral perfusion will be associated with lower mortality rates. We also hypothesize that patients assigned to PPTR will require less volume of fluids with subsequent lower positive fluid balances. Accordingly, PPTR should be associated with less organ dysfunctions, especially at respiratory, renal and gastrointestinal levels.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="methods"> |
| Methods</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="primary-objective"> |
| Primary objective</h2> |
| <div>To determine if PPTR is associated with lower mortality rates at 28 day than a LTR in patients with septic shock.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="secondary-objectives"> |
| Secondary objectives</h2> |
| <div>To determine if a PPTR is associated with less severe multiple organ dysfunction; more mechanical ventilation (MV) free days; and less vasopressor load and renal replacement therapies (RRT) than a LTR strategy in patients with septic shock.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="outcomes"> |
| Outcomes</h2> |
| <div>Primary outcome will be all-cause mortality at 28-day.<br> |
| Secondary outcomes:</div> |
| <ul> |
| <li>Free days of MV, RRT and vasopressor support during the first 28 days after randomization;</li> |
| <li>Multiple organ dysfunction during the first 72 h after randomization [26];</li> |
| <li>Intensive care unit (ICU) and hospital lengths of stay;</li> |
| <li>All-cause mortality at 90-day.</li> |
| </ul> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="tertiary-outcomes%3A"> |
| Tertiary outcomes:</h2> |
| <ul> |
| <li>Amount of resuscitation fluids at 8 and 24 -hours;</li> |
| <li>Total fluid balance at <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="7.668ex" height="1.971ex" role="img" focusable="false" viewBox="0 -677 3389.3 871"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path></g><g data-mml-node="mo" transform="translate(500,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(944.7,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1944.7,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(2389.3,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z" transform="translate(500,0)"></path></g></g></g></svg></mjx-container></span> and 72-h;</li> |
| <li>Occurrence of intraabdominal hypertension (IAH) during the first 72 h after randomization (%);</li> |
| <li>Use of RRT (%)</li> |
| <li>In-hospital mortality</li> |
| </ul> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="study-design"> |
| Study design</h2> |
| <div>ANDROMEDA-SHOCK is a prospective, multicenter, parallel-group, randomized trial aimed to compare an 8-h protocol of PPTR vs. LTR in patients with septic shock [27].</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="patients"> |
| Patients</h2> |
| <div>Consecutive adult patients ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.312ex;" xmlns="http://www.w3.org/2000/svg" width="4.651ex" height="1.819ex" role="img" focusable="false" viewBox="0 -666 2055.8 804"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z" transform="translate(500,0)"></path></g></g></g></svg></mjx-container></span> years) with septic shock will be considered eligible. Septic shock is defined as suspected or confirmed infection, plus hyperlactatemia ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.312ex;" xmlns="http://www.w3.org/2000/svg" width="11.024ex" height="1.882ex" role="img" focusable="false" viewBox="0 -694 4872.8 832"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(778,0)"></path></g><g data-mml-node="mi" transform="translate(2333.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3211.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(4089.8,0)"><path data-c="1D45C" d="M201 -11Q126 -11 80 38T34 156Q34 221 64 279T146 380Q222 441 301 441Q333 441 341 440Q354 437 367 433T402 417T438 387T464 338T476 268Q476 161 390 75T201 -11ZM121 120Q121 70 147 48T206 26Q250 26 289 58T351 142Q360 163 374 216T388 308Q388 352 370 375Q346 405 306 405Q243 405 195 347Q158 303 140 230T121 120Z"></path></g><g data-mml-node="mi" transform="translate(4574.8,0)"><path data-c="1D459" d="M117 59Q117 26 142 26Q179 26 205 131Q211 151 215 152Q217 153 225 153H229Q238 153 241 153T246 151T248 144Q247 138 245 128T234 90T214 43T183 6T137 -11Q101 -11 70 11T38 85Q38 97 39 102L104 360Q167 615 167 623Q167 626 166 628T162 632T157 634T149 635T141 636T132 637T122 637Q112 637 109 637T101 638T95 641T94 647Q94 649 96 661Q101 680 107 682T179 688Q194 689 213 690T243 693T254 694Q266 694 266 686Q266 675 193 386T118 83Q118 81 118 75T117 65V59Z"></path></g></g></g></svg></mjx-container></span> per liter) and vasopressor requirements due<br> |
| to refractory hypotension [27]. This latter is characterized as a systolic blood pressure (SBP) <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.464ex;" xmlns="http://www.w3.org/2000/svg" width="11.712ex" height="2.009ex" role="img" focusable="false" viewBox="0 -683 5176.8 888"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2933.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3811.8,0)"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="mi" transform="translate(4699.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> or a mean arterial pressure (MAP) <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.464ex;" xmlns="http://www.w3.org/2000/svg" width="11.712ex" height="2.009ex" role="img" focusable="false" viewBox="0 -683 5176.8 888"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2933.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3811.8,0)"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="mi" transform="translate(4699.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> after an intravenous fluid load of at least <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="8.312ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 3674 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(1878,0)"><path data-c="1D459" d="M117 59Q117 26 142 26Q179 26 205 131Q211 151 215 152Q217 153 225 153H229Q238 153 241 153T246 151T248 144Q247 138 245 128T234 90T214 43T183 6T137 -11Q101 -11 70 11T38 85Q38 97 39 102L104 360Q167 615 167 623Q167 626 166 628T162 632T157 634T149 635T141 636T132 637T122 637Q112 637 109 637T101 638T95 641T94 647Q94 649 96 661Q101 680 107 682T179 688Q194 689 213 690T243 693T254 694Q266 694 266 686Q266 675 193 386T118 83Q118 81 118 75T117 65V59Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(2176,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(2676,0)"><path data-c="1D458" d="M121 647Q121 657 125 670T137 683Q138 683 209 688T282 694Q294 694 294 686Q294 679 244 477Q194 279 194 272Q213 282 223 291Q247 309 292 354T362 415Q402 442 438 442Q468 442 485 423T503 369Q503 344 496 327T477 302T456 291T438 288Q418 288 406 299T394 328Q394 353 410 369T442 390L458 393Q446 405 434 405H430Q398 402 367 380T294 316T228 255Q230 254 243 252T267 246T293 238T320 224T342 206T359 180T365 147Q365 130 360 106T354 66Q354 26 381 26Q429 26 459 145Q461 153 479 153H483Q499 153 499 144Q499 139 496 130Q455 -11 378 -11Q333 -11 305 15T277 90Q277 108 280 121T283 145Q283 167 269 183T234 206T200 217T182 220H180Q168 178 159 139T145 81T136 44T129 20T122 7T111 -2Q98 -11 83 -11Q66 -11 57 -1T48 16Q48 26 85 176T158 471L195 616Q196 629 188 632T149 637H144Q134 637 131 637T124 640T121 647Z"></path></g><g data-mml-node="mi" transform="translate(3197,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span>, administered over the course of 60 min .</div> |
| <div>Patients will be excluded in case of:</div> |
| <ul> |
| <li>pregnancy;</li> |
| <li>anticipated surgery or dialysis procedure during the first 8 h after septic shock diagnosis;</li> |
| <li>Do-Not-Attempt-Resuscitation status;</li> |
| <li>active bleeding;</li> |
| <li>acute hematological malignancy;</li> |
| <li>concomitant severe acute respiratory distress syndrome (ARDS);</li> |
| <li>more than 4 h after the onset of septic shock criteria.</li> |
| </ul> |
| <div>An active daily screening for potentially eligible patients will be performed at all the participating ICUs.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="randomization"> |
| Randomization</h2> |
| <div>Eligible patients will be randomly allocated to PPTR or LTR groups. PPTR will be aimed to normalize CRT, while LTR will target lactate normalization or a decreasing rate <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="6.536ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 2888.8 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> per 2 h of lactate levels during the 8 h of the study period (Fig. 1).</div> |
| <div>A randomization sequence with an allocation of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.148ex" height="1.507ex" role="img" focusable="false" viewBox="0 -666 1833.6 666"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mo" transform="translate(777.8,0)"><path data-c="3A" d="M78 370Q78 394 95 412T138 430Q162 430 180 414T199 371Q199 346 182 328T139 310T96 327T78 370ZM78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z"></path></g><g data-mml-node="mn" transform="translate(1333.6,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></svg></mjx-container></span> will be generated by a computer program. Study-group assignment will be performed by means of randomized permuted blocks of eight. Allocation concealment will be maintained by means of central randomization.</div> |
| <div class="table" number="1"> |
| <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/07a5063c-af33-499a-9fe6-703afe32ad5c-03.jpg?height=722&width=593&top_left_y=1677&top_left_x=352" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Fig. 1 Pre-randomization phase assessments and interventions. CVC central venous catheter</div></div> |
| <div>Investigators at the sites will call a representative of the Study Coordinating Center (SCC) available <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="5.828ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 2576 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="210E" d="M137 683Q138 683 209 688T282 694Q294 694 294 685Q294 674 258 534Q220 386 220 383Q220 381 227 388Q288 442 357 442Q411 442 444 415T478 336Q478 285 440 178T402 50Q403 36 407 31T422 26Q450 26 474 56T513 138Q516 149 519 151T535 153Q555 153 555 145Q555 144 551 130Q535 71 500 33Q466 -10 419 -10H414Q367 -10 346 17T325 74Q325 90 361 192T398 345Q398 404 354 404H349Q266 404 205 306L198 293L164 158Q132 28 127 16Q114 -11 83 -11Q69 -11 59 -2T48 16Q48 30 121 320L195 616Q195 629 188 632T149 637H128Q122 643 122 645T124 664Q129 683 137 683Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(1576,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mn" transform="translate(2076,0)"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path></g></g></g></svg></mjx-container></span> days through a dedicated phone number. The group to which the patient is allocated will only be disclosed after the information is recorded by the SCC. Such a measure prevents the investigator and the medical team from predicting to which treatment group the patient will be allocated.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="interventions"> |
| Interventions</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="general-management-protocol"> |
| General management protocol</h2> |
| <div>Both study groups will be treated with a common general management protocol. Sepsis source identification and control, and antimicrobial therapy will be given at the discretion of the treating physician. A central venous catheter (CVC) and an arterial line will be inserted in all cases, while the use of CO monitoring (pulmonary artery catheter or transpulmonary thermodilution techniques) is recommended for patients with a past medical history of heart failure or concomitant ARDS but leaving decision at discretion of the attending physician. Echocardiography will be performed routinely as soon as possible after admission to evaluate basal cardiac function, and to add in assessing fluid responsiveness (FR) [28]. Other dynamic predictors of response to fluids such as pulse pressure variation (PPV), stroke volume variation (SVV) or end-expiratory occlusion test (EEOT) will be used whenever applicable (see below) [28,29]. MV will be provided (when needed) under light sedation (midazolam, propofol or dexmedetomidine) and analgesia (fentanyl, alfentanil, morphine); tidal volume ( Vt ) will be limited to <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="11.944ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 5279.4 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1722.4,0)"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path></g><g data-mml-node="mi" transform="translate(2222.4,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3100.4,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(3781.4,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(4281.4,0)"><path data-c="1D458" d="M121 647Q121 657 125 670T137 683Q138 683 209 688T282 694Q294 694 294 686Q294 679 244 477Q194 279 194 272Q213 282 223 291Q247 309 292 354T362 415Q402 442 438 442Q468 442 485 423T503 369Q503 344 496 327T477 302T456 291T438 288Q418 288 406 299T394 328Q394 353 410 369T442 390L458 393Q446 405 434 405H430Q398 402 367 380T294 316T228 255Q230 254 243 252T267 246T293 238T320 224T342 206T359 180T365 147Q365 130 360 106T354 66Q354 26 381 26Q429 26 459 145Q461 153 479 153H483Q499 153 499 144Q499 139 496 130Q455 -11 378 -11Q333 -11 305 15T277 90Q277 108 280 121T283 145Q283 167 269 183T234 206T200 217T182 220H180Q168 178 159 139T145 81T136 44T129 20T122 7T111 -2Q98 -11 83 -11Q66 -11 57 -1T48 16Q48 26 85 176T158 471L195 616Q196 629 188 632T149 637H144Q134 637 131 637T124 640T121 647Z"></path></g><g data-mml-node="mi" transform="translate(4802.4,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> and positive-end-expiratory-pressure (PEEP) will be set according to individual requirements [10]. Glycemic control will be adjusted to maintain glucose levels <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="12.696ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 5611.