Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial

Effects of dynamic versus static parameter-guided... | F1000Research "use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317073",licenseKey:"97f8f67f26",applicationID:"772317073"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317073",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}var u=r(7056);const d=()=>{const e={blockSelector:"[data-nr-block]",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:"*",maskAllInputs:!0,get blockClass(){return"nr-block"},get ignoreClass(){return"nr-ignore"},get maskTextClass(){return"nr-mask"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=",".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error("All configuration objects require an agent identifier!");if(!f[e])throw new Error("Configuration for ".concat(e," was never set"));return f[e]}function h(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],"config")}function g(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");var r=l(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.236.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=""+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&"undefined"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s="nr@context";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;fn,p:()=>i});var n=r(2177).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i="nr@original";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");var a,s,c,u="-"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,"fetch",y),t.on(y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(y+"done",[null,r],n)}else t.emit(y+"done",[e],n)})),t}const O={},j=["pushState","replaceState"];function S(e){const t=function(e){return(e||n.ee).get("history")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,"-")),t}var P=r(3239);const C={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function f(){t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}function l(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",f,(0,P.m$)(!1)),e.addEventListener("error",l,(0,P.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,"executor-",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,["onreadystatechange"],"fn-",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,f,"fn-",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,"-xhr-",E),r.on("send-xhr-start",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on("open-xhr-start",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i="nr@seenError"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i="firstbyte",o="domcontent",a="windowload"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",f="remaining",l="interaction",h="spaNode",g="jsonpNode",p="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",x="-end",A="-body",E="cb"+x,T="jsTime",_="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,"api");const h={};var g=a.ee.get(e),p=g.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>h[e]=x(m,e,!0,"api"))),h.addPageAction=x(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=x(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,x(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,f.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,f.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,f.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit("fn-err",[arguments,this,"string"==typeof e?new Error(e):e],r),e}finally{p.emit("fn-end",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,["API/"+t+"/called"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,f.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,["API/noticeError/called"],void 0,n.D.metrics,g),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,"api"),(0,h.Qy)(e,A,"exposed"),(0,h.EZ)("activatedFeatures",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:"page_action-aggregate",147:"metrics-aggregate",242:"session-manager",317:"jserrors-aggregate",348:"page_view_timing-aggregate",412:"lazy-feature-loader",439:"async-api",538:"recorder",590:"session_replay-aggregate",675:"compressor",733:"session_trace-aggregate",786:"page_view_event-aggregate",873:"spa-aggregate",898:"ajax-aggregate"}[e]||e)+"."+{78:"ac76d497",147:"3dc53903",148:"1a20d5fe",242:"2a64278a",317:"49e41428",348:"bd6de33a",412:"2f55ce66",439:"30bd804e",538:"1b18459f",590:"cf0efb30",675:"ae9f91a8",733:"83105561",786:"06482edd",860:"03a8b7a5",873:"e6b09d52",898:"998ef92b"}[e]+"-1.236.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.j=364,i.p="https://js-agent.newrelic.com/",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,"".concat(e,".enabled"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,"aggregate");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)("Downloading and initializing ".concat(this.featureName," failed..."),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),("undefined"==typeof PerformanceNavigationTiming||c.Tt)&&"undefined"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)("timing",["load",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean("hidden"===document.visibilityState),(0,N.N)((()=>(0,s.p)("docHidden",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)("pagehide",(()=>(0,s.p)("winPagehide",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(L.console=!0,-1!==R.indexOf("dev")&&(L.dev=!0),-1!==R.indexOf("nr_dev")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on("internal-error",(function(e){z(e.stack)})),L.dev&&H.ee.on("fn-err",(function(e,t,r){z(r.stack)})),L.dev&&(z("NR AGENT IN DEVELOPMENT MODE"),z("flags: "+(0,b.D)(L,(function(e,t){return e})).join(", ")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on("fn-start",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on("fn-err",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)("err",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on("fn-end",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on("internal-error",(function(t){(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener("unhandledrejection",(t=>{const r=function(e){let t="Unhandled Promise Rejection: ";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)("err",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){"function"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)("err",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||"Uncaught error with no additional information",this.sourceURL=t,this.line=r}let U=1;const q="nr@id";function G(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||"").toString()||null,i=(r.agentID||"").toString()||null,o=(r.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,"distributed_tracing")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof t.onload)&&"function"==typeof o.end)&&o.end(t)}catch(e){try{n.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(""+(i&&i instanceof Y&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||"agent")),this.start()):(0,l.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t="features";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,D.P)(n),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)("bst",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get("tracer"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get("events"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit("newURL",[""+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),f.buffer([ve],this.featureName),u.buffer(["setTimeout"+le,"clearTimeout"+fe,ve],this.featureName),d.buffer([ve,"new-xhr","send-xhr"+fe],this.featureName),l.buffer([me+fe,me+"-done",me+he+fe,me+he+le],this.featureName),h.buffer(["newURL"],this.featureName),g.buffer([ve],this.featureName),s.buffer(["propagate",be,ge,"executor-err","resolve"+fe],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),y(l,me+fe),y(l,me+"-done"),y(a,"new-jsonp"),y(a,"jsonp-end"),y(a,"cb-start"),h.on("pushState-end",m),h.on("replaceState-end",m),window.addEventListener("hashchange",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is "complete" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event "completion" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', "PixelInitialized", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { "@context": "https://schema.org", "@type": "ScholarlyArticle", "mainEntityOfPage": { "@type": "WebPage", "@id": "https://f1000research.com/articles/13-528" }, "headline": "Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized...", "datePublished": "2024-05-22T15:34:42", "dateModified": "2024-07-25T16:07:39", "author": [ { "@type": "Person", "name": "Thiti Sricharoenchai" }, { "@type": "Person", "name": "Pannarat Saisirivechakun" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": " Background Fluid resuscitation is an essential component for sepsis treatment. Although several studies demonstrated that dynamic variables were more accurate than static variables for prediction of fluid responsiveness, fluid resuscitation guidance by dynamic variables is not standard for treatment. The objectives were to determine the effects of dynamic inferior vena cava (IVC)-guided versus (vs.) static central venous pressure (CVP)-guided fluid resuscitation in septic patients on mortality; and others, i.e., resuscitation targets, shock duration, fluid and vasopressor amount, invasive respiratory support, length of stay and adverse events. Methods A single-blind randomized controlled trial was conducted at Thammasat University Hospital between August 2016 and April 2020. Septic patients were stratified by acute physiologic and chronic health evaluation II (APACHE II) <25 or ≥25 and randomized by blocks of 2 and 4 to fluid resuscitation guidance by dynamic IVC or static CVP. Results Of 124 patients enrolled, 62 were randomized to each group, and one of each was excluded from mortality analysis. Baseline characteristics were comparable. The 30-day mortality rates between dynamic IVC vs. static CVP groups were not different (34.4% vs. 45.9%, p=0.196). Relative risk for 30-day mortality of dynamic IVC group was 0.8 (95%CI=0.5-1.2, p=0.201). Different outcomes were median (interquartile range) of shock duration (0.8 (0.4-1.6) vs. 1.5 (1.1-3.1) days, p=0.001) and norepinephrine (NE) dose (6.8 (3.9–17.8) vs. 16.1 (7.6–53.6) milligrams, p=0.008 and 0.1 (0.1-0.3) vs. 0.3 (0.1-0.8) milligram⋅kilogram−1, p=0.017). Others were not different. Conclusions Dynamic IVC-guided fluid resuscitation does not affect mortality of septic patients. However, this may reduce shock duration and NE dose, compared with static CVP guidance. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-528/v2", "name": "Effects of dynamic versus static parameter-guided fluid resuscitation..." } } ] } Home Browse Effects of dynamic versus static parameter-guided fluid resuscitation... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Sricharoenchai T and Saisirivechakun P. Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.12688/f1000research.147875.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] Thiti Sricharoenchai https://orcid.org/0000-0002-2703-9285 1 , Pannarat Saisirivechakun https://orcid.org/0000-0003-0250-5670 2,3 Thiti Sricharoenchai https://orcid.org/0000-0002-2703-9285 1 , Pannarat Saisirivechakun https://orcid.org/0000-0003-0250-5670 2,3 PUBLISHED 25 Jul 2024 Author details Author details 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 2 Department of Medicine, Nakhon Pathom Hospital, Nakhon Pathom, 73000, Thailand 3 Department of Medicine, Faculty of Medicine, Nakhon Pathom Hospital, Nakhon Pathom, 73000, Thailand Thiti Sricharoenchai Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Pannarat Saisirivechakun Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Faculty of Medicine – Thammasat University collection. Abstract Background Fluid resuscitation is an essential component for sepsis treatment. Although several studies demonstrated that dynamic variables were more accurate than static variables for prediction of fluid responsiveness, fluid resuscitation guidance by dynamic variables is not standard for treatment. The objectives were to determine the effects of dynamic inferior vena cava (IVC)-guided versus (vs.) static central venous pressure (CVP)-guided fluid resuscitation in septic patients on mortality; and others, i.e., resuscitation targets, shock duration, fluid and vasopressor amount, invasive respiratory support, length of stay and adverse events. Methods A single-blind randomized controlled trial was conducted at Thammasat University Hospital between August 2016 and April 2020. Septic patients were stratified by acute physiologic and chronic health evaluation II (APACHE II) <25 or ≥25 and randomized by blocks of 2 and 4 to fluid resuscitation guidance by dynamic IVC or static CVP. Results Of 124 patients enrolled, 62 were randomized to each group, and one of each was excluded from mortality analysis. Baseline characteristics were comparable. The 30-day mortality rates between dynamic IVC vs. static CVP groups were not different (34.4% vs. 45.9%, p=0.196). Relative risk for 30-day mortality of dynamic IVC group was 0.8 (95%CI=0.5-1.2, p=0.201). Different outcomes were median (interquartile range) of shock duration (0.8 (0.4-1.6) vs. 1.5 (1.1-3.1) days, p=0.001) and norepinephrine (NE) dose (6.8 (3.9–17.8) vs. 16.1 (7.6–53.6) milligrams, p=0.008 and 0.1 (0.1-0.3) vs. 0.3 (0.1-0.8) milligram⋅kilogram −1 , p=0.017). Others were not different. Conclusions Dynamic IVC-guided fluid resuscitation does not affect mortality of septic patients. However, this may reduce shock duration and NE dose, compared with static CVP guidance. READ ALL READ LESS Keywords sepsis, dynamic parameter, static parameter, ultrasound, fluid resuscitation, mortality, norepinephrine, shock duration Corresponding Author(s) Thiti Sricharoenchai ( [email protected] ) Close Corresponding author: Thiti Sricharoenchai Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2024 Sricharoenchai T and Saisirivechakun P. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Sricharoenchai T and Saisirivechakun P. Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.12688/f1000research.147875.2 ) First published: 22 May 2024, 13 :528 ( https://doi.org/10.12688/f1000research.147875.1 ) Latest published: 25 Jul 2024, 13 :528 ( https://doi.org/10.12688/f1000research.147875.2 ) Revised Amendments from Version 1 This version added more explanations and discussions about the following issues: sample size estimation from 24% difference in mortality rate between two groups; rationale and evidence to select a CVP at 8 mmHg as a single cut-off point for assessment of fluid responsiveness regardless of mechanical ventilation support in the static CVP group; calculations for conversion of the accumulated dose of norepinephrine from microgram/kg/min (microgram⋅kg −1 ⋅min −1 ) to mg and mg per kg; the details of total fluid volume administered in the first 72 hours, and the relationship between total fluid volume in the first 72 hours vs. accumulated dose of norepinephrine, and vs. duration of shock. This version added more explanations and discussions about the following issues: sample size estimation from 24% difference in mortality rate between two groups; rationale and evidence to select a CVP at 8 mmHg as a single cut-off point for assessment of fluid responsiveness regardless of mechanical ventilation support in the static CVP group; calculations for conversion of the accumulated dose of norepinephrine from microgram/kg/min (microgram⋅kg −1 ⋅min −1 ) to mg and mg per kg; the details of total fluid volume administered in the first 72 hours, and the relationship between total fluid volume in the first 72 hours vs. accumulated dose of norepinephrine, and vs. duration of shock. See the authors' detailed response to the review by Surat Tongyoo See the authors' detailed response to the review by Jhuma Sankar READ REVIEWER RESPONSES Trial registration TCTR20160808002 in Thai Clinical Trials Registry ( https://www.thaiclinicaltrials.org/export/pdf/TCTR20160808002 ), Prospectively registered on 3 rd August 2016. List of abbreviations 95%CI 95% confidence interval APACHE II acute physiologic and chronic health evaluation II BMI body mass index BW body weight cIVC inferior vena cava collapsibility index CI confidence interval cm centimeters CONSORT Consolidated Standards of Reporting Trials CVP central venous pressure dIVC inferior vena cava distensibility index Dmax maximum diameter Dmin minimum diameter e.g. exempli gratia (for example) et al. et alia (and others) etc. et cetera (and so forth) ETT endotracheal intubation F/U follow-up h hour(s) ICU intensive care unit i.e. id est (that is) IQR interquartile range IVC inferior vena cava kg kilogram(s) kg⋅m −2 kilogram(s) per square meter KUB kidney-ureter-bladder L liter(s) LOS length of stay MAP mean arterial pressure min minute(s) mg milligram(s) mg⋅kg −1 milligram(s) per kilogram mL milliliter(s) mL⋅kg −1 milliliter(s) per kilogram mL⋅kg −1 ⋅h −1 milliliter(s) per kilogram per hour mmHg millimeters of mercury mmol⋅L −1 millimole(s) per liter MV mechanical ventilation n number NaCl sodium chloride NE norepinephrine p p-value qSOFA quick Sequential (Sepsis-Related) Organ Failure Assessment Score SBP systolic blood pressure ScvO 2 central venous oxygen saturation SD standard deviation SOFA Sequential (Sepsis-Related) Organ Failure Assessment Score SSC Surviving Sepsis Campaign Guidelines US ultrasound vs. versus Introduction Sepsis and septic shock potentially cause high mortality and burden for patients and health care system. 1 , 2 Rivers, et al. introduced early goal-directed therapy as the mainstay treatment of sepsis, which has been able to reduce the mortality rate of patients with sepsis or septic shock for more than two decades. 3 The Surviving Sepsis Campaign Bundle 2018 Update recommends to initiate rapid administration of intravenous crystalloid solution, at least 30 milliliters per kilogram (mL⋅kg −1 ), in the first hour for resuscitation in the early phase of sepsis 4 because most patients with sepsis are affected by hypovolemic status. Adequate cardiac preload is an essential component for hemodynamic restoration in patients with sepsis. Nevertheless, excessive fluid resuscitation may occur and harm patients with sepsis. 5 – 11 Several physiologic studies have shown that dynamic variables, e.g., pulse pressure variation, 12 , 13 stroke volume variation, 14 – 16 respiratory change in aortic blood velocity, 17 , 18 vena cava diameter variation, 19 – 22 etc. were more accurate for assessment of fluid responsiveness, 23 while systematic reviews found that static central venous pressure (CVP) was not highly reliable for assessment of fluid responsiveness. 24 , 25 Surviving Sepsis Campaign Guidelines 2016 suggest using dynamic variables over static variables to guide fluid resuscitation, 26 but currently, dynamic variables are not yet standard for prediction of fluid responsiveness. This study aimed to determine the effects of dynamic inferior vena cava (IVC)-guided versus static CVP-guided fluid resuscitation in patients with sepsis on mortality and other clinical outcomes, i.e., targets of resuscitation, duration of shock, amount of fluid and vasopressor administration, invasive respiratory support, length of stay (LOS) in hospital and intensive care unit (ICU), and adverse events. Methods Study design, setting and participant selection This was a single-blind randomized controlled trial conducted at the emergency department, general medical wards and medical ICU of Thammasat University Hospital (TUH) between August 2016 and April 2020. The patients were screened if they met all of the following criteria: 1. age of 15 years or more; 2. clinical suspicion of infection with quick Sequential (Sepsis-Related) Organ Failure Assessment Score (qSOFA) of 2 or more 27 ; 3. evidence of organ dysfunction shown by Sequential (Sepsis-Related) Organ Failure Assessment Score (SOFA) of 2 or more 27 ; 4. unstable hemodynamics (systolic blood pressure (SBP) 40 mmHg from baseline or mean arterial pressure (MAP) <70 mmHg) for 6 hours (h) or less; 5. fluid resuscitation required for unstable hemodynamics. The exclusion criteria were one or more of the following: 1. pregnant women; 2. cardiogenic pulmonary edema; 3. inability to lie down (e.g., scoliosis); 4. limited measurement of IVC diameter by ultrasound (US) (e.g., abdominal mass compressing IVC); 5. difficulty in performing central venous catheterization or CVP measurement (e.g., superior vena cava obstruction). The eligible patients who had given consent were included in the study. PS recruited and stratified patients by acute physiologic and chronic health evaluation II (APACHE II) of <25 or ≥25, then randomized them by blocks of 2 and 4 using sealed envelope TM program, to either measure IVC diameter variation by US or measure static CVP by central venous catheter and transducer in a ratio of 1:1, in order to guide fluid resuscitation. The allocation sequences in sealed envelopes were disclosed one by one when each patient was randomized. The process of fluid resuscitation guidance was covered from each patient by a screen. Intervention Static CVP measurement group The patients in the static CVP measurement group received central venous catheterization at right or left internal jugular vein by attending physicians. The first CVP measurement was done at the beginning of the study: CVP <8 mmHg and ≥8 mmHg were considered as fluid responsiveness and fluid non-responsiveness, respectively. 33 Fluid-responsive patients were resuscitated by crystalloid solution (mostly 0.9% sodium chloride (NaCl) solution) 500 milliliters (mL) in 15 minutes (min), then CVP was measured repeatedly. Continuous fluid resuscitations and CVP measurements were performed alternately in the same manner until fluid non-responsiveness occurred (i.e., CVP ≥8 mmHg). The CVP of ≥8 mmHg was selected for fluid non-responsiveness because this value was recommended by Surviving Sepsis Campaign Guidelines 2012 28 regardless of mechanical ventilation support, and the familiarity of attending physicians in TUH to use this CVP cut-off point for assessment of fluid responsiveness. Then patients with MAP <65 mmHg and fluid non-responsiveness received vasopressor(s) and/or inotropic agent(s) according to Surviving Sepsis Campaign Guidelines 2012, 28 intensive monitoring for 6 h, and were followed until shock recovery (i.e., MAP ≥65 mmHg and adequate tissue perfusion without vasopressor(s)), transfer or death within 30 days. Regardless of whether patients recovered from septic shock, they would receive a standard of care from TUH until discharge, transfer or death. Dynamic IVC measurement group The patients in the dynamic IVC measurement group were divided into 2 subgroups: mechanically ventilated and spontaneously breathing. The US probe was placed subcostally in order to measure the IVC diameter at 3-4 centimeters (cm) from the IVC-right atrium junction 29 as Figure 1 . while the patient was in a supine position. The first measurement of respiratory IVC diameter variation by US was done at the beginning of the study in both subgroups. Mechanically ventilated patients were measured for IVC distensibility index ((maximum diameter – minimum diameter)*100%/minimum diameter, (Dmax-Dmin)*100%/Dmin) with ≥18% and <18% considered as fluid responsiveness, and fluid non-responsiveness, respectively. 30 The maximum IVC diameter and minimum IVC diameter occurred during inspiration and expiration, respectively, in mechanically ventilated patients. Spontaneously breathing patients were measured for IVC collapsibility index ((Dmax-Dmin)*100%/Dmax) with ≥50% and <50% considered as fluid responsiveness, and fluid non-responsiveness, respectively. 31 In contrast, the maximum IVC diameter and minimum IVC diameter occurred during expiration and inspiration, respectively, for spontaneously breathing patients. Respiratory variation of IVC diameter measurement by US was used in this study because of feasibility and availability of US in our hospital settings. The measurement of respiratory variation of IVC diameter using US was performed by PS after training with 30 patients for 2 weeks and supervised by an intensivist. Dynamic IVC diameter measurement was done by using a LOGIQ C5 Premium Ultrasound Machine (GE Healthcare, Chicago, Illinois, USA). Sedative agents (midazolam and/or fentanyl) and neuromuscular blocking agents (atracurium or cisatracurium) were possibly administered in some mechanically ventilated patients to minimize respiratory effort, and maximize the validity of IVC distensibility index. Fluid-responsive patients were resuscitated continuously by crystalloid solution (also mostly 0.9% NaCl solution) 500 mL in 15 min, and IVC distensibility index or IVC collapsibility index measurements were done repeatedly and alternately until fluid non-responsiveness was achieved (i.e., IVC distensibility index <18% or IVC collapsibility index <50%) in the same way as the static CVP measurement group. The vasopressor(s) and inotropic agent(s) administration, including other treatment, monitoring and follow-up processes after the patients meeting fluid non-responsiveness until discharge, transfer or death within 30 days were similar to those of the static CVP measurement group. The flow diagram of study protocol is shown in Figure 2 . Figure 1. Ultrasonographic findings of IVC diameter measurement a . Abbreviation: IVC, inferior vena cava. a The photo was taken by TS and was not used or previously published in any journal before. Figure 2. Flow diagram of study protocol. Abbreviations: APACHE II, acute physiologic and chronic health evaluation II; cIVC, inferior vena cava collapsibility index; CVP, central venous pressure; dIVC, inferior vena cava distensibility index; F/U, follow-up; h, hours; IV, intravenous; IVC, inferior vena cava; L, liter; MAP, mean arterial pressure; min, minutes; mmHg, millimeters of mercury; SSC, Surviving Sepsis Campaign Guidelines. Data collection and outcome measures The patients’ data were recorded for baseline clinical characteristics (i.e., sex, age, weight, height, comorbidities), characteristics of sepsis (i.e., vital signs, confirmed or suspected source of infection, APACHE II at time of diagnosis), ICU admission, outcomes (i.e., survival status at 30 days after participation in the study, macrovascular targets (MAP, urine output) and microvascular targets (central venous oxygen saturation (ScvO 2 ), serum lactate) at time of diagnosis of sepsis and 6 h later, time of treatment initiation and MAP ≥65 mmHg with adequate tissue perfusion, total volume of fluid administration in first 72 h of sepsis, accumulated dose of norepinephrine (NE), status of endotracheal intubation (ETT) with mechanical ventilation (MV) throughout study period, dates of initiation and termination of MV, dates of hospital admission and discharge, dates of ICU admission and discharge), and adverse events (i.e., fluid overload and pneumothorax in 30 days after participation in the study). The primary outcome was the 30-day mortality of patients; those who were discharged or transferred to other hospitals before 30 days were tracked for survival status at 30 days by telephone. The secondary outcomes were achievements of macrovascular targets (MAP ≥65 mmHg, urine output ≥0.5 milliliter(s) per kilogram per hour (mL⋅kg −1 ⋅h −1 )) and microvascular targets (ScvO 2 ≥70%, lactate clearance ≥10%) in