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(1000,0)"></path></g><g data-mml-node="mi" transform="translate(2555.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3433.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(3910.8,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(4410.8,0)"><path data-c="1D451" d="M366 683Q367 683 438 688T511 694Q523 694 523 686Q523 679 450 384T375 83T374 68Q374 26 402 26Q411 27 422 35Q443 55 463 131Q469 151 473 152Q475 153 483 153H487H491Q506 153 506 145Q506 140 503 129Q490 79 473 48T445 8T417 -8Q409 -10 393 -10Q359 -10 336 5T306 36L300 51Q299 52 296 50Q294 48 292 46Q233 -10 172 -10Q117 -10 75 30T33 157Q33 205 53 255T101 341Q148 398 195 420T280 442Q336 442 364 400Q369 394 369 396Q370 400 396 505T424 616Q424 629 417 632T378 637H357Q351 643 351 645T353 664Q358 683 366 683ZM352 326Q329 405 277 405Q242 405 210 374T160 293Q131 214 119 129Q119 126 119 118T118 106Q118 61 136 44T179 26Q233 26 290 98L298 109L352 326Z"></path></g><g data-mml-node="mi" transform="translate(4930.8,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span>. Norepinephrine (NE) will be the vasopressor of choice, and its dose will be adjusted to maintain a MAP <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.464ex;" xmlns="http://www.w3.org/2000/svg" width="11.712ex" height="2.009ex" role="img" focusable="false" viewBox="0 -683 5176.8 888"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2933.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3811.8,0)"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="mi" transform="translate(4699.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> in all patients. Hemoglobin concentrations will be maintained at <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="6.059ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 2678 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(977,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(1477,0)"><path data-c="1D451" d="M366 683Q367 683 438 688T511 694Q523 694 523 686Q523 679 450 384T375 83T374 68Q374 26 402 26Q411 27 422 35Q443 55 463 131Q469 151 473 152Q475 153 483 153H487H491Q506 153 506 145Q506 140 503 129Q490 79 473 48T445 8T417 -8Q409 -10 393 -10Q359 -10 336 5T306 36L300 51Q299 52 296 50Q294 48 292 46Q233 -10 172 -10Q117 -10 75 30T33 157Q33 205 53 255T101 341Q148 398 195 420T280 442Q336 442 364 400Q369 394 369 396Q370 400 396 505T424 616Q424 629 417 632T378 637H357Q351 643 351 645T353 664Q358 683 366 683ZM352 326Q329 405 277 405Q242 405 210 374T160 293Q131 214 119 129Q119 126 119 118T118 106Q118 61 136 44T179 26Q233 26 290 98L298 109L352 326Z"></path></g><g data-mml-node="mi" transform="translate(1997,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span> or higher to optimize arterial <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="2.714ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 1199.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msub"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> content. The use of other therapies such as epinephrine, vasopressin analogues, steroids or different blood purification techniques like high-volume hemofiltration (HVHF) will be provided according to the usual practice at the involved centers in patients evolving with refractory septic shock. Finally, stress ulcer and venous thrombosis prophylaxis will be managed according to international recommendations [10].</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="study-protocol"> |
| Study protocol</h2> |
| <div>A sequential approach to resuscitation will be followed in both groups as shown in Fig. 2. After fulfilling inclusion criteria and discarding all exclusion conditions, an informed consent will be obtained. Basal measurements including hemodynamics and blood sampling will be</div> |
| <div class="table" number="2"> |
| <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/07a5063c-af33-499a-9fe6-703afe32ad5c-04.jpg?height=1191&width=1301&top_left_y=337&top_left_x=414" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Fig. 2 Resuscitation protocol for both groups. The figure describes the sequential approach to resuscitation. The process starts with fluid loading according to the status of fluid responsiveness. If the goal is not obtained, the second step is a vasopressor test, and then an inodilator test. CRT, capillary refill time</div></div> |
| <div>performed at Time 0 (T0) representing the starting point just after randomization. The intervention period will be extended for 8 h . All other treatments, during the intervention period and after, will be at the discretion of the treating clinicians according to their local usual clinical practices.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="tests-and-procedures-during-the-study-period-capillary-refill-time-assessment"> |
| Tests and procedures during the study period Capillary refill time assessment</h2> |
| <div>CRT will be measured by applying firm pressure to the ventral surface of the right index finger distal phalanx with a glass microscope slide. The pressure will be increased until the skin is blank and then maintained for 10 s . The time for return of the normal skin color will be registered with a chronometer. A CRT <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.09ex;" xmlns="http://www.w3.org/2000/svg" width="3.52ex" height="1.595ex" role="img" focusable="false" viewBox="0 -665 1555.8 705"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span> s will be considered as abnormal [30].</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="lactate-measurements"> |
| Lactate measurements</h2> |
| <div>A lactate value <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.312ex;" xmlns="http://www.w3.org/2000/svg" width="11.024ex" height="1.882ex" role="img" focusable="false" viewBox="0 -694 4872.8 832"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(778,0)"></path></g><g data-mml-node="mi" transform="translate(2333.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3211.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(4089.8,0)"><path data-c="1D45C" d="M201 -11Q126 -11 80 38T34 156Q34 221 64 279T146 380Q222 441 301 441Q333 441 341 440Q354 437 367 433T402 417T438 387T464 338T476 268Q476 161 390 75T201 -11ZM121 120Q121 70 147 48T206 26Q250 26 289 58T351 142Q360 163 374 216T388 308Q388 352 370 375Q346 405 306 405Q243 405 195 347Q158 303 140 230T121 120Z"></path></g><g data-mml-node="mi" transform="translate(4574.8,0)"><path data-c="1D459" d="M117 59Q117 26 142 26Q179 26 205 131Q211 151 215 152Q217 153 225 153H229Q238 153 241 153T246 151T248 144Q247 138 245 128T234 90T214 43T183 6T137 -11Q101 -11 70 11T38 85Q38 97 39 102L104 360Q167 615 167 623Q167 626 166 628T162 632T157 634T149 635T141 636T132 637T122 637Q112 637 109 637T101 638T95 641T94 647Q94 649 96 661Q101 680 107 682T179 688Q194 689 213 690T243 693T254 694Q266 694 266 686Q266 675 193 386T118 83Q118 81 118 75T117 65V59Z"></path></g></g></g></svg></mjx-container></span> per liter will be considered as abnormal. Arterial lactate levels will be measured at each center, either at point of care or central laboratories (point of care: GEM 4000, Instrumentation Lab, IL, USA; central laboratories: Cobas b221, Roche Diagnostics International; Basel, CH).</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="fluid-responsiveness-(fig.-3)"> |
| Fluid responsiveness (Fig. 3)</h2> |
| <div>FR will be assessed using a structured approach outlined in Fig. 2. Dynamic predictors of FR will be evaluated depending on the individual status, i.e., considering if under MV or spontaneous breathing, Vt, respiratory rate (RR), respiratory system compliance and the presence of arrhythmias. The protocol for patients under MV is shown in Fig. 3 [28, 29].</div> |
| <div class="table" number="3"> |
| <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/07a5063c-af33-499a-9fe6-703afe32ad5c-05.jpg?height=826&width=1307&top_left_y=338&top_left_x=412" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Fig. 3 Assessment of fluid responsiveness during the study period. The figure describes an algorithm for assessing fluid responsiveness in different settings depending on the presence or not of mechanical ventilation, arrhythmias or other conditions. Different tests are proposed with the respective cutoff values. ARDS acute respiratory distress syndrome; PLR passive leg rising; CO cardiac output; EEOT end-expiratory occlusion test; CI cardiac index; VTI velocity time integral; Vt tidal volume, PBW predicted body weight; PPV pulse pressure variation; SVV stroke volume variation, IVC inferior vena cava; SVC superior vena cava</div></div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="fluid-challenges"> |
| Fluid challenges</h2> |
| <div>In <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.048ex;" xmlns="http://www.w3.org/2000/svg" width="4.844ex" height="1.801ex" role="img" focusable="false" viewBox="0 -775.2 2141.1 796.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D439" d="M48 1Q31 1 31 11Q31 13 34 25Q38 41 42 43T65 46Q92 46 125 49Q139 52 144 61Q146 66 215 342T285 622Q285 629 281 629Q273 632 228 634H197Q191 640 191 642T193 659Q197 676 203 680H742Q749 676 749 669Q749 664 736 557T722 447Q720 440 702 440H690Q683 445 683 453Q683 454 686 477T689 530Q689 560 682 579T663 610T626 626T575 633T503 634H480Q398 633 393 631Q388 629 386 623Q385 622 352 492L320 363H375Q378 363 398 363T426 364T448 367T472 374T489 386Q502 398 511 419T524 457T529 475Q532 480 548 480H560Q567 475 567 470Q567 467 536 339T502 207Q500 200 482 200H470Q463 206 463 212Q463 215 468 234T473 274Q473 303 453 310T364 317H309L277 190Q245 66 245 60Q245 46 334 46H359Q365 40 365 39T363 19Q359 6 353 0H336Q295 2 185 2Q120 2 86 2T48 1Z"></path></g><g data-mml-node="msup" transform="translate(749,0)"><g data-mml-node="mi"><path data-c="1D445" d="M230 637Q203 637 198 638T193 649Q193 676 204 682Q206 683 378 683Q550 682 564 680Q620 672 658 652T712 606T733 563T739 529Q739 484 710 445T643 385T576 351T538 338L545 333Q612 295 612 223Q612 212 607 162T602 80V71Q602 53 603 43T614 25T640 16Q668 16 686 38T712 85Q717 99 720 102T735 105Q755 105 755 93Q755 75 731 36Q693 -21 641 -21H632Q571 -21 531 4T487 82Q487 109 502 166T517 239Q517 290 474 313Q459 320 449 321T378 323H309L277 193Q244 61 244 59Q244 55 245 54T252 50T269 48T302 46H333Q339 38 339 37T336 19Q332 6 326 0H311Q275 2 180 2Q146 2 117 2T71 2T50 1Q33 1 33 10Q33 12 36 24Q41 43 46 45Q50 46 61 46H67Q94 46 127 49Q141 52 146 61Q149 65 218 339T287 628Q287 635 230 637ZM630 554Q630 586 609 608T523 636Q521 636 500 636T462 637H440Q393 637 386 627Q385 624 352 494T319 361Q319 360 388 360Q466 361 492 367Q556 377 592 426Q608 449 619 486T630 554Z"></path></g><g data-mml-node="TeXAtom" transform="translate(792,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mo"><path data-c="2B" d="M56 237T56 250T70 270H369V420L370 570Q380 583 389 583Q402 583 409 568V270H707Q722 262 722 250T707 230H409V-68Q401 -82 391 -82H389H387Q375 -82 369 -68V230H70Q56 237 56 250Z"></path></g></g></g></g></g></svg></mjx-container></span>patients, the first resuscitation step will be to administer a fluid bolus (FB) of 500 ml of crystalloids every 30 min until normalizing CRT in the PPTR group. In the LTR group, FB will be stopped if at 2 h lactate is normalized or has decreased <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="6.536ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 2888.8 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span>, or previously if after any of the fluid boluses, central venous pressure (CVP) has increased <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.464ex;" xmlns="http://www.w3.org/2000/svg" width="10.581ex" height="2.009ex" role="img" focusable="false" viewBox="0 -683 4676.8 888"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g><g data-mml-node="mi" transform="translate(1555.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2433.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3311.8,0)"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="mi" transform="translate(4199.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> or the patients have become fluid unresponsive ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.048ex;" xmlns="http://www.w3.org/2000/svg" width="4.844ex" height="1.801ex" role="img" focusable="false" viewBox="0 -775.2 2141.1 796.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D439" d="M48 1Q31 1 31 11Q31 13 34 25Q38 41 42 43T65 46Q92 46 125 49Q139 52 144 61Q146 66 215 342T285 622Q285 629 281 629Q273 632 228 634H197Q191 640 191 642T193 659Q197 676 203 680H742Q749 676 749 669Q749 664 736 557T722 447Q720 440 702 440H690Q683 445 683 453Q683 454 686 477T689 530Q689 560 682 579T663 610T626 626T575 633T503 634H480Q398 633 393 631Q388 629 386 623Q385 622 352 492L320 363H375Q378 363 398 363T426 364T448 367T472 374T489 386Q502 398 511 419T524 457T529 475Q532 480 548 480H560Q567 475 567 470Q567 467 536 339T502 207Q500 200 482 200H470Q463 206 463 212Q463 215 468 234T473 274Q473 303 453 310T364 317H309L277 190Q245 66 245 60Q245 46 334 46H359Q365 40 365 39T363 19Q359 6 353 0H336Q295 2 185 2Q120 2 86 2T48 1Z"></path></g><g data-mml-node="msup" transform="translate(749,0)"><g data-mml-node="mi"><path data-c="1D445" d="M230 637Q203 637 198 638T193 649Q193 676 204 682Q206 683 378 683Q550 682 564 680Q620 672 658 652T712 606T733 563T739 529Q739 484 710 445T643 385T576 351T538 338L545 333Q612 295 612 223Q612 212 607 162T602 80V71Q602 53 603 43T614 25T640 16Q668 16 686 38T712 85Q717 99 720 102T735 105Q755 105 755 93Q755 75 731 36Q693 -21 641 -21H632Q571 -21 531 4T487 82Q487 109 502 166T517 239Q517 290 474 313Q459 320 449 321T378 323H309L277 193Q244 61 244 59Q244 55 245 54T252 50T269 48T302 46H333Q339 38 339 37T336 19Q332 6 326 0H311Q275 2 180 2Q146 2 117 2T71 2T50 1Q33 1 33 10Q33 12 36 24Q41 43 46 45Q50 46 61 46H67Q94 46 127 49Q141 52 146 61Q149 65 218 339T287 628Q287 635 230 637ZM630 554Q630 586 609 608T523 636Q521 636 500 636T462 637H440Q393 637 386 627Q385 624 352 494T319 361Q319 360 388 360Q466 361 492 367Q556 377 592 426Q608 449 619 486T630 554Z"></path></g><g data-mml-node="TeXAtom" transform="translate(792,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mo"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g></g></g></g></g></svg></mjx-container></span>).</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="safety-measures-during-fluid-challenges"> |