the first 6 h, 32 duration of shock (time from treatment initiation to MAP ≥65 mmHg and adequate tissue perfusion), total volume of fluid administration and total volume of fluid administration per kilogram (kg) of body weight (BW) in the first 72 h, accumulated dose of NE and accumulated dose of NE per kg of BW, ETT with MV, MV duration, hospital LOS, ICU LOS and adverse events. The accumulated dose of NE of each patient was converted to mg and mg per kg as follows: 1) mg was calculated by the rate of NE (microgram⋅kg −1 ⋅min −1 ) multiplied by the body weight (kg) and the duration of NE administration (min), then divided by 1,000; 2) mg per kg was calculated by the rate of NE (microgram⋅kg −1 ⋅min −1 ) multiplied by the duration of NE administration (min), then divided by 1,000. The clinical outcomes were selected based on feasibility and standard practice of TUH. Statistical analysis The sample size was estimated to be 122 patients (61 for each group) for the detection of 24% difference in 30-day mortality rate between the two intervention groups 33 with an alpha of 0.05 and a power of 80%. Interim analysis of efficacy was performed when the number of patients were recruited up to 50% of sample size. The trial would be terminated if 30-day mortality rates between two intervention groups were extremely different (Haybittle-Peto boundary with an alpha level of 0.002). Baseline clinical characteristics, primary and secondary outcomes were analyzed by descriptive statistics for all patients and each intervention group. Categorical variables were shown as proportion (percentage), and continuous variables were shown as mean ± standard deviation (SD) or median (interquartile range, IQR) as appropriate. Data of each intervention group were compared using Chi-square test for categorical variables, and using Independent two-sample t-test for normally distributed continuous variables or Mann-Whitney U test for non-normally distributed continuous variables. Univariable relative risk regression or univariable Poisson regression analysis was performed for binary outcomes to obtain the relative risk of dynamic IVC measurement-guided fluid resuscitation for each outcome, compared with static CVP measurement-guided fluid resuscitation. The 2-sided p-value (p) <0.05 was considered as statistical significance for comparison between the two groups and regression analysis. All data were analyzed using Stata SE , version 14.0 (StataCorp, College Station, Texas, USA), of which copyright license has been held by the Faculty of Medicine, Thammasat University. An open-access alternative software for statistical analysis is RStudio, which is available from https://posit.co/download/rstudio-desktop/ . Ethical considerations This study was conducted in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving human subjects. Ethics approval for research conduct, documentation of consent from each patient or their representative and information sheet was provided by the Human Research Ethics Committee of Thammasat University (Medicine) (Approval number: 127/2559) on 15 th July 2016. A written informed consent for the study was obtained from each patient or their legally authorized representative. No identifiable data of individual persons are presented. Consent for publication was a part of written informed consent for the study, which declared that no identifiable data of individual persons are presented. Results A total of 995 patients with sepsis or septic shock treated at the emergency department or medical wards in TUH between August 2016 and April 2020 were screened for eligibility, and 124 patients were included. After stratification by APACHE II of <25 or ≥25, 62 patients were randomized into each intervention group. Individual patients were followed until shock recovery, transfer or death within 30 days. One patient in the dynamic IVC measurement group withdrew after randomization because of discomfort for data collection, leaving 123 patients included in the modified intention-to-treat analysis. One additional patient in the static CVP measurement group was excluded from analysis for the 30-day mortality because they were referred to another hospital and their survival status could not be tracked. The study process from enrollment to analysis is shown as a Consolidated Standards of Reporting Trials (CONSORT) flow diagram in Figure 3 . The study was ended after completion of patient recruitment and follow-up. Figure 3. CONSORT flow diagram of study. Abbreviations: APACHE II, acute physiologic and chronic health evaluation II; CONSORT, Consolidated Standards of Reporting Trials; CVP, central venous pressure; IVC, inferior vena cava. *One patient withdrew informed consent because of discomfort for data collection. **One patient was transferred to other hospital on the same day of enrollment in the study, and their survival status at 30 days could not be tracked. The baseline characteristics and severity of sepsis, including ICU admission, were not significantly different between the two intervention groups, as shown in Table 1 . Of 111 patients (90.2%) who required NE, the number of patients in the dynamic IVC measurement group (52, 85.3%) was lower than that in the static CVP measurement group (59, 95.2%), but not statistically different (p = 0.064). The primary outcome and most secondary outcomes were not significantly different between both groups, i.e., mortality rates in 30 days, achievement of macrovascular target(s) (MAP ≥65 mmHg or urine output ≥0.5 mL⋅kg −1 ⋅h −1 or both) in 6 h or achievement of microvascular target(s) (ScvO 2 ≥70% or lactate clearance ≥10% or both) in 6 h, as well as total volume of fluid and total volume of fluid per kg of BW administered in the first 72 h of sepsis, ETT with MV, duration of MV, hospital LOS and ICU LOS. However, the dynamic IVC measurement group demonstrated significantly shorter median (IQR) duration of shock, considerably lower median (IQR) accumulated dose of NE and lower median (IQR) accumulated dose of NE per kg of BW. Given that majorities of both groups had durations of shock <72 h, total fluid volume and total fluid volume per kg of BW administered in the first 72 h included the volume of fluid during the shock period and after the resolution of shock until 72 h in most patients. Rates of adverse events were not different between the two intervention groups. All outcomes in detail are shown in Table 2 . Thirty-day mortality rates and significantly different secondary outcomes (i.e., duration of shock, accumulated dose of NE and accumulated dose of NE per kg of BW) are presented in Extended data Figure S1., S2., S3. and S4. All findings were based on analyses of the dataset from this study. 34 Table 1. Baseline characteristics of patients. Characteristics All patients (n = 123) Dynamic IVC measurement (n = 61) Static CVP measurement (n = 62) Age (years) 72.0 (61.0 – 80.0) 74.0 (64.0 – 81.0) 68.5 (55.0 – 78.0) Male, n (%) 66 (53.7) 32 (52.5) 34 (54.8) Height (cm) 160.8 (±8.0) 160.8 (±8.7) 160.9 (±7.4) Weight (kg) 57 (50 – 60) 54 (50 – 60) 60 (50 – 61) BMI (kg⋅m −2 ) 22.0 (19.5 – 24.0) 21.4 (19.5 – 23.9) 22.3 (20.3 – 24.0) qSOFA 2.4 (±0.5) 2.4 (±0.5) 2.3 (±0.5) Initial SOFA 7.7 (±3.7) 6.9 (±3.2) 8.4 (±4.0) APACHE II score 23 (20 – 29) 23 (17 – 28) 24 (20 – 30) Initial MAP (mmHg) 60 (53 – 72) 60 (51 – 70) 60 (53 – 73) Initial MAP <65 mmHg, n (%) 72 (58.5) 39 (63.9) 33 (53.2) Initial ScvO 2 (%) a 70.1 (±10.9) 70.7 (±11.3) 69.8 (±10.7) Initial lactate (mmol⋅L −1 ) 3.3 (1.9 – 6.3) 3.0 (1.8 – 5.2) 4.1 (2.1 – 7.0) Comorbidities, n (%) Diabetes mellitus 47 (38.2) 20 (32.8) 27 (43.6) Hypertension 72 (58.5) 31 (50.8) 41 (66.1) Coronary artery disease 15 (12.2) 7 (11.5) 8 (12.9) Cerebrovascular disease 25 (20.3) 11 (18.0) 14 (22.6) Chronic obstructive pulmonary disease 6 (4.9) 4 (6.6) 2 (3.2) Chronic kidney disease 17 (13.8) 6 (9.8) 11 (17.7) Source of infection, n (%) Respiratory system 47 (38.2) 19 (31.2) 28 (45.2) Abdomen 28 (22.8) 19 (31.2) 9 (14.5) KUB system 23 (18.7) 13 (21.3) 10 (16.1) Skin & soft tissue 8 (6.5) 5 (8.2) 3 (4.8) Neurological system 1 (0.8) 0 (0.0) 1 (1.6) Systemic infection 4 (3.3) 1 (1.6) 3 (4.8) Musculoskeletal system 1 (0.8) 1 (1.6) 0 (0.0) Other sources 1 (0.8) 0 (0.0) 1 (1.6) Unknown source 10 (8.1) 3 (4.9) 7 (11.3) ICU admission, n (%) 34 (27.6) 17 (27.9) 17 (27.4) a This characteristic was analyzed from 101 patients (39 in Dynamic IVC measurement group, and 62 in Static CVP measurement group) who received central venous catheterization. Table 2. Clinical outcomes of patients. Outcomes All patients (n = 123) Dynamic IVC measurement (n = 61) Static CVP measurement (n = 62) p-value Relative risk (95%CI) p-value Primary outcome 30-day mortality a , n (%) 49 (40.2) 21 (34.4) 28 (45.9) 0.196 $ 0.8 (0.5 – 1.2) 0.201 α Secondary outcomes Macrovascular target(s) achievement in 6 h MAP ≥65 mmHg, n (%) 111 (90.2) 54 (88.5) 57 (91.9) 0.524 $ 1.0 (0.7 – 1.4) 0.842 β MAP (mmHg) 77.9 (±10.9) 78.6 (±11.7) 77.3 (±10.2) 0.528 @ Urine ≥0.5 mL⋅kg -1 ⋅h -1 , n (%) 83 (67.5) 43 (70.5) 40 (64.5) 0.479 $ 1.1 (0.9 – 1.4) 0.480 α Urine (mL⋅kg -1 ⋅h -1 ) 0.8 (0.3 – 1.5) 0.8 (0.4 – 1.6) 0.8 (0.2 – 1.4) 0.345 # ≥1 target, n (%) 117 (95.1) 58 (95.1) 59 (95.2) 0.984 $ 1.0 (0.7 – 1.4) 0.996 β 2 targets, n (%) 77 (62.6) 39 (63.9) 38 (61.3) 0.762 $ 1.0 (0.8 – 1.4) 0.762 α Microvascular target(s) achievement in 6 h ScvO 2 ≥70% b , n (%) 67 (66.3) 30 (76.9) 37 (59.7) 0.074 $ 1.3 (1.0 – 1.7) 0.063 α ScvO 2 (%) b 73.2 (±9.4) 75.2 (±8.1) 72.0 (±9.9) 0.090 @ Lactate clearance ≥10%, n (%) 73 (59.4) 36 (59.0) 37 (59.7) 0.941 $ 1.0 (0.7 – 1.3) 0.941 α Lactate clearance (%) 15.7 (0.0 – 41.3) 14.3 ((-11.1) – 41.0) 19.0 (0.0 – 41.3) 0.962 # ≥1 target c , n (%) 102 (89.5) 49 (94.2) 53 (85.5) 0.130 $ 1.1 (0.7 – 1.6) 0.623 β 2 targets d , n (%) 38 (34.6) 17 (35.4) 21 (33.9) 0.866 $ 1.0 (0.6 – 1.8) 0.866 α Other outcomes Total fluid volume in first 72 h (mL) e 8,599.5 (±2,899.2) 8,327.3 (±2,968.7) 8,929.4 (±2,822.5) 0.381 @ Total fluid volume per kg of BW in first 72 h (mL⋅kg -1 ) e 154.8 (±59.9) 154.3 (±61.8) 155.5 (±58.4) 0.934 @ Duration of shock (days) e 1.3 (0.7 – 2.4) 0.8 (0.4 – 1.6) 1.5 (1.1 – 3.1) 0.001 # * Accumulated dose of NE (mg) f 10.8 (5.6 – 27.1) 6.8 (3.9 – 17.8) 16.1 (7.6 – 53.6) 0.008 # * Accumulated dose of NE per kg of BW (mg⋅kg -1 ) f 0.2 (0.1 – 0.6) 0.1 (0.1 – 0.3) 0.3 (0.1 – 0.8) 0.017 # * ETT with MV, n (%) 75 (61.0) 33 (54.1) 42 (67.7) 0.121 $ 0.8 (0.6 – 1.1) 0.126 α Duration of MV (days) g 7.5 (3.0 – 34.5) 5.0 (3.0 – 27.0) 16.0 (4.0 – 44.0) 0.190 # Hospital LOS (days) e 18.0 (9.0 – 44.0) 16.5 (6.5 – 36.5) 23.0 (11.0 – 51.0) 0.097 # ICU LOS (days) h 12.5 (6.0 – 33.0) 7.5 (5.5 – 30.0) 20.5 (8.0 – 49.0) 0.291 # Adverse events Fluid overload, n (%) 17 (13.8) 6 (9.8) 11 (17.7) 0.204 $ 0.6 (0.2 – 1.4) 0.214 α Pneumothorax, n (%) 0 (0) 0 (0) 0 (0) - - - $ Chi-square test. @ Independent two-sample t-test. # Mann-Whitney U test. α Relative risk regression. β Poisson regression. * Statistically significant different. a This outcome was analyzed from 122 patients (61 in Dynamic IVC measurement group, and 61 in Static CVP measurement group) because one patient in static CVP group was transferred to other hospital and their survival status at 30 days could not be tracked. b This outcome was analyzed from 101 patients who received central venous catheterization (39 in Dynamic IVC measurement group, and 62 in Static CVP measurement group). c This outcome was analyzed from 114 patients who can be assessed for achievement of ≥1 microvascular target in 6 hours (52 in Dynamic IVC measurement group, and 62 in Static CVP measurement group). d This outcome was analyzed from 110 patients who can be assessed for achievement of 2 microvascular targets in 6 hours (48 in Dynamic IVC measurement group, and 62 in Static CVP measurement group). e These outcomes were analyzed from 73 survived patients (40 in Dynamic IVC measurement group, and 33 in Static CVP measurement group). f These outcomes were analyzed from 65 survived patients who required norepinephrine (33 in Dynamic IVC measurement group, and 32 in Static CVP measurement group). g This outcome was analyzed from 32 survived patients who required endotracheal intubation and mechanical ventilation (15 in Dynamic IVC measurement group, and 17 in Static CVP measurement group). h This outcome was analyzed from 22 survived patients who were admitted to ICU (12 in Dynamic IVC measurement group, and 10 in Static CVP measurement group). Discussion Our study showed that the baseline characteristics were not different between the two intervention groups. The 30-day mortality rates were not different between both groups, nor were achievement of macrovascular and microvascular targets in 6 h, total volume of fluid administration and total volume of fluid administration per kg of BW in the first 72 h of sepsis, rate of ETT with MV, duration of MV, hospital LOS, ICU LOS and rates of adverse events. However, patients in the dynamic IVC measurement group experienced shorter duration of shock, lower accumulated dose of NE and lower accumulated dose of NE per kg of BW, compared with those in the static CVP measurement group. To our knowledge, this is the first study attempting to determine the clinical effects of fluid resuscitation guided by feasible and practical hemodynamic parameter for prediction of fluid responsiveness in patients with sepsis or septic shock in Thailand. There was no difference in the 30-day mortality rates between the two groups, which was consistent with the 28-day mortality rate of septic shock patients in a study from Richard, et al. 33 Although the 30-day mortality rates in the two groups were not statistically different, the percentage of mortality in the dynamic parameter group was somewhat lower (absolute difference about 10%) than in the static parameter group in our study, and was even considerably lower (absolute difference about 20%) in that study. 