| Safety measures during fluid challenges</h2> |
| <div>CVP and FR will be reevaluated after any fluid challenge. If CVP increases <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.464ex;" xmlns="http://www.w3.org/2000/svg" width="10.581ex" height="2.009ex" role="img" focusable="false" viewBox="0 -683 4676.8 888"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3C" d="M694 -11T694 -19T688 -33T678 -40Q671 -40 524 29T234 166L90 235Q83 240 83 250Q83 261 91 266Q664 540 678 540Q681 540 687 534T694 519T687 505Q686 504 417 376L151 250L417 124Q686 -4 687 -5Q694 -11 694 -19Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g><g data-mml-node="mi" transform="translate(1555.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2433.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3311.8,0)"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="mi" transform="translate(4199.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> and FR is still +, another FB will be administered and so on while the perfusion (CRT or lactate) goal are not attained. If CVP increases <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.464ex;" xmlns="http://www.w3.org/2000/svg" width="10.581ex" height="2.009ex" role="img" focusable="false" viewBox="0 -683 4676.8 888"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2265" d="M83 616Q83 624 89 630T99 636Q107 636 253 568T543 431T687 361Q694 356 694 346T687 331Q685 329 395 192L107 56H101Q83 58 83 76Q83 77 83 79Q82 86 98 95Q117 105 248 167Q326 204 378 228L626 346L360 472Q291 505 200 548Q112 589 98 597T83 616ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g><g data-mml-node="mi" transform="translate(1555.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2433.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3311.8,0)"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="mi" transform="translate(4199.8,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> or FR is or become negative, fluids will be stopped and the patient will be moved to the next step.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="vasopressor-test"> |
| Vasopressor test</h2> |
| <div>An open-label vasopressor test will be performed increasing MAP up to <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.464ex;" xmlns="http://www.w3.org/2000/svg" width="14.352ex" height="2.009ex" role="img" focusable="false" viewBox="0 -683 6343.4 888"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1222.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(2222.4,0)"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(3222.4,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(4100.4,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(4978.4,0)"><path data-c="1D43B" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 219 683Q260 681 355 681Q389 681 418 681T463 682T483 682Q499 682 499 672Q499 670 497 658Q492 641 487 638H485Q483 638 480 638T473 638T464 637T455 637Q416 636 405 634T387 623Q384 619 355 500Q348 474 340 442T328 395L324 380Q324 378 469 378H614L615 381Q615 384 646 504Q674 619 674 627T617 637Q594 637 587 639T580 648Q580 650 582 660Q586 677 588 679T604 682Q609 682 646 681T740 680Q802 680 835 681T871 682Q888 682 888 672Q888 645 876 638H874Q872 638 869 638T862 638T853 637T844 637Q805 636 794 634T776 623Q773 618 704 340T634 58Q634 51 638 51Q646 48 692 46H723Q729 38 729 37T726 19Q722 6 716 0H701Q664 2 567 2Q533 2 504 2T458 2T437 1Q420 1 420 10Q420 15 423 24Q428 43 433 45Q437 46 448 46H454Q481 46 514 49Q520 50 522 50T528 55T534 64T540 82T547 110T558 153Q565 181 569 198Q602 330 602 331T457 332H312L279 197Q245 63 245 58Q245 51 253 49T303 46H334Q340 38 340 37T337 19Q333 6 327 0H312Q275 2 178 2Q144 2 115 2T69 2T48 1Q31 1 31 10Q31 12 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g><g data-mml-node="mi" transform="translate(5866.4,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g></g></g></svg></mjx-container></span> by using progressive incremental doses of NE in patients with previous history of chronic hypertension and persistently abnormal CRT or unfulfilled lactate goals accompanied by a fluid unresponsive state. Parameters will be reassessed 1 h after in<br> |
| the PPTR and 2 h after in the LTR. If after the vasopressor test, CRT improves, and lactate goals are achieved in PPTR and LTR, respectively, NE will be titrated to maintain this new MAP goal throughout the study period. If goals are not achieved despite increasing MAP, or NE dose surpasses <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="15.581ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 6887 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z" transform="translate(778,0)"></path></g><g data-mml-node="mi" transform="translate(1278,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2156,0)"><path data-c="1D450" d="M34 159Q34 268 120 355T306 442Q362 442 394 418T427 355Q427 326 408 306T360 285Q341 285 330 295T319 325T330 359T352 380T366 386H367Q367 388 361 392T340 400T306 404Q276 404 249 390Q228 381 206 359Q162 315 142 235T121 119Q121 73 147 50Q169 26 205 26H209Q321 26 394 111Q403 121 406 121Q410 121 419 112T429 98T420 83T391 55T346 25T282 0T202 -11Q127 -11 81 37T34 159Z"></path></g><g data-mml-node="mi" transform="translate(2589,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(3066,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(3566,0)"><path data-c="1D458" d="M121 647Q121 657 125 670T137 683Q138 683 209 688T282 694Q294 694 294 686Q294 679 244 477Q194 279 194 272Q213 282 223 291Q247 309 292 354T362 415Q402 442 438 442Q468 442 485 423T503 369Q503 344 496 327T477 302T456 291T438 288Q418 288 406 299T394 328Q394 353 410 369T442 390L458 393Q446 405 434 405H430Q398 402 367 380T294 316T228 255Q230 254 243 252T267 246T293 238T320 224T342 206T359 180T365 147Q365 130 360 106T354 66Q354 26 381 26Q429 26 459 145Q461 153 479 153H483Q499 153 499 144Q499 139 496 130Q455 -11 378 -11Q333 -11 305 15T277 90Q277 108 280 121T283 145Q283 167 269 183T234 206T200 217T182 220H180Q168 178 159 139T145 81T136 44T129 20T122 7T111 -2Q98 -11 83 -11Q66 -11 57 -1T48 16Q48 26 85 176T158 471L195 616Q196 629 188 632T149 637H144Q134 637 131 637T124 640T121 647Z"></path></g><g data-mml-node="mi" transform="translate(4087,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(4564,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(5064,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(5942,0)"><path data-c="1D456" d="M184 600Q184 624 203 642T247 661Q265 661 277 649T290 619Q290 596 270 577T226 557Q211 557 198 567T184 600ZM21 287Q21 295 30 318T54 369T98 420T158 442Q197 442 223 419T250 357Q250 340 236 301T196 196T154 83Q149 61 149 51Q149 26 166 26Q175 26 185 29T208 43T235 78T260 137Q263 149 265 151T282 153Q302 153 302 143Q302 135 293 112T268 61T223 11T161 -11Q129 -11 102 10T74 74Q74 91 79 106T122 220Q160 321 166 341T173 380Q173 404 156 404H154Q124 404 99 371T61 287Q60 286 59 284T58 281T56 279T53 278T49 278T41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(6287,0)"><path data-c="1D45B" d="M21 287Q22 293 24 303T36 341T56 388T89 425T135 442Q171 442 195 424T225 390T231 369Q231 367 232 367L243 378Q304 442 382 442Q436 442 469 415T503 336T465 179T427 52Q427 26 444 26Q450 26 453 27Q482 32 505 65T540 145Q542 153 560 153Q580 153 580 145Q580 144 576 130Q568 101 554 73T508 17T439 -10Q392 -10 371 17T350 73Q350 92 386 193T423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 180T152 343Q153 348 153 366Q153 405 129 405Q91 405 66 305Q60 285 60 284Q58 278 41 278H27Q21 284 21 287Z"></path></g></g></g></svg></mjx-container></span> or adverse effects are observed (heart rate (HR) <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="10.045ex" height="1.971ex" role="img" focusable="false" viewBox="0 -677 4439.8 871"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(1000,0)"></path></g><g data-mml-node="mi" transform="translate(2555.8,0)"><path data-c="1D45D" d="M23 287Q24 290 25 295T30 317T40 348T55 381T75 411T101 433T134 442Q209 442 230 378L240 387Q302 442 358 442Q423 442 460 395T497 281Q497 173 421 82T249 -10Q227 -10 210 -4Q199 1 187 11T168 28L161 36Q160 35 139 -51T118 -138Q118 -144 126 -145T163 -148H188Q194 -155 194 -157T191 -175Q188 -187 185 -190T172 -194Q170 -194 161 -194T127 -193T65 -192Q-5 -192 -24 -194H-32Q-39 -187 -39 -183Q-37 -156 -26 -148H-6Q28 -147 33 -136Q36 -130 94 103T155 350Q156 355 156 364Q156 405 131 405Q109 405 94 377T71 316T59 280Q57 278 43 278H29Q23 284 23 287ZM178 102Q200 26 252 26Q282 26 310 49T356 107Q374 141 392 215T411 325V331Q411 405 350 405Q339 405 328 402T306 393T286 380T269 365T254 350T243 336T235 326L232 322Q232 321 229 308T218 264T204 212Q178 106 178 102Z"></path></g><g data-mml-node="mi" transform="translate(3058.8,0)"><path data-c="1D45D" d="M23 287Q24 290 25 295T30 317T40 348T55 381T75 411T101 433T134 442Q209 442 230 378L240 387Q302 442 358 442Q423 442 460 395T497 281Q497 173 421 82T249 -10Q227 -10 210 -4Q199 1 187 11T168 28L161 36Q160 35 139 -51T118 -138Q118 -144 126 -145T163 -148H188Q194 -155 194 -157T191 -175Q188 -187 185 -190T172 -194Q170 -194 161 -194T127 -193T65 -192Q-5 -192 -24 -194H-32Q-39 -187 -39 -183Q-37 -156 -26 -148H-6Q28 -147 33 -136Q36 -130 94 103T155 350Q156 355 156 364Q156 405 131 405Q109 405 94 377T71 316T59 280Q57 278 43 278H29Q23 284 23 287ZM178 102Q200 26 252 26Q282 26 310 49T356 107Q374 141 392 215T411 325V331Q411 405 350 405Q339 405 328 402T306 393T286 380T269 365T254 350T243 336T235 326L232 322Q232 321 229 308T218 264T204 212Q178 106 178 102Z"></path></g><g data-mml-node="mi" transform="translate(3561.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g></g></g></svg></mjx-container></span>, arrhythmias or evident cardiac ischemia), NE dose will be reduced to the level before the vasopressor test, and the protocol will move to the next step.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="inodilator-test"> |
| Inodilator test</h2> |
| <div>An open-label test of dobutamine at fixed <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="9.697ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4286 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(1378,0)"><path data-c="1D450" d="M34 159Q34 268 120 355T306 442Q362 442 394 418T427 355Q427 326 408 306T360 285Q341 285 330 295T319 325T330 359T352 380T366 386H367Q367 388 361 392T340 400T306 404Q276 404 249 390Q228 381 206 359Q162 315 142 235T121 119Q121 73 147 50Q169 26 205 26H209Q321 26 394 111Q403 121 406 121Q410 121 419 112T429 98T420 83T391 55T346 25T282 0T202 -11Q127 -11 81 37T34 159Z"></path></g><g data-mml-node="mi" transform="translate(1811,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(2288,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(2788,0)"><path data-c="1D458" d="M121 647Q121 657 125 670T137 683Q138 683 209 688T282 694Q294 694 294 686Q294 679 244 477Q194 279 194 272Q213 282 223 291Q247 309 292 354T362 415Q402 442 438 442Q468 442 485 423T503 369Q503 344 496 327T477 302T456 291T438 288Q418 288 406 299T394 328Q394 353 410 369T442 390L458 393Q446 405 434 405H430Q398 402 367 380T294 316T228 255Q230 254 243 252T267 246T293 238T320 224T342 206T359 180T365 147Q365 130 360 106T354 66Q354 26 381 26Q429 26 459 145Q461 153 479 153H483Q499 153 499 144Q499 139 496 130Q455 -11 378 -11Q333 -11 305 15T277 90Q277 108 280 121T283 145Q283 167 269 183T234 206T200 217T182 220H180Q168 178 159 139T145 81T136 44T129 20T122 7T111 -2Q98 -11 83 -11Q66 -11 57 -1T48 16Q48 26 85 176T158 471L195 616Q196 629 188 632T149 637H144Q134 637 131 637T124 640T121 647Z"></path></g><g data-mml-node="mi" transform="translate(3309,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(3786,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g></g></g></svg></mjx-container></span> min or milrinone at fixed <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="16.713ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 7387 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(778,0)"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(1278,0)"></path></g><g data-mml-node="mi" transform="translate(1778,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(2656,0)"><path data-c="1D450" d="M34 159Q34 268 120 355T306 442Q362 442 394 418T427 355Q427 326 408 306T360 285Q341 285 330 295T319 325T330 359T352 380T366 386H367Q367 388 361 392T340 400T306 404Q276 404 249 390Q228 381 206 359Q162 315 142 235T121 119Q121 73 147 50Q169 26 205 26H209Q321 26 394 111Q403 121 406 121Q410 121 419 112T429 98T420 83T391 55T346 25T282 0T202 -11Q127 -11 81 37T34 159Z"></path></g><g data-mml-node="mi" transform="translate(3089,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(3566,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(4066,0)"><path data-c="1D458" d="M121 647Q121 657 125 670T137 683Q138 683 209 688T282 694Q294 694 294 686Q294 679 244 477Q194 279 194 272Q213 282 223 291Q247 309 292 354T362 415Q402 442 438 442Q468 442 485 423T503 369Q503 344 496 327T477 302T456 291T438 288Q418 288 406 299T394 328Q394 353 410 369T442 390L458 393Q446 405 434 405H430Q398 402 367 380T294 316T228 255Q230 254 243 252T267 246T293 238T320 224T342 206T359 180T365 147Q365 130 360 106T354 66Q354 26 381 26Q429 26 459 145Q461 153 479 153H483Q499 153 499 144Q499 139 496 130Q455 -11 378 -11Q333 -11 305 15T277 90Q277 108 280 121T283 145Q283 167 269 183T234 206T200 217T182 220H180Q168 178 159 139T145 81T136 44T129 20T122 7T111 -2Q98 -11 83 -11Q66 -11 57 -1T48 16Q48 26 85 176T158 471L195 616Q196 629 188 632T149 637H144Q134 637 131 637T124 640T121 647Z"></path></g><g data-mml-node="mi" transform="translate(4587,0)"><path data-c="1D454" d="M311 43Q296 30 267 15T206 0Q143 0 105 45T66 160Q66 265 143 353T314 442Q361 442 401 394L404 398Q406 401 409 404T418 412T431 419T447 422Q461 422 470 413T480 394Q480 379 423 152T363 -80Q345 -134 286 -169T151 -205Q10 -205 10 -137Q10 -111 28 -91T74 -71Q89 -71 102 -80T116 -111Q116 -121 114 -130T107 -144T99 -154T92 -162L90 -164H91Q101 -167 151 -167Q189 -167 211 -155Q234 -144 254 -122T282 -75Q288 -56 298 -13Q311 35 311 43ZM384 328L380 339Q377 350 375 354T369 368T359 382T346 393T328 402T306 405Q262 405 221 352Q191 313 171 233T151 117Q151 38 213 38Q269 38 323 108L331 118L384 328Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(5064,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(5564,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(6442,0)"><path data-c="1D456" d="M184 600Q184 624 203 642T247 661Q265 661 277 649T290 619Q290 596 270 577T226 557Q211 557 198 567T184 600ZM21 287Q21 295 30 318T54 369T98 420T158 442Q197 442 223 419T250 357Q250 340 236 301T196 196T154 83Q149 61 149 51Q149 26 166 26Q175 26 185 29T208 43T235 78T260 137Q263 149 265 151T282 153Q302 153 302 143Q302 135 293 112T268 61T223 11T161 -11Q129 -11 102 10T74 74Q74 91 79 106T122 220Q160 321 166 341T173 380Q173 404 156 404H154Q124 404 99 371T61 287Q60 286 59 284T58 281T56 279T53 278T49 278T41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(6787,0)"><path data-c="1D45B" d="M21 287Q22 293 24 303T36 341T56 388T89 425T135 442Q171 442 195 424T225 390T231 369Q231 367 232 367L243 378Q304 442 382 442Q436 442 469 415T503 336T465 179T427 52Q427 26 444 26Q450 26 453 27Q482 32 505 65T540 145Q542 153 560 153Q580 153 580 145Q580 144 576 130Q568 101 554 73T508 17T439 -10Q392 -10 371 17T350 73Q350 92 386 193T423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 180T152 343Q153 348 153 366Q153 405 129 405Q91 405 66 305Q60 285 60 284Q58 278 41 278H27Q21 284 21 287Z"></path></g></g></g></svg></mjx-container></span> doses (at discretion of the attending physician) will be started in patients with persistent abnormal CRT or non-achieved lactate goals, and negative FR status. CRT and lactate goals will be rechecked such as in the vasopressor test. If such resuscitation goals are not reached, drugs will be discontinued and no further action will be taken during the study period, except for rechecking FR every hour and restart fluid challenges if the patient gets again <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="5.172ex" height="1.731ex" role="img" focusable="false" viewBox="0 -683 2286 765"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D439" d="M48 1Q31 1 31 11Q31 13 34 25Q38 41 42 43T65 46Q92 46 125 49Q139 52 144 61Q146 66 215 342T285 622Q285 629 281 629Q273 632 228 634H197Q191 640 191 642T193 659Q197 676 203 680H742Q749 676 749 669Q749 664 736 557T722 447Q720 440 702 440H690Q683 445 683 453Q683 454 686 477T689 530Q689 560 682 579T663 610T626 626T575 633T503 634H480Q398 633 393 631Q388 629 386 623Q385 622 352 492L320 363H375Q378 363 398 363T426 364T448 367T472 374T489 386Q502 398 511 419T524 457T529 475Q532 480 548 480H560Q567 475 567 470Q567 467 536 339T502 207Q500 200 482 200H470Q463 206 463 212Q463 215 468 234T473 274Q473 303 453 310T364 317H309L277 190Q245 66 245 60Q245 46 334 46H359Q365 40 365 39T363 19Q359 6 353 0H336Q295 2 185 2Q120 2 86 2T48 1Z"></path></g><g data-mml-node="mi" transform="translate(749,0)"><path data-c="1D445" d="M230 637Q203 637 198 638T193 649Q193 676 204 682Q206 683 378 683Q550 682 564 680Q620 672 658 652T712 606T733 563T739 529Q739 484 710 445T643 385T576 351T538 338L545 333Q612 295 612 223Q612 212 607 162T602 80V71Q602 53 603 43T614 25T640 16Q668 16 686 38T712 85Q717 99 720 102T735 105Q755 105 755 93Q755 75 731 36Q693 -21 641 -21H632Q571 -21 531 4T487 82Q487 109 502 166T517 239Q517 290 474 313Q459 320 449 321T378 323H309L277 193Q244 61 244 59Q244 55 245 54T252 50T269 48T302 46H333Q339 38 339 37T336 19Q332 6 326 0H311Q275 2 180 2Q146 2 117 2T71 2T50 1Q33 1 33 10Q33 12 36 24Q41 43 46 45Q50 46 61 46H67Q94 46 127 49Q141 52 146 61Q149 65 218 339T287 628Q287 635 230 637ZM630 554Q630 586 609 608T523 636Q521 636 500 636T462 637H440Q393 637 386 627Q385 624 352 494T319 361Q319 360 388 360Q466 361 492 367Q556 377 592 426Q608 449 619 486T630 554Z"></path></g><g data-mml-node="mo" transform="translate(1508,0)"><path data-c="2B" d="M56 237T56 250T70 270H369V420L370 570Q380 583 389 583Q402 583 409 568V270H707Q722 262 722 250T707 230H409V-68Q401 -82 391 -82H389H387Q375 -82 369 -68V230H70Q56 237 56 250Z"></path></g></g></g></svg></mjx-container></span>. Dobutamine or milrinone doses will be maintained throughout the study period in those favorably responding to the open-label inodilators test. As a safety measure,<br> |
| inodilators will be stopped if HR increases <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="6.536ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 2888.8 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(2055.8,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span>, or arrhythmias, ischemia or hypotension develop.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="management-of-peripheral-perfusion-targeted-resuscitation"> |
| Management of peripheral perfusion-targeted resuscitation</h2> |
| <div>As a safety measure, if signs of inadequate macrohemodynamics persist such as HR <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.09ex;" xmlns="http://www.w3.org/2000/svg" width="5.782ex" height="1.597ex" role="img" focusable="false" viewBox="0 -666 2555.8 706"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(1000,0)"></path></g></g></g></svg></mjx-container></span> BPM or unstable MAP with increases in vasopressors during the last hour, resuscitation will be continued even if CRT is normal.</div> |
| <div>After CRT normalization at any step, it will be reassessed hourly during the study period. If at any point it turns abnormal again, the resuscitation sequence will be restarted (Fig. 2)</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="management-of-lactate-targeted-resuscitation"> |
| Management of lactate-targeted resuscitation</h2> |
| <div>Lactate will be assessed every 2 h during the <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="5.2ex" height="1.756ex" role="img" focusable="false" viewBox="0 -694 2298.4 776"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mi" transform="translate(1722.4,0)"><path data-c="210E" d="M137 683Q138 683 209 688T282 694Q294 694 294 685Q294 674 258 534Q220 386 220 383Q220 381 227 388Q288 442 357 442Q411 442 444 415T478 336Q478 285 440 178T402 50Q403 36 407 31T422 26Q450 26 474 56T513 138Q516 149 519 151T535 153Q555 153 555 145Q555 144 551 130Q535 71 500 33Q466 -10 419 -10H414Q367 -10 346 17T325 74Q325 90 361 192T398 345Q398 404 354 404H349Q266 404 205 306L198 293L164 158Q132 28 127 16Q114 -11 83 -11Q69 -11 59 -2T48 16Q48 30 121 320L195 616Q195 629 188 632T149 637H128Q122 643 122 645T124 664Q129 683 137 683Z"></path></g></g></g></svg></mjx-container></span> study period. If after achieving lactate goals, it becomes again abnormal or the decrease rate slow down under <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="6.41ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 2833 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(1833,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mn" transform="translate(2333,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></svg></mjx-container></span> h at any of the following controls, the resuscitation sequence will be restarted (Fig. 2).</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="safety-measures"> |
| Safety measures</h2> |
| <div>The protocol can be stopped at any moment for safety considerations during the 8-h study period if the attending intensivist considers that the patient has developed unexpected and severe complications or evolves into refractory shock, conditions that under his judgment require liberalization of management. This action has to be reported on the case report form (CRF), and the patient will be followed up with major outcomes, and included in the intention-to-treat (ITT) analysis. Specific safety measures for fluid administration, vasopressor test and inodilator use are specified above.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="suspected-unexpected-serious-adverse-reactions-(susar)"> |
| Suspected unexpected serious adverse reactions (SUSAR)</h2> |
| <div>Any adverse event that occurs in a clinical trial subject, which is assessed by the study investigator as being unexpected, serious and as having a reasonable possibility of a causal relationship with the study procedure will be reported. Reports of these reactions are subject to expedited submission to health authorities. SUSAR's will be analyzed by both the SCC and the data safety monitoring committee (DSMC).</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="blinding"> |
| Blinding</h2> |
| <div>Since the intervention will be administered to critically ill patients (mostly sedated), blinding of these patients is not necessary. Because this is a non-pharmacological intervention, blinding of the medical team is not feasible.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="data-collection-and-management"> |
| Data collection and management</h2> |
| <div>Study follow-up and the variables that will be collected are described below.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="baseline"> |
| Baseline</h2> |
| <div>Demographics, comorbidities, acute physiology and chronic health evaluation (APACHE) II [31], sepsis source and treatment<br> |
| pre-ICU resuscitation and fluid balance<br> |
| Sequential Organ Failure Assessment (SOFA) [26] + and Acute Kidney Injury Network (AKI) criteria [32]</div> |
| <div>Hemodynamics: HR, SBP, diastolic blood pressure (DBP), MAP, CVP, FR status, intraabdominal pressure (IAP), NE levels, diuresis.</div> |
| <div>Perfusion: lactate, central venous <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="2.714ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 1199.