33 This may imply important clinical significance in certain clinical situations, especially for the disease with high prevalence like sepsis, because the absolute number of deaths would be magnified by the prevalence of the disease. The mortality rates (at 30 days, 35 , 36 90 days, 37 180 days, 35 and hospital mortality 38 ) of surgical ICU patients between fluid therapy guided by dynamic variables and standard care (fluid therapy guided by static variables or clinical examination) were also not different in other studies. However, a recent systematic review and meta-analysis including studies of critically ill adult patients requiring acute fluid resuscitation demonstrated that dynamic variable-guided fluid therapy decreased the mortality risk (risk ratio = 0.59, 95%CI = 0.42-0.83, p = 0.002) compared with standard care. 39 The difference between our findings and the systematic review findings in terms of mortality may be partially explained by the different types of patients and therefore different pathophysiologies of diseases. The majority of patients in our study were medical patients while most patients in that systematic review were surgical patients. Medical patients usually have more comorbidities, which poses a higher risk of complications and/or death, compared with surgical patients, and this factor may interfere with the effect of intervention on mortality. Shorter duration of shock and lower accumulated dose of NE (either total dose or total dose per kg of BW) in the dynamic IVC measurement group in our study suggests that dynamic IVC diameter variation may be able to predict fluid responsiveness better than static CVP value, so the patients received more adequate volume of fluid administration. This assumption corresponds to the study findings from Lanspa, et al., which showed that IVC collapsibility index threshold of ≥50% had a fair positive predictive value (75%) and a good negative predictive value (80%) for prediction of fluid responsiveness, although this did not reach statistical significance (p = 0.09). 31 Theoretically, patients with adequate fluid volume administration can likely maintain macrovascular and microvascular targets, and minimize duration of shock without excessive dose of vasopressors, resulting in fewer complications from prolonged shock or high dose of vasopressors. 40 – 42 However, patients in the dynamic IVC measurement group did not achieve more macrovascular or microvascular target(s) in 6 h than those in the other group in our study. The reason for this may be the fact that the timing of vasopressor initiation was not controlled because it was decided based on the individual attending physician’s discretion. Given that a higher proportion of patients who received vasopressor earlier could possibly restore macrovascular and microvascular targets as demonstrated in a study from Permpikul, et al. (CENSER trial), 43 this may confound the effect of fluid administration guidance method on achievement of macrovascular and microvascular targets. In our study, total fluid volume and total fluid volume per kg of BW administered in the first 72 h were not different between the two intervention groups, which was consistent with a study from Trof, et al. 44 but different from a study by Richard, et al. which showed lower daily intravenous fluid volume administration in a dynamic variable-guided fluid therapy group. 33 The reason for different findings can be partially explained by different time-frames of fluid administration and also different dynamic parameters guiding fluid resuscitation between our study and that study. 33 Moreover, our study protocol did not control fluid administration after shock recovery occurring within 72 h, which affected total fluid volume and total fluid volume per kg of BW in the first 72 h. Another study by Douglas, et al. demonstrated less positive fluid balance at 72 h or ICU discharge in septic patients who received dynamic stroke volume-guided fluid resuscitation, compared to those with standard usual care, 45 but this outcome cannot be directly compared to total fluid volume in 72 h of our study. Our study found no difference in rates of ETT and MV between the two intervention groups. This was a reasonable finding because indications of intubation and MV are broader than only unstable hemodynamics. Durations of MV were also not different between the two intervention groups in our study, which was the same as studies of Richard, et al., 33 Douglas, et al. 45 and Trof, et al., specifically for septic shock patients. 44 Hospital LOS in both intervention groups were not different, which was similar to some studies 35 , 45 – 47 but different from others (shorter hospital LOS in dynamic variable-guided fluid therapy group). 36 , 48 – 52 ICU LOS were not different between our two intervention groups, which also was consistent with several studies 33 , 37 , 45 , 46 , 49 but different from others. 47 , 51 , 52 The heterogeneous findings in hospital LOS and ICU LOS were likely caused by the different nature of diseases, given that most patients in these studies were various types of surgical patients, and there were specific indications for ICU admission for certain types of surgical patients (e.g., postoperative observation). There are some limitations in this study. Firstly, the sample size was quite small and possibly underpowered to be able to detect the differences of some secondary outcomes between the two intervention groups. The difference in mortality rate of 24% 33 for sample size estimation may be quite high, possibly resulting in inadequate sample size to detect the likely smaller difference in mortality rate in a real-life situation. A study with a larger sample size is warranted to clarify whether all outcomes are different. However, our sample size was comparable or even greater than other studies assessing the effects on clinical outcomes between dynamic and static hemodynamic parameters. 33 , 44 , 53 Second, treatment of sepsis for each patient was based on individual attending physicians, except for fluid resuscitation and intensive monitoring in the early phase of sepsis. This might have interfered with the effects of intervention, but clinical practices were standardized by following the Surviving Sepsis Campaign Guidelines 4 , 26 , 28 and standard of care at TUH under supervision of specialists. Third, the US measurement process of respiratory variation of IVC diameter is operator-dependent. Accordingly, all US measurements of IVC diameter variation were done by the same well-trained physician and the same US machine to eradicate interobserver variability and standardize the findings of US measurement. Fourth, the parameters for prediction of fluid responsiveness in our study were derived from right-sided cardiac preload, which indirectly reflects the variation of stroke volume or cardiac output of the left ventricle after fluid administration. Nevertheless, right-sided cardiac preload-derived parameters were selected based on availability and practicability. Fifth, the total fluid volume and total fluid volume per kg of BW administered in the first 72 h included the volume of fluid during and after shock period until 72 h in most patients, and the volume of fluid after shock resolution until 72 h was not controlled, therefore these parameters probably cannot indicate the efficacy of guidance methods for fluid resuscitation and may not be related to the accumulated dose of NE and duration of shock. Physicians should cautiously interpret the findings. Sixth, this was a single-center study, which may not be able to perfectly generalize the findings to other institutes or other hospitals. Physicians need to carefully consider the context of individual situations before adoption of our study findings for clinical practices. Strengths of this study include study design (randomized controlled trial), which could balance baseline characteristics and severity of sepsis in patients between the two intervention groups in order to minimize confounding factors affecting the outcomes, and feasibility for limited-resource hospitals. Conclusions Dynamic IVC measurement-guided fluid resuscitation in patients with sepsis or septic shock does not affect mortality, macrovascular and microvascular targets, volume of fluid administration, ETT with MV, duration of MV, hospital LOS, ICU LOS and adverse events. Nevertheless, such intervention may decrease the duration of shock and accumulated dose of NE, compared with static CVP measurement-guided fluid resuscitation. Author contributions Conceptualization: Sricharoenchai T. and Saisirivechakun P.; Data curation: Sricharoenchai T. and Saisirivechakun P.; Formal analysis: Sricharoenchai T. and Saisirivechakun P.; Investigation: Sricharoenchai T. and Saisirivechakun P.; Methodology: Sricharoenchai T. and Saisirivechakun P.; Project administration: Sricharoenchai T. and Saisirivechakun P.; Resources: Sricharoenchai T. and Saisirivechakun P.; Software: Sricharoenchai T. and Saisirivechakun P.; Supervision: Sricharoenchai T.; Validation: Sricharoenchai T.; Visualization: Sricharoenchai T. and Saisirivechakun P.; Writing − Original Draft Preparation: Sricharoenchai T.; Writing − Review & Editing: Sricharoenchai T. and Saisirivechakun P. Data availability statement Zenodo: Data for effects of dynamic vs. static parameter-guided fluid resuscitation in patients with sepsis, https://zenodo.org/records/10579408 or DOI: 10.5281/zenodo.10579407 . 34 This project contains the following underlying data: • Data for dynamic vs. static parameter-guided resuscitation in sepsis.dta (baseline characteristics and outcomes of patients with sepsis) Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Extended data Zenodo: Supplementary materials for effects of dynamic vs. static parameter-guided fluid resuscitation in patients with sepsis, https://zenodo.org/records/10594154 (Sricharoenchai 2024) or DOI: 10.5281/zenodo.10594153 . This project contains the following extended data: • Figure S1. Bar graphs showing the 30-day mortality rate. (30-day mortality rate between dynamic IVC measurement and static CVP measurement groups) • Figure S2. Box and whisker plots showing the median (IQR) duration of shock. (median (IQR) duration of shock between dynamic IVC measurement and static CVP measurement groups) • Figure S3. Box and whisker plots showing the median (IQR) accumulated dose of NE. (median (IQR) accumulated dose of NE between dynamic IVC measurement and static CVP measurement groups) • Figure S4. Box and whisker plots showing the median (IQR) accumulated dose of NE per kg of body weight. (median (IQR) accumulated dose of NE per kg of body weight between dynamic IVC measurement and static CVP measurement groups) Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Reporting guidelines Zenodo: A completed CONSORT 2010 checklist for Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial, https://zenodo.org/records/10597483 (Sricharoenchai 2024) or DOI: 10.5281/zenodo.10597239 . Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgments The authors would like to thank Nanthawan Okas (Department of Medicine, Faculty of Medicine, Thammasat University) for assistance with data collection, Assoc. Prof. Pattarin Pirompanich (Division of Pulmonary and Critical Care Medicine, Department of Medicine, Faculty of Medicine, Thammasat University) for training and supervising Pannarat Saisirivechakun to measure respiratory variation of IVC diameter by US, and Sam Ormond (Faculty of Medicine, Thammasat University) for improving the English language of this manuscript. Permission from each of those people in our acknowledgments has been granted. References 1. Angus DC, Linde-Zwirble WT, Lidicker J, et al. : Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 2001; 29 : 1303–1310. Publisher Full Text 2. Martin GS, Mannino DM, Eaton S, et al. : The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 2003; 348 : 1546–1554. PubMed Abstract | Publisher Full Text 3. Rivers E, Nguyen B, Havstad S, et al. : Early goal-directed therapy in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 2001; 345 : 1368–1377. Publisher Full Text 4. Levy MM, Evans LE, Rhodes A: The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018; 44 : 925–928. PubMed Abstract | Publisher Full Text 5. Marik PE, Linde-Zwirble WT, Bittner EA, et al. : Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med. 2017; 43 : 625–632. PubMed Abstract | Publisher Full Text 6. Acheampong A, Vincent JL: A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit. Care. 2015; 19 : 251. PubMed Abstract | Publisher Full Text | Free Full Text 7. Brotfain E, Koyfman L, Toledano R, et al. : Positive fluid balance as a major predictor of clinical outcome of patients with sepsis/septic shock after ICU discharge. Am. J. Emerg. Med. 2016; 34 : 2122–2126. PubMed Abstract | Publisher Full Text 8. Mitchell KH, Carlbom D, Caldwell E, et al. : Volume Overload: Prevalence, Risk Factors, and Functional Outcome in Survivors of Septic Shock. Ann. Am. Thorac. Soc. 2015; 12 : 1837–1844. PubMed Abstract | Publisher Full Text | Free Full Text 9. de Oliveira FS, Freitas FG, Ferreira EM, et al. : Positive fluid balance as a prognostic factor for mortality and acute kidney injury in severe sepsis and septic shock. J. Crit. Care. 2015; 30 : 97–101. PubMed Abstract | Publisher Full Text 10. Vincent JL, Sakr Y, Sprung CL, et al. : Sepsis in European intensive care units: results of the SOAP study. Crit. Care Med. 2006; 34 : 344–353. PubMed Abstract | Publisher Full Text 11. Boyd JH, Forbes J, Nakada TA, et al. : Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit. Care Med. 2011; 39 : 259–265. PubMed Abstract | Publisher Full Text 12. De Backer D, Heenen S, Piagnerelli M, et al. : Pulse pressure variations to predict fluid responsiveness: influence of tidal volume. Intensive Care Med. 2005; 31 : 517–523. PubMed Abstract | Publisher Full Text 13. Michard F, Boussat S, Chemla D, et al. : Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure. Am. J. Respir. Crit. Care Med. 2000; 162 : 134–138. PubMed Abstract | Publisher Full Text 14. Cannesson M, Musard H, Desebbe O, et al. : The ability of stroke volume variations obtained with Vigileo/FloTrac system to monitor fluid responsiveness in mechanically ventilated patients. Anesth. Analg. 2009; 108 : 513–517. PubMed Abstract | Publisher Full Text 15. Marx G, Cope T, McCrossan L, et al. : Assessing fluid responsiveness by stroke volume variation in mechanically ventilated patients with severe sepsis. Eur. J. Anaesthesiol. 2004; 21 : 132–138. Publisher Full Text 16. Hofer CK, Senn A, Weibel L, et al. : Assessment of stroke volume variation for prediction of fluid responsiveness using the modified FloTrac and PiCCOplus system. Crit. Care. 2008; 12 : R82. PubMed Abstract | Publisher Full Text | Free Full Text 17. Monnet X, Rienzo M, Osman D, et al. : Esophageal Doppler monitoring predicts fluid responsiveness in critically ill ventilated patients. Intensive Care Med. 2005; 31 : 1195–1201. PubMed Abstract | Publisher Full Text 18. Feissel M, Michard F, Mangin I, et al. : Respiratory changes in aortic blood velocity as an indicator of fluid responsiveness in ventilated patients with septic shock. Chest. 2001; 119 : 867–873. PubMed Abstract | Publisher Full Text 19. Feissel M, Michard F, Faller JP, et al. : The respiratory variation in inferior vena cava diameter as a guide to fluid therapy. Intensive Care Med. 2004; 30 : 1834–1837. PubMed Abstract | Publisher Full Text 20. Vieillard-Baron A, Chergui K, Rabiller A, et al. : Superior vena caval collapsibility as a gauge of volume status in ventilated septic patients. Intensive Care Med. 2004; 30 : 1734–1739. PubMed Abstract | Publisher Full Text 21. Moretti R, Pizzi B: Inferior vena cava distensibility as a predictor of fluid responsiveness in patients with subarachnoid hemorrhage. Neurocrit. Care. 2010; 13 : 3–9. PubMed Abstract | Publisher Full Text 22. Wang Y, Jiang Y, Wu H, et al. : Assessment of fluid responsiveness by inferior vena cava diameter variation in post-pneumonectomy patients. Echocardiography. 2018; 35 : 1922–1925. PubMed Abstract | Publisher Full Text | Free Full Text 23. Michard F, Teboul JL: Predicting fluid responsiveness in ICU patients: a critical analysis of the evidence. Chest. 2002; 121 : 2000–2008. Publisher Full Text 24. Marik PE, Cavallazzi R: Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit. Care Med. 2013; 41 : 1774–1781. PubMed Abstract | Publisher Full Text 25. Eskesen TG, Wetterslev M, Perner A: Systematic review including re-analyses of 1148 individual data sets of central venous pressure as a predictor of fluid responsiveness. Intensive Care Med. 2016; 42 : 324–332. PubMed Abstract | Publisher Full Text 26. Rhodes A, Evans LE, Alhazzani W, et al. : Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017; 43 : 304–377. PubMed Abstract | Publisher Full Text 27. Singer M, Deutschman CS, Seymour CW, et al. : The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315 : 801–810. PubMed Abstract | Publisher Full Text | Free Full Text 28. Dellinger RP, Levy MM, Rhodes A, et al. : Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013; 39 : 165–228. PubMed Abstract | Publisher Full Text | Free Full Text 29. Preau S, Bortolotti P, Colling D, et al. : Diagnostic Accuracy of the Inferior Vena Cava Collapsibility to Predict Fluid Responsiveness in Spontaneously Breathing Patients With Sepsis and Acute Circulatory Failure. Crit. Care Med. 2017; 45 : e290–e297. PubMed Abstract | Publisher Full Text 30. Barbier C, Loubieres Y, Schmit C, et al. : Respiratory changes in inferior vena cava diameter are helpful in predicting fluid responsiveness in ventilated septic patients. Intensive Care Med. 2004; 30 : 1740–1746. PubMed Abstract | Publisher Full Text 31. Lanspa MJ, Grissom CK, Hirshberg EL, et al. : Applying dynamic parameters to predict hemodynamic response to volume expansion in spontaneously breathing patients with septic shock. Shock. 2013; 39 : 155–160. PubMed Abstract | Publisher Full Text | Free Full Text 32. Arnold RC, Shapiro NI, Jones AE, et al. : Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock. 2009; 32 : 35–39. PubMed Abstract | Publisher Full Text 33. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19 : 5. PubMed Abstract | Publisher Full Text | Free Full Text 34. Sricharoenchai T, Saisirivechakun P: Data for effects of dynamic vs. static parameter-guided fluid resuscitation in patients with sepsis. Pathum Thani, Thailand: Thammasat University; 2024. [cited 31 Jan 2024]. Reference Source 35. Pearse RM, Harrison DA, MacDonald N, et al. : Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review. JAMA. 2014; 311 : 2181–2190. PubMed Abstract | Publisher Full Text 36. Colantonio L, Claroni C, Fabrizi L, et al. : A randomized trial of goal directed vs. standard fluid therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. J. Gastrointest. Surg. 2015; 19 : 722–729. PubMed Abstract | Publisher Full Text 37. Parke RL, McGuinness SP, Gilder E, et al. : A randomised feasibility study to assess a novel strategy to rationalise fluid in patients after cardiac surgery. Br. J. Anaesth. 2015; 115 : 45–52. PubMed Abstract | Publisher Full Text 38. Jhanji S, Vivian-Smith A, Lucena-Amaro S, et al. : Haemodynamic optimisation improves tissue microvascular flow and oxygenation after major surgery: a randomised controlled trial. Crit. Care. 2010; 14 : R151. PubMed Abstract | Publisher Full Text | Free Full Text 39. Bednarczyk JM, Fridfinnson JA, Kumar A, et al. : Incorporating Dynamic Assessment of Fluid Responsiveness Into Goal-Directed Therapy: A Systematic Review and Meta-Analysis. Crit. Care Med. 2017; 45 : 1538–1545. PubMed Abstract | Publisher Full Text | Free Full Text 40. Balis JU, Rappaport ES, Gerber L, et al. : A primate model for prolonged endotoxin shock. Blood-vascular reactions and effects of glucocorticoid treatment. Lab. Investig. 1978; 38 : 511–523. PubMed Abstract 41. Hollenberg SM: Vasoactive drugs in circulatory shock. Am. J. Respir. Crit. Care Med. 2011; 183 : 847–855. Publisher Full Text 42. Auchet T, Regnier MA, Girerd N, et al. : Outcome of patients with septic shock and high-dose vasopressor therapy. Ann. Intensive Care. 2017; 7 : 43. PubMed Abstract | Publisher Full Text | Free Full Text 43. Permpikul C, Tongyoo S, Viarasilpa T, et al. : Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am. J. Respir. Crit. Care Med. 2019; 199 : 1097–1105. PubMed Abstract | Publisher Full Text 44. Trof RJ, Beishuizen A, Cornet AD, et al. : Volume-limited versus pressure-limited hemodynamic management in septic and nonseptic shock. Crit. Care Med. 2012; 40 : 1177–1185. PubMed Abstract | Publisher Full Text 45. Douglas IS, Alapat PM, Corl KA, et al. : Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial. Chest. 2020; 158 : 1431–1445. PubMed Abstract | Publisher Full Text | Free Full Text 46. Buettner M, Schummer W, Huettemann E, et al. : Influence of systolic-pressure-variation-guided intraoperative fluid management on organ function and oxygen transport. Br. J. Anaesth. 2008; 101 : 194–199. PubMed Abstract | Publisher Full Text 47. Kumar L, Rajan S, Baalachandran R: Outcomes associated with stroke volume variation versus central venous pressure guided fluid replacements during major abdominal surgery. J. Anaesthesiol. Clin. Pharmacol. 2016; 32 : 182–186. PubMed Abstract | Publisher Full Text | Free Full Text 48. Lopes MR, Oliveira MA, Pereira VO, et al. : Goal-directed fluid management based on pulse pressure variation monitoring during high-risk surgery: a pilot randomized controlled trial. Crit. Care. 2007; 11 : R100. PubMed Abstract | Publisher Full Text | Free Full Text 49. Mayer J, Boldt J, Mengistu AM, et al. : Goal-directed intraoperative therapy based on autocalibrated arterial pressure waveform analysis reduces hospital stay in high-risk surgical patients: a randomized, controlled trial. Crit. Care. 2010; 14 : R18. PubMed Abstract | Publisher Full Text | Free Full Text 50. Zheng H, Guo H, Ye JR, et al. : Goal-directed fluid therapy in gastrointestinal surgery in older coronary heart disease patients: randomized trial. World J. Surg. 2013; 37 : 2820–2829. PubMed Abstract | Publisher Full Text 51. Goepfert MS, Richter HP, Zu Eulenburg C, et al. : Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: a prospective, randomized controlled trial. Anesthesiology. 2013; 119 : 824–836. PubMed Abstract | Publisher Full Text 52. Kapoor PM, Kakani M, Chowdhury U, et al. : Early goal-directed therapy in moderate to high-risk cardiac surgery patients. Ann. Card. Anaesth. 2008; 11 : 27–34. PubMed Abstract | Publisher Full Text 53. Liu Y, Lu YH, Xie JF, et al. : Passive leg raising predicts volume responsiveness in patients with septic shock. Zhonghua wai ke za zhi [Chinese Journal of Surgery]. 2011; 49 : 44–48. PubMed Abstract Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 22 May 2024 ADD YOUR COMMENT Comment Author details Author details 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 2 Department of Medicine, Nakhon Pathom Hospital, Nakhon Pathom, 73000, Thailand 3 Department of Medicine, Faculty of Medicine, Nakhon Pathom Hospital, Nakhon Pathom, 73000, Thailand Thiti Sricharoenchai Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Pannarat Saisirivechakun Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 25 Jul 2024, 13:528 https://doi.org/10.12688/f1000research.147875.2 version 1 Published: 22 May 2024, 13:528 https://doi.org/10.12688/f1000research.147875.1 Copyright © 2024 Sricharoenchai T and Saisirivechakun P. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Sricharoenchai T and Saisirivechakun P. Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.12688/f1000research.147875.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 25 Jul 2024 Revised Views 0 Cite How to cite this report: Sankar J. Reviewer Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.169516.r306941 ) The direct URL for this report is: https://f1000research.com/articles/13-528/v2#referee-response-306941 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 22 Aug 2024 Jhuma Sankar , Division of Pediatric Pulmonology and Intensive Care, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India Approved VIEWS 0 https://doi.org/10.5256/f1000research.169516.r306941 No ... Continue reading READ ALL No further comments. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Septic shock; sepsis; hemodynamic monitoring; scoring systems; anti microbial resistance I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Sankar J. Reviewer Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.169516.r306941 ) The direct URL for this report is: https://f1000research.com/articles/13-528/v2#referee-response-306941 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 24 Aug 2024 Thiti Sricharoenchai , Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 24 Aug 2024 Author Response We appreciate your invaluable time, opinions and responses. Competing Interests: No competing interests were disclosed. We appreciate your invaluable time, opinions and responses. We appreciate your invaluable time, opinions and responses. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 24 Aug 2024 Thiti Sricharoenchai , Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 24 Aug 2024 Author Response We appreciate your invaluable time, opinions and responses. Competing Interests: No competing interests were disclosed. We appreciate your invaluable time, opinions and responses. We appreciate your invaluable time, opinions and responses. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Tongyoo S. Reviewer Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.169516.r306940 ) The direct URL for this report is: https://f1000research.com/articles/13-528/v2#referee-response-306940 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 01 Aug 2024 Surat Tongyoo , Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand Approved VIEWS 0 https://doi.org/10.5256/f1000research.169516.r306940 ... Continue reading READ ALL Approved Competing Interests: No competing interests were disclosed. Reviewer Expertise: Septic shock I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Tongyoo S. Reviewer Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.169516.r306940 ) The direct URL for this report is: https://f1000research.com/articles/13-528/v2#referee-response-306940 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 07 Aug 2024 Thiti Sricharoenchai , Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 07 Aug 2024 Author Response We are very grateful for your invaluable time, opinions and responses. Competing Interests: No competing interests were disclosed. We are very grateful for your invaluable time, opinions and responses. We are very grateful for your invaluable time, opinions and responses. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 07 Aug 2024 Thiti Sricharoenchai , Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 07 Aug 2024 Author Response We are very grateful for your invaluable time, opinions and responses. Competing Interests: No competing interests were disclosed. We are very grateful for your invaluable time, opinions and responses. We are very grateful for your invaluable time, opinions and responses. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 22 May 2024 Views 0 Cite How to cite this report: Tongyoo S. Reviewer Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.162119.r282206 ) The direct URL for this report is: https://f1000research.com/articles/13-528/v1#referee-response-282206 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 20 Jun 2024 Surat Tongyoo , Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.162119.r282206 I would like to support this article for approval in F1000Research, but after a minor revision. The following are my comments. 1.Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me ... Continue reading READ ALL I would like to support this article for approval in F1000Research, but after a minor revision. The following are my comments. 1.Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me it seem to be too low level for that. 2.Conventionally, we used follow up CVP with an elevation of CVP from baseline > 5-7 mmHg as a cut point for fluid responsive, why the author did not use this. 3.For IVC US, author provide 2 cut point of IVC variation for fluid responsive, why you not provide different cut point for CVP as the positive intra-thoracic pressure might increase baseline CVP as well. 4. Please provide more detail in your results manuscript section. 5. Norepinephrine should be microgram/kg/min, not mg. 6. Please discuss more about even patient in both group received fluid in same volume, why they received NE in different dose, and also the different in shock duration. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Septic shock I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Tongyoo S. Reviewer Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.162119.r282206 ) The direct URL for this report is: https://f1000research.com/articles/13-528/v1#referee-response-282206 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 25 Jul 2024 Thiti Sricharoenchai , Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 25 Jul 2024 Author Response Reviewer's Comment 1. Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me it seem to be too low level for ... Continue reading Reviewer's Comment 1. Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me it seem to be too low level for that. Authors' Response: Thank you for your comment. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP at least 8 mmHg to be adequate volume status. The CVP of 8 mmHg was used as the cut-off point for fluid responsiveness in other studies (reference 33 and 51 of the manuscript). 2, 3 This CVP cut-off point (8 mmHg) is also usually used in our hospital settings, most attending physicians are familiar with this CVP value for assessment of fluid responsiveness. This would help the process of study to be consistent for all patients in the static CVP group. The explanations were presented in Intervention of Methods section. Reviewer's Comment 2. Conventionally, we used follow up CVP with an elevation of CVP from baseline > 5-7 mmHg as a cut point for fluid responsive, why the author did not use this. Authors' Response: We appreciate your comment. While we agree that an elevation of CVP from baseline > 5-7 mmHg is usually considered as a cut-off point for fluid responsiveness, the elevation of CVP from baseline usually refers to the increased value of CVP after the patient receives fluid administration, which is more likely to be a dynamic parameter, not a static parameter as we intended to determine the effect of fluid resuscitation guidance. Therefore, we used the CVP of 8 mmHg as a cut-off point for assessment of fluid responsiveness. Reviewer's Comment 3. For IVC US, author provide 2 cut point of IVC variation for fluid responsive, why you not provide different cut point for CVP as the positive intra-thoracic pressure might increase baseline CVP as well. Authors' Response : We are grateful for your comment and concern. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP of 8-12 mmHg regardless of respiratory variation of intrathoracic pressure. Our study followed this by considering the CVP of ≥ 8 mmHg as adequate volume status in the static CVP group, as well as the study by Richard, et al. (reference 33 of the manuscript). 2 The reasons were provided in Intervention of Methods section. Reviewer's Comment 4. Please provide more detail in your results manuscript section. Authors' Response: We acknowledge your advice. We have revised your concerned issues in Methods, Results and Discussion sections. Reviewer's Comment 5. Norepinephrine should be microgram/kg/min, not mg. Authors' Response: Thank you for your suggestion. We used the rate of norepinephrine as “microgram/kg/min”. However, we calculated further for the dose of norepinephrine to be “mg” as follows: 1) Accumulated dose of norepinephrine received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) multiplied by the body weight (kg) and the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg”. 2) Accumulated dose of norepinephrine per kg of body weight received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) was multiplied by the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg per kg”. The details of unit conversion of norepinephrine were shown in Data collection and outcome measures of Methods section. Reviewer's Comment 6 . Please discuss more about even patient in both group received fluid in same volume, why they received NE in different dose, and also the different in shock duration. Authors' Response : We are very grateful for your comment. The total fluid volume administered in the first 72 hours in most patients included the volume of fluid during the shock period and after the resolution of shock until 72 hours, because durations of shock were less than 72 hours in majorities of both groups. Furthermore, fluid volume after the resolution of shock until 72 hours for individual patients depended on the attending physicians’ discretion and was not controlled in this study. Therefore, total fluid volume in the first 72 hours cannot reflect the efficacy of guidance methods for fluid resuscitation, and may not be related to the accumulated dose of norepinephrine and duration of shock. This was explained in Results and Discussion sections. References 1. Dellinger RP, Levy MM, Rhodes A, et al.: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165–228. 2. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19 :5. 3. Goepfert MS, Richter HP, Zu Eulenburg C, et al.: Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: a prospective, randomized controlled trial. Anesthesiology. 2013;119:824–836. Reviewer's Comment 1. Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me it seem to be too low level for that. Authors' Response: Thank you for your comment. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP at least 8 mmHg to be adequate volume status. The CVP of 8 mmHg was used as the cut-off point for fluid responsiveness in other studies (reference 33 and 51 of the manuscript). 2, 3 This CVP cut-off point (8 mmHg) is also usually used in our hospital settings, most attending physicians are familiar with this CVP value for assessment of fluid responsiveness. This would help the process of study to be consistent for all patients in the static CVP group. The explanations were presented in Intervention of Methods section. Reviewer's Comment 2. Conventionally, we used follow up CVP with an elevation of CVP from baseline > 5-7 mmHg as a cut point for fluid responsive, why the author did not use this. Authors' Response: We appreciate your comment. While we agree that an elevation of CVP from baseline > 5-7 mmHg is usually considered as a cut-off point for fluid responsiveness, the elevation of CVP from baseline usually refers to the increased value of CVP after the patient receives fluid administration, which is more likely to be a dynamic parameter, not a static parameter as we intended to determine the effect of fluid resuscitation guidance. Therefore, we used the CVP of 8 mmHg as a cut-off point for assessment of fluid responsiveness. Reviewer's Comment 3. For IVC US, author provide 2 cut point of IVC variation for fluid responsive, why you not provide different cut point for CVP as the positive intra-thoracic pressure might increase baseline CVP as well. Authors' Response : We are grateful for your comment and concern. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP of 8-12 mmHg regardless of respiratory variation of intrathoracic pressure. Our study followed this by considering the CVP of ≥ 8 mmHg as adequate volume status in the static CVP group, as well as the study by Richard, et al. (reference 33 of the manuscript). 2 The reasons were provided in Intervention of Methods section. Reviewer's Comment 4. Please provide more detail in your results manuscript section. Authors' Response: We acknowledge your advice. We have revised your concerned issues in Methods, Results and Discussion sections. Reviewer's Comment 5. Norepinephrine should be microgram/kg/min, not mg. Authors' Response: Thank you for your suggestion. We used the rate of norepinephrine as “microgram/kg/min”. However, we calculated further for the dose of norepinephrine to be “mg” as follows: 1) Accumulated dose of norepinephrine received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) multiplied by the body weight (kg) and the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg”. 2) Accumulated dose of norepinephrine per kg of body weight received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) was multiplied by the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg per kg”. The details of unit conversion of norepinephrine were shown in Data collection and outcome measures of Methods section. Reviewer's Comment 6 . Please discuss more about even patient in both group received fluid in same volume, why they received NE in different dose, and also the different in shock duration. Authors' Response : We are very grateful for your comment. The total fluid volume administered in the first 72 hours in most patients included the volume of fluid during the shock period and after the resolution of shock until 72 hours, because durations of shock were less than 72 hours in majorities of both groups. Furthermore, fluid volume after the resolution of shock until 72 hours for individual patients depended on the attending physicians’ discretion and was not controlled in this study. Therefore, total fluid volume in the first 72 hours cannot reflect the efficacy of guidance methods for fluid resuscitation, and may not be related to the accumulated dose of norepinephrine and duration of shock. This was explained in Results and Discussion sections. References 1. Dellinger RP, Levy MM, Rhodes A, et al.: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165–228. 2. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19 :5. 3. Goepfert MS, Richter HP, Zu Eulenburg C, et al.: Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: a prospective, randomized controlled trial. Anesthesiology. 2013;119:824–836. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 25 Jul 2024 Thiti Sricharoenchai , Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 25 Jul 2024 Author Response Reviewer's Comment 1. Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me it seem to be too low level for ... Continue reading Reviewer's Comment 1. Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me it seem to be too low level for that. Authors' Response: Thank you for your comment. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP at least 8 mmHg to be adequate volume status. The CVP of 8 mmHg was used as the cut-off point for fluid responsiveness in other studies (reference 33 and 51 of the manuscript). 2, 3 This CVP cut-off point (8 mmHg) is also usually used in our hospital settings, most attending physicians are familiar with this CVP value for assessment of fluid responsiveness. This would help the process of study to be consistent for all patients in the static CVP group. The explanations were presented in Intervention of Methods section. Reviewer's Comment 2. Conventionally, we used follow up CVP with an elevation of CVP from baseline > 5-7 mmHg as a cut point for fluid responsive, why the author did not use this. Authors' Response: We appreciate your comment. While we agree that an elevation of CVP from baseline > 5-7 mmHg is usually considered as a cut-off point for fluid responsiveness, the elevation of CVP from baseline usually refers to the increased value of CVP after the patient receives fluid administration, which is more likely to be a dynamic parameter, not a static parameter as we intended to determine the effect of fluid resuscitation guidance. Therefore, we used the CVP of 8 mmHg as a cut-off point for assessment of fluid responsiveness. Reviewer's Comment 3. For IVC US, author provide 2 cut point of IVC variation for fluid responsive, why you not provide different cut point for CVP as the positive intra-thoracic pressure might increase baseline CVP as well. Authors' Response : We are grateful for your comment and concern. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP of 8-12 mmHg regardless of respiratory variation of intrathoracic pressure. Our study followed this by considering the CVP of ≥ 8 mmHg as adequate volume status in the static CVP group, as well as the study by Richard, et al. (reference 33 of the manuscript). 