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msub"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> saturation ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="6.25ex" height="1.934ex" role="img" focusable="false" viewBox="0 -705 2762.6 855"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D446" d="M308 24Q367 24 416 76T466 197Q466 260 414 284Q308 311 278 321T236 341Q176 383 176 462Q176 523 208 573T273 648Q302 673 343 688T407 704H418H425Q521 704 564 640Q565 640 577 653T603 682T623 704Q624 704 627 704T632 705Q645 705 645 698T617 577T585 459T569 456Q549 456 549 465Q549 471 550 475Q550 478 551 494T553 520Q553 554 544 579T526 616T501 641Q465 662 419 662Q362 662 313 616T263 510Q263 480 278 458T319 427Q323 425 389 408T456 390Q490 379 522 342T554 242Q554 216 546 186Q541 164 528 137T492 78T426 18T332 -20Q320 -22 298 -22Q199 -22 144 33L134 44L106 13Q83 -14 78 -18T65 -22Q52 -22 52 -14Q52 -11 110 221Q112 227 130 227H143Q149 221 149 216Q149 214 148 207T144 186T142 153Q144 114 160 87T203 47T255 29T308 24Z"></path></g><g data-mml-node="mi" transform="translate(645,0)"><path data-c="1D450" d="M34 159Q34 268 120 355T306 442Q362 442 394 418T427 355Q427 326 408 306T360 285Q341 285 330 295T319 325T330 359T352 380T366 386H367Q367 388 361 392T340 400T306 404Q276 404 249 390Q228 381 206 359Q162 315 142 235T121 119Q121 73 147 50Q169 26 205 26H209Q321 26 394 111Q403 121 406 121Q410 121 419 112T429 98T420 83T391 55T346 25T282 0T202 -11Q127 -11 81 37T34 159Z"></path></g><g data-mml-node="mi" transform="translate(1078,0)"><path data-c="1D463" d="M173 380Q173 405 154 405Q130 405 104 376T61 287Q60 286 59 284T58 281T56 279T53 278T49 278T41 278H27Q21 284 21 287Q21 294 29 316T53 368T97 419T160 441Q202 441 225 417T249 361Q249 344 246 335Q246 329 231 291T200 202T182 113Q182 86 187 69Q200 26 250 26Q287 26 319 60T369 139T398 222T409 277Q409 300 401 317T383 343T365 361T357 383Q357 405 376 424T417 443Q436 443 451 425T467 367Q467 340 455 284T418 159T347 40T241 -11Q177 -11 139 22Q102 54 102 117Q102 148 110 181T151 298Q173 362 173 380Z"></path></g><g data-mml-node="msub" transform="translate(1563,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> ), central venous arterial <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="5.571ex" height="2.034ex" role="img" focusable="false" viewBox="0 -705 2462.6 899"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D45D" d="M23 287Q24 290 25 295T30 317T40 348T55 381T75 411T101 433T134 442Q209 442 230 378L240 387Q302 442 358 442Q423 442 460 395T497 281Q497 173 421 82T249 -10Q227 -10 210 -4Q199 1 187 11T168 28L161 36Q160 35 139 -51T118 -138Q118 -144 126 -145T163 -148H188Q194 -155 194 -157T191 -175Q188 -187 185 -190T172 -194Q170 -194 161 -194T127 -193T65 -192Q-5 -192 -24 -194H-32Q-39 -187 -39 -183Q-37 -156 -26 -148H-6Q28 -147 33 -136Q36 -130 94 103T155 350Q156 355 156 364Q156 405 131 405Q109 405 94 377T71 316T59 280Q57 278 43 278H29Q23 284 23 287ZM178 102Q200 26 252 26Q282 26 310 49T356 107Q374 141 392 215T411 325V331Q411 405 350 405Q339 405 328 402T306 393T286 380T269 365T254 350T243 336T235 326L232 322Q232 321 229 308T218 264T204 212Q178 106 178 102Z"></path></g><g data-mml-node="mi" transform="translate(503,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(1263,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> gradient ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="13.932ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 6158 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D443" d="M287 628Q287 635 230 637Q206 637 199 638T192 648Q192 649 194 659Q200 679 203 681T397 683Q587 682 600 680Q664 669 707 631T751 530Q751 453 685 389Q616 321 507 303Q500 302 402 301H307L277 182Q247 66 247 59Q247 55 248 54T255 50T272 48T305 46H336Q342 37 342 35Q342 19 335 5Q330 0 319 0Q316 0 282 1T182 2Q120 2 87 2T51 1Q33 1 33 11Q33 13 36 25Q40 41 44 43T67 46Q94 46 127 49Q141 52 146 61Q149 65 218 339T287 628ZM645 554Q645 567 643 575T634 597T609 619T560 635Q553 636 480 637Q463 637 445 637T416 636T404 636Q391 635 386 627Q384 621 367 550T332 412T314 344Q314 342 395 342H407H430Q542 342 590 392Q617 419 631 471T645 554Z"></path></g><g data-mml-node="mo" transform="translate(751,0)"><path data-c="28" d="M94 250Q94 319 104 381T127 488T164 576T202 643T244 695T277 729T302 750H315H319Q333 750 333 741Q333 738 316 720T275 667T226 581T184 443T167 250T184 58T225 -81T274 -167T316 -220T333 -241Q333 -250 318 -250H315H302L274 -226Q180 -141 137 -14T94 250Z"></path></g><g data-mml-node="mi" transform="translate(1140,0)"><path data-c="1D450" d="M34 159Q34 268 120 355T306 442Q362 442 394 418T427 355Q427 326 408 306T360 285Q341 285 330 295T319 325T330 359T352 380T366 386H367Q367 388 361 392T340 400T306 404Q276 404 249 390Q228 381 206 359Q162 315 142 235T121 119Q121 73 147 50Q169 26 205 26H209Q321 26 394 111Q403 121 406 121Q410 121 419 112T429 98T420 83T391 55T346 25T282 0T202 -11Q127 -11 81 37T34 159Z"></path></g><g data-mml-node="mi" transform="translate(1573,0)"><path data-c="1D463" d="M173 380Q173 405 154 405Q130 405 104 376T61 287Q60 286 59 284T58 281T56 279T53 278T49 278T41 278H27Q21 284 21 287Q21 294 29 316T53 368T97 419T160 441Q202 441 225 417T249 361Q249 344 246 335Q246 329 231 291T200 202T182 113Q182 86 187 69Q200 26 250 26Q287 26 319 60T369 139T398 222T409 277Q409 300 401 317T383 343T365 361T357 383Q357 405 376 424T417 443Q436 443 451 425T467 367Q467 340 455 284T418 159T347 40T241 -11Q177 -11 139 22Q102 54 102 117Q102 148 110 181T151 298Q173 362 173 380Z"></path></g><g data-mml-node="mo" transform="translate(2280.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mi" transform="translate(3280.4,0)"><path data-c="1D44E" d="M33 157Q33 258 109 349T280 441Q331 441 370 392Q386 422 416 422Q429 422 439 414T449 394Q449 381 412 234T374 68Q374 43 381 35T402 26Q411 27 422 35Q443 55 463 131Q469 151 473 152Q475 153 483 153H487Q506 153 506 144Q506 138 501 117T481 63T449 13Q436 0 417 -8Q409 -10 393 -10Q359 -10 336 5T306 36L300 51Q299 52 296 50Q294 48 292 46Q233 -10 172 -10Q117 -10 75 30T33 157ZM351 328Q351 334 346 350T323 385T277 405Q242 405 210 374T160 293Q131 214 119 129Q119 126 119 118T118 106Q118 61 136 44T179 26Q217 26 254 59T298 110Q300 114 325 217T351 328Z"></path></g><g data-mml-node="mo" transform="translate(3809.4,0)"><path data-c="29" d="M60 749L64 750Q69 750 74 750H86L114 726Q208 641 251 514T294 250Q294 182 284 119T261 12T224 -76T186 -143T145 -194T113 -227T90 -246Q87 -249 86 -250H74Q66 -250 63 -250T58 -247T55 -238Q56 -237 66 -225Q221 -64 221 250T66 725Q56 737 55 738Q55 746 60 749Z"></path></g><g data-mml-node="mi" transform="translate(4198.4,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(4958.4,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> ), Hb , central venous and arterial blood gases, CRT, mottling score.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="evolution"> |
| Evolution</h2> |
| <div>SOFA and AKI criteria at <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="7.668ex" height="1.971ex" role="img" focusable="false" viewBox="0 -677 3389.3 871"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path></g><g data-mml-node="mo" transform="translate(500,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(944.7,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1944.7,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(2389.3,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z" transform="translate(500,0)"></path></g></g></g></svg></mjx-container></span> and 72 h<br> |
| Hemodynamics hourly up to 8 h<br> |
| Fluid administration and balance at <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="7.668ex" height="1.971ex" role="img" focusable="false" viewBox="0 -677 3389.3 871"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path></g><g data-mml-node="mo" transform="translate(500,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(944.7,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1944.7,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(2389.3,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z" transform="translate(500,0)"></path></g></g></g></svg></mjx-container></span> and 72 h<br> |
| Complete perfusion assessment when the targeted parameter is normalized and then at <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="7.668ex" height="1.971ex" role="img" focusable="false" viewBox="0 -677 3389.3 871"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path></g><g data-mml-node="mo" transform="translate(500,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(944.7,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z" transform="translate(500,0)"></path></g><g data-mml-node="mo" transform="translate(1944.7,0)"><path data-c="2C" d="M78 35T78 60T94 103T137 121Q165 121 187 96T210 8Q210 -27 201 -60T180 -117T154 -158T130 -185T117 -194Q113 -194 104 -185T95 -172Q95 -168 106 -156T131 -126T157 -76T173 -3V9L172 8Q170 7 167 6T161 3T152 1T140 0Q113 0 96 17Z"></path></g><g data-mml-node="mn" transform="translate(2389.3,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z" transform="translate(500,0)"></path></g></g></g></svg></mjx-container></span> and 72 h<br> |
| Register of vasoactive drugs and dobutamine/milrinone use<br> |
| Register of MV and RRT<br> |
| Source control re-analysis at 4 h<br> |
| Rescue therapies: HVHF, vasopressin, epinephrine, steroids, others.<br> |
| Echocardiography at least once during the study period Follow-up till 28 days for use of MV, RRT and vasopressors<br> |
| All-cause mortality at hospital discharge, 28 and 90 days Cause of death.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="quality-control"> |
| Quality control</h2> |
| <div>Several procedures will assure data quality, including (1) all investigators will attend a training session before the start of the study to standardize procedures, including data collection (2) the investigators may contact the SCC to solve issues or problems that may arise; (3) CRFs provided by the centers will be subjected to various checks by members of the SCC for missing data, plausible, possible or non-permitted value ranges, and logic checks on a weekly basis. (4) centers will be notified of the inconsistencies or missing data as queries and asked to correct them; (5) the SCC will review detailed reports on screening, enrollment, follow-up, inconsistencies and completeness of data. Immediate actions will follow to solve problems that arise; (6) only after the CRFs are cleared by the SCC, data will be entered in the final electronic database by the data digitizer.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="sample-size"> |
| Sample size</h2> |
| <div>Mortality in patients with increased lactate levels in circulatory dysfunction has been shown to exceed <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> [9]. In addition, several studies have shown that abnormal peripheral perfusion is associated with a mortality exceeding 40% as well, whereas a normal CRT in the early phase of septic shock has been associated with a less than <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> mortality [19, 30].</div> |
| <div>A total sample size of 420 patients ( 210 per group), analyzing the data using the ITT principle, is expected to provide approximately <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> power to detect a reduction in 28 -day mortality from 45 to <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span>, considering logistic regression, with a two-sided alpha level of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="3.016ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1333 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span>. We consider a decrease of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> in mortality to have direct clinical implementation effect. Similar effects on mortality have been shown in early resuscitation studies. In addition, limiting fluid administration in patients with septic shock and normal peripheral perfusion has been shown to decrease organ failure, which is the leading cause of death in these patients [25].</div> |
| <div>However, if a smaller decrease in mortality (such as <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> ) is observed at interim analyses, our initial calculated sample size would have only a <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> power to detect benefit. Therefore, we will use an adaptive approach [33] that will allow for a sample-size re-estimation at a preplanned interim analysis after <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> of the sample has been recruited. The sample-size re-estimation will be conducted by the DSMC only if the size effect observed in the interim analysis is between 10 and <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> absolute reduction in mortality [32].</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="statistical-analysis-plan"> |
| Statistical analysis plan</h2> |
| <div>We will report a detailed statistical analysis plan in a separate document.</div> |
| <div>Briefly, all analysis will follow the intention-to-treat principle.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="primary-outcome"> |
| Primary outcome</h2> |
| <div>We will assess the effect of PPTR compared to LTR on the primary outcome using time-to-event analysis. Results of our main analysis will be calculated with Cox proportional hazards models, with adjustment for five pre-specified baseline covariates. APACHE II score, SOFA score, lactate level, CRT and source of infection, as fixed (individual-level) effects. Results will be reported as hazard ratios with <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> confidence intervals (CI) and <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="1.138ex" height="1.439ex" role="img" focusable="false" viewBox="0 -442 503 636"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D45D" d="M23 287Q24 290 25 295T30 317T40 348T55 381T75 411T101 433T134 442Q209 442 230 378L240 387Q302 442 358 442Q423 442 460 395T497 281Q497 173 421 82T249 -10Q227 -10 210 -4Q199 1 187 11T168 28L161 36Q160 35 139 -51T118 -138Q118 -144 126 -145T163 -148H188Q194 -155 194 -157T191 -175Q188 -187 185 -190T172 -194Q170 -194 161 -194T127 -193T65 -192Q-5 -192 -24 -194H-32Q-39 -187 -39 -183Q-37 -156 -26 -148H-6Q28 -147 33 -136Q36 -130 94 103T155 350Q156 355 156 364Q156 405 131 405Q109 405 94 377T71 316T59 280Q57 278 43 278H29Q23 284 23 287ZM178 102Q200 26 252 26Q282 26 310 49T356 107Q374 141 392 215T411 325V331Q411 405 350 405Q339 405 328 402T306 393T286 380T269 365T254 350T243 336T235 326L232 322Q232 321 229 308T218 264T204 212Q178 106 178 102Z"></path></g></g></g></svg></mjx-container></span> values. We will also present Kaplan-Meier curves.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="secondary-outcomes"> |
| Secondary outcomes</h2> |
| <div>We identified several secondary outcomes. First, binary outcomes will be compared through Chi-squared tests, and we will present the results risk ratios (RR), with 95% CI and <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="1.138ex" height="1.439ex" role="img" focusable="false" viewBox="0 -442 503 636"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D45D" d="M23 287Q24 290 25 295T30 317T40 348T55 381T75 411T101 433T134 442Q209 442 230 378L240 387Q302 442 358 442Q423 442 460 395T497 281Q497 173 421 82T249 -10Q227 -10 210 -4Q199 1 187 11T168 28L161 36Q160 35 139 -51T118 -138Q118 -144 126 -145T163 -148H188Q194 -155 194 -157T191 -175Q188 -187 185 -190T172 -194Q170 -194 161 -194T127 -193T65 -192Q-5 -192 -24 -194H-32Q-39 -187 -39 -183Q-37 -156 -26 -148H-6Q28 -147 33 -136Q36 -130 94 103T155 350Q156 355 156 364Q156 405 131 405Q109 405 94 377T71 316T59 280Q57 278 43 278H29Q23 284 23 287ZM178 102Q200 26 252 26Q282 26 310 49T356 107Q374 141 392 215T411 325V331Q411 405 350 405Q339 405 328 402T306 393T286 380T269 365T254 350T243 336T235 326L232 322Q232 321 229 308T218 264T204 212Q178 106 178 102Z"></path></g></g></g></svg></mjx-container></span> values.</div> |
| <div>Continuous outcomes with normal distribution will be analyzed with <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.025ex;" xmlns="http://www.w3.org/2000/svg" width="0.817ex" height="1.441ex" role="img" focusable="false" viewBox="0 -626 361 637"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D461" d="M26 385Q19 392 19 395Q19 399 22 411T27 425Q29 430 36 430T87 431H140L159 511Q162 522 166 540T173 566T179 586T187 603T197 615T211 624T229 626Q247 625 254 615T261 596Q261 589 252 549T232 470L222 433Q222 431 272 431H323Q330 424 330 420Q330 398 317 385H210L174 240Q135 80 135 68Q135 26 162 26Q197 26 230 60T283 144Q285 150 288 151T303 153H307Q322 153 322 145Q322 142 319 133Q314 117 301 95T267 48T216 6T155 -11Q125 -11 98 4T59 56Q57 64 57 83V101L92 241Q127 382 128 383Q128 385 77 385H26Z"></path></g></g></g></svg></mjx-container></span> test and reported as mean difference <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> CI and <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="1.138ex" height="1.439ex" role="img" focusable="false" viewBox="0 -442 503 636"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D45D" d="M23 287Q24 290 25 295T30 317T40 348T55 381T75 411T101 433T134 442Q209 442 230 378L240 387Q302 442 358 442Q423 442 460 395T497 281Q497 173 421 82T249 -10Q227 -10 210 -4Q199 1 187 11T168 28L161 36Q160 35 139 -51T118 -138Q118 -144 126 -145T163 -148H188Q194 -155 194 -157T191 -175Q188 -187 185 -190T172 -194Q170 -194 161 -194T127 -193T65 -192Q-5 -192 -24 -194H-32Q-39 -187 -39 -183Q-37 -156 -26 -148H-6Q28 -147 33 -136Q36 -130 94 103T155 350Q156 355 156 364Q156 405 131 405Q109 405 94 377T71 316T59 280Q57 278 43 278H29Q23 284 23 287ZM178 102Q200 26 252 26Q282 26 310 49T356 107Q374 141 392 215T411 325V331Q411 405 350 405Q339 405 328 402T306 393T286 380T269 365T254 350T243 336T235 326L232 322Q232 321 229 308T218 264T204 212Q178 106 178 102Z"></path></g></g></g></svg></mjx-container></span> value. Continuous outcomes with asymmetrical distribution will be analyzed using bootstrapping techniques and reported as absolute difference between medians, <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="7.007ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 3097 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g><g data-mml-node="mi" transform="translate(1833,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="mi" transform="translate(2593,0)"><path data-c="1D43C" d="M43 1Q26 1 26 10Q26 12 29 24Q34 43 39 45Q42 46 54 46H60Q120 46 136 53Q137 53 138 54Q143 56 149 77T198 273Q210 318 216 344Q286 624 286 626Q284 630 284 631Q274 637 213 637H193Q184 643 189 662Q193 677 195 680T209 683H213Q285 681 359 681Q481 681 487 683H497Q504 676 504 672T501 655T494 639Q491 637 471 637Q440 637 407 634Q393 631 388 623Q381 609 337 432Q326 385 315 341Q245 65 245 59Q245 52 255 50T307 46H339Q345 38 345 37T342 19Q338 6 332 0H316Q279 2 179 2Q143 2 113 2T65 2T43 1Z"></path></g></g></g></svg></mjx-container></span> and <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.439ex;" xmlns="http://www.w3.org/2000/svg" width="1.138ex" height="1.439ex" role="img" focusable="false" viewBox="0 -442 503 636"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D45D" d="M23 287Q24 290 25 295T30 317T40 348T55 381T75 411T101 433T134 442Q209 442 230 378L240 387Q302 442 358 442Q423 442 460 395T497 281Q497 173 421 82T249 -10Q227 -10 210 -4Q199 1 187 11T168 28L161 36Q160 35 139 -51T118 -138Q118 -144 126 -145T163 -148H188Q194 -155 194 -157T191 -175Q188 -187 185 -190T172 -194Q170 -194 161 -194T127 -193T65 -192Q-5 -192 -24 -194H-32Q-39 -187 -39 -183Q-37 -156 -26 -148H-6Q28 -147 33 -136Q36 -130 94 103T155 350Q156 355 156 364Q156 405 131 405Q109 405 94 377T71 316T59 280Q57 278 43 278H29Q23 284 23 287ZM178 102Q200 26 252 26Q282 26 310 49T356 107Q374 141 392 215T411 325V331Q411 405 350 405Q339 405 328 402T306 393T286 380T269 365T254 350T243 336T235 326L232 322Q232 321 229 308T218 264T204 212Q178 106 178 102Z"></path></g></g></g></svg></mjx-container></span> values.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="subgroup-analyses"> |
| Subgroup analyses</h2> |
| <div>We will analyze the effects of resuscitation strategies on the primary outcome in the following subgroups:<br> |
| (a) Patients with lactate <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="13.696ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 6053.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="3E" d="M84 520Q84 528 88 533T96 539L99 540Q106 540 253 471T544 334L687 265Q694 260 694 250T687 235Q685 233 395 96L107 -40H101Q83 -38 83 -20Q83 -19 83 -17Q82 -10 98 -1Q117 9 248 71Q326 108 378 132L626 250L378 368Q90 504 86 509Q84 513 84 520Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(778,0)"></path></g><g data-mml-node="mi" transform="translate(2333.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3211.8,0)"><path data-c="1D45A" d="M21 287Q22 293 24 303T36 341T56 388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(4089.8,0)"><path data-c="1D45C" d="M201 -11Q126 -11 80 38T34 156Q34 221 64 279T146 380Q222 441 301 441Q333 441 341 440Q354 437 367 433T402 417T438 387T464 338T476 268Q476 161 390 75T201 -11ZM121 120Q121 70 147 48T206 26Q250 26 289 58T351 142Q360 163 374 216T388 308Q388 352 370 375Q346 405 306 405Q243 405 195 347Q158 303 140 230T121 120Z"></path></g><g data-mml-node="mi" transform="translate(4574.8,0)"><path data-c="1D459" d="M117 59Q117 26 142 26Q179 26 205 131Q211 151 215 152Q217 153 225 153H229Q238 153 241 153T246 151T248 144Q247 138 245 128T234 90T214 43T183 6T137 -11Q101 -11 70 11T38 85Q38 97 39 102L104 360Q167 615 167 623Q167 626 166 628T162 632T157 634T149 635T141 636T132 637T122 637Q112 637 109 637T101 638T95 641T94 647Q94 649 96 661Q101 680 107 682T179 688Q194 689 213 690T243 693T254 694Q266 694 266 686Q266 675 193 386T118 83Q118 81 118 75T117 65V59Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(4872.8,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(5372.8,0)"><path data-c="1D43F" d="M228 637Q194 637 192 641Q191 643 191 649Q191 673 202 682Q204 683 217 683Q271 680 344 680Q485 680 506 683H518Q524 677 524 674T522 656Q517 641 513 637H475Q406 636 394 628Q387 624 380 600T313 336Q297 271 279 198T252 88L243 52Q243 48 252 48T311 46H328Q360 46 379 47T428 54T478 72T522 106T564 161Q580 191 594 228T611 270Q616 273 628 273H641Q647 264 647 262T627 203T583 83T557 9Q555 4 553 3T537 0T494 -1Q483 -1 418 -1T294 0H116Q32 0 32 10Q32 17 34 24Q39 43 44 45Q48 46 59 46H65Q92 46 125 49Q139 52 144 61Q147 65 216 339T285 628Q285 635 228 637Z"></path></g></g></g></svg></mjx-container></span> as set by SSC [10]<br> |
| (b) Patients without a confirmed source of infection (as this could increase the translation of the study to other critically ill).<br> |
| (c) Patients with low APACHE II/SOFA scores<br> |
| (d) Patients with a more than <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> difference in lactate levels between the very first one measured and the baseline when starting the study.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="ethical-aspects"> |
| Ethical aspects</h2> |
| <div>Each investigator center will submit the study protocol to its Institutional Review Board (IRB). The study will start only after being approved by the IRB. Written informed consent will be obtained from a legal representative of all participants. This study is in compliance with local and international declarations.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="trial-organization-and-management-study-coordinating-center"> |
| Trial organization and management Study Coordinating Center</h2> |
| <div>A team based on the Departmento de Medicina Intensiva, Facultad de Medicina of Pontificia Universidad Católica, Chile, will manage the trial on a day-to-day basis. The SCC is comprised by the chief and co-chair investigators, four project managers, a statistician and a data digitizer. The statistician is based on the Research Institute HCor, São Paulo, Brazil.</div> |
| <div>The responsibilities of the SCC include:</div> |
| <ol> |
| <li>Planning and conducting the study designing the protocol; designing the CRF; designing the operation guide; managing and controlling data quality; designing, testing and maintaining the electronic database; data quality control; assisting the steering committee;</li> |
| <li>Managing the research centers selecting and training the research centers; helping the centers prepare a regulatory report to be submitted to the IRBs and assisting the centers with the submission; monitoring recruitment rates and the actions to increase recruitment; monitoring follow-up and implementing actions to prevent follow-up losses; auditing; sending study materials to the research centers; producing<br> |
| a monthly study newsletter; developing supporting material for the study;</li> |
| <li>Statistical analysis and research reporting complete statistical analysis; helping to write the final manuscript.</li> |
| </ol> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="trial-steering-committee"> |
| Trial Steering Committee</h2> |
| <div>The Trial Steering Committee (TSC) is responsible for the overall study supervision, assisting in developing the study protocol and preparing the final manuscript. All other study committees report to the TSC. The TSC members are investigators trained in designing and conducting randomized clinical trials in critically ill patients.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="study-centers"> |
| Study centers</h2> |
| <div>The study centers for ANDROMEDA-SHOCK were selected through a rigorous process. This started with a survey of professional and technical resources as well as processes of care. Centers were contacted trying to make this process representative across public, private and university hospitals, different countries and cultures, and hospital size.</div> |
| <div>At the end, 34 centers were selected and all applied for IRB approval, leaving finally 26 active centers to start on March 1, 2017, in 5 countries. Brazil is still pending</div> |
| <div>Details of the centers which accepted to participating in the trial at the time of this manuscript submission are given in the Appendix.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="publication-policy"> |
| Publication policy</h2> |
| <div>The ANDROMEDA-SHOCK study success depends on all its collaborators. Therefore, the primary results of the trial will be published under the name of ANDROM-EDA-SHOCK Investigators. The contributions of all collaborators, their names and respective institutions, will be acknowledged in the manuscript. To safeguard the scientific integrity of the study, data from this study will be submitted to publication only after the final approval from the TSC.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="data-safety-monitoring-committee"> |
| Data Safety Monitoring Committee</h2> |
| <div>The DSMC is set up with independent epidemiologists and intensivists. The DSMC is in charge of providing recommendations for the SCC of continuing the study as planned or discontinuing the recruitment based on evidence that the intervention causes increased mortality in the experimental group (PPTR) as compared to the control group (LTR). Interim analyses will be conducted after recruitment of the first 100 patients and at <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> of the sample.</div> |
| <div>In addition, the DSMC will discuss and potentially recommend a re-estimation of the sample size according to the interim analysis after recruitment of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.127ex;" xmlns="http://www.w3.org/2000/svg" width="4.147ex" height="1.824ex" role="img" focusable="false" viewBox="0 -750 1833 806"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="25" d="M465 605Q428 605 394 614T340 632T319 641Q332 608 332 548Q332 458 293 403T202 347Q145 347 101 402T56 548Q56 637 101 693T202 750Q241 750 272 719Q359 642 464 642Q580 642 650 732Q662 748 668 749Q670 750 673 750Q682 750 688 743T693 726Q178 -47 170 -52Q166 -56 160 -56Q147 -56 142 -45Q137 -36 142 -27Q143 -24 363 304Q469 462 525 546T581 630Q528 605 465 605ZM207 385Q235 385 263 427T292 548Q292 617 267 664T200 712Q193 712 186 709T167 698T147 668T134 615Q132 595 132 548V527Q132 436 165 403Q183 385 203 385H207ZM500 146Q500 234 544 290T647 347Q699 347 737 292T776 146T737 0T646 -56Q590 -56 545 0T500 146ZM651 -18Q679 -18 707 24T736 146Q736 215 711 262T644 309Q637 309 630 306T611 295T591 265T578 212Q577 200 577 146V124Q577 -18 647 -18H651Z"></path></g></g></g></svg></mjx-container></span> of the<br> |
| patients. A sample-size re-estimation design is a flexible, adaptive design with the primary purpose of allowing sample size of a study to be reassessed in the mid-course of the study to ensure adequate power.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="discussion"> |