2 The reasons were provided in Intervention of Methods section. Reviewer's Comment 4. Please provide more detail in your results manuscript section. Authors' Response: We acknowledge your advice. We have revised your concerned issues in Methods, Results and Discussion sections. Reviewer's Comment 5. Norepinephrine should be microgram/kg/min, not mg. Authors' Response: Thank you for your suggestion. We used the rate of norepinephrine as “microgram/kg/min”. However, we calculated further for the dose of norepinephrine to be “mg” as follows: 1) Accumulated dose of norepinephrine received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) multiplied by the body weight (kg) and the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg”. 2) Accumulated dose of norepinephrine per kg of body weight received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) was multiplied by the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg per kg”. The details of unit conversion of norepinephrine were shown in Data collection and outcome measures of Methods section. Reviewer's Comment 6 . Please discuss more about even patient in both group received fluid in same volume, why they received NE in different dose, and also the different in shock duration. Authors' Response : We are very grateful for your comment. The total fluid volume administered in the first 72 hours in most patients included the volume of fluid during the shock period and after the resolution of shock until 72 hours, because durations of shock were less than 72 hours in majorities of both groups. Furthermore, fluid volume after the resolution of shock until 72 hours for individual patients depended on the attending physicians’ discretion and was not controlled in this study. Therefore, total fluid volume in the first 72 hours cannot reflect the efficacy of guidance methods for fluid resuscitation, and may not be related to the accumulated dose of norepinephrine and duration of shock. This was explained in Results and Discussion sections. References 1. Dellinger RP, Levy MM, Rhodes A, et al.: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165–228. 2. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19 :5. 3. Goepfert MS, Richter HP, Zu Eulenburg C, et al.: Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: a prospective, randomized controlled trial. Anesthesiology. 2013;119:824–836. Reviewer's Comment 1. Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me it seem to be too low level for that. Authors' Response: Thank you for your comment. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP at least 8 mmHg to be adequate volume status. The CVP of 8 mmHg was used as the cut-off point for fluid responsiveness in other studies (reference 33 and 51 of the manuscript). 2, 3 This CVP cut-off point (8 mmHg) is also usually used in our hospital settings, most attending physicians are familiar with this CVP value for assessment of fluid responsiveness. This would help the process of study to be consistent for all patients in the static CVP group. The explanations were presented in Intervention of Methods section. Reviewer's Comment 2. Conventionally, we used follow up CVP with an elevation of CVP from baseline > 5-7 mmHg as a cut point for fluid responsive, why the author did not use this. Authors' Response: We appreciate your comment. While we agree that an elevation of CVP from baseline > 5-7 mmHg is usually considered as a cut-off point for fluid responsiveness, the elevation of CVP from baseline usually refers to the increased value of CVP after the patient receives fluid administration, which is more likely to be a dynamic parameter, not a static parameter as we intended to determine the effect of fluid resuscitation guidance. Therefore, we used the CVP of 8 mmHg as a cut-off point for assessment of fluid responsiveness. Reviewer's Comment 3. For IVC US, author provide 2 cut point of IVC variation for fluid responsive, why you not provide different cut point for CVP as the positive intra-thoracic pressure might increase baseline CVP as well. Authors' Response : We are grateful for your comment and concern. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP of 8-12 mmHg regardless of respiratory variation of intrathoracic pressure. Our study followed this by considering the CVP of ≥ 8 mmHg as adequate volume status in the static CVP group, as well as the study by Richard, et al. (reference 33 of the manuscript). 2 The reasons were provided in Intervention of Methods section. Reviewer's Comment 4. Please provide more detail in your results manuscript section. Authors' Response: We acknowledge your advice. We have revised your concerned issues in Methods, Results and Discussion sections. Reviewer's Comment 5. Norepinephrine should be microgram/kg/min, not mg. Authors' Response: Thank you for your suggestion. We used the rate of norepinephrine as “microgram/kg/min”. However, we calculated further for the dose of norepinephrine to be “mg” as follows: 1) Accumulated dose of norepinephrine received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) multiplied by the body weight (kg) and the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg”. 2) Accumulated dose of norepinephrine per kg of body weight received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) was multiplied by the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg per kg”. The details of unit conversion of norepinephrine were shown in Data collection and outcome measures of Methods section. Reviewer's Comment 6 . Please discuss more about even patient in both group received fluid in same volume, why they received NE in different dose, and also the different in shock duration. Authors' Response : We are very grateful for your comment. The total fluid volume administered in the first 72 hours in most patients included the volume of fluid during the shock period and after the resolution of shock until 72 hours, because durations of shock were less than 72 hours in majorities of both groups. Furthermore, fluid volume after the resolution of shock until 72 hours for individual patients depended on the attending physicians’ discretion and was not controlled in this study. Therefore, total fluid volume in the first 72 hours cannot reflect the efficacy of guidance methods for fluid resuscitation, and may not be related to the accumulated dose of norepinephrine and duration of shock. This was explained in Results and Discussion sections. References 1. Dellinger RP, Levy MM, Rhodes A, et al.: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165–228. 2. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19 :5. 3. Goepfert MS, Richter HP, Zu Eulenburg C, et al.: Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: a prospective, randomized controlled trial. Anesthesiology. 2013;119:824–836. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Sankar J. Reviewer Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.162119.r282204 ) The direct URL for this report is: https://f1000research.com/articles/13-528/v1#referee-response-282204 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 14 Jun 2024 Jhuma Sankar , Division of Pediatric Pulmonology and Intensive Care, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.162119.r282204 Abstract: No comments Introduction: Optimal Methods: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to produce such a large ... Continue reading READ ALL Abstract: No comments Introduction: Optimal Methods: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to produce such a large difference in mortality. Ten % at the most would have been optimal. This should be addressed as a limitation. Results: No comments Discussion: Please address the limitations. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Septic shock; sepsis; hemodynamic monitoring; scoring systems; anti microbial resistance I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Sankar J. Reviewer Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.162119.r282204 ) The direct URL for this report is: https://f1000research.com/articles/13-528/v1#referee-response-282204 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 23 Jul 2024 Thiti Sricharoenchai , Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 23 Jul 2024 Author Response Reviewer's Comment: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to ... Continue reading Reviewer's Comment: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to produce such a large difference in mortality. Ten % at the most would have been optimal. This should be addressed as a limitation. Authors' Response: Thank you so much for your comment. The difference in mortality rate was selected based on the study findings from Richard, et al. (28-day mortality rates in preload dependence group vs. control group were 23% vs. 47%, respectively) (reference 33 of the manuscript). 1 However, we agreed that the difference in mortality rate of 24% was quite high. This issue was explained in the limitations of Discussion section. References 1. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19: 5. Reviewer's Comment: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to produce such a large difference in mortality. Ten % at the most would have been optimal. This should be addressed as a limitation. Authors' Response: Thank you so much for your comment. The difference in mortality rate was selected based on the study findings from Richard, et al. (28-day mortality rates in preload dependence group vs. control group were 23% vs. 47%, respectively) (reference 33 of the manuscript). 1 However, we agreed that the difference in mortality rate of 24% was quite high. This issue was explained in the limitations of Discussion section. References 1. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19: 5. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 23 Jul 2024 Thiti Sricharoenchai , Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand 23 Jul 2024 Author Response Reviewer's Comment: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to ... Continue reading Reviewer's Comment: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to produce such a large difference in mortality. Ten % at the most would have been optimal. This should be addressed as a limitation. Authors' Response: Thank you so much for your comment. The difference in mortality rate was selected based on the study findings from Richard, et al. (28-day mortality rates in preload dependence group vs. control group were 23% vs. 47%, respectively) (reference 33 of the manuscript). 1 However, we agreed that the difference in mortality rate of 24% was quite high. This issue was explained in the limitations of Discussion section. References 1. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19: 5. Reviewer's Comment: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to produce such a large difference in mortality. Ten % at the most would have been optimal. This should be addressed as a limitation. Authors' Response: Thank you so much for your comment. The difference in mortality rate was selected based on the study findings from Richard, et al. (28-day mortality rates in preload dependence group vs. control group were 23% vs. 47%, respectively) (reference 33 of the manuscript). 1 However, we agreed that the difference in mortality rate of 24% was quite high. This issue was explained in the limitations of Discussion section. References 1. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19: 5. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 22 May 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 25 Jul 24 read read Version 1 22 May 24 read read Jhuma Sankar , All India Institute of Medical Sciences, New Delhi, India Surat Tongyoo , Mahidol University, Bangkok, Thailand Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Sankar J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 22 Aug 2024 | for Version 2 Jhuma Sankar , Division of Pediatric Pulmonology and Intensive Care, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India 0 Views copyright © 2024 Sankar J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions No further comments. Competing Interests No competing interests were disclosed. Reviewer Expertise Septic shock; sepsis; hemodynamic monitoring; scoring systems; anti microbial resistance I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 24 Aug 2024 Thiti Sricharoenchai, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand We appreciate your invaluable time, opinions and responses. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Sankar J. Peer Review Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.169516.r306941) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-528/v2#referee-response-306941 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Tongyoo S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 01 Aug 2024 | for Version 2 Surat Tongyoo , Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand 0 Views copyright © 2024 Tongyoo S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Approved Competing Interests No competing interests were disclosed. Reviewer Expertise Septic shock I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 07 Aug 2024 Thiti Sricharoenchai, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand We are very grateful for your invaluable time, opinions and responses. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Tongyoo S. Peer Review Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.169516.r306940) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-528/v2#referee-response-306940 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Tongyoo S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 20 Jun 2024 | for Version 1 Surat Tongyoo , Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand 0 Views copyright © 2024 Tongyoo S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I would like to support this article for approval in F1000Research, but after a minor revision. The following are my comments. 