| Discussion</h2> |
| <div>ANDROMEDA-SHOCK is a relevant study in septic shock for several reasons: (1) it determines the value of a simple, bedside, universally available parameter to be used as a resuscitation goal in early septic shock; (2) it proposes an early goal-directed resuscitation strategy based on a holistic physiological view of the reperfusion process; (3) it challenges the gold-standard parameter of lactate since this latter is not universally available and has many interpretation difficulties.<br> |
| If our hypothesis proves to be correct, resuscitation algorithms might be simplified, assessing almost in realtime the reperfusion process, and in pursuing more physiologically sound objectives through a peripheral perfusion-based strategy, it could prevent the risk of over-resuscitation and lead to a better utilization of ICU resources.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="study-status"> |
| Study status</h2> |
| <div>ANDROMEDA-SHOCK study started recruiting on March 1 in 26 centers from five countries. At the submission of this manuscript, already 388 patients have been recruited.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="abbreviations"> |
| Abbreviations</h2> |
| <div>CO: cardiac output; CRT: capillary refill time; RCT: randomized controlled trial; PPTR: peripheral perfusion-targeted resuscitation; LTR: lactate-targeted resuscitation; MV: mechanical ventilation; RRT: renal replacement therapy; ICU: intensive care unit; IAH: intraabdominal hypertension; SBP: systolic blood pressure; MAP: mean arterial pressure; SCC: Study Coordinating Center; CVC: central venous catheter; FR: fluid responsiveness; PPV: pulse pressure variation; SVV: stroke volume variation; EEOT: end-expiratory occlusion test; Vt: tidal volume; PEEP: positive-end-expiratory-pressure; NE: norepinephrine; HVHF: highvolume hemofiltration; RR: respiratory rate; VTI: aortic velocity time integral; PLR: passive leg raising; HR: heart rate; CRF: case report form; ITT: intention-to-treat; DSMC: data safety monitoring committee; APACHE: acute physiology and chronic health evaluation; AKI: acute kidney injury network; DBP: diastolic blood pressure; SUSAR: suspected unexpected serious adverse reactions; IAP: intraabdominal pressure; <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="6.25ex" height="1.934ex" role="img" focusable="false" viewBox="0 -705 2762.6 855"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D446" d="M308 24Q367 24 416 76T466 197Q466 260 414 284Q308 311 278 321T236 341Q176 383 176 462Q176 523 208 573T273 648Q302 673 343 688T407 704H418H425Q521 704 564 640Q565 640 577 653T603 682T623 704Q624 704 627 704T632 705Q645 705 645 698T617 577T585 459T569 456Q549 456 549 465Q549 471 550 475Q550 478 551 494T553 520Q553 554 544 579T526 616T501 641Q465 662 419 662Q362 662 313 616T263 510Q263 480 278 458T319 427Q323 425 389 408T456 390Q490 379 522 342T554 242Q554 216 546 186Q541 164 528 137T492 78T426 18T332 -20Q320 -22 298 -22Q199 -22 144 33L134 44L106 13Q83 -14 78 -18T65 -22Q52 -22 52 -14Q52 -11 110 221Q112 227 130 227H143Q149 221 149 216Q149 214 148 207T144 186T142 153Q144 114 160 87T203 47T255 29T308 24Z"></path></g><g data-mml-node="mi" transform="translate(645,0)"><path data-c="1D450" d="M34 159Q34 268 120 355T306 442Q362 442 394 418T427 355Q427 326 408 306T360 285Q341 285 330 295T319 325T330 359T352 380T366 386H367Q367 388 361 392T340 400T306 404Q276 404 249 390Q228 381 206 359Q162 315 142 235T121 119Q121 73 147 50Q169 26 205 26H209Q321 26 394 111Q403 121 406 121Q410 121 419 112T429 98T420 83T391 55T346 25T282 0T202 -11Q127 -11 81 37T34 159Z"></path></g><g data-mml-node="mi" transform="translate(1078,0)"><path data-c="1D463" d="M173 380Q173 405 154 405Q130 405 104 376T61 287Q60 286 59 284T58 281T56 279T53 278T49 278T41 278H27Q21 284 21 287Q21 294 29 316T53 368T97 419T160 441Q202 441 225 417T249 361Q249 344 246 335Q246 329 231 291T200 202T182 113Q182 86 187 69Q200 26 250 26Q287 26 319 60T369 139T398 222T409 277Q409 300 401 317T383 343T365 361T357 383Q357 405 376 424T417 443Q436 443 451 425T467 367Q467 340 455 284T418 159T347 40T241 -11Q177 -11 139 22Q102 54 102 117Q102 148 110 181T151 298Q173 362 173 380Z"></path></g><g data-mml-node="msub" transform="translate(1563,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> : central venous oxygen saturation; <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="13.932ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 6158 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D443" d="M287 628Q287 635 230 637Q206 637 199 638T192 648Q192 649 194 659Q200 679 203 681T397 683Q587 682 600 680Q664 669 707 631T751 530Q751 453 685 389Q616 321 507 303Q500 302 402 301H307L277 182Q247 66 247 59Q247 55 248 54T255 50T272 48T305 46H336Q342 37 342 35Q342 19 335 5Q330 0 319 0Q316 0 282 1T182 2Q120 2 87 2T51 1Q33 1 33 11Q33 13 36 25Q40 41 44 43T67 46Q94 46 127 49Q141 52 146 61Q149 65 218 339T287 628ZM645 554Q645 567 643 575T634 597T609 619T560 635Q553 636 480 637Q463 637 445 637T416 636T404 636Q391 635 386 627Q384 621 367 550T332 412T314 344Q314 342 395 342H407H430Q542 342 590 392Q617 419 631 471T645 554Z"></path></g><g data-mml-node="mo" transform="translate(751,0)"><path data-c="28" d="M94 250Q94 319 104 381T127 488T164 576T202 643T244 695T277 729T302 750H315H319Q333 750 333 741Q333 738 316 720T275 667T226 581T184 443T167 250T184 58T225 -81T274 -167T316 -220T333 -241Q333 -250 318 -250H315H302L274 -226Q180 -141 137 -14T94 250Z"></path></g><g data-mml-node="mi" transform="translate(1140,0)"><path data-c="1D450" d="M34 159Q34 268 120 355T306 442Q362 442 394 418T427 355Q427 326 408 306T360 285Q341 285 330 295T319 325T330 359T352 380T366 386H367Q367 388 361 392T340 400T306 404Q276 404 249 390Q228 381 206 359Q162 315 142 235T121 119Q121 73 147 50Q169 26 205 26H209Q321 26 394 111Q403 121 406 121Q410 121 419 112T429 98T420 83T391 55T346 25T282 0T202 -11Q127 -11 81 37T34 159Z"></path></g><g data-mml-node="mi" transform="translate(1573,0)"><path data-c="1D463" d="M173 380Q173 405 154 405Q130 405 104 376T61 287Q60 286 59 284T58 281T56 279T53 278T49 278T41 278H27Q21 284 21 287Q21 294 29 316T53 368T97 419T160 441Q202 441 225 417T249 361Q249 344 246 335Q246 329 231 291T200 202T182 113Q182 86 187 69Q200 26 250 26Q287 26 319 60T369 139T398 222T409 277Q409 300 401 317T383 343T365 361T357 383Q357 405 376 424T417 443Q436 443 451 425T467 367Q467 340 455 284T418 159T347 40T241 -11Q177 -11 139 22Q102 54 102 117Q102 148 110 181T151 298Q173 362 173 380Z"></path></g><g data-mml-node="mo" transform="translate(2280.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mi" transform="translate(3280.4,0)"><path data-c="1D44E" d="M33 157Q33 258 109 349T280 441Q331 441 370 392Q386 422 416 422Q429 422 439 414T449 394Q449 381 412 234T374 68Q374 43 381 35T402 26Q411 27 422 35Q443 55 463 131Q469 151 473 152Q475 153 483 153H487Q506 153 506 144Q506 138 501 117T481 63T449 13Q436 0 417 -8Q409 -10 393 -10Q359 -10 336 5T306 36L300 51Q299 52 296 50Q294 48 292 46Q233 -10 172 -10Q117 -10 75 30T33 157ZM351 328Q351 334 346 350T323 385T277 405Q242 405 210 374T160 293Q131 214 119 129Q119 126 119 118T118 106Q118 61 136 44T179 26Q217 26 254 59T298 110Q300 114 325 217T351 328Z"></path></g><g data-mml-node="mo" transform="translate(3809.4,0)"><path data-c="29" d="M60 749L64 750Q69 750 74 750H86L114 726Q208 641 251 514T294 250Q294 182 284 119T261 12T224 -76T186 -143T145 -194T113 -227T90 -246Q87 -249 86 -250H74Q66 -250 63 -250T58 -247T55 -238Q56 -237 66 -225Q221 -64 221 250T66 725Q56 737 55 738Q55 746 60 749Z"></path></g><g data-mml-node="mi" transform="translate(4198.4,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(4958.4,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> : central venous-arterial <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="6.132ex" height="1.934ex" role="img" focusable="false" viewBox="0 -705 2710.6 855"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D443" d="M287 628Q287 635 230 637Q206 637 199 638T192 648Q192 649 194 659Q200 679 203 681T397 683Q587 682 600 680Q664 669 707 631T751 530Q751 453 685 389Q616 321 507 303Q500 302 402 301H307L277 182Q247 66 247 59Q247 55 248 54T255 50T272 48T305 46H336Q342 37 342 35Q342 19 335 5Q330 0 319 0Q316 0 282 1T182 2Q120 2 87 2T51 1Q33 1 33 11Q33 13 36 25Q40 41 44 43T67 46Q94 46 127 49Q141 52 146 61Q149 65 218 339T287 628ZM645 554Q645 567 643 575T634 597T609 619T560 635Q553 636 480 637Q463 637 445 637T416 636T404 636Q391 635 386 627Q384 621 367 550T332 412T314 344Q314 342 395 342H407H430Q542 342 590 392Q617 419 631 471T645 554Z"></path></g><g data-mml-node="mi" transform="translate(751,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(1511,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> gradient; IRB: Institutional Review Board; TSC: Trial Steering Committee.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="authors'-contributions"> |
| Authors' contributions</h2> |
| <div>JB and GH are guarantors of the entire manuscript; JB, JLT, GH, GOT, AD, GF, MC, JH, AC, RC, LA designed the study; All the authors will help in the data interpretation and the final manuscript draft. All authors read and approved this final manuscript.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="author-details"> |
| Author details</h2> |
| <div>1Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Santiago, Chile. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> Research Institute HCor, Hospital do Coração, R. Des. Eliseu Guilherme, 147 - Paraíso, São Paulo, Brazil. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.885ex" role="img" focusable="false" viewBox="0 -833.2 436.6 833.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></g></g></svg></mjx-container></span> Department of Intensive Care Medicine, Fundación Valle del Lili, Universidad ICESI, Carrera 98 # 18-49, Cali, Colombia. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.904ex" role="img" focusable="false" viewBox="0 -841.7 436.6 841.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g></g></g></g></g></svg></mjx-container></span> Servicio de Terapia Intensiva, Sanatorio Otamendi y Miroli, Azcuénaga 894, Ciudad Autónoma de</div> |
| <div>Buenos Aires, Argentina. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z"></path></g></g></g></g></g></svg></mjx-container></span> Centro de Tratamiento Intensivo, Hospital Español, Escuela de Medicina, Universidad de la República, Avda. Gral. Garibaldi, 1729 esq. Rocha, Montevideo, Uruguay. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="36" d="M42 313Q42 476 123 571T303 666Q372 666 402 630T432 550Q432 525 418 510T379 495Q356 495 341 509T326 548Q326 592 373 601Q351 623 311 626Q240 626 194 566Q147 500 147 364L148 360Q153 366 156 373Q197 433 263 433H267Q313 433 348 414Q372 400 396 374T435 317Q456 268 456 210V192Q456 169 451 149Q440 90 387 34T253 -22Q225 -22 199 -14T143 16T92 75T56 172T42 313ZM257 397Q227 397 205 380T171 335T154 278T148 216Q148 133 160 97T198 39Q222 21 251 21Q302 21 329 59Q342 77 347 104T352 209Q352 289 347 316T329 361Q302 397 257 397Z"></path></g></g></g></g></g></svg></mjx-container></span> Departamento de Medicina Interna, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, R. Ramiro Barcelos 2350 - Santa Cecilia, Porto Alegre, Brazil. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.903ex" role="img" focusable="false" viewBox="0 -841 436.6 841"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path></g></g></g></g></g></svg></mjx-container></span> St George's University Hospitals NHS Foundation Trust, Rd, London SW17 0QT, UK. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="38" d="M70 417T70 494T124 618T248 666Q319 666 374 624T429 515Q429 485 418 459T392 417T361 389T335 371T324 363L338 354Q352 344 366 334T382 323Q457 264 457 174Q457 95 399 37T249 -22Q159 -22 101 29T43 155Q43 263 172 335L154 348Q133 361 127 368Q70 417 70 494ZM286 386L292 390Q298 394 301 396T311 403T323 413T334 425T345 438T355 454T364 471T369 491T371 513Q371 556 342 586T275 624Q268 625 242 625Q201 625 165 599T128 534Q128 511 141 492T167 463T217 431Q224 426 228 424L286 386ZM250 21Q308 21 350 55T392 137Q392 154 387 169T375 194T353 216T330 234T301 253T274 270Q260 279 244 289T218 306L210 311Q204 311 181 294T133 239T107 157Q107 98 150 60T250 21Z"></path></g></g></g></g></g></svg></mjx-container></span> Service de Réanimation médicale, Hôpitaux universitaires Paris-Sud, Assistance PubliqueHôpitaux de Paris, Paris, France. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="39" d="M352 287Q304 211 232 211Q154 211 104 270T44 396Q42 412 42 436V444Q42 537 111 606Q171 666 243 666Q245 666 249 666T257 665H261Q273 665 286 663T323 651T370 619T413 560Q456 472 456 334Q456 194 396 97Q361 41 312 10T208 -22Q147 -22 108 7T68 93T121 149Q143 149 158 135T173 96Q173 78 164 65T148 49T135 44L131 43Q131 41 138 37T164 27T206 22H212Q272 22 313 86Q352 142 352 280V287ZM244 248Q292 248 321 297T351 430Q351 508 343 542Q341 552 337 562T323 588T293 615T246 625Q208 625 181 598Q160 576 154 546T147 441Q147 358 152 329T172 282Q197 248 244 248Z"></path></g></g></g></g></g></svg></mjx-container></span> Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center, 630 W 168th St, New York, USA. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span> Department Intensive Care Adults, Erasmus MC University Medical Center, Rotterdam, CA, The Netherlands. <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="1.788ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 790.1 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z" transform="translate(500,0)"></path></g></g></g></g></g></svg></mjx-container></span> Division of Pulmonary, and Critical Care Medicine, New York University-Langone, New York, USA.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="acknowledgements"> |
| Acknowledgements</h2> |
| <div>We acknowledge the support from the Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="competing-interests"> |
| Competing interests</h2> |
| <div>The authors declare that they have no competing interests.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="funding"> |
| Funding</h2> |
| <div>The study is financed in part by an internal grant from the Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="ethics-approval-and-consent-to-participate"> |
| Ethics approval and consent to participate</h2> |
| <div>Each investigator center will submit the study protocol to its Institutional Review Board (IRB). The study will start only after being approved by the IRB. Written informed consent will be obtained from a legal representative of all participants. This study is in compliance with local and international declarations.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="andromeda-shock-investigators-consists-of%3A-writing-and-steering-committee"> |
| ANDROMEDA-SHOCK Investigators consists of: Writing and Steering Committee</h2> |
| <div>Glenn Hernandez (chair), Gustavo Ospina-Tascón, Alexandre Cavalcanti, Arnaldo Dubin, Javier Hurtado, Gilberto Friedman, Ricardo Castro, Leyla Alegría, Jean-Louis Teboul, Maurizio Cecconi, Fernando Zampieri, Lucas Petri Damiani, Jan Bakker (co-chair). Study Coordinating Center: Glenn Hernandez, Leyla Alegría, Giorgio Ferri, Nicolás Rodriguez, Patricia Holger, Natalia Soto, Mario Pozo, Lucas Petri Damiani, Jan Bakker. Data Safety Monitoring Committee: Deborah Cook, Jean-Louis Vincent, Andrew, Rhodes, Bryan Kavanagh, Phil Dellinger, Wim Rietdijk. Study Centers: Chile: Pontificia Universidad Católica de Chile, Santiago: David Carpio, Nicolás Pavéz, Elizabeth Henriquez, Sebastian Bravo, Emilio Daniel Valenzuela; Hospital Barros-Luco Trudeau, Santiago: Maria Alicia Cid, Ronald Pairumani, Macarena Larroulet, Edward Petruska, Claudio Sarabia; Hospital San Juan de Dios, Santiago: David Gallardo, Juan Eduardo Sanchez, Hugo González, José Miguel Arancibia, Alex Muñoz, Germán Ramirez, Florencia Aravena; Hospital Dr. Sótero del Río, Santiago: Andrés Aquevedo, Fabián Zambrano; Hospital Del Salvador, Santiago: Milan Bozinovic, Felipe Valle, Manuel Ramirez, Victor Rossel, Pilar Muñoz, Carolina Ceballos; Hospital Herminda Martinez, Chillán: Christian Esveile, Cristian Carmona, Eva Candia, Daniela Mendoza; Hospital San Juan de Dios, Curicó: Aída Sanchez; Hospital Guillermo Grant Benavente, Concepción: Paula Fernández, Daniela Ponce, Jaime Lastra, Bárbara Nahuelpán, Fabrizio Fasce; Hospital Clínico Universidad de Chile, Santiago: Cecilia Luengo, Nicolas Medel, Cesar Cortés.<br> |
| Argentina: Clínica La Pequeña Familia, Junín: Luz Campassi; Sanatorio Otamendi y Miroli, Buenos Aires: Arnaldo Dubin, Paolo Rubatto, Brenda Nahime Horna, Mariano Furche; Hospital Provincial del Centenario, Rosario: Juan Carlos Pendino, Lisandro Bettini; Sanatorio Parque, Rosario: Carlos Lovesio, María Cecilia González, Jésica Rodruguez; Hospital Interzonal San Martín, La Plata: Elisa Estenssoro, Héctor Canales, Francisco Caminos; Sanatorio Allende Nueva Córdoba: Cayetano Galletti, Estefanía Minoldo, María José Aramburu, Daniela Olmos; Uruguay: Hospital Español Juan J Crottogini, Montevideo: Javier Hurtado, Nicolás Nin, Jordán Tenzi, Carlos Quiroga, Pablo Lacuesta, Agustín Gaudín, Richard Pais, Ana Silvestre, Germán Olivera; Hospital de Clínicas, Montevideo: Gloria Rieppi, Dolores Berrutti. Ecuador: Hospital Universitario del Rio, Cuenca: Marcelo Ochoa, Paul Cobos, Fernando Vintimilla; Hospital Eugenio Espejo, Quito: Vanessa Ramirez, Milton Tobar, Manuel Jibaja, Fernanda García, Fabricio Picoita, Nelson Remache; Hospital San Francisco de Quito, Quito: Vladimir Granda, Fernando Paredes, Eduardo Barzallo, Paul Garcés; Hospital Carlos Andrade Marín, Quito: Fausto Guerrero, Santiago Salazar, German Torres,</div> |
| <div>Cristian Tana, José Calahorrano, Freddy Solis; Hospital IESS Ibarra, Ibarra: Pedro Torres, Luís Herrera, Antonio Ornes, Verónica Peréz, Glenda Delgado, Alexei Carbonell, Eliana Espinosa, José Moreira; Hospital General Docente Calderón, Quito: Diego Barahona, Blanca Salcedo, Ivonne Villacres, Jhonny Suing, Marco Lopez, Luis Gomez, Guillermo Toctaquiza, Mario Cadena Zapata, Milton Alonso Orazabal, Ruben Pardo Espejo, Jorge Jimenez, Alexander Calderón. Hospital Enrique Garcés, Quito: Gustavo Paredes, José Luis Barberán, Tatiana Moya.<br> |
| Colombia: Hospital San Vicente de Paul, Medellín: Horacio Atehortua, Rodolfo Sabogal; Hospital de Santa Clara, Bogotá: Guillermo Ortiz, Antonio Lara; Hospital Universitario de Ñarino E.S.E, Pasto: Fabio Sanchez, Alvaro Hernán Portilla, Humberto Dávila, Jorge Antonio Mora; Fundación Valle del Lili, Cali: GustavoOspina Tascón, Luis Eduardo Calderón, Ingrid Alvarez, Elena Escobar, Alejandro Bejarano, Luis Alfonso Bustamante.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="publisher's-note"> |
| Publisher's Note</h2> |
| <div>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</div> |
| <div>Received: 19 January 2018 Accepted: 12 April 2018<br> |
| Published online: 23 April 2018</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="references"> |
| References</h2> |
| <ol> |
| <li>Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369:1726-34.</li> |
| <li>Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, et al. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensiv Care Med. 2014;40:1795-815.</li> |
| <li>Shoemaker WC, Appel PL, Kram HB. Tissue oxygen debt as a determinant of lethal and nonlethal postoperative organ failure. Crit Care Med. 1988;16:1117-20.</li> |
| <li>Vallet B. Vascular reactivity and tissue oxygenation. Intensiv Care Med. 1998;24:3-11.</li> |
| <li>Bellomo R, Reade MC, Warrillow SJ. The pursuit of a high central venous oxygen saturation in sepsis: growing concerns. Crit Care. 2008;12:130.</li> |
| <li>PRISM Investigators, Rowan KM, Angus DC, Bailey M, Barnato AE, Bellomo R, et al. Early, goal-directed therapy for septic shock-a patient-level meta-analysis. N Engl J Med. 2017;376:2223-34.</li> |
| <li>Bakker J, Gris P, Coffernils M, Kahn R, Vincent J. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg. 1996;171:221-6.</li> |
| <li>Friedman G, De Backer D, Shahla M, Vincent JL. Oxygen supply dependency can characterize septic shock. Intensiv Care Med. 1998;24:118-23.</li> |
| <li>Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, et al. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010;182:752-61.</li> |
| <li>Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensiv Care Med. 2017;43:304-77.</li> |
| <li>Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014;18:503.</li> |
| <li>Hernandez G, Bruhn A, Castro R, Regueira T. The holistic view on perfusion monitoring in septic shock. Curr Opinion Crit Care. 2012;18:280-6.</li> |
| <li>Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensiv Care Med. 2017;43:625-32.</li> |
| <li>Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettilä V, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensiv Care Med. 2016;42:1695-705.</li> |
| <li>Hernandez G, Luengo C, Bruhn A, Kattan E, Friedman G, Ospina-Tascon GA, et al. When to stop septic shock resuscitation: clues from a dynamic perfusion monitoring. Ann Intensive Care. 2014;4:30.</li> |
| <li>Brunauer A, Koköfer A, Bataar O, Gradwohl-Matis I, Dankl D, Bakker J, et al. Changes in peripheral perfusion relate to visceral organ perfusion in early septic shock: a pilot study. J Crit Care. 2016;35:105-9.</li> |
| <li>Lima A, Bakker J. Clinical assessment of peripheral circulation. Curr Opin Crit Care. 2015;21:226-31.</li> |
| <li>Hernandez G, Pedreros C, Veas E, Bruhn A, Romero C, Rovegno M, et al. Evolution of peripheral vs metabolic perfusion parameters during septic shock resuscitation. J Crit Care. 2012;27:283-8.</li> |
| <li>Ait-Oufella H, Lemoinne S, Boelle PY, Galbois A, Baudel JL, Lemant J, et al. Mottling score predicts survival in septic shock. Intensive Care Med. 2011;37:801-7.</li> |
| <li>Lima A, Jansen TC, Van Bommel J, Ince C, Bakker J. The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients. Crit Care Med. 2009;37:934-8.</li> |
| <li>Coudroy R, Jamet A, Frat JP, Veinstein A, Chatellier D, Goudet V, et al. Incidence and impact of skin mottling over the knee and its duration on outcome in critically ill patients. Intensive Care Med. 2015:41:452-9.</li> |
| <li>Ait-Oufella H, Bige N, Boelle PY, Pichereau C, Alves M, Bertinchamp R, et al. Capillary refill time exploration during septic shock. Intensive Care Med. 2014;40:958-64.</li> |
| <li>van Genderen ME, Paauwe J, de Jonge J, van der Valk RJ, Lima A, Bakker J, et al. Clinical assessment of peripheral perfusion to predict postoperative complications after major abdominal surgery early: a prospective observational study in adults. Crit Care. 2014;18:R114.</li> |
| <li>Dünser MW, Takala J, Brunauer A, Bakker J. Re-thinking resuscitation: leaving blood pressure cosmetics behind and moving forward to permissive hypotension and a tissue perfusion-based approach. Crit Care. 2013;17:326.</li> |
| <li>van Genderen ME, Engels N, van der Valk RJP, Lima A, Klijn E, Bakker J, et al. Early peripheral perfusion-guided fluid therapy in patients with septic shock. Am J Respir Crit Care Med. 2015;191:477-80.</li> |
| <li>Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the work-ing group on sepsis-related problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707-10.</li> |
| <li>Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315:801-10.</li> |
| <li>Miller A, Mandeville J. Predicting and measuring fluid responsiveness with echocardiography. Echo Res Pract. 2016;3:G1-12.</li> |
| <li>Monnet X, Teboul JL. Assessment of volume responsiveness during mechanical ventilation: recent advances. Crit Care. 2013;17:217.</li> |
| <li>Lara B, Enberg L, Ortega M, Leon P, Kripper C, Aguilera P, et al. Capillary refill time during fluid resuscitation in patients with sepsis-related hyperlactatemia at the emergency department is related to mortality. PLOS ONE. 2017;12:e0188548.</li> |
| <li>Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-29.</li> |
| <li>Kellum JA, Lameire N. KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013;17:204.</li> |
| <li>Bhatt DL, Mehta C. Adaptive designs for clinical trials. N Engl J Med. 2016;375:65-74.</li> |
| </ol> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="submit-your-manuscript-to-a-springeropen-%5C(%7B-%7D%5E%7B(j)%7D%5C)-journal-and-benefit-from%3A"> |
| Submit your manuscript to a SpringerOpen <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="2.445ex" height="2.021ex" role="img" focusable="false" viewBox="0 -893.3 1080.7 893.3"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mo"><path data-c="28" d="M94 250Q94 319 104 381T127 488T164 576T202 643T244 695T277 729T302 750H315H319Q333 750 333 741Q333 738 316 720T275 667T226 581T184 443T167 250T184 58T225 -81T274 -167T316 -220T333 -241Q333 -250 318 -250H315H302L274 -226Q180 -141 137 -14T94 250Z"></path></g><g data-mml-node="mi" transform="translate(389,0)"><path data-c="1D43D" d="M447 625Q447 637 354 637H329Q323 642 323 645T325 664Q329 677 335 683H352Q393 681 498 681Q541 681 568 681T605 682T619 682Q633 682 633 672Q633 670 630 658Q626 642 623 640T604 637Q552 637 545 623Q541 610 483 376Q420 128 419 127Q397 64 333 21T195 -22Q137 -22 97 8T57 88Q57 130 80 152T132 174Q177 174 182 130Q182 98 164 80T123 56Q115 54 115 53T122 44Q148 15 197 15Q235 15 271 47T324 130Q328 142 387 380T447 625Z"></path></g><g data-mml-node="mo" transform="translate(1022,0)"><path data-c="29" d="M60 749L64 750Q69 750 74 750H86L114 726Q208 641 251 514T294 250Q294 182 284 119T261 12T224 -76T186 -143T145 -194T113 -227T90 -246Q87 -249 86 -250H74Q66 -250 63 -250T58 -247T55 -238Q56 -237 66 -225Q221 -64 221 250T66 725Q56 737 55 738Q55 746 60 749Z"></path></g></g></g></g></g></svg></mjx-container></span> journal and benefit from:</h2> |
| <ul> |
| <li>Convenient online submission</li> |
| <li>Rigorous peer review</li> |
| <li>Open access: articles freely available online</li> |
| <li>High visibility within the field</li> |
| <li>Retaining the copyright to your article</li> |
| </ul> |
| <div>Submit your next manuscript at - <a href="http://springeropen.com" target="_blank" rel="noopener" style="display: inline-block">springeropen.com</a></div> |
| <hr class="footnotes-sep"> |
| <section class="footnotes" style="margin-bottom: 1em;"> |
| <ol class="footnotes-list" style="padding-left: 20px; margin-bottom: 0;"> |
| <li id="fn1" class="footnote-item" style="list-style-type: none;"><div>*Correspondence: <a href="mailto:glennguru@gmail.com" target="_blank" rel="noopener" style="display: inline-block">glennguru@gmail.com</a><br> |
| <span class="math-inline " data-overflow="visible"> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span> Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362, Santiago, Chile<br> |
| Full list of author information is available at the end of the article</div> |
| </li> |
| </ol> |
| </section> |
|
|
| </div> |
| </div> |
| </body> |
| </html> |