1.Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me it seem to be too low level for that. 2.Conventionally, we used follow up CVP with an elevation of CVP from baseline > 5-7 mmHg as a cut point for fluid responsive, why the author did not use this. 3.For IVC US, author provide 2 cut point of IVC variation for fluid responsive, why you not provide different cut point for CVP as the positive intra-thoracic pressure might increase baseline CVP as well. 4. Please provide more detail in your results manuscript section. 5. Norepinephrine should be microgram/kg/min, not mg. 6. Please discuss more about even patient in both group received fluid in same volume, why they received NE in different dose, and also the different in shock duration. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Septic shock I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 25 Jul 2024 Thiti Sricharoenchai, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand Reviewer's Comment 1. Please explain why the author used CVP at 8 mmHg as a cut point for fluid responsiveness. For me it seem to be too low level for that. Authors' Response: Thank you for your comment. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP at least 8 mmHg to be adequate volume status. The CVP of 8 mmHg was used as the cut-off point for fluid responsiveness in other studies (reference 33 and 51 of the manuscript). 2, 3 This CVP cut-off point (8 mmHg) is also usually used in our hospital settings, most attending physicians are familiar with this CVP value for assessment of fluid responsiveness. This would help the process of study to be consistent for all patients in the static CVP group. The explanations were presented in Intervention of Methods section. Reviewer's Comment 2. Conventionally, we used follow up CVP with an elevation of CVP from baseline > 5-7 mmHg as a cut point for fluid responsive, why the author did not use this. Authors' Response: We appreciate your comment. While we agree that an elevation of CVP from baseline > 5-7 mmHg is usually considered as a cut-off point for fluid responsiveness, the elevation of CVP from baseline usually refers to the increased value of CVP after the patient receives fluid administration, which is more likely to be a dynamic parameter, not a static parameter as we intended to determine the effect of fluid resuscitation guidance. Therefore, we used the CVP of 8 mmHg as a cut-off point for assessment of fluid responsiveness. Reviewer's Comment 3. For IVC US, author provide 2 cut point of IVC variation for fluid responsive, why you not provide different cut point for CVP as the positive intra-thoracic pressure might increase baseline CVP as well. Authors' Response : We are grateful for your comment and concern. The Surviving sepsis campaign guidelines 2012 (reference 28 of the manuscript) 1 recommended to keep CVP of 8-12 mmHg regardless of respiratory variation of intrathoracic pressure. Our study followed this by considering the CVP of ≥ 8 mmHg as adequate volume status in the static CVP group, as well as the study by Richard, et al. (reference 33 of the manuscript). 2 The reasons were provided in Intervention of Methods section. Reviewer's Comment 4. Please provide more detail in your results manuscript section. Authors' Response: We acknowledge your advice. We have revised your concerned issues in Methods, Results and Discussion sections. Reviewer's Comment 5. Norepinephrine should be microgram/kg/min, not mg. Authors' Response: Thank you for your suggestion. We used the rate of norepinephrine as “microgram/kg/min”. However, we calculated further for the dose of norepinephrine to be “mg” as follows: 1) Accumulated dose of norepinephrine received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) multiplied by the body weight (kg) and the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg”. 2) Accumulated dose of norepinephrine per kg of body weight received by each patient throughout the total vasopressor duration; the rate of norepinephrine (microgram/kg/min) was multiplied by the duration of norepinephrine administration (min), then divided by 1,000. Thus, the accumulated dose of norepinephrine was converted to “mg per kg”. The details of unit conversion of norepinephrine were shown in Data collection and outcome measures of Methods section. Reviewer's Comment 6 . Please discuss more about even patient in both group received fluid in same volume, why they received NE in different dose, and also the different in shock duration. Authors' Response : We are very grateful for your comment. The total fluid volume administered in the first 72 hours in most patients included the volume of fluid during the shock period and after the resolution of shock until 72 hours, because durations of shock were less than 72 hours in majorities of both groups. Furthermore, fluid volume after the resolution of shock until 72 hours for individual patients depended on the attending physicians’ discretion and was not controlled in this study. Therefore, total fluid volume in the first 72 hours cannot reflect the efficacy of guidance methods for fluid resuscitation, and may not be related to the accumulated dose of norepinephrine and duration of shock. This was explained in Results and Discussion sections. References 1. Dellinger RP, Levy MM, Rhodes A, et al.: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165–228. 2. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19 :5. 3. Goepfert MS, Richter HP, Zu Eulenburg C, et al.: Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: a prospective, randomized controlled trial. Anesthesiology. 2013;119:824–836. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Tongyoo S. Peer Review Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.162119.r282206) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-528/v1#referee-response-282206 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Sankar J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 14 Jun 2024 | for Version 1 Jhuma Sankar , Division of Pediatric Pulmonology and Intensive Care, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India 0 Views copyright © 2024 Sankar J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Abstract: No comments Introduction: Optimal Methods: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to produce such a large difference in mortality. Ten % at the most would have been optimal. This should be addressed as a limitation. Results: No comments Discussion: Please address the limitations. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Septic shock; sepsis; hemodynamic monitoring; scoring systems; anti microbial resistance I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 23 Jul 2024 Thiti Sricharoenchai, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Thammasat University, Pathum Thani, 12120, Thailand Reviewer's Comment: The effect size for calculation of sample size is too large 24%. How was this number chosen? An ultrasound method to guide resuscitation may not be able to produce such a large difference in mortality. Ten % at the most would have been optimal. This should be addressed as a limitation. Authors' Response: Thank you so much for your comment. The difference in mortality rate was selected based on the study findings from Richard, et al. (28-day mortality rates in preload dependence group vs. control group were 23% vs. 47%, respectively) (reference 33 of the manuscript). 1 However, we agreed that the difference in mortality rate of 24% was quite high. This issue was explained in the limitations of Discussion section. References 1. Richard JC, Bayle F, Bourdin G, et al. : Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial. Crit. Care. 2015; 19: 5. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Sankar J. Peer Review Report For: Effects of dynamic versus static parameter-guided fluid resuscitation in patients with sepsis: A randomized controlled trial [version 2; peer review: 2 approved] . F1000Research 2024, 13 :528 ( https://doi.org/10.5256/f1000research.162119.r282204) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-528/v1#referee-response-282204 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = "Effects of dynamic versus static parameter-guided...".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/13-528/v2" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/13-528/v2&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/13-528/v2" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Sricharoenchai T and Saisirivechakun P'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_expanded : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_custom : [ { name: "LinkedIn", url: linkedInUrl, icon:"/img/icon/at_linkedin.svg" }, { name: "Mendeley", url: "http://www.mendeley.com/import/?url=https://f1000research.com/articles/13-528/v2/mendeley", icon:"/img/icon/at_mendeley.svg" }, { name: "Reddit", url: redditUrl, icon:"/img/icon/at_reddit.svg" }, ] }; var addthis_share = { url: "https://f1000research.com/articles/13-528", templates : { twitter : "Effects of dynamic versus static parameter-guided fluid resuscitation.... Sricharoenchai T and Saisirivechakun P, published by " + "@F1000Research" + ", https://f1000research.com/articles/13-528/v2" } }; if (typeof(addthis) != "undefined"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(".f1r-shares-twitter").attr("href", "https://twitter.com/intent/tweet?text=" + addthis_share.templates.twitter); $(".f1r-shares-facebook").attr("href", "https://www.facebook.com/sharer/sharer.php?u=" + addthis_share.url); $(".f1r-shares-linkedin").attr("href", addthis_config.services_custom[0].url); $(".f1r-shares-reddit").attr("href", addthis_config.services_custom[2].url); $(".f1r-shares-mendelay").attr("href", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(".addthis_button_expanded").each(function(){ var count = $(this).text(); if (count !== "" && count != "0") $(this).removeClass("is-hidden"); else $(this).addClass("is-hidden"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get("/articles/acj/147875/169516") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("articles", "article", "169516"); $(document).ready(function() { $( "#frame1" ).on('load', function() { var mydiv = $(this).contents().find("div"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(".interactive-living-figure-label .icon-more-info"), titleLivingFigure = tooltipLivingFigure.attr("title"); tooltipLivingFigure.simpletip({ fixed: true, position: ["-115", "30"], baseClass: 'small-tooltip', content:titleLivingFigure + " " }); tooltipLivingFigure.removeAttr("title"); $("body").on("click", ".cite-living-figure", function(e) { e.preventDefault(); var ref = $(this).attr("data-ref"); $(this).closest(".living-figure-list-container").find("#" + ref).fadeIn(200); }); $("body").on("click", ".close-cite-living-figure", function(e) { e.preventDefault(); $(this).closest(".popup-window-wrapper").fadeOut(200); }); $(document).on("mouseup", function(e) { var metricsContainer = $(".article-metrics-popover-wrapper"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(".article-metrics-close-button").click(); } }); var articleId = $('#articleId').val(); if($("#main-article-count-box").attachArticleMetrics) { $("#main-article-count-box").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(".new_figshare_widget"); if (figshareWidget.length > 0) { window.figshare.load("f1000", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr("figshare_articleId") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { "282212": 0, "282213": 0, "282208": 0, "287520": 0, "282209": 0, "287521": 0, "282210": 0, "287522": 0, "282211": 0, "287516": 0, "282204": 31, "306940": 90, "282205": 1, "287517": 0, "306941": 15, "287518": 0, "282206": 108, "282207": 0, "287519": 0, "287513": 0, "287514": 0, "287515": 0, }; $(".referee-response-container,.js-referee-report").each(function(index, el) { var reportId = $(el).attr("data-reportid"), reportCount = reportIds[reportId] || 0; $(el).find(".comments-count-container,.js-referee-report-views").html(reportCount); }); var uuidInput = $("#article_uuid"), oldUUId = uuidInput.val(), newUUId = "ba1043b7-0b0e-4cc4-89b1-314e4330ed1f"; uuidInput.val(newUUId); $("a[href*='article_uuid=']").each(function(index, el) { var newHref = $(el).attr("href").replace(oldUUId, newUUId); $(el).attr("href", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: "f1000research", displayName: "F1000Research", hostName: "f1000research.com", id: "1", editorialEmail: "[email protected]", infoEmail: "[email protected]", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(".cookie-warning").is(":visible")) { $(".sticky").css("margin-bottom", "35px"); $(".devices").addClass("devices-and-cookie-warning"); } $(".cookie-warning .close-button").click(function (e) { $(".devices").removeClass("devices-and-cookie-warning"); $(".sticky").css("margin-bottom", "0"); }); $("#tweeter-feed .tweet-message").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(".partner").on("mouseenter mouseleave", function() { $(this).find(".gray-scale, .colour").toggleClass("is-hidden"); }); }); Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $("a[id=googleSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("GOOGLE"); $("form[id=oAuthForm]").submit(); }); $("a[id=facebookSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("FACEBOOK"); $("form[id=oAuthForm]").submit(); }); $("a[id=orcidSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("ORCID"); $("form[id=oAuthForm]").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });